3.

01 Introduction to Volume 3
K Rissanen, University of Jyväskylä, Jyväskylä, Finland
Ó 2017 Elsevier Ltd. All rights reserved.

Since the birth of Supramolecular Chemistry in 1980s, initiated by the Nobel Price to Donald Cram, Jean-Marie Lehn, and Charles
Pedersen 30 years ago in 1987 “for their development and use of molecules with structure-specific interactions of high selectivity,” it
has taken giant leaps for chemical science. This is even truer now 29 years after the earlier mentioned first Nobel Prize to Supramo-
lecular Chemistry as the 2016 Nobel Prize in Chemistry was awarded to the leading supramolecular chemists Jean-Pierre Sauvage,
Fraser Stoddart, and Ben Feringa for “the design and synthesis of molecular machines.” The relative simple chemical systems to
which the Nobel Prize in 1987 was awarded have developed tremendously over the last 30 years into complex interlocked or rota-
tionally controlled systems with functions emulating those found in Nature. A cornerstone in the Supramolecular Chemistry liter-
ature is the highly praised and influential 11 volume book series “Comprehensive Supramolecular Chemistry” published in Jun. 16,
1996 with Jerry Atwood, Eric Davies, David Macnicol, and Fritz Vögtle as the executive editors.
This volume focuses on contemporary supramolcular receptors and it cannot or does not try to cover all the developments in this
field; instead, it intends to put forward those areas that have advanced most during the last two decades, having brought more visi-
bility to the receptor families and thus have broadened the repertoire of supramolecular receptors. The volume opens with accounts
on the “classical” receptors, viz crown ethers, calixarenes, resorcinarenes, cavitands, and cryptands, listing some of the newest aspects
of these “iconic” receptors. Much has happened since 1996 in the development of new receptor families and the volume brings
forward new macrocyclic or macrobicyclic receptors such as synthetic lectins, cucurbiturils, hemicucurbiturils, pillararenes, triangl-
amines, and amino acid-based receptors, some of which have been very recently developed. Extended or modulated p-systems can
be used as receptors too, and the volume offers chapters both on curved and electron-deficient p-receptors. A receptor family that
has, as a larger set of the chemical systems, been developed very extensively is for anion binding, and the volume continues with
chapters on shape-persistent macrocyclic and amide based tripodal anion receptors. As halogen bonding is the newest interaction
utilized in various receptors, a chapter on halogen bond-based receptors deals this matter. The volume is closed with two chapters
dealing with metal-ion containing receptors and a chapter on endo-fullerenes and carboranes, linking the volume to the 2016 Nobel
Prize in Chemistry on Molecular Machines (which in many cases are also receptors).
On the whole, the contributors to this volume have provided personal accounts on the “new frontiers” in contemporary supra-
molecular receptors. As a volume editor, I have been truly privileged to have the opportunity to work with my very distinguished
colleagues, who have been in the forefront of their research areas for many years. Thanks to their meticulous dedication I am very
much convinced that this volume will be a valuable and widening reading experience for researchers and students willing to learn
more about supramolecular receptors.
Jyväskylä, December 2016, Kari Rissanen

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12508-9 1

 3.02 Crown Ethers
GW Gokel, S Negin, and R Cantwell, University of Missouri-St. Louis, St. Louis, MO, United States
Ó 2017 Elsevier Ltd. All rights reserved.

3.02.1 Introduction 3
3.02.1.1 Naming Crown Ethers and Cryptands 5
3.02.1.2 The Synthetic Surge 6
3.02.1.3 Structural Classes of Macrocycles 6
3.02.1.4 Crown Ether Polymers 9
3.02.2 Synthetic Access to Crown Ethers 10
3.02.2.1 Crown Synthesis and the Template Effect 10
3.02.2.2 Azacrown Ethers 10
3.02.2.3 Lariat Ethers 11
3.02.2.4 Other Heteroatoms and Subcyclic Units 12
3.02.3 Cation Binding by Crown Ethers 13
3.02.3.1 Complex Structures 13
3.02.3.2 Cation Binding Dynamics 15
3.02.3.3 Cation Binding, Macroring Hole Sizes, and Symmetry 16
3.02.3.3.1 Ammonium ion binding 17
3.02.3.3.2 Conformation and symmetry 17
3.02.3.4 Thermodynamics of Binding 17
3.02.3.5 Molecular Cation Binding 18
3.02.3.6 Anion Binding 18
3.02.3.7 Experimental Binding Determination Techniques 19
3.02.3.7.1 The picrate extraction technique 19
3.02.3.7.2 Transport studies 19
3.02.3.8 Lariat Ethers 19
3.02.3.9 Enthalpy–Entropy Compensation and Solvent Effects 20
3.02.4 Cation–Pi Interactions 20
3.02.5 Chiral Crown Compounds 22
3.02.6 Crown Ether Biological Activity 23
3.02.6.1 Early Biological and Toxicological Studies 24
3.02.6.2 Antimicrobial Activity of Crown Ether Derivatives 27
3.02.6.3 Activity of Crown Ether Derivatives in Plant Cells or Plants 30
3.02.6.4 Cellular Activity of Crown Ether Derivatives 32
3.02.6.5 Biological Activity of Lariat Ethers and Hydraphiles 32
3.02.6.6 Biological Applications of Hydraphiles 38
3.02.7 Application of Crown Ethers 41
3.02.7.1 Membranes 41
3.02.7.2 Cation-Conducting Channels 41
3.02.7.3 Crown Ethers as Catalysts and Enzyme Mimics 42
3.02.7.4 Crown Ethers as Sensors 42
3.02.7.5 Switching Crown Ether Properties 42
3.02.7.6 Catenanes, Rotaxanes, and Knots 44
3.02.7.7 Cyclams and Other All-Nitrogen Macrocycles 44
3.02.8 Conclusions 44
Acknowledgments 45
References 45

3.02.1 Introduction

In the period after the discovery of crown ethers, it was often stated that the discovery had been an accident. Certainly, there was
some serendipity, but the pathway that led to the discovery was well thought out. The first compounds called crown ethers were
reported by Charles Pedersen, a chemist employed by the Dupont Company in Delaware, USA. He held a master of science degree
in chemistry and worked in the Elastomer Chemicals Department.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12519-3 3

4 Crown Ethers

Pedersen’s goal was to prepare a new binding agent for divalent cations, particularly vanadium. He reasoned that he could link
two of the four hydroxyl groups that were present in two molecules of 1,2-dihydroxybenzene or catechol. He did this by using dihy-
dropyran to protect one of the two adjacent hydroxyl groups. A problem with the approach is that a mixture is obtained of unpro-
tected, monoprotected, and diprotected catechols. The monoprotected catechol is the major product and this was carried forward in
a Williamson ether synthesis reaction with diethylene glycol dichloride (ClCH2CH2)2O. He obtained the expected linked dihydroxy
binding agent but he found a small quantity of another compound in the mixture that he identified and named as dibenzo-18-
crown-6.1
The compound shown in Fig. 1 was precisely the one that was envisioned and sought. After he obtained this divalent binder,
Pedersen demonstrated its ability to bind divalent cations and he eventually patented it and related compounds.2 Of course, there
still remained the conundrum of the fluffy crystals that had been isolated as a by-product.3 Their surprising property was that
although they contained no free hydroxyl group, they still showed an interaction with sodium cations. Pedersen deduced that
two unreacted catechol molecules had linked with two molecules of diethylene glycol dichloride and had formed a ring. The
ring, at 18-members, is formally a macrocycle. The fact that his neutral macrocycle could bind alkali metal cations was something
of a revelation as this was a sought-after receptor property in the 1960s. Hydrogenation of the two aromatic rings produced dicy-
clohexano-18-crown-6 (Fig. 2) as a mixture of isomers. Even though the relative stereochemistry of the cyclohexane-to-oxygen
bonds was unknown, the aliphatic derivative was a more effective alkali metal binding as both compounds were extensively modi-
fied and studied. Pedersen embarked on a program that resulted in numerous analogs of varied structures and ring sizes.
Pedersen recognized what he had achieved and elaborated it extensively before he retired from DuPont. For this seminal work,
Pedersen shared the 1987 Nobel Prize4 in Chemistry with Donald J. Cram (UCLA, USA)5 and with Jean-Marie Lehn (University of
Strasbourg and College de France).6
Howard Simmons (of the Simmons–Smith reaction) was a coworker of Pedersen’s working in the Central Research Department
at DuPont. He was also interested in large ring systems and devised an interesting group of large ring bicyclics that he named “in–
out bicyclic amines.”7 Fig. 3 shows the equilibrium between conformers in which the bridgehead nitrogen atoms are either both
pointed inward or both pointed outward. Obviously, intermediate conformers can be envisioned.

Figure 1 Pedersen’s successful synthesis of a divalent cation complexing agent.

Figure 2 Dibenzo-18-crown-6 and dicyclohexano-18-crown-6, prepared from the formed by hydrogenation. The dicyclohexano-18-crown-6 ob-
tained from this reaction is a mixture of stereoisomers.

Figure 3 Two conformation isomers of so-called “in-out bicyclic amines.”.

 Crown Ethers 5

Figure 4 Structure of the compound designated [2.2.2]cryptand, named using a variant of the nomenclature applied to bicyclic compounds. The
compound is illustrated with the nitrogen atoms turned inward as would be the case when a cation is within the receptor.

Figure 5 Complexation of potassium cation by [2.2.2]cryptand to give a cryptate complex.

Figure 6 Examples of early heteroatom-containing macrocycles.

Simultaneous with these developments, an alternate approach to receptors that was, in a sense, a combination of in–out bicyclic
amines and crown ethers was evolving separately in the laboratory of Jean-Marie Lehn. These studies resulted in the landmark report
by Dietrich, Lehn, and Sauvage of cryptands Fig. 4.8
Although the cryptands were conceived and developed separately, they may be considered crown ethers with a third, cavity
enveloping chain. This permits them to bind cations in a three-dimensional sense rather than in only two dimensions as is typical
of crown ethers. The size analog of 18-crown-6, [2.2.2]cryptand, is shown in Fig. 5 encapsulating a Kþ cation. The 8-coordinate
binding arrangement differs from that observed with crown ethers. In the latter, a Kþ cation would be surrounded in a plane by
six oxygen atoms and additional axial solvation of the complex would typically arise from a counteranion or a counteranion
hydrogen bonded to a water molecule in apical contact with the bound cation.
Once the concepts related to crown ethers and cryptands were clearly outlined, it was apparent that earlier studies had afforded
compounds that could fit within the emerging area. Certain macrocycles that contained heteroatoms within the ring structures had
been reported in late the nineteenth century.9 The compounds Baeyer formed by acid-catalyzed condensation of pyrrole with
acetone have been given new life as anion binders that are called “calixpyrroles.”10 A similar condensation was reported in 1955
in which the starting materials were acetone and furan.11 The “calix” part of the name calixpyrrole was first applied to the extensively
studied family of compounds known as calixarene. These are acid-catalyzed condensation products of phenol and formaldehyde,
a reaction that was developed by Baekeland.12 Early work made clear that a broad range of ring sizes was possible. As early as the
mid-1950s, it was found the ethylene oxide (oxirane) could be treated with an alkylaluminum catalyst to prepare what would now
be considered a crown ether called 12-crown-4 Fig. 6.13

3.02.1.1 Naming Crown Ethers and Cryptands

The systematic name for 18-crown-6 is 1,4,7,10,13,16-hexaoxacyclooctadecane. 18-Crown-6 is one of the simplest of the polyoxy-
gen macrocycles. The nomenclature by systematic methods becomes even more cumbersome when one or more aromatic rings or
heterocycles are fused or appended to the macroring. Pedersen simplified the nomenclature by suggesting the name “crown”
6 Crown Ethers

Figure 7 Examples of cryptand nomenclature.

Figure 8 Structures of 12-crown-4, 21-crown-7, and the pseudo-meta and pseudo-para isomers of dibenzo-18-crown-6.

because he analogized cations wearing regal crowns. Lehn used the crypt analogy and proposed the name cryptand. Lehn suggested
the name cryptate for complexes. In an attempt to systematize the nomenclature for crowns, Voegtle14 suggested the name “coro-
nand” for crown and “coronate” for the corresponding complexes. Lehn introduced a logical but nonsystematic method to desig-
nate substituents on cryptands as shown at the left of Fig. 7.
Fig. 8 shows four crown ethers. The compounds 12-crown-4 and 21-crown-7 are unencumbered by substituents and naming is
simple. The two regioisomers of dibenzo-18-crown-6 require some further designation to distinguish the two. One approach is to
designate them pseudo-meta and pseudo-para. It is more likely that the reader encountering either of these two compounds would find
them designated simply dibenzo-18-crown-6, but accompanied by an illustration that would make the structural arrangement
unambiguous. Admittedly, this is a kind of hieroglyphics or picture-writing, but it is not less acceptable than calling a specific steroid
cholesterol.

3.02.1.2 The Synthetic Surge

Synthesis is arguably the central core of organic chemistry. As soon as the Pedersen and Lehn concepts and findings were known to
the field, a vast effort began to probe the structural limits of cation complexation. As described later, not only were alkali metals
a focus of these studies, “inorganic” metal ions and organic cations were also a focus. Structures were devised in some cases that
it was expected would select for group II or group III metal ions, and in other cases, the possible complexation of organic cations.
A description of some synthetic methods devised for crown synthesis may be found in section “Synthetic Access to Crown Ethers”.

3.02.1.3 Structural Classes of Macrocycles

There are now thousands of crown ethers known. It would be impossible to place them into a few discrete classes. A few major
groups can be identified, however. Seven of these are (1) ring sizes, (2) variations in heteroatoms, (3) nondonor fused rings, (4)
donor-containing fused rings, (5) pendant residues, (6) multicrowns, and (7) polymeric crowns.
In an early work,1–4 Pedersen reported crown ethers that possessed ring sizes up to 60 atoms. Among the thousands of crown
ethers that are now known, it is probable that all of the intermediate rings have been prepared as well. While there is no official
designation for the transition from simple ring compound to crown ether, the transition probably occurs between 9-crown-3
and 12-crown-4. Aliphatic rings in this size range suffer from conformational and strain problems that are ameliorated to some
extent by the presence of oxygen. Unfavorable H–H interactions in medium rings are eliminated by oxygen for methylene
substitutions.
Ethyleneoxy units are favorable for ring formation because they exhibit greater conformation flexibility than do the correspond-
ing alkyl chains owing to fewer methylene–methylene interactions. Many cyclic aliphatic, aromatic, and heteroaromatic entities
have been fused to crown ethers. When the oxygen or sulfur of furan or thiophene is turned inward (i.e., 2,5-linkage to the
 Crown Ethers 7

Figure 9 Examples of crown ethers having different ring sizes and structures.

macroring), these heteroatoms replace the aliphatic oxygens that would be present in the unadorned macrocycle. The presence of an
aromatic oxygen, sulfur, or nitrogen will affect the molecule’s physical and binding properties. Four compounds that would reason-
ably be called crown ethers are shown in Fig. 9. In these four examples, only oxygen atoms are present in the ring although a con-
formationally unfavorable butylene residue is present in 17-crown-5.
The replacement of crown ether oxygen by nitrogen make little difference in the ring size, but the heteroatom donicity and
basicity are both altered. Typically, the presence of one or more nitrogen atoms in the ring alters the binding selectivity toward group
II and group III metals instead of alkali metals. Examples of crown ether variants have been reported that take advantage of the
basicity of nitrogen and of its ability to serve as a hydrogen bond donor. If the nitrogen is amidic, it may serve as an N–H donor,
but it not be basic.
Di- and trivalent metal cations tend to be smaller than alkali metals that have a single charge. Nitrogen also has a greater affinity
for cations in the third long row of the periodic table.15 A compound that the traditional organic chemist would designate as tetraza-
14-crown-4 has been given the name 14-ane-4 by the inorganic community. This compound has also received the cognomen
cyclam.16 A vast range of nitrogen-containing crown ethers has been prepared. Four compounds are illustrated in Fig. 10 that
suggest the various ways in which nitrogen atoms may be incorporated into crown ethers.
While N for O replacement may be the most common macroring substitution, numerous other variations exist. Fig. 11 shows
nitrogen incorporated into the macroring as an imine. This particular macrocycle also incorporates three sulfur atoms. The
compound is a traditional crown ether only by analogy as it contains no oxygen and would favor binding soft cations. A second
macrocycle is pictured that incorporates two pyrazine residues. Typically, only one of the nitrogen atoms per heterocycle would
be counted as comprising part of the macroring. The last two macrocycles shown contain either silicon or phosphonate. The ability
of the latter to bind a cation will depend on whether the macroring can adopt a conformation in which the polar oxygen (of P]O)

Figure 10 Macrocycles containing combinations of N and O in various ring sizes and functional group arrangements.

Figure 11 Examples of heteroatoms variations in macrocycles.

8 Crown Ethers

Figure 12 Structures of lariat ethers.

can contact an encircled guest. The mobility of the ring is diminished by its small size and by the presence of the rigidifying fused
benzene rings.
The six structures shown in Fig. 12 as A–F are referred to as lariat ethers. Compound A is a carbon–pivot lariat ether, which has
restricted side arm motion and exists as a racemic pair.17 Notwithstanding, the side arm can provide secondary solvation for a mac-
roring bound cation. Compound B is a nitrogen pivot lariat ether that has a reducible side arm. Electron transfer to nitrobenzene
enhances the donicity of the side arm and the nitrogen pivot provides greater flexibility.18 The side chains of C and D provide envel-
oping coverage of a ring bound cation. Compound C complexes in a cryptate-like structure. Compound D binds Naþ using both
arms above the macroring and Kþ by adopting an anti-side arm arrangement.19 Compound E is formally an octaaza-16-crown-8
derivative. It possesses a nitrobenzene side arm and the authors refer to the structure as a “lariat azacalix[4]pyridine.”20 Compound
F represents a large class of alkyl and dialkyl substituted crown ethers that possess side arms lacking donors. These compounds do
not show enhanced binding,21 but they are biologically active.22
Fig. 13 illustrates structures that can correctly be referred to as bis(crowns). The four structures represent distinct types of connec-
tions. The spiro-joined crowns are approximately perpendicular to each other and a cooperative interaction between them with

Figure 13 Bis(crown ether)s linked in four different ways.

 Crown Ethers 9

a spherical cation guest is not likely to be effective. This is also the case for the azobenzene derivative shown in its trans ground state.
Azobenzene, of course, is photoactive and can undergo a light-triggered trans–cis isomerization. If this occurs, the two benzene rings
will be on the same side of the azo linkage and could form a sandwich complex with a cation. The use of azobenzene as a photo-
switchable, conformation changer has been used extensively23 in supramolecular chemistry generally and in crown ether chemistry
in particular. The two benzo-15-crown-5 macrocycles that are linked by a diethyleneoxy bridge can cooperate in binding in a fashion
similar to that described for the cis-azobenzene compound.
The bis(crown) system built on the 2.2-paracylophane base is rather like the spiro-connected bis(crowns) shown in Fig. 13.
Unless that paracyclophane undergoes a reaction that causes the rings to lie on the same side of the scaffold, no cooperation
between the macrorings can occur. Despite the inherent strain in paracyclophane, it does not ring open readily. Even if it did
have both rings on the same side of the crowded arenes, it would be sterically unfavorable. A family of bis and tris(benzocrowns)
has recently been reported that are linked as benzophenones.24

3.02.1.4 Crown Ether Polymers

Fig. 14 illustrates three approaches to polymeric or polycrowns. Polymers have been fashioned from crown monomers by both
addition and condensation polymerization. In addition, crowns have been formed on polymeric matrices. Probably the simplest
polymerization involves 4-vinylbenzo-15-crown-5. It can be polymerized by using typical styrene polymerization methods. This
approach will afford a polyethylene chain to which are appended benzo-15-crown-5 residues at the expected intervals.
Dibenzo-18-crown-6 has been copolymerized with trichloroacetaldehyde under Lewis acid catalysis (BF3). In the resulting
condensation polymer, the benzocrowns are linked by methylene groups, each of which has a trichloromethyl group attached. It
is not known whether the linkages are what might be called pseudo-meta, pseudo-para, or both.
Another, and different, type of polycrown was prepared in a nontraditional way. In this case, a chlorinated polystyrene matrix
(Merrifield’s resin) is exposed to oligoethyleneoxide chains. Macrocycles are formed when both ends of the ethyleneoxy oligomer
replace chlorine atoms in the chloromethylated matrix. This is unlikely to be a regular process, and various sizes of macrocycles may
be present depending on the distances between the bridged residues. Polymeric crowns have been applied early on in a range of
analytical applications, such as ion chromatography.26 They also comprise elements of nanotubes27 and light emitting diodes.28
Polymeric systems have also been devised for chiral separations, some of which are commercially available. For example, a poly-
mer may be formed from aza-18-crown-6 bound as amides to a polymeric matrix by pendant benzoic acid residues. This affords
a chromatographic system that can interact with amino acids by H-bond interactions. Although these interactions are individually
weak, the process is enhanced by what may be called numerous theoretical plates.29 Chiral crowns bound through silica linkers were
devised originally by Sogah and Cram30 and more recently these ideas have been expanded to include a number of silica-linked
polymeric systems.31

Figure 14 Structural types of polymeric crown ether cation binders. The compound shown in the lower right is a polymeric polyelectrolyte.25
10 Crown Ethers

Supported liquid membranes (SLMs) represent a somewhat different vehicle for use in separations. In a recent example, electro-
membrane extractions were fostered by incorporation of several different 18-crown-6 derivatives added to 1-ethyl-2-nitrobenzene.
Dibenzo-18-crown-6 was found to be the most successful additive because of its Kþ ion selectivity in a study involving several other
ions: NHþ 2þ 2 þ 32
4 , Ca , and Mg .

3.02.2 Synthetic Access to Crown Ethers

3.02.2.1 Crown Synthesis and the Template Effect
Pedersen’s original synthesis of dibenzodiaza-18-crown-6 has often been referred to as a “shotgun” approach in which two mole-
cules of catechol and two molecules of O[(CH2)2Cl]2 were treated with base. The synthesis requires that four bonds are made and
that a rather large, 18-membered ring is formed. A typical solution to the formation of large rings is to use high dilution and such
a method is used in crown ether synthesis when appropriate. In this case, however, a so-called “template effect” appears to play
a role.
When two catechol molecules react with O[(CH2)2Cl]2, the product will be as shown in Fig. 15. The cation is captured by the
dihydroxyl receptor that Pedersen originally intended to form (see above). When the third ether bond is formed, the bound cation
helps to organize the assembly for ring closure. In the high dilution method, the odds of one end of a molecule finding its other end
for ring closure is enhanced. In the templated method, an organizing element is present and the ring closure is inherently less
random.
Although Pedersen used oligoethyleneoxy dichlorides in many of his syntheses, the leaving groups have often been better, if less
economical, tosylates. In addition, larger cations have been used either to produce larger rings or to enhance anion potency by
changing the hard–hard relationship in NaOH to a soft–hard base such as CsOH.33
It should be noted that evidence for the template effect has certainly been acquired for a number of reactions. It is often invoked
when a reaction is successful, but often, no attempt is made to conduct a control reaction. This is, of course, completely understand-
able as it is usually the product that is required rather than mechanistic information about the preparation.

3.02.2.2 Azacrown Ethers

Azacrowns differ from the all-aliphatic counterparts by the presence of a nitrogen that can form three, rather than two, bonds. If
a substituent is desired to be present on the nitrogen, it can readily be attached by alkylation as shown in Scheme 1. Here the substit-
uent R is an alkylating agent. If and when over-alkylation is a problem, acylation followed by reduction is a solution. If no substit-
uent is desired on the nitrogen, a protecting group is required. Tosyl is often chosen and offers the advantages of stability and, in

Figure 15 An illustration of crown synthesis involving a template effect. The sphere represents an alkali metal cation, typically sodium or
potassium.

Scheme 1
 Crown Ethers 11

Scheme 2

many cases, crystallinity in the product. It is relatively difficult to remove, however, and should be used only when the hydrolytic
conditions will not otherwise damage the desired structure.
Tosyl is desirable as a leaving group although the commercial availability of diethylene glycol dichloride and triethylene glycol
dichloride make them convenient alternatives. For the longer diols, H(OCH2CH2)nOH, where n  4, the tosylates are usually
preferred. A problem with the longer diols is that they are hard to separate from the oligomers having nþ 1 ethyleneoxy groups.
The separation becomes more difficult as the chains increase in length because the boiling points are high and close because the
oligomers differ only by 44 Da.
The cyclization can easily be done using a range of bases such as KO–t-Bu in THF, NaH, or even KOH in THF. The alkali metal
hydroxides are strong bases in aprotic media and even though there is some water in reagent grade KOH, it is usually not a problem.
Scheme 1 shows a sequence in which an N-substituted aza-15-crown-5 is synthesized.
Diazacrowns can incorporate nitrogen atoms in a variety of ways and positions. Diethanolamine, substituted or protected, can be
treated with, for example, diethylene glycol dichloride and base to give a diaza-24-crown-8 product, as shown in Scheme 2. An alternate
approach is to form a diamide and then reduce. The lower panel of Scheme 2 shows a sequence in which triethylene glycol is oxidized to
the corresponding diacid. This, in turn, is converted into the diacid chloride. Cyclization is accomplished by forming the diamide. Reduc-
tion of the two amide residues yields the unsubstituted 4,13-diaza-18-crown-6. The preparations of azacrowns are shown in Scheme 2.

3.02.2.3 Lariat Ethers

In the sequence shown in Scheme 1, the presence of the R group on nitrogen could make the azacrown identifiable as a lariat ether.
Originally, lariat ethers were crowns to which were attached side arms having donor groups. Scheme 3 shows the preparation of
macrocycles having single side arms. In one case, the sidearm is attached at carbon (“carbon-pivot”) and is a racemic mixture
and the side arm is attached at invertable nitrogen (“nitrogen pivot”) in the other.
When two or more side arms are present on lariat ethers, the term bracchial, from the Greek word for arm, is used to signify their
presence. Thus a two-armed lariat ether would be called a bibracchial lariat ether or a BiBLE. A versatile synthesis of the diaza-18-
crowns used benzylamine (R ¼ PhCH2NH2) and triethylene glycol diiodide. Cyclization is effected by using Na2CO3 in CH3CN.
Other primary amines afford similar products, but benzylamine offers the advantage that the side arms can be hydrogenolyzed to
afford the parent compounds, 4,13-diaza-18-crown-6, as shown in Scheme 2.
The nature of the compounds shown in of Scheme 4 can vary from aliphatic to aromatic. However, an attempt to make the 18-
crown from 4-methoxyaniline (p-anisidine) was found to proceed slowly and produced only the 9-crown-3 derivative in low yield.
4-Methoxybenzylamine produced the desired 18-crown in about 30% yield, which is typical of this process. The yield was 28% of
the 2-hydroxyethyldiazacrown when the starting aliphatic amine was HOCH2CH2NH2. The corresponding methoxyethyl derivative
was made from the parent diaza-18-crown-6 by acylation with methoxyacetyl chloride followed by reduction of the diamide using
diborane in THF.
12 Crown Ethers

Scheme 3

Scheme 4

Scheme 5 Upper equation “A” shows the formation of a photo-switched azobenzene side armed lariat ether. A lariat ether having various urea-
linked side chains (“R”) and various ring sizes (“n”) is shown in B. Structure C shows a lariat ether possessing both the urea and azobenzene
modules.

Two interesting lariat ethers that incorporate azobenzene residues are shown in Scheme 5. The compounds designated A34 and
C in the figure possess azobenzene side chains which permit colorimetric detection and the possibility of photochemical trans–cis
35

isomerization. Compound B36 does not incorporate the azobenzene unit but, like C, has a ureido link that may foster aggregation of
the compounds into orderly stacks.

3.02.2.4 Other Heteroatoms and Subcyclic Units

Quite a range of so-called subcyclic units have been incorporated into crown ethers. In general, the incorporation of sulfur into the
macroring is accomplished by using sulfur as a nucleophile in ring formation. As indicated above, nitrogen may be a part of an
element such as diethanolamine or it may be incorporated by forming an amide ( NHeCO ) followed by reduction (/
NHeCH2). A third method is to form an imine, which may be retained in the ring ( CH]N ) or reduced (/  CH2eNH ).
A further variant of this approach is to use an oxime as a synthetic module with the formation of a  CH]NeO linkage.
 Crown Ethers 13

Figure 16 Saccharide azacrown cryptands in which the ovals represent glucose, lactose, or cellobiose.

Figure 17 Crown ethers incorporating thiophene, pyridine, and diazine as subcyclic units.

A recent example of a ditopic receptor system is shown in Fig. 16. It incorporates diaza-15 and -18 crowns in a cryptand-like
assembly in which the “sides” of the box are sugars. The authors report receptors that include glucose, lactose, or cellobiose in
the assemblies.37
An unusual crown has been reported recently that is a dynamic system: an iridium is bound to a benzene ring, which has oxygen
in one ortho position and the amine of an azacrown linked by a methylene at the other.38 Depending on the conditions, the crown
may be pendant (i.e., a lariat ether) or incorporate a 2,3-diazafuran within it. The authors refer to these compounds as “iridium
hydride pincer-crown ether complexes.”
Subcyclic units may be incorporated either as nucleophiles or electrophiles. Thus, 2,6-dichloromethylpyridine can be treated with
tetraethylene glycol and base to form an 18-crown-6 analog in which pyridine’s nitrogen replaces a macroring oxygen atom. A similar
strategy can be used to prepare a 2,5-disubstituted furan analog. For electron poor systems such as dichlorodiazines, direct nucleophilic
attack on the ring either by oxygen or by sulfur nucleophiles will afford a product such as shown later and in Fig. 17.
Literally thousands of new macrocycles were prepared and reported.39 In some cases, complexation of cations was not the main
goal. Rather, the effort was mounted to determine what structural variations could be created in this new and exciting class of mole-
cules. As the sophistication of the field increased, crown ethers became scaffolds for or modules in the development of sensors,
probes, or in other applications.

3.02.3 Cation Binding by Crown Ethers40

The discussion of cation binding by crown ethers is a vast subject and the discussion here outlines a few facts and principles that
were important in understanding the scope and utility of crowns.

3.02.3.1 Complex Structures

Pedersen’s suggestion of the name “crown” implied that the receptor or host surrounded the cation. In fact, the regal crown image is
closer to reality in many cases than might have been thought. When a cation is too large to fit in the crown’s “hole,” the macrocycle–
cation interaction will adjust for maximum efficacy commensurate with steric requirements. In the case of 18-crown-6, the fit with
Kþ is essentially ideal and the guest fits nicely within the host. When the macrocycle is larger than the cation as would be the case for
the 18-crown-6 complex of Naþ, the crown contracts to achieve the correct O–Naþ binding distances. This requires the crown to
pucker. Additional binding may occur that involves the sixth oxygen atom and water or anions may occupy apical positions in
the complexes.
When the macrocycle’s hole is smaller than the cation, a sandwich complex may form. In such a case, a larger number of donor
atoms solvate the cation. The result of this is that the Mþ–O distances are longer than those observed when the fit is nearer to ideal.
14 Crown Ethers

Figure 18 Solid state structures of (a) 18-crown-6; (b) 18-crown-6 $H3NþeNH2; (c) 18-crown-6$ H2O; (d) (18-crown-6)2$ Csþ; (e) dibenzo-18-
crown-6; (f) 18-crown-6$Kþ$(H2O)2.

Fig. 18 shows solid state structures selected from literally thousands that have been catalogued in the Cambridge Crystallographic
Structural Data Base. The six structures are deliberately diverse and show the different ways in which crown ethers may interact with
cations.
It is sometimes difficult to discern interactions from a single illustration of a solid state structure. Fig. 19 shows the same six
structures in the same order as presented in Fig. 18, but in structural drawings. The structure of 18-crown-6 is shown in (A) in
the conformation it adopts when binding Kþ. Typically, though, noncomplexed crown ethers do not show such an open confor-
mation. Rather, the chains rotate so that the internal void is partly filled. This is apparent in (E), which showed the structure of

Figure 19 Schematic representation of the compounds illustrated in Fig. 18 and discussed in the text.
 Crown Ethers 15

dibenzo-18-crown-6 in the absence of any cationic guest. However, a recent electron microscopic and computational study has
drawn attention to the similarity between 18-crown-6 in the D3d conformation and graphene.41
It is not only cations that bind to crown ethers, the macrocycle’s heteroatoms can serve as H-bond acceptors for a variety of
donors. Panels (B) and (C) show examples of H-bond interactions. In (B), the hydrazinium (H2N–NHþ 3 ) ion is bound within
18-crown-6. The complex is stabilized by three O–H–N interactions. Numerous ammonium salts have been found to bind in
a similar fashion. Two water molecules are complexed by H-bond interactions in the structure shown in (C). The single H2O
apparent in the structure bridges the 1,7-oxygen atoms in a fashion similar to that apparent for ammonium binding but obviously
lacking the third H-bond.
Alkali metal cations are bound by macrocycles in the structures shown in (D) and (F) of Figs. 18 and 19. The host molecule in
(F) is dicyclohexano-18-crown-6 and its macroring fits the Kþ ion well. Note that the bulk and complexity of the fused cyclohexanes
compared to the benzene rings in (E). The potassium cation fits an 18-membered ring crown but the larger cesium cation does not.
The ionic diameter of Kþ is  3 Å but Csþ cation is larger (3.6–4.0 Å diameter depending on coordination number)42 than Kþ (six-
coordinate ¼ 3.0, 12 coordinate ¼ 3.2 Å diameter). Since the large Csþ ion cannot nestle within the crown’s available hole, the
sandwich structure shown in panel d results. Structurally related complexes have been reported for [12-crown-4]2Naþ and [15-
crown-5]2Kþ. As noted above, in cases such as 18-crown-6 complexing Naþ, the receptor forms a 5-oxygen ring Naþ. The sixth
oxygen is puckered above the plane of the other five oxygen atoms and provides additional solvation to the ring-bound cation.

3.02.3.2 Cation Binding Dynamics

Pedersen immediately recognized that crown ethers could bind the spherical, featureless alkali metal cations whereas other receptors
had failed to do so. In some of his early work, Pedersen reported cation binding.43 He also collaborated with Frensdorff,44 who
amplified these studies. A vast number of cation binding studies were reported in the ensuing years. Christensen, Izatt, Bradshaw,
and their coworkers45 summarized and systematized much of this work in a number of reviews. A monograph that details several
areas of crown complexation behavior describes advances through the first two decades of study.40
Simple host–guest binding can be described by a simple equilibrium expression. The position of the equilibrium is defined by
the equilibrium constant, which in turn is defined by the complexation and decomplexation rates. The equilibrium constant is
usually expressed as the variable KS. Since the binding constants of crown ethers with various cations can range over many powers
of ten, KS is often expressed as the decadic logarithm, i.e, log10 KS.
The rates of binding and release of ions by crowns depends not only on the structure of the host and the identity of the guest, but
also to a significant extent on the solvent polarity. The equilibrium constant for formation of a Kþ$ 18-crown-6 complex lies far to
the right in chloroform or dichloromethane but less so as solvent polarity increases (see Fig. 20). The Kþ$ 18-crown-6 complex is
weak in water. The binding rates for the formation of this complex have been measured in water and are kcomplex 108 s 1 and kde-
6 1 þ 8 1
complex  10 s . The equilibrium constant is therefore 10 /10 or  100. The corresponding rates for Na in water are  10 s
8 6
7 1 þ þ
and  10 s , giving KS z 10. The selectivity for K /Na is only about 10 in water.
46

It is interesting to note that the strongly complexing cryptands bind more slowly than do crown ethers. This is not surprising as
one of the bridging chains must move out of the way to accommodate a cation. Desolvation of any guest within the cryptand must
also slow the process. The decomplexation rate of the complex once formed, however, is very slow, resulting in the high binding
strength. Complexation data for 18-crown-6 and [2.2.2]cryptand are shown in Table 1.
As noted earlier, the position of the complexation equilibrium depends appreciably on the solvent. As noted earlier, the binding
constant for Kþ by 18-crown-6 in water is  100 (log10 ¼ 2). In anhydrous methanol, the equilibrium constant is  106 (log10 KS ¼
6). This is obviously a difference of 10,000-fold. Even though the binding is stronger in less polar solvents, much of the data that

Figure 20 The equilibrium constant for complexation of Kþ by 18-crown-6 is defined by the ratio of binding and release rate constants.

Table 1 Cation binding constants determined in anhydrous methanol

Binding Constant KS (as log10)

Compound Naþ Kþ NHþ4 Ca2 þ

18-Crown-6 4.35 6.08 4.2 3.9
[2.2.2]Cryptand 8.0 10.6 NRa 8.14
a
NR means not reported.
16 Crown Ethers

Table 2 Cation binding and release rates for selected crown ethers in methanola

Host Cation Kbind (M$ s 1) Krelease (M 1$ s 1)

15-crown-5 Naþ 2.6  108 5.1  107

15-crown-5 Kþ 4.3  108 5.1  107
18-crown-6 Naþ 2.2  108 3.4  107
18-crown-6 Kþ 4.3–6.3  108 2.7–12  106
a
Data taken from reference 40.

have been reported have used anhydrous methanol as solvent. Methanol is essentially a compromise between dynamic range in
measuring the binding constant and the solubility of an organic host and an inorganic guest (salt). Table 1 shows complexation
data for 18-crown-6 and for [2.2.2]cryptand in dry methanol. The anions associated with the indicated cations were Cl. Note
that the binding constants recorded in the tables are expressed in logarithmic form.
There is no standard for the measurement of crown–ion binding studies. As noted earlier, methanol is a reasonable compromise
in terms of binding strength and solubility. It is important to note the solvent when interpreting data and it is important for data to
be reported for a single solvent or uniform solvent system so that valid comparisons can be made.
Data for binding and release rates for 15-crown-5 and 18-crown-6 are shown in Table 2. The values reported for binding
and release rates of Kþ in methanol are 6.8  105 and 36, respectively. This results in a binding constant of  20,000 or log10
KS ¼ 4.28. This compares with a KS value of about 100 (log KS ¼ 2) for the same equilibrium in water. Binding strength is
typically greater in ethanol than in methanol and differs further in acetone, which is approximately as polar as ethanol but
is aprotic.

3.02.3.3 Cation Binding, Macroring Hole Sizes, and Symmetry

A common misunderstanding concerning crown ethers and cation binding is the so-called “hole-size relationship.” This concept is
attractive because it is so structurally intuitive: a small cation fits a small host and big cation fits a large host. Table 1 shows that the
binding constant in methanol for Naþ by 18-crown-6 is 4.35. In the same solvent, Naþ is bound by 15-crown-5 with a KS value of
3.24. Converting these values, the difference in binding strength is  1,800 compared to  34,000. This is very significant by any
measure. The binding constants for simple crowns with Naþ, Kþ, NHþ 4 , and Ca
2þ
are compared in the graph in Fig. 21.47 The
top line (blue open circles) shows that Kþ is bound more strongly by all of the macrocycles than is any other cation. The significant
selectivity in 18-crown-6 binding of Kþ over Naþ is obvious from the peak in the blue line.
The hole-size notion is not the only concept that has endured from the earliest work in crown ether chemistry.48 There is certainly
evidence that the presence of, for example, potassium cation helps to organize the two ends of a reacting species to give a crown. In
a dramatic demonstration of a template effect, Cram showed that guanidinium cation templated the formation of 27-crown-9,
presumably by multiple hydrogen bond formation.49 Despite these results, it is not always possible to predict if a template effect
will play a role in the synthesis of a crown ether. Examples exist where no template effect can be identified. Thus, macrocycle
syntheses are often conducted under high dilution conditions.50
Macrorings not exactly commensurate with cation diameters form complexes. This is accomplished by sandwiching the cation as
shown in Fig. 18(D), by contracting around the cation and folding remaining donors into other positions, or even by complexing
two cations within the same macrocycle. One place where size complementarity is critical is in binding ammonium ions. A study
conducted by Cram and coworkers revealed important information about structural relationships, rigidity, and basicity.51

Figure 21 Relationship of cation binding strength to crown ether size for Naþ, Kþ, Ca2 þ, and NHþ
4 in methanol solution.
 Crown Ethers 17

Figure 22 Six 18-membered ring crowns and their chloroform:water distribution constants (log10 K) in the presence of t-butylammonium
thiocyanate.

3.02.3.3.1 Ammonium ion binding

The three NeH bonds of a primary ammonium cation are focused in the same direction and at an angle of 120 . Of course, the
nitrogen is tetrahedral so the H–N–H angle per se is  109 . A complex that forms between 18-crown-6 and a primary ammonium
cation will involve three hydrogen bonds linked to alternate oxygen atoms within the macroring. This arrangement is illustrated in
Fig. 18(B) and in Fig. 22. One possible pair of interactions is illustrated in the latter. The alternate arrangement, which is just as
stable, would involve the other three oxygen atoms. The equilibrium distribution constants (CDCl3:H2O) are shown in the figure
as their decadic logarithms. The distribution constant for 18-crown-6 is 750,000 (log10 K ¼ 5.88). If the macroring is rigidified by
incorporating one of the oxygen donors into a furan ring, the equilibrium constant increases to 1.1 million. If the ring is rigidified
and a more basic donor is included within it, the binding constant increases further to 1.4 million.
Most cation binding constants are determined in a single solvent so the distribution constants noted here are not directly compa-
rable but they are nevertheless informative. The methodology used to determine distribution constants is described in a later
section.

3.02.3.3.2 Conformation and symmetry

Benzo-18-crown-6 is more rigid than 18-crown-6, but the two oxygens linked to the arene are conjugated to it. This rehybridizes the
two oxygens toward sp2 and lowers their Lewis basic donicity. Thus, the equilibrium constant for binding to ammonium ion, which
must always involve one of the two oxygens, is reduced to 13,000. This is a reduction of nearly two orders of magnitude compared
to either the furanyl or pyridyl subcyclic unit. The greatest loss of affinity is witnessed, however, when a methylene or an aryl CH
replaces oxygen within the ring. The equilibrium constant for xylyl-18-crown-5 is 1,500 and for 18-crown-5, it is only 500. The small
difference in binding affinity probably results from slightly better organization of the macroring (greater rigidity) in the xyxyl crown
than in all the aliphatic systems. These binding data are not directly comparable with alkali metal cation binding determined in
methanol solution (see Table 1), but the internally consistent comparisons are very informative.
In other early work, both Lehn and Sutherland and their coworkers prepared compounds that might have been called ditopic
receptors or cryptands that bound diammonium salts. This may be considered an example of molecular complexation or cavity-
selective H-bond complexation. In either case, a range of receptors and diammonium salts was studied and selectivity was observed
for diammonium dication chains that corresponded in length to the internal cavities of the bis(crown) receptors (Fig. 23).52

3.02.3.4 Thermodynamics of Binding

As noted earlier, extensive work has been reported for a vast range of cations and crowns in many solvents.45 A few data are collected
in Table 3 to give the reader a sense for the strength of the binding interaction and the cost of solvent reorganization. As expected,
the equilibrium constant, expressed as log10 KS, is significantly higher in methanol than in water. It is generally true that binding
strength increases as solvent polarity decreases although, to the author’s knowledge, there is no straightforward correlation of dielec-
tric with binding. Still, the trend is clear and can be discerned in the data tabulated. The binding strength of Kþ by 18-crown-6 is
18 Crown Ethers

Figure 23 Example of a family of ditopic receptors that selectively binds diammonium salts of appropriate length.

Table 3 Thermodynamic parameters for complexation of cations by 18-crown-6.

Mþ Solvent log10 KS DH (kJ/mol) T DS (J/(K mole))

þ
Na H2O 0.8 9.41 15.5
Naþ CH3OH 4.36 35.1 34.3
Kþ H2O 2.03 26.0 47.7
Kþ CH3OH 6.06 56.1 72.2
Rbþ CH3OH 5.32 50.6 67.8
t-BuNHþ
3 CH3OH 2.90 32.5 53.1

Data from Gustowski et al.23

Figure 24 Molecular complexation of an arenediazonium cation by a crown ether.

about four powers of ten higher in methanol (ε ¼ 32.6) than in water (ε ¼ 81.5). Likewise, the enthalpy of interaction is  56.1 kJ/
mol ( 13.4 kcal/mol) in methanol vs.  26.0 kJ/mol ( 6.2 kcal/mol) in water.

3.02.3.5 Molecular Cation Binding

Extensive studies of molecular binding that were focused on ammonium ions, described briefly above and reported by Cram and
coworkers, helped greatly to define the variables at work in molecular complexation. These studies were important for defining
structural requirements that are more stringent for ammonium ion binding than for the featureless, spherical alkali metal cations.
Primary ammonium ions, secondary ammonium ions, acidic hydrogens of many types, and a range of other cationic species have
been reported. Examples may be found in Inoue et al.40
The solid state structures illustrated in Fig. 18 demonstrate that organic cations, i.e, molecules, can be bound by crown ethers as
can metal cations. One of the earliest examples of such complexation involved arenediazonium cations.53 The initial notion was
that the cylindrical diazonium ion had a diameter of about 2.4 Å and not only should fit into the hole of the macrocycle, but it
should be stabilized by the Lewis basic donor groups in the macroring. This proved to be the case for para-methylbenzenediazo-
nium ion, but not for the sterically hindered 2,6-dimethyl analog. Bartsch and coworkers showed that diazonium reactivity was
diminished by complexation in crown ethers and that 21-crown-7 was a more effective complexing agent (Fig. 24).54

3.02.3.6 Anion Binding

Crown ethers have been studied, in the main, as cation and molecular binders. If one considers crown ethers not exclusively as
a host that has an electron-rich center, it is clearly a macrocyclic scaffold that could accommodate other types of guests. Newcomb
and coworkers55 prepared a variety of tin-containing macrocycles that bound such anions as fluoride, well before the anion binding
field burgeoned to its present prominence.56 Another pioneer in this field was Schmidtchen who prepared three-dimensional
cationic hosts to encapsulate various anions.57 These are illustrated in Fig. 25 (left) where X indicates alkyl chains of varying lengths.
 Crown Ethers 19

Figure 25 Anion binders devised by Schmidtchen (left) and Lehn and their coworkers.

The cryptand structure shown at the right in Fig. 25 incorporates twin “tren” elements, adding six nitrogens that can be proton-
ated. The cationic and cylindrical cavity was found to encapsulate azide anion, which has the form charge structure N]Nþ]N.58
Interesting as these studies are, they are more appropriate to a discussion of anion binding, to which the reader is directed. Two
recent monographs are cited above that give an excellent overview of the field.33b,c

3.02.3.7 Experimental Binding Determination Techniques

3.02.3.7.1 The picrate extraction technique
There are numerous methods by which cation binding can be measured. As noted earlier, extensive binding data have been reported
that were determined by calorimetry. This is an excellent methodology but it is often unavailable in the laboratories where new
compounds are prepared as a priority. A convenient assay of binding that requires essentially only a separatory funnel is the so-
called picrate extraction technique.59
Picric acid, 2,4,6-trinitrophenol, is a bright yellow compound. It’s alkali metal salts are likewise bright yellow. If, for example,
Kþpicrate is dissolved in an aqueous phase and contacted by a crown-containing immiscible organic solvent, the amount of cation
can be assessed by measuring the amount of picrate co-transferred. The amount of salt extracted can be measured colorimetrically
and corresponds to the binding affinity of the host for the cation.60 Such experiments can be done routinely using only a UV–vis
spectrometer.43
Simple as these experiments may appear, care must be taken to obtain reliable and comparable results. These types of experi-
ments have been conducted using different concentrations of host molecules and salts and different solvent pairs. The combination
of chloroform and water is obvious and results obtained in a dichloromethane–water solvent pair are likely to be similar. Because
a solvent system such as nitrobenzene–butanol is very different from water–chloroform, one must be cautious about direct compar-
isons between quite different solvent systems.
It has also generally been found that it is easier to form the picrate salt by adding picric acid to a basic solution than to prepare,
dry, weigh, and dissolve the pure salt. The use of a basic solution raises the question of how much base should be used to be certain
that all of the picric acid is converted to its salt vs. how much the pH and/or the ionic strength of the aqueous phase is altered. There
is no formal rule about how to conduct experiments, but the more similar the conditions are to those previously used, the more
comparable and valuable new data will be.

3.02.3.7.2 Transport studies

Alkali metal and alkaline earth metals do not cross natural bilayer membranes in the absence of transport agents. The concentrations
of these ions are closely regulated in cells and channel proteins are generally required to mediate their transport. It was not long after
alkali metal cation binding by crown ethers was confirmed that studies of transport began. Such studies generally involved transport
by a carrier mechanism and typically involved a U-shaped tube sometimes called a “Pressman cell.” Pressman had used such a device
to demonstrate transport by naturally occurring antibiotics across membranes.61
The principle of the U-tube is simple. A dense solvent such as chloroform is placed in the bottom of the tube. Water is added to
one arm and a salt solution to the other. A carrier molecule like dicyclohexano-18-crown-6 is added to the chloroform. As the crown
diffuses through the organic solvent, it binds and transports the salt in one arm to the other. This process continues as long as the
experiment is conducted but the chemical potential is lost when the salt concentration in each side arm is equal. Transport can be
assayed by measuring cation concentration in the receiving arm using an ion selective electrode (ISE). Alternately, the picrate coun-
terion transported with the cation can be determined colorimetrically. Fig. 26 illustrates two variants of such a device.

3.02.3.8 Lariat Ethers

Cation binding and transport are linked by the need for binding strength and selectivity and the dynamics required to both bind and
to release cations. Cryptands have the advantage over simple crown ethers in binding strength and selectivity. Crown ethers are more
dynamic and permit fast release of cations once transport has occurred. Lariat ethers were developed to confer both dynamics and
20 Crown Ethers

Figure 26 A U-shaped tube transport apparatus shown (left) and a concentric tube device used to accomplish transport (right). In either case the
host or transporter compound is in the water-immiscible organic phase shown here as chloroform.

Table 4 Comparison of cryptand and lariat ether bindinga

Complexation Constant (log KS) in Methanol a

Compound Naþ Kþ
18-Crown-6 4.35 6.08
[2.2.1]cryptand 9 8.5
<18N>CH2CH2OCH3 4.58 5.67
[2.2.2]cryptand 8.0 10.6
<18N>(CH2CH2O)2CH3 4.33 6.07
CH3OCH2CH2<N18N>CH2CH2OCH3 4.75 5.46
a
Data from Supramol. Chem. 1995, 5, 45–60 and references therein.

three-dimensional complexation capability on the transport agent. Four lariat ethers are illustrated in Fig. 12. Note that when two
side arms are present, they are called bibracchial lariat ethers, from the Greek brachium for limb or arm. The C-pivot molecules are
less pH sensitive than the N-pivot compounds but the latter have side arms attached at invertable nitrogen. When not protonated,
the nitrogen pivot confers greater flexibility on the structure and obviates the issue of stereoisomers.
The dynamics for binding by lariat ethers is generally superior to that of cryptands, but the covalent coupling of three chains
confers superior selectivity on the latter. Table 4 compares binding by N-pivot lariat ethers with cryptands that have a corresponding
number of donor groups. Note in Table 4, the common abbreviations of < 18N > and < N18N > are used to represent aza-18-
crown-6 and 4,13-diaza-18-crown-6, respectively.

3.02.3.9 Enthalpy–Entropy Compensation and Solvent Effects

A principle that sometimes confounds our expectations about complexation is enthalpy–entropy compensation.62 A full discussion
of this issue is well beyond the present article. The notion is that a higher level of organization in the receptor and host–guest
complex results from better enthalpic interactions. The increase in favorable contacts makes the complex more organized. This,
in turn, requires the solvation to become more organized as well. Increasing solvent order affects the entropy of the system and
decreases the overall free energy as the enthalpic contributions are increasing it.
The topic of enthalpy–entropy compensation63 has been very broadly examined both in supramolecular chemistry64 where
multiple weak forces comprise the association energy65 and in drug–receptor interactions where similar issues obtain.66 It should
be noted that skepticism about the importance of enthalpy–entropy compensation had also been expressed.67
It is now well established that the strength of binding between, for example, a crown ether and a metallic cation depends signif-
icantly on polarity. It is known, for example, that the binding constant for 18-crown-6 in water increases with increasing methanol
in the medium. A plot of log10 KS for the results of this experiment gives a nearly linear result although there is no fundamental
principle that should lead it to be so. The extraction of ammonium ions from water into chloroform or dichloromethane is signif-
icantly aided by the lack of competition from water for hydrogen bonds. It is rather obvious to state that solvents or solvent systems
should always be clearly specified when the results of any binding study are reported.

3.02.4 Cation–Pi Interactions

Crown ethers have played a significant role in understanding the interactions. A detailed survey is beyond the scope of this article
but a brief summary should be included for completeness. Early work was undertaken with azalariats in the expectation that an
 Crown Ethers 21

Figure 27 Structures of N,N0 -disubstituted-4,13-diaza-18-crown-6 compounds having phenyl-, hydroxylphenyl-, and 3-indolyl-arenes terminating
ethylene spacer chains.

appropriately placed side arm donor would augment the binding to a cation within the macroring. This seemed plausible because as
early as 1981, Atwood and coworkers reported a structure of a macroring bound Kþ ion with a benzene molecule in the apical (pi-
donor) position.68 N,N0 -Disubstituted-4,13-diaza-18-crown-6 compounds were chosen as the vehicle for study.69 Compounds
having n-propyl, allyl, propargyl, cyanomethyl, benzyl, and methoxyethyl were chosen for study. An attempt was made to obtain
Kþ complexes of each compound so that solid state structures could be used to make detailed comparisons. In all of the cases in
which structures were obtained, no secondary side arm interaction was apparent. However, data for KS and DH, obtained for
complexation in CH3OH by using the van’t Hoff method, were encouraging. It was found, however, that although KS and DH
increased as the side arms were varied from CH2CH2CH3 to CH2CH]CH2 to CH2ChCH, the trend was not followed by CH2ChN
and CH2C6H5.
A second attempt to address the cation–pi problem used almost the same approach but the side arms were lengthened by a single
methylene. It seemed possible that the earlier study failed only because the hoped-for orientation could not be achieved for steric
reasons. As targets for the study, N,N0 -disubstituted-4,13-diaza-18-crown-6 compounds were again chosen, but ethylene side arms
were terminated with benzene, phenol, and indole. These are the three electron-rich side chain arenes among the 20 common
amino acids. They correspond to phenylalanine, tyrosine, and tryptophan, respectively. Among the common amino acids, there
is a fourth arene:histidine. It is electron deficient and it possesses two nitrogen sigma-donors. The structures of the compounds
studied are shown in Fig. 27.
Solid state structures were obtained for the three compounds illustrated in Fig. 27, both as free receptors and as complexes with
KI.70 All three complexes showed the type of pi-interactions apparent in the structure of Fig. 28. When the side arm was either
phenol or indole, the iodide ion in the solid matrix was H-bonded either by indole’s NH71 or phenol’s OH. In the structure in which

Figure 28 Potassium iodide complex of N,N0 -di(2-(3-indolylethyl)-4,13-diaza-18-crown-6. The five membered ring in each side arm is closest to the
ring bound cation.
22 Crown Ethers

benzene was the side arm, the position of iodide was similar, although no H-bond donor was available in the arene. Thus, an analog
of the bis(phenylethyl) compound was prepared in which each benzene rings was replaced by a pentafluorophenyl ring. When the
KI complex of this receptor was crystallized, Kþ was located in the macroring, but the electron deficient side arms were turned
away.72
The success of these studies led to a reexamination of the double and triple bond side armed compounds. Receptors
identical to those studied before were prepared, except that the double bond was contained in 3-butenyl side chains73
and propargyl became homopropargyl.74 In both cases, clear solid state evidence was obtained for secondary donor interac-
tions between the ring bound cation and the side arm unsaturations. As expected, when the histidine model imidazole
was used as a donor, sigma interactions prevailed.75 Recent work has focused on the role of the anion in cation–pi
interactions.76
The indole side arm structure shown in Fig. 28 was particularly interesting. Computational studies had predicted that cation–pi
interactions involving tryptophan would use the five-, rather than the six-membered ring.77 The structure obtained clearly showed
no such preference. The inference drawn is that indole is a versatile donor and that it will use either portion of its pi-cloud to interact
with an electron deficient species so long as it is sterically accessible. Additional perspective may be found in two recent reviews of
cation–pi interactions.78

3.02.5 Chiral Crown Compounds

Chirality has been a sought-after property in macrocycles since their discovery. Wudl and Gaeta prepared one of the first chiral mac-
rocycles, a dibenzo 18-crown-6 relative, that incorporated proline subunits.79 The property has resulted from the incorporation of
a chiral element such as a sugar into the macrocyclic framework.80 An example of this is shown in the lower left structure of Fig. 29.
Stoddart and coworkers incorporated mannitol directly into the macroring.81 Chirality is incorporated in two different ways into the
structure shown in the upper right of Fig. 29. The two norbornyl units are chiral and the stereochemistry of the two thiomethyl
groups is also fixed.82
The steroidal crown was prepared to study the effect of a strongly hydrophobic side chain on membrane transport activity.83
Recently, the compound 3b[N-(N0 ,N0 -dimethylaminopropyl)carbamoyl]cholesterol was reported to be mixed with the
lipid dioleoylphosphatidylethanolamine (DOPE) to which mixture was added plasmid DNA. The goal was then to use these
lipoplexes to transfect human embryonic kidney (HEK-293) cells.84 Of course, the chirality in the steroidal side chain will have
little effect on a simple cation bound with the ring, but it may interact quite differently with helical DNA.
The binaphthyl crown ether shown in the upper right of Fig. 29 has proved to be an important compound that led to a range of
applications. It was devised by Cram who envisioned that it would selectively complex chiral ammonium salts.85,86 The two naph-
thyl rings in each binaphthyl unit cannot readily pass each other owing to the interfering peri interactions. Thus the two binaphthyl
units have fixed stereochemistry (absent chemical or thermal stress). Cram showed that these compounds could selectively complex
enantiomers of amines and amino acids.60 He demonstrated that they could be bound to a silica surface and used for chromato-
graphic separations.
Numerous other chiral macrocycles are known. In many cases they have been adapted for separations of amino acids as origi-
nally envisioned by Cram, or for applications to mixtures of drugs, peptides, or other combinations. A number of recent reports
comprise a useful starting point for a more detailed consideration of this area.87

Figure 29 Early examples of chiral crown ethers.

 Crown Ethers 23

3.02.6 Crown Ether Biological Activity

A limitation in the earliest biological studies was the availability of compounds. Although a vast number of compounds had been
prepared, in many cases only the simplest structures were available in biological laboratories. For the first two decades after the
discovery of crowns and cryptands, the bulk of the studies of biological activity studies were conducted on the small group of struc-
tures shown in Fig. 30.
Dale and coworkers developed early methods to cyclo-oligomerize ethylene oxide to prepare the simple macrocycles 1–3. Ped-
ersen had reported a range of macrocycles in the report cited above1 and in his Organic Syntheses6 preparation that made compounds
12 and 13 readily available. Smaller (10, 11) and larger dibenzocrowns could be prepared by minor modifications of these proce-
dures. Further, electrophilic substitution of a single benzo ring (7–9) or di- or multiple alkylation or acylation on 10–13 produced
compounds that were frequently substituted on the benzene rings by acetyl or other acyl or t-butyl groups.
Some early studies involved the aliphatic crowns to which various side chains were appended. We suggested the name lariat
ethers17 for the compounds having secondary donor groups in side arms of the type shown generically as 7–9. The early structures
having an alkyl side chain but absent additional donors were pioneered by Okahara and his coworkers.88 Of course, many more
individuals would become involved in such studies but the early biological studies were often constrained by the availability of
the few compounds shown in Fig. 30 and their simple relatives.
Studies of crown biological activity can be placeddonly approximatelydin three historical groups. The earliest studies used the
relatively few available macrocycles to assess what biological activity might be exhibited by this new class of structures. Although
this stage often used limited compounds, a range of organisms and tissues was evaluated. The second stage explored a wider range of
structures and biological activity was typically assayed against a range of bacteria and fungi. This stage continues until today, but

Figure 30 The crown ethers that were most commonly available for the earliest biological studies. The R groups shown in compounds 7–9 could
be present on any of the benzo groups shown in any position thereupon and typically were alkyl, especially t-butyl, and acyl.
24 Crown Ethers

such studies have often neither been quantitative nor have they presented informative comparisons with earlier work. The third
stage involves an effort to understand structure–activity relationships in limited families of compounds and to determine if crowns
can be used in applications beyond simple toxicity. An effort has been made in this review to record these diverse efforts within
contextual groups and in a historical sweep, to the extent that is possible and sensible.

3.02.6.1 Early Biological and Toxicological Studies

The earliest biological studies of crown ethers were reported in the 1970s, including Pedersen’s mention of toxicity to canines in his
Organic Syntheses procedures.3 Ts’o and Chenoweth studied the toxicity of what would generally be called 12-crown-4 (1).89 They
found that the cyclic tetramer of ethylene oxide caused testicular atrophy in rats exposed to its vapors. This finding caused concern in
the crown ether community and may have retarded biological studies. By the late 1970s, however, a number of biological insights
were reported.
A study related to the physical properties of an 18-crown-6 (3)$ sulfamonomethoxine complex was conducted90 using healthy
male beagle dogs. The only information given in the paper is that an 18-crown-6 complex was formed “with sulfamonomethoxine
(SMM) in solid state.” (Fig. 31) The structure is shown in Fig. 2. In a control experiment, 18-crown-6 was administered in a single
dose of 200 mg in a wafer taken orally. The authors reported that the following reactions were observed: “a tremulous movement,
a salivation and a paralysis of the hind legs between 2-12 hours after administration. These symptoms disappeared around 24 hr
after administration.”
A more comprehensive study was reported by Hendrixson and coworkers91 shortly thereafter that contained LD50 data for 12-
crown-4 (1), 15-crown-5 (2), and 18-crown-6 (3) in white male mice. A value was also reported for dioxane, which was referred to
in the paper as 6-crown-2. The LD50 values (in g/kg) were as follows: dioxane, 6; 12-crown-4 (1), 3.15; 15-crown-5 (2), 1.02; and 18-
crown-6 (3), 0.705. Differences in onset times were noted as were variations in the symptoms apparent in the mice. For context, if
the LD50 values translated directly, the amount of 18-crown-6 required to be ingested by an 80 kg (176 lb) human would be 56 g.
The reported LD50 for aspirin in mice is 1.1 g/kg.92 The corresponding toxic dose for an 80 kg humandagain assuming correspon-
dencedwould be 88 g. At a typical adult dose of 325 mg per tablet, so this equates to 270 tablets. These equivalence values are
noted only to demonstrate that the toxicity of many of these compounds is not as great as might have originally been thought.
In an approximately contemporaneous study,93 the bioavailability of a 1:1 complex of 18-crown-6 (3) and sulfamonomethox-
ine was examined. The authors report that “[t]he dissolution study was done by a dispersed amount method and a stationary disk
method, and the in vivo absorption study by an oral administration in dogs.” In this study, only the effect of the complex was re-
ported and neither the toxicity of the crown ether nor its independent effect on the subject dogs was reported. It is interesting to note
that a “complex” between 18-crown-6 and sulfamonomethoxine could take different forms. The nature of the complex is not
revealed in the report. Since the drug is an aromatic sulfonamide, it can readily be deprotonated by base to give, for example,
a sodium salt. The crown complex could be a crown $ Naþ complex in which the drug is the counter ion. A few such complexes
have been studied. On the other hand, the complex might simply be a coordinated assembly in which the amino group and amide
hydrogens bond to the crown oxygen atoms.
Another early study of crown toxicity was focused on substituted benzo-15-crown-5 ethers (8) and several structurally related
compounds (Fig. 32). The effort was directed to discover synthetic analogues of known anticoccidial ionophores such as monensin.
The authors note that none of the crowns was active against the parasite Eimeria tenella in chickens at a concentration in feed up to 1

Figure 31 Structure of sulfamonomethoxine.

Figure 32 Benzo-15-crown-5 derivatives tested for anticoccidial activity.

 Crown Ethers 25

Figure 33 Macrocycles containing 15- and 18-membered rings had having pendant basic amine functions.

part per thousand (103 ppm). The benzo-15-crown-5 derivative (Fig. 32) in which R ¼ CH3 and R1 ¼ H was found to be quite active
in tissue culture. Acyclic analogs were inactive either in live animals or tissue culture.
The previously observed biological activity of various crowns engendered a study of (aminoacetyl)aza-4,7,10,13-
tetraoxacyclopentadecane $HCl (Fig. 32).94 It was given orally to mice at a dosing of 100 mg/kg but was found to be rapidly metab-
olized. The metabolic products did not accumulate in tissues but were eventually found in the liver and plasma. In another study,95
three diaza-18-crown-6 compounds bearing nitrogen containing substituents were tested in mice and rats to determine their toxic
effects. The compounds, N,N0 -bis(pyrrolidinomethyl)diaza-18-crown-6, N,N0 -bis(gamma-aminobutyryl)diaza-18-crown-6, and
N,N0 -bis(succinylimidomethyl)diaza-18-crown-6, exhibited anticonvulsant and tranquilizing effects on the rodents but all three
compounds were found to be too toxic to have any application as a therapeutic agent (Fig. 33). Additional toxicity data were re-
ported for mono- and dibenzocrowns having macrorings of 15- or 18-members. It was found that larger rings and a greater extent
of alkyl substitution increased the toxicity.
15-Crown-5 (2), 18-crown-6 (3), and several corresponding mono- and dibenzocrown analogs as well were studied for toxic
effects in mice.96 Assays were also conducted to determine if any antihypoxic or psychotropic effects on the mice were apparent.
A general increase in toxicity among the nine compounds studied was observed as the number of aromatic rings increased. This
work was extended in a structure–activity relationship that examined antihypoxic and anticonvulsant activity of nearly 100 macro-
cycles that included both sulfur and phosphorus in the macrorings.97 A sampling of the structures is shown in Fig. 34. In most cases,
ring sizes vary and the aromatic rings are substituted by alkyl, aryl, or polar groups such as NO2 or NH2. In many earlier biological

Figure 34 Representatives of a large group of compounds studied to assay antihypoxic or psychotropic effects in mice.
26 Crown Ethers

Figure 35 Diprotonated 4,13-diaza-18-crown-6 salts having varied counterions that were assayed for immunosupressive and anti-proliferative
activity in mice.

studies, the number of compounds and the structural variations were limited, especially because the compounds were not available
in the laboratories in which the biological testing was done. In this work, a structure–activity relationship was sought and although
correlations resulted, no clear predictive model emerged. It was noted by the authors that “polyethers with high antihypoxic activity
were usually highly toxic (LD50  100 mg/kg). The antihypoxic activity of compounds of benzo-12-crown-4, dibenzo-l8-crown-6,
and of their derivatives was slightly lower, but these crown ethers had a much weaker toxicity (LD50 > 500 mg/kg) and their side
effects were less pronounced.”
The biological activity of diprotonated 4,13-diaza-18-crown-6 derivatives was tested for antiproliferative activity in mice
(Fig. 35).98 The four compounds shown in Fig. 35 differ in the anions associated with the diazacrown salt. Immunosupressive
activity was found for the salts having the indolethioacetic and 4-chlorophenylthioacetic acid counterions.
Another recent example of antiproliferative activity is reported in United States Patent 8,389,505.99 Kralj and colleagues
prepared a library of lariat ethers based on the 18-crown-6 framework. One or two adamantyl side arms were attached to nitrogen
within the ring either by an alkyl chain or linked as an amide. The structures prepared are illustrated in Fig. 36.

Figure 36 Adamantyl side chained lariat ethers that exhibit antiproliferative and are cytotoxic to several tumor cell lines.
 Crown Ethers 27

Figure 37 Structure of di-t-butyldibenzo-30-crown-10.

Testing of the compounds shown was undertaken on human cell lines. The lines used were MCF-7 (breast carcinoma), SW 620
(colon carcinoma), HCT 116 (colon carcinoma), MOLT-4 (acute lymphoblastic leukemia), H 460 (lung carcinoma), HeLa (cervical
carcinoma), MiaPaCa-2 (pancreatic carcinoma). A detailed description of how the biological evaluation was conducted is reported
in the patent. Tabular data are presented that record the IC50 values against the cell lines indicated above. The activity of 4,13-diaza-
18-crown-6 was low. When a single adamantine-terminated side arm was present, activity was good whether the ring-adamantane
linker was ethylene or propylene. When the side chain was amidomethyl, activity was lost, but insertion of an additional carbon
atom in the spacer chain led to recovery. Good activity against these cell lines was obtained with twin-chained lariats irrespective
of chain length or the presence of an amide. Although the IC50 values ranged to greater than 100 mM, in a number of cases, efficacy
was in the range of 400 nM.
A number of benzo- and dibenzocrowns of ring sizes from 15 to 30 atoms was surveyed in rat liver mitochondria by Harris
et al.100 for their ionophoretic activity. The most active transporter for Kþ, Rbþ, and Csþ was found to be di-t-butyldibenzo-30-
crown-10 (Fig. 37). Owing to the mitochondrial properties, it was impossible to measure Naþ transport with confidence.
Compounds having two, rather than just one, benzo group were found to show greater cation uptake within a given size series.
The authors found that smaller rings that could form sandwich complexes favored Kþ uptake and larger rings favored either Rbþ
or Csþ. They report that uptake by mitochondria was correlated with the apparent association constants as determined in CH3OH.
The studies that were conducted to evaluate biological activity of crowns, be it beneficial or deleterious, have proved to be some-
what eclectic. There is clear evidence that crowns do exhibit biological effects, but the disparity in the compound structures used and
the animals studied, make direct comparisons difficult or impossible. It should be noted, however, that in many cases, the biological
effects of crowns on animals, when administered at modest doses, appear to be minor and/or reversible.

3.02.6.2 Antimicrobial Activity of Crown Ether Derivatives

During the 1980s, studies conducted in laboratories throughout the world showed that macrocyclic polyethers possessed antimi-
crobial activity. Okahara, Kato, and their coworkers101 examined the antimicrobial activity of alkyl-substituted crown ethers (e.g., 4)
and N-alkyl substituted azacrowns (e.g., 6). A shorthand that can simplify discussion of diverse compounds and that is often used
for crowns is to enclose the ring size in angle brackets. Thus, 15-crown-5 (2) would be < 15 >. A diaza-18-crown-6 having a propyl
group attached to each nitrogen atom could be represented as C3< N18N>C3 or Pr<N18N>Pr. Among the alkyl substituted
compounds studied, n-dodecyl-15-crown-5 (< 15>C12H25) and n-decyl-18-crown-6 (< 18>C10H21) were the most active against
B. subtilis (G þ), B. cereus (G þ), and Staphylococcus aureus (G þ). The minimum inhibitory concentrations reported for both of these
macrocycles were in the range 2.5–5 mg/mL. The < 15>C12H25 compound has a molecular weight of 388 g/mol. If we use the value
4 mg/mL as a representative potency, this translates to  40 mM.
Both compounds were effective against the yeast at a concentration of 10 mg/mL. The larger ring macrocycle was equally effective
against Candida utilis and nearly as potent (20 mg/mL) against Aspergillus niger. The 15-membered ring compound showed poor
activity against the latter two fungi. The N-alkyl crowns, < 15N>R or < 18N>R where R was C10 or C12, studied in this work
were less potent.
Yagi et al.102 studied the effect of 26 different crown ethers on a range of fungi including Tyromyces palustris, Picnoporous coccineus,
Coriolous versicolor, Pyricularia filamentosa, Fusarium sp., Trichophyton rubrum, Trichophyton sp., and others. The authors did not specify
why these particular strains were chosen. The highest activity was found for 3,5-di-tert-butylbenzo-15-crown-5 for which the median
effective dose against 50% (ED50) of the fungi was 8 mM. It was found in this effort that unsubstituted crowns or cryptands showed
little or no activity.
In a study of crown activity against bacteria,103 the growth of B. subtilis (G þ) showed a lag time in the presence
of < 15>C10, < 18>C12, < 15N>C10, < 18N>C12, < 12>CH2OC10, or < 12>CH2OC12. The longest lag times were observed
with the alkyl substituted azacrowns. Tso, Fung, and Tso104 reported lag times in the growth of Escherichia coli (G ) in the presence
of either 18-crown-6 or dicyclohexano-18-crown-6. Bacterial growth was affected differently by the crowns in the presence of either
NaCl or KCl compared to in their absence in the growth broth. Moreover, the presence of NaCl and KCl affected the lag times in the
growth curves differently. The authors suggested two possible explanations for this: differential solubility of the complexes and
differential toxicity of the complexes. They state that “a lag thus observed may represent a resultant of interacting inhibitory factors
acting on the organism.”
28 Crown Ethers

Figure 38 Ammonium and N-oxide crown derivatives studied for potency against bacteria and yeast.

Figure 39 Examples from a larger family of redox-sensitive macrocycles tested for antimicrobial and antifungal activity.

An extensive study of antimicrobial activity was reported by Konup and coworkers.105 Twenty six different crowns including (see
Fig. 30) unsubstituted, benzo, dibenzo, dicyclohexano, and various substitutions on the 6-membered rings were tested against
E. coli (G ), B. subtilis (G þ), Streptococcus faecalis (G þ), Staphylococcus aureus (G þ), and Micrococcus lysodeikticus (G þ). Of the
compounds tested, the substituted dibenzo-18-crown-6 compounds were most potent. Di-t-butyldibenzo- and its saturated analog
dicyclohexano-18-crown-6, showed good activity against the four Gram positive strains but little potency against E. coli (G ).
Devinsky and coworkers addressed the effect of charge on biological activity in N-alkyl-substituted azacrown ethers (azalar-
iats).106,107 Experimental descriptions are provided in this work only for the two compounds shown in Fig. 38.27 Data for the anti-
microbial activity were recorded in the patent.28 Both the N-oxide and the quaternary ammonium salt were used against
Staphylococcus aureus (G þ), E. coli (G ), and the fungus Candida albicans. Both compounds showed better activity against Gram
positive bacteria and fungi than Gram negative E. coli (G ). The MIC values reported in the patent are as follows for the two
compounds shown in Fig. 38. The MIC values for the N-oxide are reported in (mol/dm3  104) as Staphylococcus aureus (G þ)
1.24, E. coli (G ) 24.8, Candida albicans 4.96. Corresponding MIC for the salt (mol/dm3  104) are Staphylococcus aureus (G þ)
8.6, E. coli (G ) 57.6, Candida albicans 23.0. Moles/liter and “mol/dm3” so, for example, the N-oxide against E. coli (G ) is
24.8  10 4 M/L or 2480  10 6 M/L or  2500 mM. Indeed, all MICS were at least in the 100 þ mM range, suggesting low activity
of these compounds against any of the organisms.
Erk and coworkers studied the biological activity of benzo-18-crown-6 (9, R ¼ H), dibenzo-18-crown-6 (12), and the analog of
the latter, dibenzo-24-crown-8.108 These basic modules were functionalized on the arenes with undecanoyl, hexadecanoyl, or octa-
decanoyl residues. The authors used the disk diffusion method to assay the potency of these compounds against E. coli (G ), Staph-
ylococcus epidermidis (G þ), B. subtilis (G þ), Staphylococcus aureus (G þ), Salmonella typhimurium (G ), Klebsiella pneumoniae (G ),
Pseudomonas aeruginosa (G ), Enterobacter faecalis (G þ), and the fungus Candida albicans. None of these compounds exhibited
a toxic effect according to the report, although the concentrations of the various crowns are not specified.
A quite different type of crown family contained naphthoquinone substituents (Fig. 39).109 The hypothesis was that the naph-
thoquinone residue is redox sensitive and that cation complexation could change its properties and its biological effect. Two fami-
lies of compounds were prepared. Examples are shown in Fig. 39. The ring sizes for the mono-quinones were 9, 12, 15 (illustrated),
18, and 21 atoms. The bis(quinone) was prepared with ring sizes ranging from 18 (shown) to 42 atoms. Minimum inhibitory
concentrations (MICs) were determined for the families of compounds against Staphylococcus aureus (G þ) having methicillin resis-
tance, E. coli (G ), Mycobacterium ranae (G þ), Pseudomonas aeruginosa (G ), K. pneumoniae (G ), Proteus vulgaris (G ), Candida
albicans, and Trichophyton mentagrophytes. Relatively little activity (i.e., MIC < 200 mM) was observed for any but the smallest ring
size compounds in each family. The most potent compounds were the bis(quinone)s illustrated in Fig. 39 administered against
Staphylococcus aureus (G þ). The MIC values for the monoquinone having a 9-membered ring and the bis(quinone) illustrated
showed MIC values of 5.31 and 2.68 mM, respectively. The latter compound had MICs of 21 and 10.7 mM against E. coli and Candida
albicans.
Another family of sulfur-containing macrocycles was reported by Sadeghian et al.110 These authors reported a group of
compounds that incorporated 2–4 sulfur atoms in the macroring and the R-groups shown in Fig. 40 included H, methyl, ethyl,
propyl, CH2OPr, CH2O–i-Pr, CH2O–t-Bu, and CH2OCH2Ph. The stereochemical relationships of the cyclohexano and R groups
were not specified. None of the compounds having the specified R groups or the fused bis(cyclohexano) 4-sulfur compound showed
any activity (i.e., MIC < 400 mg/mL) against Staphylococcus aureus (G þ), Pseudomonas aeruginosa (G ), or Candida albicans. MIC
values ranging from 63 to 884 mg/mL were presented for the family of compounds having the R groups noted against
K. pneumoniae (G ). The tetrasulfur macrocycle was inactive against this organism. An effort was made to establish a quantitative
structure–activity relationship (QSAR) for these compounds. The octanol–water partition coefficients (log P), the polar surface
areas, unsaturation indices, and other parameters were calculated. Graphical data were included that showed correlations of potency
 Crown Ethers 29

Figure 40 Representative thiamacrocycles tested for potency against bacteria and fungi.

Figure 41 Sulfur-containing macrocycles having toxicity to bacteria and fungi.

with log P and the related Moriguchi constants. The authors state that the “results confirm the capability of the proposed approach
to give predictive models for MIC values of K. pneumoniae (G ).”
A family of macrocycles that variously contained chlorophenyl, sulfonamide, and disulfide residues was reported to have anti-
microbial activity against Bacillus cereus (G þ), Staphylococcus aureus (G þ), E. coli (G ), and the fungi Aspergillus niger, Fusarium oxy-
sporum, and Flammulina velutipes.111 The studies were done by using the disk diffusion method. In this test, the larger the inhibition
“halo” surrounding the cellulose disk, the more potent the compound embedded in it. The two most potent compounds are shown
in Fig. 41. The bis(sulfonamide)-containing macrocycle (top of Fig. 40) was most effective against B. cereus (G þ) and the naphtha-
lene derivative was most potent against E. coli (G ). The former compound was slightly less effective than streptomycin, which was
used as a control, and the latter compound was slightly more effective than the commercial antibiotic.
Two very recent reports disclose pyridine-containing dibenzo macrocycles that exhibit biological activity against microbes112 or
carcinoma cells.113 The compounds are represented in Fig. 42. The pyrido-diamides varied with X being CH2, CH2CH2, S, SS, and
CH2eSeCH2. The various derivatives were tested by using both disk diffusion and by determination of MIC values. The compounds
were assayed against a wide range of organisms, including Staphylococcus aureus (G þ), B. cereus (G þ), Micrococcus luteus (G þ), Myco-
bacterium smegmatis (G þ), Listeria monocytogenes (G þ), E. coli (G ), Proteus vulgaris (G ), K. pneumoniae (G ), Pseudomonas aeru-
ginosa (G ), Kluyveromyces fragilis, Rhodotorula rubra, Candida albicans, Hanseniaspora guilliermondii, and Debaryomyces hansenii. The
MIC values reported ranged from  3 to  50 mg/mL. The best overall activity was apparent for the macrocycle having (X ¼) a disul-
fide bridge. For the disulfide bridged compound, 3 mg/mL corresponds to 6 mM.
A family of 15-crown-5 derivatives having a fused coumarin ring was studied for complexation with a wide variety of metals and
against a range of microbes.114 The structure is illustrated in Fig. 43. The pendant CH2X residues included piperidine, morpholine,
piperazine, diethylamine, dihydroxyethylamine, and diphenylamine. Antimicrobial potency was assayed by using the disk diffu-
sion method against the bacteria E. coli (G ), Staphylococcus aureus (G þ), Mycobacterium smegmatis (G þ), Mycobacterium tuberculosis,
Mycobacterium simiae, Mycobacterium kansasii, Mycobacterium terrae, Mycobacterium szulgai, and the Candida albicans. Not every
compound was tested against every organism, but the largest inhibition zone (i.e., highest apparent efficacy) was observed for Myco-
bacterium smegmatis when treated with the 4-methylpiperazinyl derivative (i.e., X ¼ 4-methylpiperazine).

Figure 42 Pyridine-containing macrocycles exhibiting toxicity to bacteria and fungi.

30 Crown Ethers

Figure 43 Coumarin-containing macrocycles having toxicity to bacteria and fungi.

Figure 44 Phosphazene-containing macrocycles having toxicity to bacteria and fungi.

A recently reported variant that includes a pendant phosphazene residue was reported by Yildiz and coworkers.115 Four
compounds were prepared. When the X groups shown in Fig. 44 were Cl, n was either 1 or 2. Both ring sizes were also prepared
when X was t-butylamino. Only the two tetrachloro and the larger ring t-butylamino compounds were studied as antimicrobials.
The disk diffusion method was used to assay activity against the bacteria B. subtilis (G þ), B. cereus (G þ), E. coli (G ), Staphylococcus
aureus (G þ), Staphylococcus epidermidis (G þ), Enterobacter aerogenes (G ), S. typhimurium (G ), S. typhi (G ), L. monocytogenes
(G þ), Micrococcus luteus (G þ), P. vulgaris (G ), Pseudomonas aeruginosa (G ), Pseudomonas fluorescens (G ), H. guilliermondii, Kluy-
veromyces fragilis, and the Candida albicans, Candida parapsilosis, Candida tropicalis, R. rubra, D. hansenii.
Although no obvious trend could be discerned, the di-t-butylamino macrocycle seemed to be the most generally potent
(Fig. 44). Notwithstanding, it showed poor activity against Gram negative E. coli (G ). It should be noted that this lab had earlier
reported antimicrobial activity by 10- and 12-membered rings fused to two benzenes.116 The 10-membered ring included two-
oxygen atoms and the larger ring three. Each of the benzene rings was substituted by a sidechain terminated by a pendant phenolic
residue. These were studied against a range of microbes and some potency was observed.
During the past several decades, a remarkable range of crown structures has been prepared. In the cases catalogued above, the
biological data are not correlated to organism type (e.g., Gram negative vs. Gram positive) or to structural features of the various
macrocycles. In most cases studied, E. coli (G ) and B. subtilis (G þ) were targets of the macrocycles as was a fungus such as Saccha-
romyces cerevisiae or Candida albicans. When a broad range of organisms was evaluated, a discernable pattern failed to emerge. The
use of the disk diffusion method to assay activity rather than the more quantitative minimum inhibitory concentration protocol
likewise encumbers any attempt to compare activity.
Some cautious generalizations can be offered. It appears that biological activity against various organisms does, in some cases or
to some extent, parallel binding strength and transport ability. In the latter case, where reasonable comparisons were possible, the
more lipophilic compounds proved generally more potent. Likewise, in macrocycle families, larger rings generally showed greater
potency than smaller ones. Of course, this parallels cation binding strengths as well.117
In the section that follows, an attempt has been made to understand structural relationships and to compare activity among
various cell types. To be sure, complete success in such an endeavor is distant, but progress is being made.

3.02.6.3 Activity of Crown Ether Derivatives in Plant Cells or Plants

Huang, Wang, and their coworkers studied the ability of benzo-15-crown-5 (8) to affect ion transport. They monitored ion transport
in young wheat roots and found that Kþ flux was promoted to a greater extent than that of was Naþ.118 They found that the azo-
benzene dye derivative of benzo-15-crown-5 shown in Fig. 45 could “penetrate through the cell membrane of the root [and] is
absorbed on the surface of micelles.”
Benzo-18-crown-6 (9, R ¼ H) was the focus of a study by Pemadasa.119 The effect of this macrocycle was evaluated on abaxial
(upper) and adaxial (lower leaf surface) stomatal responses either individually or in the presence of abscisic acid (ABA, Fig. 46). The
vehicle for study was the epidermes of Commelina communis, commonly called the Asian day lily. An increase in macrocycle concen-
tration, reduced abaxial opening while the opposite effect was observed on the upper leaf (adaxial) surface. If Kþ concentration was
increased, the biophysical effect of the macrocycle was reversed. The authors state that the “effects of the ionophore and ABA were
strongly antagonistic.” The authors note that the benzocrown shows a similar effect on stomata behavior as observed with the plant
auxin phenylacetic acid.
The effect of various crown ethers on excised plant root segments and on seedlings was studied in conjunction with ion binding
and transport studies. Three macrocycles were studied in this context: 18-crown-6 (3), t-butylbenzo-18-crown-6 (9, R ¼ t-butyl) and
 Crown Ethers 31

Figure 45 Ionophores studied for their effect on ion balance in wheat roots.

Figure 46 Structure of abscisic acid (ABA), a natural plant hormone.

di-t-butyldibenzo-30-crown-10. The latter is shown above in Fig. 32. The study was designed to assess the effect of altered Kþ trans-
port on onion root segments and on wheat and mung bean seedlings. The hypothesis was that more effective binding and transport
by a crown would result a greater effect on the biological target.120
Potassium influx and efflux was monitored by using 42Kþ as the radiotracer. The three crowns noted were assayed in onion root
segments and in mung bean wheat seedlings. The complexation constants and the lipophilicities of the three crowns noted were
considered for their effects on the plants. Generally high crown concentrations resulted in reduced growth, with the effects of 9 being
observed at the lowest concentrations. The least effect on growth was apparent with the seedlings. Overall, the ability of these three
crowns to transport Kþ through the membranes appeared to be the key factor contributing to biological activity.
The catechol derivatives called urishiols are a mixture of hydrophobic 1,2-dihydroxybenzenes that are a principal irritant in
poison ivy. Urishiols are mixtures of catechols having saturated and unsaturated pentadecyl chains. Huang and coworkers hydro-
genated the mixture to afford saturated urishiols (“SU”) from which disubstituted dibenzo-18-crown-6 derivatives were
prepared.121 Although the side chains were saturated and uniform, the dibenzocrown was obtained as positional isomers. A further
group of monosubstituted dibenzocrowns was prepared from the saturated urishiol (referred to as SU crowns) using catechol, resor-
cinol, or hydroquinone as the second arene. The dipentadecyldibenzo-18-crown-6 derivative and the three isomeric monopenta-
decyl derivatives are shown in Fig. 47.

Figure 47 Dibenzocrowns synthesized from saturated urishiols.

32 Crown Ethers

Figure 48 A 22-crown-6 tetraester.

Compounds of the type benzo-15-crown-5 and pentadecylbenzo-15-crown-5 were studied for their effect on rice and wheat.122
The presence of these crowns generally promoted growth and affected the chlorophyll content of both plants. The primary focus of
this work was to determine if the presence of crowns would enhance the rice panicles or wheat spikes so that more nutrients would
be available per plant. Relatively small differences in the seedling growth of wheat were witnessed between the two macrocycles and
the average height of plants in the presence of or absence of macrocycles after 10 days was similar. Plant heights between wheat and
rice were found to differ but the overall conclusions of the work were the urishiol crown was more advantageous in its biological
effects than the parent and that the former offered advantages in the quality of the plants produced.
A recent study of the effect of tris(crown) hydraphile synthetic amphiphiles on Arabidopsis thaliana is discussed below.

3.02.6.4 Cellular Activity of Crown Ether Derivatives

During the 1980s, a range of studies was reported directed to evaluating specific effects of crowns on cells or organs. Kolbeck et al.
studied the effect of crowns, many of which possessed donor-group-containing side arms (lariat ethers), in vitro in guinea pig
tracheal and in heart preparations. The varied crown ether effects on cardiac function were studied in guinea pig heart muscle cells
and myocardium by Luk’yanenko and coworkers.123 The study of several crown ethers, in combination with the cardiac glycoside
strophanthin, suggested that the biological activity observed might involve a decrease in the rate of passive Ca2 þ transport across
myocyte membranes. A general increase in phospholipid bilayer membrane permeability was mediated by the presence of various
dialkyl substituted crown ethers.124 In this study, ammonium and methylammonium ion transport was monitored. Various unsub-
stituted and substituted benzo and dibenzocrowns in addition to side-armed structures were the permeability enhancing agents.
However, one unusual tetraester compound was reported as well (see Fig. 48).
The inhibition of kidney Na,K-ATPase, reconstituted in bilayers, by various mono- and disubstituted crown ethers was exam-
ined.125 Relatively little effect on the enzyme was observed although a Mg2 þ dependence was noted. An effort to assay the effect
of crown ethers on frog nerve fibers (measured at the node of Ranvier), showed a Naþ and Kþ dependence that unfortunately could
not be correlated to the ionophoretic activity of the macrocycles.126
The tetra-aromatic compound family varied by the substituents in the pendant phenyl ring.113 The substituents were 2-bromo-,
2- or 4-chloro-, 2- or 4-hydroxyl-, 4-methoxyl-, and 4-nitro. Cytotoxicity tests were performed in vitro on human rhabdomyosar-
coma (RD), human breast adenocarcinoma (MCF7), human uterine (FL), human hepatocellular carcinoma (HepG2), and lung
(Lu) cell lines. The most active of the macrocycles was the 4-chlorophenyl derivative which showed activity against all five cell lines,
although potency against Lu was low (lower structure in Fig. 42, R ¼ eC4H4Cl).
Bethge and coworkers127 examined the effect of various channel blockers on myelinated nerve ionic currents. Compounds such
as triethylammonium ion, n-decyltriethylammonium ion, capsaicin, and dicyclohexano-18-crown-6 (13) were studied for their
effect on myelinated nerve fibers. As might have been expected, the macrocycle influenced Kþ kinetics and altered the transients
observed when using electrophysiological methods.

3.02.6.5 Biological Activity of Lariat Ethers and Hydraphiles

As noted earlier, lariat ethers are macrocycles that were designed to have secondary donor groups in the side arms.17 The name
derived from the concept that the macroring could “rope” and the side chain could further “tie” the cation by providing axial solva-
tion. The lariat designation has been generally applied to crowns having side chains whether or not they contain donors within
them. When two chains are present, the crowns are referred to as bibracchial lariat ethers.128 The four compounds shown in
Fig. 12 (above) as A–D illustrate some of the structural variations. Note that when the side arms are attached at nitrogen, there
is no stereochemical issue (sidedness) as there is when the arm is attached at carbon. As noted above, the term C-pivot or
carbon-pivot means that the side chain is attached to carbon. The side chain or chains are attached to macroring nitrogen atoms
in N-pivot molecules. When two side arms are present, the compounds are referred to as bibracchial lariat ethers or BiBLEs.
Our studies of lariat ethers as complexing agents and as transporters were extensive,129 but we recognized that nature prefers
channels for the transport of ions and molecules. Indeed, a remarkable percentage of the human genome codes for channel func-
tion. We were inspired to attempt the design and synthesis of a cation-conducting channel that would function within a phospho-
lipid bilayer. We succeeded in this by developing the family of compounds that we call hydraphiles.130 A typical hydraphile is
shown in Fig. 49. These compounds conduct cations through phospholipid bilayers, they show cation selectivity, they function
unimolecularly, and they show the type of open–close behavior usually observed only with peptide or protein channels.131
 Crown Ethers 33

Figure 49 A hydraphile synthetic ion-conducting channel. The values of “n” range from 6 to 20.

We examined the biological activity of hydraphiles by using a Kirby–Bauer or disk diffusion test.132 In this experiment, cellulose
disks are impregnated with a test substance, a control, and solvent. We used two hydraphiles in this experiment having different
overall lengths. Earlier studies had shown that when the hydraphile spacers were octylene (8 methylenes), little if any ion transport
was apparent in liposomal experiments.133 In contrast, when the spacers were dodecylene (12 methylenes) ion release from vesicles
was almost 30% of that observed with the bacterial channel Gramicidin.134 Our notion was that if the channels penetrated the
bacterial outer membranes, the nonrectifying channels would allow Kþ to escape and Naþ to invade. This disruption of ion homeo-
stasis should kill bacteria.
In the actual experiment, a significant zone of inhibition was observed for the benzyl C12 hydraphile and only a minor zone was
observed for benzyl C8 hydraphile.135 More quantitative analysis showed that the difference in potency between the C8 and C12
hydraphiles was  7:1. The activity observed for the C8 compound was attributed to its ability to serve as a carrier. To the extent
that it could transport cations through the bacterial membranes by any mechanism, it would also disrupt ion homeostasis. It
was also shown in this report that a hydraphile having dansyl fluorescent side chains136 could be detected in the E. coli (G )
periphery by fluorescent microscopy. It is interesting to note that one of the controls in this study was N,N-di-n-dodecyl-4,13-
diaza-18-crown-6 (C12< N18N>C12). Although it is a carrier known to transport both Naþ and Kþ through bulk organic and bilayer
membranes, it shows no activity in the disk diffusion assay.
An obvious question concerning the hydraphiles is whether they could function as channels in vital mammalian cells. The bio-
logical studies with bacteria described earlier suggested that they might simply invade the cells and kill them. Vital human embry-
onic kidney cells (HEK 293) were exposed to benzyl C12 hydraphile in a patch clamp experiment.137 As soon as the cell was exposed
to a saline solution containing the hydraphile, increased electrical activity was detected in the membrane. After an appropriate
observation time, the cell was bathed with saline solution. The hydraphile gradually partitioned out of the cell and electrical activity
declined. The cell remained vital throughout the experiment.
It was of particular interest to compare the biological potency of the hydraphiles against Gram negative E. coli (G ), Gram posi-
tive B. subtilis (G þ), and the yeast Saccharomyces cerevisiae.138 Since the hypothesis was that the hydraphiles that were most effective
as ion transporters should be most harmful to microorganisms, the toxicity data were compared with the rates of Naþ transport
through liposomal membranes. The compounds studied are shown in Fig. 50. In all cases, the spacer chains that separate the macro-
cycles were n-dodecylene [(CH2)12]. The span of each methylene–methylene bond in a fully gauche conformation is  1.25 Å so the
spacer chains in each case have an overall length of (1.25 Å  12 ¼)  15 Å.
Compounds 14–17 are identical except for the distal macrorings and the side chains attached to the macrocycles when the link is
to nitrogen. Compound 14 has two aza-18-crown-6 rings as the distal macrocycles. In hydraphiles 15–17, the second nitrogen in the
macrocycle is unsubstituted (15), alkyl- (16) or aryl-substituted. Hydraphile 18 is a tetramacrocyclic compound that was prepared
to demonstrate that the central macrocycle of the three-crown system is perpendicular rather than parallel to the other rings.
The minimum biocidal concentration139 of these hydraphiles was assayed using standard protocols against E. coli (G ),
B. subtilis (G þ), and Saccharomyces cerevisiae. E. coli and B. subtilis are both bacteria and might be expected to show some similar
behavior despite the fact that they are Gram negative and Gram positive, respectively. The response of the yeast Saccharomyces cer-
evisiae, a primary eukaryote, to hydraphiles was less predictable. The graph in Fig. 51 shows the toxicity of E. coli (open squares),
B. subtilis (filled circles), and Saccharomyces cerevisiae (filled diamonds) to the various hydraphiles. The heavy black line in the graph
connecting the open diamonds shows the rate measured for Naþ transport through a phospholipid bilayer mediated by the five
compounds. What can be stated with some confidence is that for 14, which is a nontransporter, there is little toxicity to any of
the three microbes. Effective transporters 15–18 are toxic to both bacteria, but a correlation is less apparent for yeast.
It was found that hydraphiles that are analogs of 17 but that have spacer chains of 8, 10, 12, 14, 16, 18, and 20 methylene groups
showed significant variations in Naþ transport.140 Typically, transport rates were poorest for the two shortest compounds. Transport
efficacy was best in the range of 12–16 methylenes and then declined at the two longer lengths studied. To the extent that the hydra-
philes were penetrating the microbial membranes and disrupting ion transport, their toxicity should correlate to spacer chain
length. The minimum bactericidal (E. coli, B. subtilis) or minimum fungicidal concentration (Saccharomyces cerevisiae) was measured
for each microbe and the values obtained are compared with transport rates in Fig. 52. The rates were determined by detecting Naþ
efflux from liposomes using an ISE technique.22
The Naþ release data (shown as open diamonds and labeled “Rate”) were normalized to 100 for ease of comparison. Note that
there is an approximately inverse correlation between transport rates and toxicity to the bacteria. As above, yeast does not respond as
uniformly and that data are less complete for the Saccharomyces cerevisiae series. Notwithstanding, it seems clear that disruption of
ion homeostasis is inimical to microbial vitality. An additional study was conducted to assay the kinetics of toxicity to E. coli. This
34 Crown Ethers

Figure 50 Compounds used to study the effect of side chains in the C12 hydraphile series.

Figure 51 Graph showing the relationship of toxicity as the minimum biocidal concentration (MBC) of hydraphiles against E. coli (G), B. subtilis
(Gþ), and Saccharomyces cerevisiae.
 Crown Ethers 35

Figure 52 Comparison of hydraphile chain lengths with toxicity to E. coli (G), B. subtilis (Gþ), and Saccharomyces cerevisiae (yeast).

Figure 53 Toxicity of hydraphiles 14–18 to E. coli (G) at pH values of 5.5, 6.0, and 7.1 compared to the Naþ transport rate observed for the
same compounds through liposomal membranes at pH 7.

was done by using a bioluminescent strain of E. coli treated with 15, 16, and the C14 analog of 17. In all cases, half the population
was killed within 12.5 min or less as compared to the action of the aminoglycoside antibiotic kanamycin, which took nearly 45 min
despite having an MBC against E. coli of 1.3 mM.
Compounds 14–18 were further studied to determine how toxicity to E. coli varied with transport rates as a function of pH.141 Of
course, such studies can be conducted only over a relatively limited pH range because high and low pH values are themselves toxic
to E. coli. The relationship of transport and pH to E. coli toxicity is shown in the graph in Fig. 53. Lowering pH had an effect of
generally lowering toxicity. Compound 16, for example, shows a clear decrease in toxicity as the pH drops. Transport was not
measured over a similar range of pH values because liposomal stability is limited in acidic solutions. It was reported in the
same study that the carrier valinomycin and the pore-former melittin were toxic to E. coli at concentrations of > 100 and 18 mM,
respectively, at pH 7.1.
A range of hydraphile compounds were prepared to address two additional questions (Fig. 54). The first of these was what, if
any, effect on ion transport and microbial toxicity would be observed when the aliphatic spacer chains of compounds such as 16
and 17 incorporated aromatic residues. The presence of aromatic residues within the hydrophobic portion of the pore could
diminish transport by a favorable cation–pi interaction between Naþ and the electron-rich rings.142 To the extent such energetically
favorable interactions occur, transient complexation diminishes transport rates. Studies were conducted to determine if rates,
indeed, decrease when cation–pi interactions were potentially favorable. In all cases, those hydraphiles having aromatic spacers
(19,20 compared to 16 and 21,22 compared to 17) showed reduced transport. The transport of Naþ was found to be in the order
19 > 20 > 21 > 22. These same compounds were assayed for biological activity against B. subtilis and found to have MICs in the
range 0.5–9 mM. The order of toxicity was 20  19 > 22 > 21. The difference in potency between 19 and 20 and between 21 and 22
was approximately twofold.
A related study was conducted to determine if conversion of free nitrogen atoms within the macrocycle into amides would affect
ion transport and biological potency.143 Four compounds closely related to 16 were prepared that had amide residues in all three
possible positions within the structure. Fig. 55 shows the structures as 16, and the amides as 23–25.
As in previous studies, transport rates for the hydraphiles were measured and MIC values were determined for 16 and 23–25
against E. coli and B. subtilis. An initial surprise was that 25 was a much more active Naþ transporter than the parent compound,
16. Indeed, of the four, only 25 showed high transport. This is apparent in the graph in Fig. 27, which also shows MIC data for
the four hydraphiles against E. coli and B. subtilis. In our studies and many of those undertaken in other labs, Gram negative
36 Crown Ethers

Figure 54 Hydraphiles incorporating structural variations intended to assess the effect of aromatic residues in the spacer chains.

E. coli proved less susceptible to the amphiphiles than did Gram positive B. subtilis or other Gram positive bacteria for that matter.
The conundrum is apparent in the data shown in Fig. 56 for 25. It is the most active transporter, the least against E. coli and potent
against B. subtilis, but no more so than poor transporter 24.
An interesting effect of hydraphiles was observed on the growth of the widely used experimental plant Arabidopsis thaliana. It is
well established that Arabidopsis thaliana typically grows with a single primary root. This is the major root extending into the growth
medium from the plant’s stem. Secondary or lateral roots are atypical in this plant unless acted upon by some stimulating factor
such as natural plant hormones called auxins. Three analogs of hydraphile 17 having spacer chains of 8, 14, or 16 methylene groups
were infused into plant nutrient growth media. Plant nutrient media having added sucrose is abbreviated as PNS. The concentration
of any of these compounds used in a single experiment was typically 20 mM and never more than 50 mM in PNS.
Earlier studies involving yeast and bacteria that involved interactions with hydraphiles suggested a strong correlation between
ion transport efficacy and toxicity. Transport of Naþ through liposomal membranes by benzyl C8 hydraphile, benzyl C14 hydra-
phile, and benzyl C16 hydraphile is known to occur with efficacy in the order C14  C16 [ C8. A similar correspondence appeared
to be at work in the case of Arabidopsis thaliana. When the plants were grown in PNS in the absence of any additive or in the presence
of 0.2 vol.% of DMSO, the primary root was  36  4 mm in length (average of  70 plants in each experimental batch). When
benzyl C8 hydraphile [17, Y ¼ (CH2)8] was added to PNS at a final concentration of either 20 or 50 mM, the primary root length
was  34  7 mm. A much more significant effect was observed when benzyl C14 hydraphile [17, Y ¼ (CH2)14] or benzyl C16 hydra-
phile [17, Y ¼ (CH2)16] was added at concentrations of either 20 or 50 mM. Thus, the primary root lengths observed when either of
these two hydraphiles was added at 20 mM were 14  2 and 15  0.5 mm, respectively. When present in the grown nutrient medium
at a concentration of 50 mM, the primary root lengths diminished to 0.7  0.2 (C14) and 4  0.2 mm (C16). As the primary root
length reduced, the number of lateral roots that appeared increased. However, at the 50 mM concentration, the C14 hydraphile
produced chlorosis and other signs of stress on the plants.
In some respects, these macrocycles acted like plant auxins. When compared with such plant growth regulators as indoleacetic
acid, similar effects were observed only when far greater concentrations of the macrocycles were used. Of course, some similarity in
effect does not establish a mechanism.
As noted above, lariat ethers are ion carriers and the potency of various single-armed compounds against a range of microorganisms
was studied in the 1980s. Although several lariat ethers having one side arm had been prepared, we undertook a study of a family of
N,N-dialkyl-4,13-diaza-18-crown-6 compounds (R<N18N>R).22 The side arms ranged from n-octyl (H17C8< N18N>C8H17) to
n-octadecyl (H21C10< N18N>C10H21). The diacyl precursors to the didecyl (H19C9CO<N18N>COC9H19) and didodecyl lariats
(H23C11CO<N18N>COC11H23) were also examined. The three organisms tested were E. coli (G), B. subtilis (Gþ), and Saccharomyces
cerevisiae and the results are presented in the graph in Fig. 57.
It is clear from the graph that when the side arms are 14–18 carbons, there is no significant inhibition of bacterial or fungal
growth. For the shorter-chained lariats, only di-n-decyl lariat (27) shows potency against all three microbes. When the side chains
 Crown Ethers 37

Figure 55 Hydraphiles containing two amide groups in varied positions.

Figure 56 Sodium cation transport data for amide substituted compounds 16 and 23–25. The transport rates were measured as ion release from
liposomes and are adjusted to correspond to transport for 25 ¼ 100 arbitrary units. The MIC data for all four compounds are expressed in mM.
38 Crown Ethers

Figure 57 Potency of N,N-dialkyl-4,13-diaza-18-crown-6 compounds against E. coli (G), B. subtilis (Gþ), and Saccharomyces cerevisiae. The dia-
lkyl side chains are n-octyl (26), n-decyl (27), n-dodecyl (28), n-tetradecyl (29). The data for n-hexadecyl (30) and n-octadecyl (31) are identical to
those for 29 and are not shown.

Figure 58 Effect of n-alkyl side chain length on 4,13-diaza-18-crown-6 lariat ethers having 8, 10, 12, or 14 atoms in each side arm.

are longer (28) or shorter (26) than decyl, there is little potency against E. coli and toxicity to B. subtilis and Saccharomyces cerevisiae
are mixed. An effort was therefore made to determine what, if any, effect of chain length was apparent in the release of Naþ ions
from liposomes. These studies were done with liposomes prepared from dioleylphosphatidylcholine [DOPC, 16 carbon fatty acids
(16:1)] and with dierucoylphosphatidylcholine [DEPC, 22 carbon fatty acids (22:1)]. The results were nearly identical for the two
phospholipids. The transport rates, normalized to 100, were C8 (26), 65; C10 (27), 100; C12 (28) 85; C14 (29), 5; C16 (30),  0; and
C18 (31),  0. To the extent that there is any correlation between chain length and antimicrobial potency, it is apparent for 26–28.
Of course, the response of the different organisms to chain length is, at the very least, mixed.
Despite an obvious overall correlation, it seemed reasonable to associate potency against these three microbes with ion transport
that disrupted ion homeostasis. This possibility was probed by using the fluorescent dye 3,30 -dipropylthiadicarbocyanine
[DiSC3(5)], which exhibits different fluorescent behavior depending on whether the bilayer membrane is polarized or not.144
The dye is absorbed by either E. coli or B. subtilis because the bacterial membranes have a negative internal membrane potential.
When the dye is added to a suspension of bacteria, the fluorescence decreases as the dye is absorbed. As the concentration within
the bacteria increases, self-quenching does as well. When the cells are then treated with Kþ, the membrane potential comes to zero,
the dye is released, and fluorescence can be used to quantify the event.
These studies showed that the behavior of lariat ethers is remarkably different in the bulk phase compared to a lipid bilayer
membrane. In a bulk organic membrane, transport correlates well with cation binding strength and shows no discontinuous
behavior.145 It is clear that the interaction of the crown and its side chains with the phospholipid monomers confers selectivity on
the ion transport process (Fig. 58). It is interesting to observe, however, that the discontinuous transport behavior of the lariat ethers
in bilayers is not dependent on whether the phospholipids are DOPC or DEPC. The selective interactions of certain lariat ethers in
simple membranes are presumably extensible to interactions with microbes, although the nature of these interactions remains unclear.

3.02.6.6 Biological Applications of Hydraphiles

The effects of a range of crown ethers and more complex amphiphiles have been described above. For the most part, these have been
studies in which there was a direct application of the crown to microbes, tissues, plants, or animals. Recently, hydraphiles have been
studied in combination with other agents in an effort to achieve a variety of goals.
 Crown Ethers 39

Figure 59 Antibiotics surveyed for hydraphile enhanced potency against E. coli (G).

In order for hydraphiles to form unimolecular pores in bilayers, they must span the membrane. Sodium cation transport shows
a clear dependence on hydraphile length that comports with this presumption. To the extent that penetration of the bilayer by
hydraphiles causes local disruption of membrane organization, it might be possible for the passage of molecules might be facili-
tated. We speculated that this would occur in bacteria and that antibiotics would permit any change in their potency against the
microbe to be used as a metric. As noted above, hydraphiles at their MICs are inimical to cell growth and/or survival (lethal concen-
trations). Experiments were designed to assay changes in antibiotic potency toward bacteria in the presence of sublethal concentra-
tions of hydraphiles.146
Erythromycin, kanamycin, rifampicin, and tetracycline were selected for these studies (Fig. 59). Each compound represents
a distinct structural type and the mechanism of action of each is known to be different from the others. The assay was conducted
by determining the MIC separately for each antibiotic and for each hydraphile against E. coli. The MIC was then determined for the
antibiotic in the presence of hydraphile at half of its MIC. At half MIC, the hydraphiles tested showed a minor change in the lag time
for bacterial growth but no ultimate impediment to growth. If the MIC of the antibiotic was reduced in the presence of hydraphile, it
would mean that some cooperative interaction occurred.
The MICs for the four antibiotics were determined by using standard protocols against the DH5a nonpathogenic strain of E. coli.
Benzyl C14 hydraphile (see Fig. 20, n ¼ 14) was added to the bacterial suspension and the MIC for the antibiotic under study was
added. Some of the results are illustrated in the graph in Fig. 60, which shows increases in potency of 8-fold for erythromycin and
16-fold for rifampicin.

Figure 60 Potency of antibiotics against E. coli (G) enhanced by the presence of benzyl C14 hydraphile at half its MIC.
40 Crown Ethers

Figure 61 Smith’s fluorescent dipicolylzinc probe (top) for anionic lipids and the non-binding control (bottom).

Hydraphiles have also been used as direct injection chemotherapeutic agents. The concept of direct injection is that a toxin may
be administered directly to a tumor site where it will kill the cells it contacts. Agents such as ethanol and acetic acid are useful in this
application, but they diffuse rapidly through tissues and can cause collateral damage. Hydraphiles do not diffuse as readily as these
lower molecular weight substances and they kill cells by disrupting ion homeostasis.145
In order to demonstrate that hydraphiles localized in living tissues, Smith’s fluorescent dipicolylamine-zinc dye was used.147 It
binds such anionic lipids as phosphatidylglycerol (PG) and phosphatidylserine (PS) and emits in the near infrared region. As such,
it is visible over signals from such fluorescent amino acid side chains as the indole residue of tryptophan. The structure of the dye is
illustrated at the top of Fig. 61 and the control, which lacks the binding site, is shown at the bottom.
Five compounds were injected intramuscularly into mouse leg muscle and their persistence and cellular damage were monitored
by using the zinc probe’s fluorescence. Three hydraphiles that were expected to show good ion transport activity were studied along
with two diazacrowns that should be carriers rather than pore-formers. Their structures are shown in Fig. 62. As expected, the hydra-
philes proved to be localized, persistent, and toxic to the cells contacted.148

Figure 62 Hydraphiles (top) and lariat ethers assayed for their ability to function as direct injection chemotherapeutic agents in mice.
 Crown Ethers 41

Figure 63 Membrane-forming lariat ether amphiphiles (R ¼ linear alkyl groups of various lengths) and a bolaamphiphile having a 12 carbon spacer
chain.

3.02.7 Application of Crown Ethers

The number of applications that have involved crown ethers, azacrown ether, or various macrocyclic hybrids is too numerous even
to contemplate a complete discussion. The biological activity of crowns was given a separate section in this review as the literature
has not been presented in a collected form. Even so, a number of elaborate macrocyclic systems designed for biological applications
have been reported but are beyond the scope of the present discussion. A number of monographs have described crown ethers and
their behavior and numerous individual articles are available on many aspects of crown chemistry and applications. The reader is
referred to other monographs149–157 for more detailed information.

3.02.7.1 Membranes
Membranes form from amphiphiles. Crown ethers are polar enough to comprise head groups for amphiphiles that contain a suit-
able alkyl side chain. The formation of membranes from amphiphilic macrocycles was reported by Kuwamura and coworkers158
and by Okahara and collaborators.159 A number of amphiphilic macrocycles form membranes that exhibit varying stability.160
In addition, compounds commonly referred to as bolaamphiphiles or bolytes can also form bilayer membranes.161 It is interesting
to note that the C12 bolyte shown in Fig. 63 forms stable vesicles as does its C10 analog. However, the analogs containing C16 and
C22 spacers formed micelles.

3.02.7.2 Cation-Conducting Channels

The hydraphile compounds we developed studied are discussed in section “Chiral Crown Compounds” with respect to their bio-
logical activity. It should be noted that hydraphile variants have recently been reported that incorporate azobenzene residues as
switching elements.162 Ours were not the first synthetic ion channels based on macrocycles.163 The first crown ether based synthetic
ion channels were based on macrocycles incorporating tartaric acid residues as the central units. Jullien and Lehn reported a cylin-
drical amphiphile that they dubbed a “chundle” inspired by a channel that is formed from a bundle of fibers.164 In a later work, the
crown central unit of their channel system was replaced by cyclodextrin and the system referred to as a bouquet molecule.165
Fyles and coworkers devised a family of channel structures also based on tartaric acid crowns and demonstrated cation trans-
port.166 Fyles and coworkers have elaborated their initial compounds167 into families have quite different structural elements.168
Much of this work has recently been reviewed.169 Fig. 64 shows the essential elements of these early channels.
A very different approach was taken by Voyer and Robataille.170 They used a peptide backbone of the form (Leu-CrPhe-Leu-Leu-
Leu-CrPhe-Leu)3, where CrPhe represents a phenylalanine having a fused 21-crown-7 macrocycle appended. The poly-leucine back-
bone creates a coil in which the macrocycles are largely aligned. An analog having a peptide backbone too short to span a bilayer was

Figure 64 Channel family designed by Fyles and coworkers. The chain compositions indicated by A  and B vary in length and polarity and
havrious polar elements were incorporated as head groups.
42 Crown Ethers

Figure 65 A membrane spanning synthetic ion channel based on a peptide backbone that incorporates crown ethers.

used as a control. Ion transport, e.g., Csþ, was monitored by using a proton sensitive dye (Fig. 65). In a later work, it was shown that
such structures exhibited cytolytic activity.171 Studies of this interesting system are ongoing.172

3.02.7.3 Crown Ethers as Catalysts and Enzyme Mimics

Like the cyclodextrins before them,173 crown ethers have been used as scaffolds to develop enzyme mimics (Fig. 66). One of the
earliest of these was reported by Matsui and Koga.174 They used the crown to bind a protonated amino acid ester. This positioned
the acyl group for thiol–ester exchange. The meso arrangement of the thiolated, reduced tartaric acid residue ensured that the bound
ester would be appropriately positioned for thiolysis irrespective of the side to which the cation was bound. Of course, much more
recent work has elaborated the concept.175

3.02.7.4 Crown Ethers as Sensors

Ion binding sensors have been a major area of endeavor for most of the time crown ethers have been known. Extensive early work
was conducted in Japan by Misumi,176 Kimura and Shono,177 Tsukube,178 Shinkai,179 Takagi,180 and others. The early work in chro-
moionophores has been reviewed181 and a more recent review of crown sensors has also appeared.182 Numerous interesting exam-
ples continue to appear. An example is shown in Fig. 67. The lariat ether shown there has a pendant coumarin chromophore
connected by click chemistry. The latter connection method approaches affords either the C- or N-linked coumarin (illustrated
as indeterminant in the figure). The sensor is stated to detect Kþ under simulated physiologic conditions.183

3.02.7.5 Switching Crown Ether Properties

Echegoyen184 and Kaifer185 developed a number of novel sensors based on electrochemical switching, as did Shinkai and
coworkers. Eight different compounds are illustrated as A–H in Fig. 68. These compounds embrace quite a range of structural vari-
ations and innovations.

Figure 66 Supramolecular scaffold for aminoester thiolysis.

 Crown Ethers 43

Figure 67 A lariat ether-based, potassium-selective fluoroionophore.

Figure 68 Three approaches to interlocking molecules.

Compound A was designed as a chromoionophore.186 An early example was prepared by Matsui and Koga in which the para-
position of the meta-xylyl unit was a nitro group.187 Any change in the electronic environment of the macroring will be reflected in
the UV–vis spectrum of the dinitroazobenzene. The system is further switchable as the phenol is ionizable. Loss of the proton will
alter the spectrum as will binding of an anion within the ring.

Compounds B and G are both switchable, but the latter can be altered in two different ways. Nitrophenyl lariat ether B can be
reduced to its radical ion. This is a more potent binder than a neutral nitro group.188 As such, binding strength can be increased or
decreased by reduction or oxidation respectively. The binding strength of azobenzene cryptand can similarly be enhanced by reduc-
tion of the arene, but trans–cis photoisomerization will also alter binding behavior by changing the size of then binding cavity.23
Two interesting switchable receptors developed by Shinkai and coworkers are shown as E and H. In the ground state trans
arrangement, the two macrorings are distant and independent. When photoswitched, the two rings can come into proximity
44 Crown Ethers

and form a sandwich complex with a ring-bound cation.189 A similar principle is involved in structure H. In this case, photoisome-
rization caused the azobenzene to fold over and bring the ammonium salt into proximity with the macrocycle. When the orienta-
tion of the macroring and the ammonium salt are appropriate, a unique intramolecular complex forms.190
Structures C and D are both redox switchable binders, but they obviously differ in their constituents. Compound C was designed
to use the redox switchability of anthraquinone191 as was done for nitrobenzene in B. The latter is reducible but it is sensitive to
oxygen and water. As a transport agent, B lacks versatility. Anthraquinone, on the other hand, survives water and can be used as
an ion transport agent. Even the open-chained analog of C, a podand, can transport ions in a redox controlled fashion.192 Dix
and Voegtle showed that anthraquinone can be joined to an N-phenylaza-18-crown-6 as a monoamine.193 Recent work shows
that anthraquinone podands can be used as redox-switched carriers in SLMs.194
Cryptand D uses the well-established electrochemistry of ferrocene to control binding.195 Ferrocene differs from nitrobenzene
and anthraquinone because it oxidizes readily taking the iron atom from a formal ferrous to a ferric state. A cation bound within the
cavity would be repelled by the positive charge. When neutral, however, the iron lone pairs comprise a strong donor group. The
redox switchable capability of ferrocene has been exploited in several synthetic ion channels.196
Yet another variation on the redox theme is represented by compound F.197 The compound is shown as a cryptand but reduction
of the disulfide link is facile. When reduced, the compound reverts to what might be called a bibracchial lariat ether.

3.02.7.6 Catenanes, Rotaxanes, and Knots

In the 1960s, a book by Schill appeared titled “Catenanes, Rotaxanes, and Knots.” This recently reprinted volume conveys the fasci-
nation organic chemists have felt about large rings and interlinked structures.198 The ability of crown ethers to bind metal and
organic cations has permitted organization of structures about one another with the result that numerous examples of these
sought-after structures are now known. Fig. 68 shows three structures that are representative of a large effort in several laboratories
to develop structures having novel topologies, novel functions, or both.
Compound A is a catenane that was prepared by Sanders and coworkers in 60% in a copper-catalyzed Glaser coupling reaction.
Rotaxane B was designed by Stoddart and involves charge transfer interactions between the dibenzocrown and viologen (also called
paraquat). The knot shown as C was reported by Sauvage and coworkers and is representative a large family of large ring compounds
having unusual topologies. The compound shown is a copper complex of a 78-membered ring.

3.02.7.7 Cyclams and Other All-Nitrogen Macrocycles

Cyclams are all nitrogen macrocycles and, as such, they have been of greatest interest to inorganic chemistry. The templated
synthesis of tetraaza-14-crown-4, cyclam, or [14]aneN4 was a milestone199 that led to innumerable novel complexes.200 Another
important family of all nitrogen receptors was the so-called expanded porphyrins. Porphyrin is, of course, a natural macrocycle
that binds iron and magnesium. Expanded porphyrins dramatically enrich this chemistry. The following figure shows cyclam, a bis(-
cyclam), and an expanded porphyrin that was developed for use as an imaging agent, when complexing either gadolinium or
lutecium.

3.02.8 Conclusions

The earliest studies of crown ether biological activity were limited, owing to the availability of diverse structural types in the labo-
ratories in which biological studies were conducted. This likely prevented follow-on studies that could clarify scope and mechanism.
For example, only one of the studies cited for whole animal activity reports metabolic products. This may be due to limited supply
of compound or lack of interest owing to toxicity. It also seems likely that there was industrial interest in crowns that has not been
disclosed in the general literature.
Two broad, if not universal, generalizations can be made. First, whether microbes, plants, or animals were surveyed, it appears
that either cation binding strength and/or host molecule lipophilicity increased activity. Of course, limited compound samples and
 Crown Ethers 45

limited data sets make this only an inference. Second, in studies of microbes, it appears that macrocycles generally affect Gram posi-
tive bacteria more strongly than they do Gram negative bacteria. This is likely due to differences in the boundary membranes, which
are more elaborate in Gram negative species. No conclusions, even tentative ones, can be drawn from a very broad array of organ-
isms surveyed by using the disk diffusion method.
More recently, a number of applications have been developed for macrocycles. It has been shown that the potency of antibiotics
can be enhanced and crowns themselves can be adapted for use as direct injection chemotherapeutic agents. It is hoped that orga-
nizing the data reported for crown biological activity will reveal other applications and perhaps more systematic studies when
surveys are undertaken.

Acknowledgments

We thank the NIH, PRF, and NSF (currently CHE 1307324) for their support over many years.

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 3.03 Calixarenes
C Talotta, C Gaeta, M De Rosa, A Soriente, and P Neri, Università di Salerno, Salerno, Italy
Ó 2017 Elsevier Ltd. All rights reserved.

3.03.1 Calixarene Macrocycles 49

3.03.1.1 History 49
3.03.1.2 Nomenclature 52
3.03.1.3 Synthesis 52
3.03.1.3.1 One-Pot Procedures 52
3.03.1.3.2 Multistep Synthesis and Fragment Condensation 53
3.03.1.4 Conformational and Stereochemical Features 54
3.03.1.4.1 Conformational Aspects 54
3.03.1.4.2 Inherent Chirality 55
3.03.2 Calixarene Functionalization 56
3.03.2.1 Functionalization of Endo Rim 56
3.03.2.1.1 Exhaustive Alkylation 56
3.03.2.1.2 Partial Alkylation 56
3.03.2.1.3 Intramolecular Bridging 58
3.03.2.2 Functionalization of Exo Rim 59
3.03.2.2.1 Electrophilic Aromatic Substitutions and Other Classical Routes 60
3.03.2.2.2 Novel Routes: The p-Bromodienone Route 60
3.03.2.2.3 Novel Routes: Meta-Functionalization via Organomercurial Chemistry 61
3.03.2.3 Chemical Modification of Methylene Bridges 61
3.03.2.4 Functionalization of Aromatic Walls 62
3.03.3 Supramolecular Applications of Calixarene Macrocycles 63
3.03.3.1 Biomolecular Recognition 63
3.03.3.2 Cation Recognition and Sensing 65
3.03.3.3 Anion Recognition and Sensing 66
3.03.3.4 Catalysis 68
3.03.3.5 Threaded Architectures: Rotaxanes and Catenanes 68
3.03.3.6 Self-Assembly 69
3.03.3.6.1 Self-Assembly in Solution 69
3.03.3.6.2 Self-Assembly in the Solid State 70
3.03.4 Conclusions 71
References 72

3.03.1 Calixarene Macrocycles

3.03.1.1 History
Calixarenes 1 are a well-known family of macrocyclic compounds obtained by phenol/formaldehyde condensation and widely used
in supramolecular chemistry where they have found many applications. Calix[n]arenes have the general structure 1 reported in
Fig. 1 in which the number n of phenolic units ranges from 4 to 20. However, the most studied members are those constituted
by 4–8 aromatic units.
The calixarene history begins with the pioneering work of Adolf von Baeyer in 1872 2 who first studied the phenol formaldehyde
reaction obtaining a resinous material. Successively, Leo Baekeland (1905–09) developed a procedure for the synthesis of bakelite3
from phenol and formaldehyde in basic media. Prompted by the growing interest toward this material, Zinke (1950) and Ziegler
studied4 the condensation of p-alkylphenols and formaldehyde in the presence of NaOH. They assumed that under these condi-
tions, only the tetramers (e.g., 1a) were formed. In 1955, Sir John Cornforth5 highlighted the presence of different species that
he attributed to different conformational isomers of the tetramer. Finally, the studies of Gutsche6 showed the presence of cyclic
homologues and in particular the tetramer 1a, hexamer 1c, and octamer 1e, while the odd members, pentamer 1b and heptamer
1d, were present in small quantities.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12509-0 49

50 Calixarenes

Figure 1 The calix[n]arene family (n ¼ 4–20). 1

Successively, Gutsche and coworkers reported how the most common calixarene macrocycles 1a–e can be singly obtained
in good yield by choosing the appropriate reaction conditions 7 (i.e., nature of the base, formaldehyde source, solvent, and
temperature). Finally, during the years 1979–87, Andreetti, Ugozzoli, and Ungaro reported the X-ray structures of derivatives
1a, 1c, and 1e.8

Year Author Discovery

1872 Adolf von Baeyer From the reaction between phenol and formaldehyde, the
formation of a cement-like polymeric material was
observed. The characterization of this material was not
possible with the techniques of that period

1908 Leo Baekeland Bakelite, a heavily cross-linked polymer obtained by

condensation of phenol and formaldehyde, was
marketed
 Calixarenes 51

Year Author Discovery

1941 Alois Zinke and Erich Ziegler Inhibiting the cross-linking polymer through the use of
a para-substituted phenol, a crystalline solid with a high
melting point, rather than a resin, was obtained. A
cyclic tetrameric structure was assigned (n ¼ 4; Fig. 1)

1955 Sir John Cornforth The structural resolution by X-ray crystallography was
attempted with limited success, the structural
resolution was attempted. The Petrolite company
begins to use calixarenes as demulsifiers in the oil
industry

1978 C. David Gutsche A simple and reproducible general procedure for the
synthesis of calixarenes on a large scale was developed
52 Calixarenes

Figure 2 Numbering and rims of calix[4]arene skeleton.

The synthetic and supramolecular peculiarities of calixarene derivatives have encouraged the design of related macrocycles in
which the phenol rings and/or the methylene bridges have been replaced by different moieties. 1d Thus, replacing the phenol
ring of calixarenes with resorcinol and catechol units, resorcinarenes9 and cyclotriveratrylenes10 are obtained, respectively. Recently,
heteracalixaromatics11 have been investigated in which the CH2 bridges and/or the phenol rings are replaced, respectively, by
heteroatoms (N and O) and/or heteroaromatic rings (e.g., pyrrole, pyridine, and pyrimidine). Finally, replacing the methylene
bridges with CH2XCH2 groups (X ¼ N and O), homoazacalixarenes11 and homooxacalixarenes,12 respectively, are obtained.
Recently, new members have entered the enlarged calixarene family, and among them, pillararenes,13 constituted by para-linked
1,4-dialkoxybenzene units, have shown remarkable supramolecular properties.

3.03.1.2 Nomenclature
The term “calixarene” was introduced by C. David Gutsche who was inspired by the similarity of the cone conformation of calix[4]
arene 1a with a Greek vase (calix crater). 6 Subsequently, this name was also extended to the other calixarene homologues. In detail,
the name is obtained by indicating the number of aromatic units of the macrocycle with a bracketed number between the words calix
and arene and also specifying the nature of the substituent at the para position of the phenolic unit. Thus, for example, the cyclic hex-
amer obtained by condensation of p-tert-butylphenol with formaldehyde is called “p-tert-butylcalix[6]arene.” The term “calix[n]arene”
has been officially accepted by the IUPAC to indicate the carbonious macrocyclic skeleton with a specific position numbering (Fig. 2).
In the calixarene nomenclature, two faces can be distinguished: the exo face (exo, upper or wide rim) bearing the p-substituents
and the endo face (endo, lower or small rim) bearing the OH groups ( Fig. 2).

3.03.1.3 Synthesis
Calixarene macrocycles can be obtained using two different synthetic strategies 1:
l One-pot procedure
l Multistep synthesis and fragment condensation

3.03.1.3.1 One-Pot Procedures

By means of one-pot procedures, calixarene macrocycles are obtained by direct reaction between a p-alkylphenol and formaldehyde
in a basic or acid medium. 7 Currently, this is the most common way to obtain the basic calixarene macrocycles.7 The one-pot proce-
dure has been optimized for p-tert-butylphenol as the starting material and gives rise to p-tert-butylcalix[n]arenes (Fig. 1).7 By
varying the reaction conditions (source of formaldehyde, solvent, temperature, and base), the individual members of the calixarene
family (Fig. 1) can be selectively obtained as shown in Scheme 1.
In detail, p-tert-butylcalix[4]arene 1a 7a is obtained by reaction between p-tert-butylphenol and a commercial solution of form-
aldehyde in water in the presence of sodium hydroxide (0.045 equiv). The mixture is heated for 2 h at 110–120 C leading to the
formation of a viscous paste called “precursor.” The “precursor” is refluxed in diphenyl ether for 2 h. Under these conditions, the
cyclic tetramer 1a is recovered by precipitation from ethyl acetate and recrystallized from toluene.7a The nature of the base plays an
important role in addressing the synthesis toward a specific cyclooligomer. In particular, NaOH allows the synthesis in high yields of
the cyclic octamer 1e7c and of the tetramer 1a7a by changing the solvent from xylene to diphenyl ether, respectively, while KOH in
xylene gives high yields (80–85%) of the cyclic hexamer 1c.7b
Usually, the synthesis of the even-membered calixarenes proceeds in higher yields with respect to the odd homologues. For this
reason, calix[4,6,8]arenes are called “major” ( Scheme 1) while calix[5,7]arenes have been termed “minor” calixarenes.1 In fact,
Stewart and Gutsche7d reported a one-pot procedure for the synthesis of p-tert-butylcalix[5]arene 1b in 15–20% yield, while p-
tert-butylcalix[7]arene 1d was obtained in 26% yield by an acid-catalyzed procedure (p-TsOH as the catalyst and s-trioxane as
the formaldehyde source, in CHCl3 as the solvent).7e Under these conditions, it is also possible to isolate the larger calix[9–20]are-
nes 1f–q by gradient flash chromatography and selective precipitation.7e More recently, the synthesis of p-tert-butylcalix[9]arene 1f7f
has been obtained in 36% yield by treatment of p-tert-butylphenol with s-trioxane and SnCl4 in CH2Cl2. Finally, the synthesis of p-
tert-butylcalix[10–12]arene 1g–i has been reported by Lamartine and coworkers under basic conditions.7g
 Calixarenes 53

Scheme 1 Calix[n]arene synthesis.

Generally, the previously described syntheses have been optimized for p-tert-butylphenol as the starting material, but different
para-substituted phenols have been also used, often with poorer results. 1 Among the most interesting examples, Ungaro and
coworkers14 reported the one-pot synthesis of p-(benzyloxy)calix[8]arene in good yield (48%) using p-benzyloxyphenol, parafor-
maldehyde, and NaOH in refluxing xylene. Kovalev and coworkers15 obtained p-1-adamantylcalix[8]arene in excellent yield (71%)
by treatment of p-1-adamantylphenol with KOH in diphenyl ether.

3.03.1.3.2 Multistep Synthesis and Fragment Condensation

Historically, the main advantage of the multistep synthesis is that it makes available calixarene derivatives bearing different substit-
uents along the macrocycle. The first example of a multistep synthesis was reported by Hayes and Hunter 16 who synthesized p-
methylcalix[4]arene 7 by a 10-step procedure (Scheme 2).

Scheme 2 Synthesis of p-methylcalix[4]arene with a nonconvergent stepwise approach. 16

54 Calixarenes

Scheme 3 Examples of 2 þ 2 and 3 þ 1 fragment condensations.

The multistep syntheses were long and tedious; therefore, many efforts were devoted to improve this strategy. 17 Thus, Böhmer
and coworkers18 developed convergent syntheses that required fewer reaction steps. In particular, four different ways are possible:
a 3 þ 1, 2 þ 2, 2 þ 1 þ 1, and 1 þ 1 þ 1 þ 1 fragment condensation (Scheme 3).

3.03.1.4 Conformational and Stereochemical Features

3.03.1.4.1 Conformational Aspects
One fascinating aspect of calixarenes is related to their ability to assume different conformations thanks to the rotational freedom
around the methylene bridges, which leads to different molecular shapes. Calix[n]arenes undergo conformational interconversion
by means of the “oxygen-through-the-annulus” or the “tert-butyl-through-the-annulus” passages ( Fig. 3A).1
In the case of p-tert-butylcalix[4]arene, the “tert-butyl-through-the-annulus” passage is impossible for geometric reasons, and conse-
quently, the only active interconversion route is the “oxygen-through-the-annulus” passage. By this way, four discrete conformations of
the calix[4]arene macrocycle can be obtained, namely, cone, partial-cone, 1,2-alternate, and 1,3-alternate ( Fig. 3B).
NMR 19 and X-ray studies8a have shown that p-tert-butylcalix[4]arene 1a preferentially adopts, both in solution and in the solid
state, the cone conformation, stabilized by a strong circular array of hydrogen bonds between the OH groups (Fig. 4). Regarding p-

Figure 3 The four calix[4]arene basic conformations.

 Calixarenes 55

Figure 4 Cone-to-cone inversion of p-substituted calix[4]arenes.

tert-butylcalix[6]arene 1c and p-tert-butylcalix[8]arene 1e, X-ray studies showed that they adopt in the solid state a cone and pleated-
loop conformation, respectively.8
1
H VT NMR studies showed that at 25 C, the 1H NMR spectrum of p-tert-butylcalix[4]arene 1a presents a pair of doublets (AX
system) relative to ArCH2Ar bridges that became a sharp singlet at 60 C. 19 This behavior is due to the cone-to-cone conformational
interconversion (Fig. 4), which displays a coalescence temperature of 52 C in CDCl3 (100 MHz)14 and an energy barrier of
15.7 kcal/mol.19
The conformational interconversion of calix[4]arene macrocycle (e.g., 1a) can be blocked by attaching appropriately bulky
substituents at the phenolic OH groups. 20 Detailed studies have shown that with methyl21 and ethyl22 groups, the calix[4]arene
is still conformationally mobile, whereas with propyl groups, it is conformationally blocked.22 1H VT NMR studies revealed for
p-tert-butylcalix[5]arene 1b a coalescence temperature of  2 C and a 6Gz of 13.2 kcal/mol in chloroform (100 MHz).19 Analogous
studies (100 MHz) for calix[6]arene 1c and calix[8]arene 1d revealed a coalescence temperature and a barrier energy, respectively, of
11 C/13.3 kcal/mol and 53 C/15.7 kcal/mol.19
The number of conformations of calix[n]arenes rapidly increases by increasing the number n of aryl units. Thus, if only the up–
down orientation of Ar rings is considered, we will have four, eight, and sixteen conformations, respectively, for calix[5]arene, calix
[6]arene, and calix[8]arene macrocycles. The conformations of calixarenes can be identified by NMR spectroscopy, through the Gut-
sche “1H NMR Dd” rule 23 and the de Mendoza “single 13C NMR” rule.24 In particular, when two adjacent aryl units are in a syn
orientation (cone), the 13C chemical shift of the methylene carbon is approximately 31 ppm (de Mendoza’s rule) and the 1H
NMR chemical shift separation of the ArCH2Ar protons is Dd ¼ 0.7–1.0 ppm. For the anti orientation of adjacent Ar rings (typical
of the alternate conformations), a value of about 37 ppm is expected for the 13C chemical shift of the methylene carbon, while a 1H
NMR Dd ¼ 0.0–0.3 ppm should be observed for ArCH2Ar protons. More recently, theoretical surface maps have been obtained in
which QM GIAO calculated 13C and 1H chemical shift values of ArCH2Ar group that have been related to the pertinent 4 and c
dihedral angles.20 Fitting of the experimental 13C and 1H chemical shift data on the maps allows one to obtain useful structural
information.25
Regarding the larger calix[n]arenes (n > 6), they undergo conformational interconversion by means of both the “oxygen-through-
the-annulus” and the “p-substituent-through-the-annulus” passages ( Fig. 5). Consequently, in order to inhibit the conformational inter-
conversion of those macrocycles, both mechanisms have to be blocked through intramolecular bridging (vide infra) (Fig. 5).26,27

3.03.1.4.2 Inherent Chirality

Thanks to their three-dimensional bowl-shaped structure, calixarenes, having an appropriate number of different substituents on
their rings, show a special case of chirality, which has been termed “inherent chirality” because it is not linked to any stereogenic
center ( Fig. 6). According to another definition,28 inherent chirality “arises from the introduction of a curvature in an ideal planar
structure that is devoid of perpendicular symmetry planes in its bidimensional representation.”
In particular, calix[4]arene macrocycles bearing at least three different substituents at the exo or endo rim (e.g., 13 29) (ABCC or
ABCD pattern) show inherent chirality. Alternatively, it is possible to generate inherent chirality through the meta-functionalization
of the calixarene phenolic ring (e.g., 1428). Inherently chiral calixarene hosts have found applications in the recognition of chiral
guests30 and as enantioselective organocatalysts.31

Figure 5 Conformational interconversion in unbridged and bridged p-tert-butylcalix[n]arenes. 26

56 Calixarenes

Figure 6 Examples of inherently chiral calix[4]arene derivatives.

Usually, inherently chiral calixarenes (e.g., 14) are obtained as racemates, 32 which require an appropriate resolution.33 Then, the
absolute configuration of the two enantiomers has to be assigned by an appropriate method such as the comparison between
measured and DFT-calculated chiroptical properties (optical rotation dispersion and electronic circular dichroism).33

3.03.2 Calixarene Functionalization

The chemical modification of calix[n]arenes has been deeply investigated with the main aim to synthesize hosts with novel supra-
molecular properties. The easiest and most common transformations regard
l phenolic hydroxyl groups (the lower, narrow, or endo rim), through alkylation and acylation reactions;
l para position of the aromatic rings (the upper, wide, or exo rim), by aromatic electrophilic substitution (halogenation, nitration,
sulfonation, etc.);
l methylene bridges;
l aromatic walls.

3.03.2.1 Functionalization of Endo Rim

The most popular and widely studied functionalization concerns the alkylation of the endo rim of calix[n]arenes, which gives rise to
robust ether bonds, but more labile ester bonds have been also obtained by acylation. Using appropriate reaction conditions,
partially and totally O-alkylated products can be obtained directly from the parent calix[n]arene. 1 The progress of the reaction is
dependent on several factors, such as the nature of the p-substituent at the exo rim, solvent, temperature, and base.

3.03.2.1.1 Exhaustive Alkylation

Usually, totally O-alkylated calix[n]arene derivatives are obtained in the presence of a strong base with an excess of alkylating
agent. 22 As said in the preceding text, the reaction of p-tert-butylcalix[4]arene 1a with n-PrI can allow the immobilization of the
four basic conformations (atropisomers): cone, partial-cone, 1,2-alternate, and 1,3-alternate. In fact, when 1a is tetra-alkylated
in the presence of NaH in THF/DMF, a tetra-O-propyl-ether 18 in the cone structure is obtained.22b In the presence of Cs2CO3
in acetonitrile, the 1,3-alternate atropisomer 19 is obtained in high yield,22b while potassium t-butoxide in benzene gives a 1:1
mixture of partial-cone 21 and 1,3-alternate 1922d isomers. These results can be rationalized by referring to the template effect
of the corresponding cation (Fig. 7).
Regarding the cone tetra-O-alkylated calix[4]arenes, NMR and computational studies reveal that they do not adopt a regular C4v-
symmetrical structure. In fact, two distal rings became almost parallel to each other to give a C2v-symmetrical “pinched” structure,
and a fast (with respect to the NMR timescale) interconversion takes place between the two possible ones. 20,34
The exhaustive alkylation of calix[5]arenes has been also described. 35 p-tert-Butylcalix[7]arene can be exhaustively alkylated in
excellent yields36 by using Cs2CO3 as the base. The exhaustive alkylation of p-tert-butylcalix[8]arene has been performed37 with
strong bases such as NaH and BaO/Ba(OH)2 and a large excess of alkylating agent. The complete alkylation of the endo rim of p-
tert-butylcalix[9]arene38 has been obtained in good yields by treatment with large excesses of K2CO3 and alkylating agent.

3.03.2.1.2 Partial Alkylation

Di-O-alkylation of calix[4]arenes can be carried out with two different regiochemistries: distal (1,3, or A,C- 17,39) and proximal func-
tionalization (1,2- or A,B-40) (Fig. 8). In detail, 1,3-di-O-alkylated calix[4]arenes are obtained when K2CO3 is used as the base in
 Calixarenes 57

Figure 7 Synthesis of all possible calix[4]arene atropisomers.

Figure 8 Partial O-alkylation of calix[4]arenes.

acetone or acetonitrile as the solvent.22,39 The regiochemical outcome of the reaction is ascribed to the presence of the weak base
K2CO3, which can only give monodeprotonations. After the first deprotonation, the second one involves the distal OH group,
which is stabilized by two H bonds with the proximal OH groups (Scheme 4).
Proximal di-O-alkylated derivatives 20 can be obtained with a strong excess of base and a stoichiometric amount of alkylating
agent. In addition, 1,2-di-O-alkylated products can be obtained by selective dealkylation of tetra-alkylated calixarenes. 40 Tri-O-
alkylation (21) can be obtained by using BaO/Ba(OH)2 in DMF.22b Mono-O-alkylation (19) is usually carried out with 0.6 equiv
of K2CO3 or 1.2 equiv of CsF (Fig. 8).41
Regarding the selective alkylation of large calix[n]arenes, 42 (n  6) the number of expected products increases by increasing the
number n of phenolic units. Thus, 10, 16, 28, and 46 partially O-alkylated products are expected for calix[6]-, calix[7]-, calix[8]-, and
58 Calixarenes

Scheme 4 Mechanism of weak base-promoted regioselective 1,3-dialkylation of calix[4]arenes (dashed red lines represent H bonds).

calix[9]arenes, respectively. Notwithstanding this inherent difficulty, the regioselective functionalization at the endo rim of those
calixarenes has been widely studied in the last three decades. Interestingly, the 1,3,5-tri-O-alkylation of calix[6]arene macrocycle
has been reported,43 while examples of 1,4-diethers and 1,2,4,5-tetraethers are known.43 The selective 1,2,4,6-tetra-O-alkylation36
of p-tert-butylcalix[7]arene has been obtained by using a weak base (K2CO3)-promoted O-alkylation or O-benzoylation.36 Analo-
gously, K2CO3 was effective in the synthesis of 1,3,5,7-tetra-O-alkylated calix[8]arenes.44

3.03.2.1.3 Intramolecular Bridging

The introduction of bridging elements at the calixarene endo rim has been particularly studied. In the case of calix[4]arenes, very
common is the distal bridging. 45 The first example a calix[4]arene bridged with a crown ether moiety (calix[4]crown) was reported
by Ungaro45 in 1995. In this case, the final product 26 was obtained in the 1,3-alternate conformation thanks to the presence of
Cs2CO3 to promote the reaction between 1,3-dialkoxycalix[4]arene 25 and pentaethylene glycol ditosylate45 (Scheme 5). Examples
of 1,2-crowned calix[4]arenes are also known.46 These derivatives were obtained in two steps through a selective 1,2-bis-demethy-
lation of tetramethoxy-p-tert-butylcalix[4]arene and a successive alkylation with an oligoethylene glycol ditosylate. In successive
studies, a large variety of bridging moieties have been used for calix[4,5]arenes.47
The intramolecular bridging is the preferred way for immobilizing the larger calix[n]arene (n  6) macrocycles. In fact, as said in
the preceding text, they undergo conformational interconversion by means of the “oxygen-through-the-annulus” or “p-substituent-
through-the-annulus” passages. Consequently, in order to immobilize their structure, both mechanisms have to be blocked by intra-
molecular bridging ( Fig. 9).26,42 Several examples are known of calix[n]arenes intramolecularly bridged with aliphatic, aromatic,
and crown bridges. Thus, singly bridged calix[7]arenes48 were obtained by direct O-alkylation of 1d with BrCH2Cl, oligoethylene
glycol ditosylates, and 1,4-bis(bromomethyl)benzene. Regarding the regiochemistry of the bridged products, the 1,2-bridging (e.g.,
27) was favored with “short bridging element,” while the longer ones gave the 1,4-isomer (e.g., 28) (Fig. 9) in good yield.48,49 Phos-
phorus multiple-bridged calix[7]arene derivatives50 were obtained by treatment of 1d with phosphorus pentachloride.
Interestingly, the regioselectivity of the single bridging of calix[8]arenes (e.g., 1e) ( Fig. 10) can be also controlled by the reaction
conditions and in particular by the nature of the base and by the length of the bridge.51 Among the four possible regioisomers,
namely, 1,2-, 1,3-, 1,4-, and 1,5-bridged compounds, the 1,5-bridging can be obtained in high yields (80–90%) with ortho-,

Scheme 5 1,3-Alternate calix[4]crown-6: a cesium-selective ionophore. 45

 Calixarenes 59

Figure 9 Singly bridged calix[7]arene derivatives.

Figure 10 Singly bridged calix[8]arene derivatives.

meta-, and para-bis(bromomethyl)benzene and Cs2CO3 as the base.52 Calix[8]crowns 29a–k51,53 were also obtained by direct regio-
selective alkylation of 1e under various conditions.
Recently, an example of intramolecular bridging of calix[9]arene 1f with phosphoryl groups has been obtained, 54 while regio-
selective crowned calix[10]arenes have been also reported.54

3.03.2.2 Functionalization of Exo Rim

Historically, many synthetic efforts have been devoted to the introduction of functionalities on the exo rim (para position) of cal-
ixarene macrocycles. 1 Over the years, this has brought to the synthesis of novel supramolecular hosts with intriguing recognition
and self-assembly abilities.1
60 Calixarenes

3.03.2.2.1 Electrophilic Aromatic Substitutions and Other Classical Routes

For p-tert-butylcalix[n]arenes, there is the fortunate circumstance that tert-butyl groups can be easily replaced with other ones,
making this the preferred approach for exo rim functionalization over other possible ones, like the long and tedious multistep
synthesis. In the first instance, the p-tert-butyl groups can be easily removed by a complete or selective trans-tert-butylation reaction
(a reverse Friedel–Crafts) using AlCl3 as a Lewis acid catalyst ( Scheme 6) and phenol or toluene as butyl acceptor.55 Subsequent
SEAr reactions at the freed para position enable the introduction of new groups. New functionalities56 can be introduced by acyl-
ation,57 bromination,56a chlorosulfonation,56c formylation,58 diazo coupling,59 nitration,60 sulfonation,61 chloromethylation,62
Mannich reaction,63 and the Claisen rearrangement of O-allyl to p-allyl derivatives(Scheme 6).64 The newly introduced groups
can then be converted to other ones: For example, the bromo derivatives can be converted to carboxy derivatives after a lithiation
step65; p-nitro derivatives can be reduced to amino compounds,22a which are synthetic precursors of amides and ureas.
In 1990, Reinhoudt and coworkers 22a reported an interesting work on the selective functionalization of calix[4]arene exo rim. In
particular, 1,3-di-para-substituted calix[4]arenes were prepared in good yields by exploiting the different reactivity between phenols
and their ethers and esters. In this way, the selective O-substitution of the endo rim can be transferred at the exo rim. Thus, selective
partial ipso-substitutions, electrophilic substitutions, or rearrangements were realized under mild conditions. An interesting example
of 1,3-selective formylation of 1,3-dialkoxycalix[4]arenes was reported by Ungaro and coworkers.66
A particular interest has been also devoted to bis-calixarene derivatives ( Fig. 11) in which two calixarenes are linked through
a bridging element, such as alkyl, alkenyl, and alkynyl chains, diesters, diamides, metallocenes, ethers, polyethers, sulfides, and dii-
mines.67 An example of bridgeless double calix[4]arene in which the two macrocycles were coupled by a direct para–para linkage
was reported by Neri and coworkers.68

3.03.2.2.2 Novel Routes: The p-Bromodienone Route

Differently from the common synthetic paths previously described, which include electrophilic aromatic substitutions, recently, the
p-bromodienone route 69 has been introduced for the functionalization of the calixarene exo rim with nucleophilic agents, in a sort of
“aromatic ring umpolung.”
In detail, calix[n]arene p-bromodienone derivatives (n ¼ 4 and 6), bearing one or two 4-tert-butyl-4-bromo-2,5-
cyclohexadienone moieties (shortly, the p-bromodienone moiety), 70 undergo the nucleophilic substitution of bromine through
a silver ion-mediated displacement with O-nucleophiles (alcohols and carboxylates) to give p-alkoxy- or p-acyloxycalixarenes in

Scheme 6 Examples of exo rim functionalization.

 Calixarenes 61

Figure 11 Bis-calixarene derivatives.

workable yields (Fig. 12).70 The p-bromodienone route with activated aromatic C-nucleophiles allows the introduction of aromatic
moieties at the para or meta position of calixarene aromatic rings.32 The inherently chiral C–C meta-coupled products are formed
through a dienone–phenol rearrangement (Fig. 12).

3.03.2.2.3 Novel Routes: Meta-Functionalization via Organomercurial Chemistry

Very recently, Lhoták 71 introduced a novel synthetic route for the meta-functionalization of calixarenes via organomercurial chem-
istry. In detail, the treatment of tetrapropoxycalix[4]arene 41 with Hg(TFA)2 afforded a monomercurated compound 43 in high
yield (Scheme 7), which was subjected to a Pd-catalyzed arylation to give 44.72 Successively, this route has been also exploited
for the synthesis of an unusual cone-shaped meta-bridged calix[4]arene 45,72b which showed interesting recognition abilities
toward small guests (Scheme 7).

3.03.2.3 Chemical Modification of Methylene Bridges

The introduction of substituents at the methylene bridges is an interesting method for the rigidification of the calixarene backbone.
In contrast to the ready derivatization of endo and exo rims, the functionalization of ArCH2Ar groups requires more elaborated

Figure 12 The p-bromodienone route.

62 Calixarenes

Scheme 7 Meta-functionalization of calixarenes via organomercurial chemistry.

synthetic pathways. Among them, the “fragment condensation” method 73 introduced by Böhmer et al. requires the use of fragments
specifically functionalized, which subsequently cyclomerize to give bridge-substituted calixarenes (Scheme 8).
Recently, Biali and coworkers introduced a more convenient route for bridge functionalization starting from bromo or keto
derivatives. 74 In detail, bromo derivatives, with all the methylene bridges monosubstituted by bromine atoms, were prepared
with NBS (N-bromosuccinimide) in a chlorinated solvent via photochemical or radical reaction,74 while keto derivatives were
obtained via oxidation of the ArCH2Ar groups of a calix[4]arene tetraacetate followed by hydrolysis of the product.75 These
two intermediates can undergo nucleophilic substitution or addition reactions (Fig. 13) in order to introduce new O, N, S,
and C bonds.76a-c Generally, these reactions were conducted at high temperature using an ionizing solvent as the reaction
medium.

3.03.2.4 Functionalization of Aromatic Walls

Less investigated has been the chemical modification of the aromatic “walls” of the calix cavity, which would give rise to
nonaromatic hosts with different supramolecular properties. This modification includes the hydrogenation 76d of the aromatic
ring to cyclohexane-based rings or their oxidation to quinone78 and dienone,76e which are amenable of further elaboration.
Another approach79 is related to the base-promoted direct addition of O2 to the calixarene phenol rings to obtain epoxy-
p-quinol and diepoxy-p-quinol derivatives 56. This kind of functionalization allows the introduction of oxygenated groups
in the calix walls giving polar derivatives with new supramolecular properties (Fig. 14). Calix[4]quinone 57 was synthesized
in 198980 through a multistep synthesis, while the direct oxidation of calix[4]arene to 57 was obtained with ClO2.81 In addi-
tion, the calixquinone derivatives can be obtained by treatment of partially etherified calixarene macrocycle with
Tl(CF3COO)3.81

Scheme 8 “Fragment condensation” method for bridge-substituted calixarenes.

 Calixarenes 63

Figure 13 Functionalization of methylene bridges.

Figure 14 Functionalization of the calixarene aromatic walls.

3.03.3 Supramolecular Applications of Calixarene Macrocycles

3.03.3.1 Biomolecular Recognition
In the past two decades, a special interest has been devoted to biomolecular recognition by calixarenes with more emphasis to drug-
gable biomolecular targets. 82 In a pioneering work, Hamilton and coworkers screened a library of peptidocalixarenes identifying
a compound (GFB-111) able to bind to PDGF growth factor and resulting in a significant inhibition of tumor growth and angio-
genesis in vivo.82b In particular, GFB-111 (Fig. 15) contains four identical peptide loops, with negative and hydrophobic residues
GDGY, which are complementary to the PDGF surface.
Interestingly, the studies of Hamilton and coworkers 82b showed the lack of toxicity of the calixarene framework in several in vivo
biological tests. Analogously, Liu83 reported that the mortality rate in mice poisoned with viologen derivatives was significantly
decreased when p-sulfonatocalix[n]arenes were dispensed, showing once again the nontoxicity of the calixarene skeleton. Interest-
ingly, inhibitors of transglutaminase enzymes by surface recognition were identified by screening a library of peptidocalix[4]arene
diversomers.84
In addition to the experimental library screening, a second strategy to identify bioactive calixarenes was based on molecular
docking. Thus, de Mendoza 85 reported a computer-assisted design of a tetramethylguanidinium calix[4]arene derivative, which
was able to recognize the tetrameric protein p53TD–R337H mutant. The design by molecular docking screening allowed the iden-
tification of some arylamidocalix[4]arenes as effective histone deacetylase inhibitors.86
In a third radically different strategy, very recently, an Mass-Spectrometry-based chemoproteomic 87 fishing approach has been
explored for the identification of possible biomolecular targets for a given, potentially active, calixarene derivative. In detail, this
procedure (Fig. 16) consists in the chemical immobilization of the chosen calixarene derivative on a solid support, its incubation
with cell lysates, and finally MS identification of its interactors and evaluation of its bioactivity by in vitro and in cell assays.
64 Calixarenes

Figure 15 Derivative GFB-111, able to bind to platelet-derived growth factor (PDGF).

Figure 16 Fishing for biomolecular partners of a p-acetamidocalixarene by MS-based chemical proteomics.

 Calixarenes 65

Figure 17 Guanidino-calix[4]arene 59, used as nonviral vector for gene delivery, and calix[4]arene 60, bearing pyrenyl groups at the exo rim, used
as DNA-intercalating agent.

Following this approach, it was demonstrated that p-acetamidocalix[4]arene 58 is able to recognize and inhibit protein disulfide
isomerase, which is an interesting druggable target.87
Interesting studies by Cunsolo and coworkers 88 showed that polycationic calix[8]arenes were able to recognize and neutralize
heparin. Calix[4]arenes bearing guanidino groups (e.g., 59) (Fig. 17) have shown interesting properties as nonviral vectors for gene
delivery (cell transfection).89 Regarding the recognition of nucleic acids, dimers of ammonium-calix[4]arene derivatives were able to
bind DNA by the major groove.90 Recently, calix[4]arene bearing polycyclic aromatic hydrocarbons at their exo rims have been
synthesized as DNA-intercalating agents, and their in vitro cytotoxic activities were evaluated. The most potent one, 60, reached
an IC50 of 95 nM toward the follicular thyroid carcinoma. Docking and circular dichroism studies evidenced the intercalating abil-
ities of 60 from the DNA minor groove.91
Glycocalixarenes 92 bearing mannose units anchored to gold nanoparticles93 have shown improved abilities in targeting cancer
cells compared with those of nanoparticles bearing a monovalent mannosylated derivative.

3.03.3.2 Cation Recognition and Sensing

The recognition of cationic guests by calixarene derivatives was very likely their first supramolecular application. 1 In a pioneering
work of 1986, Ungaro and coworkers77 showed that cone-shaped calix[4]arene tetraester 61b (Fig. 18) displays a high Naþ affinity
and selectivity. Successively, 61b was used to build the first Naþ-selective sensor.
A prominent position in cation recognition is occupied by calixarenes bridged with crown ether moieties (calixcrowns). A beauti-
ful example is given by 1,3-alternate calix[4]crown-6 24, which is a cesium-selective ionophore. 45 This Csþ selectivity has been
exploited for the treatment of nuclear wastes.94 Interestingly, by changing the length of the bridge, the selectivity of calix[4]crowns
can be shifted toward different cations (crown-5/Kþ and crown-4/Naþ).95
Very recently, Kim and coworkers 96 have reported a prototype of a light-driven molecular shuttle based on calixcrown 62
(Fig. 19) bearing two photoactive crown moieties. Derivative 62 was able to complex Kþ and to translocate it between the two
crown sites upon photoexcitation.
Interesting studies have been conducted by Rao and coworkers 97 on the abilities of calixarene 63, anchored on a gold surface, to
recognize metal cationic guests. By different techniques, such as grazing incidence FT-IR, contact angle measurement, cyclic

Figure 18 Calix[4]arene-tetraesters 61a,b.

66 Calixarenes

Figure 19 Calixcrown-based, light-driven molecular shuttle 62 and on-gold-anchored calixarene 63 able to sense cationic guests.

voltammetry, and scanning tunneling microscopy, the authors showed a Cu2 þ selectivity of the system with respect to other tran-
sition metals, such as Mnþ 2, Feþ 3, Znþ 2, Niþ 2, and Coþ 2. Interestingly, no selectivity was evidenced in solution. Calixarene deriv-
atives bearing carbamoylmethylphosphine oxide (cmpo) functioning at the exo or endo rim were able to complex lanthanides and
actinides.94 Thus, cmpo-like calix[6,8]arene derivatives 64 (Fig. 20) were used to extract actinides and lanthanides from radioactive
wastes.98

3.03.3.3 Anion Recognition and Sensing

The synthetic versatility of calixarene macrocycles permits the introduction of appropriate functional groups to create a suitable
complementarity to anionic guests. 99 Moreover, the interest toward anion recognition has steadily grown in recent years due to
the important role that anionic species play in environmental and biological fields.100 Consequently, a plethora of calixarene hosts
for anion recognition have been reported in the last two decades. In particular, electroneutral calixarene derivatives have been inten-
sively investigated thanks to their ability to recognize anions over a large interval of pH. Thus, numerous examples of calixarene
macrocycle bearing amide101 or urea/thiourea102 groups at the exo or endo rim have been reported, which showed interesting recog-
nition abilities toward anionic guests. Recently,103 calix[6]arene 65 (Fig. 21) bearing thiourea groups at the endo rim was able to
recognize selectively F on nineteen anions. VT 1H NMR studies and DFT calculations evidenced that 65 adopts a flattened-cone
conformation in the F@65 complex.103 Calix[4]arene–porphyrin conjugates 66 bearing ureido functions at the exo rim have
been reported,104 which exhibited pronounced complexation ability toward halides and nitrates.
Aramidocalix[4]arene 67 bearing amide groups at the exo rim showed a strong selectivity toward trigonal planar anions (nitrate
and benzoate) with respect to spherical and tetrahedral ones. 105 Spherical anions induce the dimerization of p-squaramidocalix[4]
arene 68106 thanks to H-bonding interactions between squaramide NH protons and the anion (Fig. 22).
 Calixarenes 67

Figure 20 Cmpo-like calix[n]arene derivatives 64 able to extract actinides and lanthanides from radioactive wastes.

Figure 21 Calixarenes 65-67 as typical neutral receptors for anions.

Figure 22 Self-assembly of p-squaramidocalix[4]arene 68 induced by spherical anions [ 106].

68 Calixarenes

Figure 23 Calix[6]arene funnel complex 69 108 and artificial calixarene-based ribonuclease 70.109

3.03.3.4 Catalysis
The use of calixarenes as catalysts and enzyme mimics was foreseen by Gutsche in his early papers. 107 In this regard, numerous
studies have been conducted on metallocalixarene systems as biomimetics of metalloenzymes. In particular, Reinaud and
coworkers have reported calix[6]arene-based ligands in which the metallic site was inside the calix cavity to give a calix-funnel archi-
tecture 69 (Fig. 23), which was able to mimic the active site of a metalloenzyme such as the galactose oxidase.108 Casnati et al. repor-
ted109a calix[4]arene 70 bearing at the exo rim a guanidinium and a Cu(II) ion ligated to a 1,4,7-triazacyclononane. This complex
was able to catalyze the cleavage of phosphodiester bonds. Ribonuclease mimics were also shown by a guanidino-calixarene that, in
the absence of metal ions, gave the cleavage of phosphodiester bonds through a general acid–base catalysis.109b
Recently, a calix[8]arene skeleton was used as a flexible ligand for a Ti(IV) cluster active in the ring opening polymerization of
lactide. 110 Several calix[4]arene/Ti(IV) complexes have been used in the catalysis of aldol reaction between Chan’s silyloxydiene
and a range of aldehydes (Scheme 9).111 Its extension to asymmetrical aldol reaction using chiral calix[4]arenes gave interesting
results.111c Recently, a polyoxomolybdate-calix[4]arene (POM) hybrid material112 has been applied as a heterogeneous catalyst
in the sulfoxidation of thioethers to sulfoxides and to sulfones.
Following the current trends in metal-free catalysis, the use of chiral calixarene derivatives as organocatalysts in asymmetrical
reactions has been particularly investigated. Very recently, Dumaz et al. reported a calix[4]arene functionalized at the endo rim
with chiral squaramide units as an effective organocatalyst in Michael reaction with enantiomeric excess up to 94%. 113

3.03.3.5 Threaded Architectures: Rotaxanes and Catenanes

Interpenetrated molecules, such as (pseudo)rotaxanes and catenanes, 114 have shown intriguing supramolecular properties as
molecular machines,115 sensors,116 and more recently catalysts.117
Rotaxanes 114 have been defined as interlocked supramolecular systems in which a linear molecular axle bearing two bulky
groups (stoppers) at the ends is threaded through a macrocyclic wheel. Differently, catenanes are interlocked architectures consti-
tuted by two or more interpenetrated macrocycles. Rotaxanes and catenanes are commonly synthesized through a template-directed
procedure114 exploiting the threading of a linear molecular axle through a macrocyclic wheel to give a pseudorotaxane architecture,
which is considered as the precursor of both rotaxanes and catenanes. Following this strategy, calixarene macrocycles have also been
exploited as the basic wheel undergoing threading with a complementary axle.118
The first example of through-the-annulus threading of a calixarene was reported by Arduini and coworkers who used viologen axles
(e.g., 75) ( Fig. 24) and triureidocalix[6]arene wheels (e.g., 74) to obtain pseudorotaxanes like 76.119 From these studies, viologen-
based calix-rotaxanes 79 (Fig. 25)119 and catenanes120 were subsequently obtained. In 2010, we reported the through-the-annulus
threading of conformationally mobile calix[6–7]arenes with dialkylammonium ions.121 It was shown that the threading of scarcely
preorganized calix[6,8]arene macrocycles was possible only if the cations were coupled with the weakly coordinating TFPB
anion.121

Scheme 9 Aldol reaction between the Chan’s silyloxydiene and aldehydes catalyzed by calix[n]arene/Ti(IV) complexes.
 Calixarenes 69

Figure 24 Calixarene-based pseudorotaxane architectures.

Exploiting this method, it was possible to introduce into the calix cavity primary, secondary, 122 and tertiary123 alkylammonium
cations. This approach was effective in the synthesis of calixarene-based interlocked architectures such as (pseudo)[2]rotaxanes (77)
(Fig. 25),124 (pseudo)[3]rotaxanes,125 [2]catenane (78),126 and [3]rotaxane.127
Recently, 128 the self-sorting capabilities of calix[6]arene threading have been also investigated. In particular, from a mixture of
different macrocycles and different bis-ammonium axles, the self-sorting of a specific pseudo[3]rotaxane was observed, even when
the structural differences were small and remotely located from the binding sites. Thus, the specific formation of hetero-pseudo[3]
rotaxane 80 (Fig. 26) was observed through an integrative self-sorting process in which two very similar calixarene macrocycles were
able to discriminate between alkylbenzyl and dibenzylammonium moieties along the axle. In addition, a stereochemical preference
for the head-to-tail stereo sequence of the two calixarenes was also observed.

3.03.3.6 Self-Assembly
In supramolecular chemistry, much emphasis has been given to the study of all those artificial processes able to mimic the biological
ones. Among them, the self-assembly phenomena of calixarene derivatives have attracted much interest. 129 Self-assembly130 is the
spontaneous and reversible aggregation of properly designed molecules to give complex and defined aggregates. Thanks to their
synthetic and conformational versatility, calixarene derivatives have been used to create beautiful self-assembled structures.

3.03.3.6.1 Self-Assembly in Solution

As one interesting example, Reinhoudt and coworkers 131 reported the self-assembly of calixarene derivative 81 (Fig. 27), bearing
melamine moieties at the exo rim, with barbiturates/isocyanurates to give boxlike architectures. The system was constituted by nine
molecular components, which were held together by 36 H bonds.
70 Calixarenes

Figure 25 Calixarene-based rotaxane and catenane architectures.

Figure 26 Integrative self-sorting of calixarene derivatives with a bis-ammonium axle: formation of a hetero-pseudo[3]rotaxane.

Another self-assembling system exploiting the strong directionality of H bonds was independently reported by Böhmer and
Rebek. 132 In particular, calix[4]arene tetraureas 82 (Fig. 28) are able to self-assemble by forming dimeric capsules sealed by
16 H bonds.

3.03.3.6.2 Self-Assembly in the Solid State

The growing interest toward nanoporous solid materials for the storage of small molecules has led many scientists to investigate the
solid-state self-assembly properties of calixarene macrocycles. 133 Thus, Atwood134 showed that in the solid state, p-H-calix[4]arene
24, upon sublimation in vacuo at 300 C, gives rise to crystals in which three calix molecules form a hexagonal close-packed (hcp)
lattice involving simple van der Waals interactions without intermolecular H bonds. The interstitial voids of  153 Å3 are able to
accommodate CCl4, CF3Br, C2F6, or CF4 with a remarkable thermal stability.
Differently, p-tert-butylcalix[4]arene 1a after sublimation forms a solid-state structure in which facing calixarene molecules give
rise to a bilayer-type arrangement with large voids of  235 Å3 able to absorb gases such as N2, O2, and CO2. 135
More recently, we have shown that 1,2-dimethoxy-p-tert-butylcalix[4]dihydroquinone 83 ( Fig. 29) forms a solid-state architec-
ture in which large cavities of about 900 Å3 are present.136 The nanoporous structure is able to capture CO2 at room temperature.137
 Calixarenes 71

Figure 27 Self-assembly of a calixarene double rosette. 131

Figure 28 Self-assembly of calix[4]tetraureas. 132

Figure 29 1,2-dimethoxy-p-tert-butylcalix[4]dihydroquinone 83 [ 137] and calix[4]tetrahydroquinone 84 [138] used for solid-state self-assembly.

Other calixarenes bearing hydroquinone moieties have shown intriguing self-assembly properties in the solid state thanks to their
ability to form H bonds between OH groups. Thus, calix[4]tetrahydroquinone 84 self-assembles in nanotubes138 able to capture
silver ions that have been reduced under photochemical irradiation to nanorods of silver neutral atoms.

3.03.4 Conclusions

Since the pioneering work of C. David Gutsche in the early 1970s, calixarene macrocycles have always attracted the attention of
supramolecular chemists. The large number of synthetic routes for the functionalization of these compounds has allowed the
72 Calixarenes

synthesis of a plethora of calixarene hosts, which have found numerous supramolecular applications ranging from molecular recog-
nition to self-assembly. To date, the continued and growing interest toward calixarene macrocycles is evidenced by the study of new
and alternative synthetic routes for their functionalization, new supramolecular applications such as biomolecular recognition,
organocatalysis, and interlocked architectures. All these aspects, here shortly reviewed, give an idea of the “(almost) unlimited possi-
bilities” of calixarene macrocycles, which will be surely expanded in the near future.

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 3.04 Inherently Chiral Resorcin[4]arenes
M Paletta, Miele & Cie. KG, Gütersloh, Germany
S Wiegmann, Bundeswehr Schule für ABC-Abwehr und Gesetzliche Schutzaufgaben, Sonthofen, Germany
H Berke and J Mattay, Bielefeld University, Bielefeld, Germany
Ó 2017 Elsevier Ltd. All rights reserved.

3.04.1 Introduction 75
3.04.2 Chiral Structures of Resorcin[4]arenes and Cavitands Based on Chiral Auxiliaries 75
3.04.3 Inherently Chiral Resorcin[4]arenes 78
3.04.4 New Results on Cavity-Extended Chiral Resorcinarenes 80
3.04.5 Concepts for Improving the Functionality of Chiral Resorcin[4]arenes 83
3.04.6 Applications (A Brief Outlook) 83
References 85

3.04.1 Introduction

In supramolecular chemistry non-covalent interactions control recognition processes between complementary binding sites of
substrates and receptors.1,2 Beside almost countless possibilities macrocycles and among them calixarenes provide defined struc-
tures with an inner cavity like a bowl and a specific arrangement of functional groups. Especially the class of resorcin[4]arenes
and cavitands offers a hollow space with adjustable flexibility and a wide range of functionality.3,4 These macrocycles were used
as hosts for encapsulating small guest molecules to form eg, host-guest complexes,5 anion complexes,6 and supramolecular assem-
blies.7,8 All these examples only deal with achiral structures. To differentiate between chiral substrates enantiomerically pure
receptor molecules are needed. In early days, for example, cyclodextrins were used as receptors easily accessible from the natural
chiral pool9 as well as chiral crown ethers which can easily be synthesized by standard procedures.10 To mention only one early
example a calixarene-based receptor with enantiodiscrimination properties was already reported by Kubo et al. in 1996.11
In this contribution we especially focus on the structural features and the synthesis of inherently chiral resorcin[4]arenes which,
from our point of view, offer a high potential as enantiodiscriminating artificial receptors. In special, we will discuss selected exam-
ples from the literature as well as some results from our own studies. We prefer to use the term “inherently chiral” rather than “cyclo-
chiral” since the latter term originally introduced by Prelog and Gerlach12 has some restrictions for application in calixarene
chemistry (for details see Chapter 3).

3.04.2 Chiral Structures of Resorcin[4]arenes and Cavitands Based on Chiral Auxiliaries

Resorcin[4]arenes are three-dimensional macrocycles that are used in various aspects of supramolecular chemistry, for example, as
building blocks and in molecular recognition2,5,13 as well as in chiral assemblies.7 In an acid catalyzed condensation reaction these
building blocks are generated from resorcinol and an aliphatic or aromatic aldehyde.3,4,14 The possible conformations of the tetra-
meric macrocycles are shown in Fig. 1, whereas the residues are arranged axially (Ra) or equatorially (Re).
The thermodynamically controlled reaction leads to products wherein the residues are all cis-oriented (c) to one reference moiety
(r), giving a (rccc)-configuration for the boat and the crown conformation (eg, Re ¼ H, Ra ¼ alkyl). In solution, these two conforma-
tions interconvert. There are few examples given for functionalizations introduced in the upper rim shown in Fig. 2A. In methylene
bridged cavitands the conformation is fixed (Fig. 2B) and the scaffold becomes very rigid. Both the resorcin[4]arenes and the cav-
itands generate a bowl-shaped cavity that can easily be functionalized as shown for some examples given in the next sections.
The resorcin[4]arene scaffold provides a platform for the attachment of various groups. In the following macromolecular
systems are presented from the vantage point of chirality. To turn achiral resorcin[4]arenes and cavitands into chiral entities, a chiral
moiety can be simply attached either to the hydroxyl groups or to the ortho position at the upper rim. Schurig et al. prepared an octa-
functionalized resorcin[4]arene 1 in 1999, that was immobilized on dimethylpolysiloxane.15 This material is suitable as stationary
phase in gas chromatography (Fig. 3A). A series of N(O,S)-TFA-(S,R)-amino acid methyl esters was successfully separated with enan-
tioselectivities indicating the degree of peak separation up to aS/R ¼ 1.10 for leucine derivatives.16
Sherman et al. presented a pyrogallol based cavitand 2 bearing four (S)-phenylalanine ethyl ester residues with a short linking
(Fig. 3B).17,18 This system was the precursor for a series of de novo synthetic proteins with C- and N-terminally linked peptides with
native-like properties, offering the design of artifcial proteins.19,20 A benzyl amine cavitand was used by Feigel et al. as the rigid basis
for the C-terminal attachment of dipeptides (Fig. 3C).21,22 The cavity of compound 3 encloses acetonitrile and forms a very stable
complex in chloroform solution.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12510-7 75

76 Inherently Chiral Resorcin[4]arenes

Figure 1 Conformations of resorcin[4]arenes.

Figure 2 (a) Scaffolds of the resorcin[4]arene and (b) the methylene-bridged cavitand.

Figure 3 (a) Resorcin[4]arenes with amino acid residues by Schurig. Peptidocavitands by (b) Sherman and (c) Feigel.
 Inherently Chiral Resorcin[4]arenes 77

Figure 4 (a) Cavitand with eight (S)-2-methylbutanamide residues and (b) unsymmetrically substituted cavitands.

Cavitands with phenyl ether bridges were prepared via nucleophilic aromatic substitution.23,24 The extended upper rim was
further functionalized with eight amide residues to give cavitand 4 (Fig. 4A). In crystal structure analysis the intramolecular
hydrogen bonding was shown to be of cycloenantiomeric character that switches between the two cycloenantiomers in solution.
Beside chiral substituents, chirality in cavitands 5 and 6 originates from an unsymmetrical substitution pattern at the upper rim
(Fig. 4B).25 The vaselike cavity encloses aromatic compounds as well as solvent molecules.
The known examples of peptidocalixarenes based on resorcin[4]arenes all have a very flexible linkage as there are benzylamine
functionalities21,22 or 2-phenoxyacetyl groups.15,17–20 The cavitands are more rigid than the resorcin[4]arenes with chiral moieties
at the upper rim that interconvert between the crown and the boat conformation. The most flexible systems are the methylated resorcin
[4]arenes with chiral lateral chains.26–31 In complexation experiments in the gas phase and theoretical studies, the upper rim cavity of
amido[4]resorcinarenes 7a–d (Fig. 5) was shown to be less important for the complexation behavior. In these systems the chiral
lateral chains take part in enantioselective interactions. The chiral distinction strongly depends on the orientation the flexible chains
adopt in the gas phase.32
A rigid structure of a resorcin[4]arene with phosphorus bridging units was built up by Pietraszkiewicz et al. (Fig. 6).33
The bridges are substituted with (S)-1-phenylethylamine forming a chiral environment inside the cavity. In water the

Figure 5 Chiral amido[4]resorcinarenes with different side chains that contain valine and leucine residues.
78 Inherently Chiral Resorcin[4]arenes

Figure 6 Phosphorus-bridged cavitand with (S)-1-phenylethanamine residues. Tryptophan (9) and valine (10) were investigated in aqueous
solution.

cavitands of 8 form Langmuir monolayers that discriminate the (S)- and the (R)-enantiomers of tryptophan (9) and
valine (10), respectively, at low pH values.

3.04.3 Inherently Chiral Resorcin[4]arenes

Two decades ago chiral 1,3-oxazine derivatives were already prepared from achiral resorcin[4]arenes via Mannich reaction with
(R)-and (S)-(1-phenylethyl)amine (Fig. 7A).34 These cavity extended diastereomers of macrocycle 11 form complexes with the
enantiomerically pure phenylethylamine guests 12 in chloroform, benzene, and THF.35 Titration experiments were performed
and monitored by differential UV/Vis spectroscopy. The association constants are different for each diastereomeric complex and
the difference gives the chiral discrimination as a ratio of the formation constants (ratio of 0.79 for phenylethylamine; K(þ)-
amine/K()-amine). The absolute configuration of the benzylamine moieties in 11 was known, but at that time the configuration of
the methylene bridges was not known and consequently the diastereomers of 11 were characterized by their optical rotation prop-
erties only. Rissanen et al. investigated the chiral discrimination properties of the similar compound 13 (Fig. 7B) towards chiral
ammonium salts by MS.36 The chiral ammonium salts 14 and 15 were investigated as quasi-racemate with one enantiomer isoto-
pically labeled. In Fig. 7B one of the investigated quasi-racemates is displayed. The low mass difference of the quasi-enantiomers
(3 amu) results in an insufficiently resolved isotope pattern. From analysis of the isotope pattern no significant difference in the
relative peak intensities of the charged, diastereomeric complexes were obtained due to discrimination effects.
Due to their curvature in most cases these macrocycles have been assigned “inherently chiral”. However, occasionally these
compounds have also been called “cyclochiral”. The first term was already introduced by Böhmer in 199437 and later used by

Figure 7 (a) 1,3-Oxazine derivative and a chiral guest investigated by Iwanek, (b) oxazines and quasi-enantiomers of ammonium guests studied by
Rissanen, (c) (S)-1-phenylethylamine of a benzylamine resorcinarene studied by Szumna.
 Inherently Chiral Resorcin[4]arenes 79

Mandolini and Schiaffino for various “curved” molecules in a more general sense.38 The second term was introduced by Prelog and
Gerlach originally for cyclopeptides.12 The crucial point is that cyclochiral cyclopeptides cannot interconvert simply by inversion
processes as it is possible for calixarenes by inversion of the curvature without breaking bonds.39 In this contribution we are using
the assignment “inherently chiral” rather than “cyclochiral” following Szumna’s discussion.
A stable chiral form of the benzylamine derivative 16 was observed by Szumna in the solid state as well as in solution (Fig. 7C).40
The chiral residues are arranged in an inherently chiral manner of C4 symmetry at the upper rim. The direction of the hydrogen bonds
results from the diastereomeric preference depending on the chiral moiety. For 17a and 17b (Fig. 8A) the diastereomeric excess was
determined by NMR spectroscopy as > 95% and for 17c and 17d as 72%. The split-Cotton effect between 275 and 325 nm arises
from the inherently chiral hydrogen bonding (Fig. 8B). The chiral residues exhibit a monosignate signal < 260 nm. Semiempirical
calculations (AM1) support the conformational stability based on hydrogen bonding. Recently switching of inherent chirality
driven by self-assembly was reported from the same group for this type of resorcin[4]arenes.40a Additionally, dynamic formation
of hybrid peptidic capsules by chiral self-sorting and self-assembly was published by Szumna and Rissanen.40b
Under acidic conditions, the tetrabenzoxazine diastereomers 11, 13, and 16 are labile. The oxazine moiety can be transferred
into the other C4 symmetric regioisomer. Hence, for complexation experiments with eg, chiral acids these systems are not suitable
due to epimerization. It should be noted that this process can be inhibited by methylation of the free phenol groups as shown by
Page and Heaney.41b
Turning back to the basic structure, the chirality of inherently chiral resorcin[4]arenes 18 originates from the topology of the
nonplanar structure (Fig. 9) although these macrocycles are prepared from achiral building blocks. The methylene bridges become
stereogenic centers due to the substitution pattern at the upper rim. In contrast to benzoxazines derivatives (eg, 11 and 13) these
scaffolds are stable towards acidic and basic conditions.
The tetrameric macrocycles 18a–e were synthesized in one step from 3-alkoxyphenols and an aldehyde or a corresponding
acetal under Lewis acid catalysis. This procedure was first applied in 2000 by the group of Mocerino42 and was improved
substantially by Heaney et al. 3 years later.41 By starting from the dimethyl acetals of the respective aldehyde even 3-
benzyloxy phenol was successfully reacted to the macrocycle 18e despite the high lability of the benzyl ether functionality
towards Lewis acids.
Following these reports, the absolute configuration of the C4-symmetric tetramethylresorcin[4]arene 19 (Fig. 10) with pendant
isobutyl groups was determined by X-ray crystallographic analysis of the separated diastereomers 20a and 20b containing four (S)-
(þ)-10-camphorsulfonyl esters as auxiliaries.43a,b The internal chirality reference revealed the configuration of the methylene
bridges. After hydrolysis, the ()-enantiomer of rccc-2,8,14,20-tetraisobutyl-6,12,18,24-tetra-O-methylresorcin[4]arene 19, shortly
denoted as tetramethoxyresorcin[4]arene, was shown to be of (M,R)-chirality and the (þ)-enantiomer of 19 (rccc-2,8,14,20-
tetraisobutyl-4,10,16,22-tetra-O-methylresorcin[4]arene) of (P,S)-chirality (Fig. 10). The assignment was confirmed by analysis
and alkaline hydrolysis of the tetra-(R)-()-10-camphorsulfonyl ester diastereomers. These results correct the assignment published
in earlier studies44 wherein the enantiomers were accidentally interchanged. Details of the P and M notification in relation to the
central chirality rules (Cahn-Ingold-Prelog) were discussed by Heaney et al.,43a,b Iwanek,35b McIldowie,38b and Szumna.39
Up to date, only few cavity extended resorcinarenes built up from the inherently chiral scaffold are known. For example, Odgen
et al. presented the racemic pyridine-functionalized inherently chiral resorcin[4]arene 21 (Fig. 11A) which forms diastereomeric
complexes with (S)-(þ)-10-camphorsulfonic acid in chloroform.45 In NMR studies significantly shifted resonances for both the pyr-
idyl moiety and the chiral guest were observed upon complexation. However, the resolution of these racemic macrocycles by forma-
tion and crystallization of a diastereomeric salt was not successful. The resolution of the precursor resorcin[4]arenes with covalently
attached auxiliaries as described in the previous section and a subsequent reaction to the pyridyl resorcinarenes was not carried out
so far.
The O-alkylated resorcin[4]arenes46 were used by Rissanen as a platform to build up Fréchet-type dendrimers.47 In Fig. 11B the
dendrimer 22 of generation 1 is shown. The macromolecular compounds were synthesized up to generation 3 with the purpose to
generate a chiral core. Until now, the enantiomers of the dendrimer compound 22 have not been resolved.

Figure 8 CD spectra of C4 symmetric oxazine resorcin[4]arenes 17a–d in CHCl3.

80 Inherently Chiral Resorcin[4]arenes

Figure 9 Synthesis of the inherently chiral resorcin[4]arenes from 3-alkoxyphenols and an aldehyde or a corresponding acetal under Lewis acid
catalysis.

Figure 10 The assignment according to the absolute configuration of tetramethoxyresorcin[4]arene 19. The alkaline hydrolysis of 20a and 20b
gives (M,R)-()-19 and (P,S)-(þ)-19, respectively.

3.04.4 New Results on Cavity-Extended Chiral Resorcinarenes

More than one decade ago host-guest complexation experiments with chiral ammonium ions showed some effect of chiral discrim-
ination.48 For the purpose of complex formation with a larger variety of guest molecules resorcin[4]arenes with extended cavities are
of great interest.
A very convenient one-step procedure to synthesize cavity-enlarged chiral 1,3-oxazine derivates was already reported by us two
decades ago.34 However, although enantiomerically pure, these compounds suffer from instability under protic conditions. In the
following a new method is presented to enlarge the cavity of simple resorcin[4]arenes using Pd-catalyzed intramolecular C-C-cross
coupling reactions in order to get more stable macrocycles of this type.49 The four phenolic hydroxy groups of the enantiomerically
pure tetramethoxyresorcin[4]arene 23 provide the advantage of introducing an aryl halide component as ether 24 for a subsequent
intramolecular C-C-cross-coupling reaction (Fig. 12).50,51 It should be noted that in this case no further activation of the aryl posi-
tion at the upper rim of the resorcin[4]arene is required which is otherwise necessary for intermolecular cross-coupling reactions. To
 Inherently Chiral Resorcin[4]arenes 81

Figure 11 (a) Racemic, inherently chiral resorcin[4]arene with pyridyl residues and (b) a Fréchet-type dendrimer of generation 1 based on
a resorcin[4]arene scaffold.

Figure 12 Synthesis of the tetrakis-(20 -bromobenzyl)ether 24 and the cyclic tetrabiaryl ether 25. (a) (i) NaH, DMF, (ii) 2-bromobenzyl bromide,
92%; (b) Pd(OAc)2, PCy3$HBF4, K2CO3, DMA, 130 C, 20 h, 18%.
82 Inherently Chiral Resorcin[4]arenes

Figure 13 Synthesis of bora-oxazino-oxazolidine derivatives of resorcin[4]arenes 28: (i) L-prolinol, formaldehyde, MeOH, rt, 24 h; (ii) PhB(OH)2,
toluene, reflux, 4 h, 65%.

our knowledge intramolecular arylation reactions generating four carbon-carbon bonds in one step have not been reported in the
literature so far. Details of this intramolecular arylation process are reported elsewhere by one of us.52
Crystal structural analysis and circular-dichroism studies of the enantiomers as well as time-dependent Pariser-Parr-Pople
(TDPPP) calculations gave further insight to the structures of these compounds.49 The CD spectra of (M,R)-()-26 and (P,S)-
(þ)-26 are mirror images showing their enantiomeric nature. On the basis of the X-ray data, the spectra were simulated by TDPPP
calculations and reproduced the experimental data in a very good manner.
Unfortunately, attempts to extend this procedure to further functionalized chiral resorcin[4]arenes, eg, with ester functionalities,
failed so far.52
Although the first C4-symmetrical 1,3-oxazine derivates are easily accessible34 these compounds suffer from instability in protic
solvents due to epimerization by reversible ring opening and closure of the oxazine ring.53 One possibility to prevent from this
process is protecting the free phenolic groups, eg, by alkylation.54 Another way was developed by Iwanek by stabilizing analogous
boron heterocyclic rings through intramolecular acid-base adduct formation (28 in Fig. 13).55
Nissinen and Rissanen reported on Fréchet-type tetramethylated resorcin[4]arene dendrimers, which to some extend also
provide an extended cavity, however, without stiffness due to their strong flexibility.56a This also applies to resorcin[4]arene-
crownethers, eg, reported by Nissinen.56b
Cavitands with an extended cavity are known for a long time due to Rebek’s pioneering studies d see eg, 29.57a Recently the
same group developed a procedure to synthesize deep cavitands bearing eight chiral centers on their upper rim (Fig. 14).57b The
asymmetric nature of the cavity of 30a and 30b was examined by binding experiments with achiral guests. In the 1H-NMR spectra
of the nonchiral (control) cavitand 30c in the presence of 3-caprolactam all the equivalent protons of the bound guest were isochro-
nous whereas the signals bound to cavitand 30a were non-equivalent indicating a chiral magnetic environment. Similar behavior

Figure 14 Synthesis of chiral cavitands 30a and 30b (non-chiral: 30c).

 Inherently Chiral Resorcin[4]arenes 83

was observed with other achiral guests such as norbornene or quinuclidine. In addition, the chiral steric environment shows modest
enantioselectivity (55% de) for chiral guests such as pinane diols bound inside the cavitand.

3.04.5 Concepts for Improving the Functionality of Chiral Resorcin[4]arenes

In the beginning the synthesis of chiral resorcin[4]arenes with further functionalities remained somewhat limited due to less reac-
tivity of the methoxy group (see eg, 23). The facile access to the basic chiral scaffold42 allowed the resorcin[4]arenes to expand their
complexing properties in host guest interaction by a variety of further functionalizations. For this purpose there are three reactive
sites at the upper rim of the resorcin[4]arenes available (Fig. 15).
For example the ortho position (II) can be used in Mannich reactions with different building blocks as already discussed in detail
(see Chapter 4 and eg, Ref. [34]). Position I can be activated to the basic phenol group (33) by a new method recently reported by us
using the demethylating reagent 9-I-9-BBN (Fig. 16).58
Finally, the original phenol group (III) can be converted using various alkylating agents.59 For example, a new strategy reported
by Heaney et al. involves the introduction of a triflate (trifluoromethanesulfonate) group at this position (34 / 35) and their use in
Pd-catalyzed Buchwald-Hartwig aminations leading to aminoalkoxyresorcin[4]arenes 36 (Fig. 17).60
Triflates are also known for their use in cyanation reactions.61 We have applied this method for the synthesis of nitrile-
substituted resorcin[4]arenes 38 and a wide range of further functionalizations at this new reactive group at the upper rim
such as ketones 39, aldehydes 40, amides 41, and amines 42 and in further reaction tertiary alcohols 44 (Fig. 18).62 The
reactivity of these compounds can further be increased by demethylation of the methoxy group as shown for ketone 39
(under formation of 43). The new functional groups like amine, aldehyde or alcohol are promising starting points themselves
for functionalization and extending the cavity of the resorcin[4]arenes to increase the host guest interactions.
The derivatizations of the inherently chiral aminomethyl-resorcin[4]arene 42 to the macrocycles with urea and amide side chains
at the upper rim (45–47) allows not only to expand the host cavity, but also to introduce the multiple recognition sites to the
periphery of the host molecule (Fig. 19).63 This host design secures a multiple interaction motif composed of a hydrophobic cavity
surrounded by the aromatic rings in the core and multiple recognition sites in the periphery. Indeed, a preliminary chiral recogni-
tion experiment revealed that one of the urea-incorporated resorcin[4]arenes can discriminate the enantiomers of hexahydroman-
delic acid with an R/S-selectivity of 2.1.

3.04.6 Applications (A Brief Outlook)

In molecular recognition processes, specific interactions between a substrate and a receptor are responsible for the strength of
the binding and the discrimination of different substrates. The steric fit and complementary arranged binding sites are based on
the spatial arrangement of the functional groups. As discussed in the above-mentioned chapters especially resorcin[4]arenes
and cavitands offer a hollow space with adjustable flexibility and a wide range of functionality. Although we have focused

Figure 15 Reactive positions at the inherently chiral resorcin[4]arene scaffold.

Figure 16 Activation of chiral resorcin[4]arenes by demethylation of the phenolic methoxy group.

84 Inherently Chiral Resorcin[4]arenes

Figure 17 Synthesis of aminoalkoxyresorcin[4]arenes from tetrakistriflates.

Figure 18 Synthetic pathways of the nitrile-substituted resorcin[4]arene 38. (a) Zn(CN)2, Pd(PPh3)4, LiCl, DMF, 130 C, 7 days, 99%. (b) first MeLi,
THF, 78 C d r.t., 18 h, then TFA, THF/H2O, reflux, 2.5 h, 60%. (c) DIBAL-H, THF, 0 C d r.t., 2 days, 49%. (d) KOH, EtOH/H2O, reflux, 6 days,
41%. (e) LiAlH4, Et2O, r.t., 18 h, 41%. (f) 9-iodo-9-BBN, CH2Cl2, r.t., 20 min, 50% (g) MeLi, THF, 78 C d r.t., 5 days, 28%.

on the structural features and the synthesis of inherently chiral resorcin[4]arenes we will briefly mention some important
applications.
One of the very early applications for analytic chemistry is related to chromatography. As an example the extensive work of the
Schurig group is mentioned.16,64 Other analytical techniques have been used as well such as mass spectrometry,5,65 NMR,66 and
fluorescence spectroscopy using a chiral boronic acid based resorcinarene macrocycle for the enantiomeric discrimination of amino
acids.67
Due to their great variability, in future, more interesting applications in catalysis will be envisaged. Pioneering examples were
reported by Heaney for resorcin[4]arenes68 as well as Lüning69 and Rebek70 for calixarenes.
 Inherently Chiral Resorcin[4]arenes 85

Figure 19 Reactions starting from the aminomethylated resorcin[4]arene 42. (a) R-NCO, CH2Cl2, r.t., 1 day, 89–27%. (b) R-COCl, Et3N, CHCl3, r.t.,
1 day, 83–71%. (c) (S)-()-1-phenylethyl isocyanate, CH2Cl2, r.t., 1 day, 33% and 31%.

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 3.05 Cavitands
R Pinalli, A Pedrini, and E Dalcanale, University of Parma, Parma, Italy
Ó 2017 Elsevier Ltd. All rights reserved.

3.05.1 Introduction 87
3.05.2 Gas-Phase Preconcentrators and Sensors 88
3.05.2.1 Preconcentrators 88
3.05.2.2 Gas Sensors 91
3.05.3 Liquid-Phase Sensors 94
3.05.3.1 Detection of Sarcosine in Urine 94
3.05.3.1.1 The Conductimetric Sensor 94
3.05.3.1.2 The Electroluminescent Sensor 96
3.05.3.2 Detection of Drugs in Water 97
3.05.3.3 Detection of Acetylcholine in Water 98
3.05.4 Molecular Grippers 99
3.05.5 Supramolecular Catalysts 101
3.05.6 Supramolecular Polymers 104
3.05.6.1 Polymer Blending 108
3.05.7 Membrane Functionalization for Protein Recognition and Polymer Growth 109
3.05.8 Conclusions and Outlook 113
References 113

3.05.1 Introduction

Cavitands are the brainchild of Don Cram, one of the founders of supramolecular chemistry. He envisioned a completely new
class of organic molecules presenting rigidly preorganized concave surfaces. 1 In his vision, cavitands were programmable abiotic
receptors, capable of mimicking the molecular recognition properties of enzymes and widening at the same time the roster of
candidate guests to nonbiological targets.2 He based his design on the principles of complementarity to impart structural recog-
nition and preorganization to provide binding power. To transform his vision into a molecular reality, he selected resorcinarenes3
as the most versatile scaffold to work with. Like calixarenes, resorcinarenes can be functionalized both at the upper and lower rims
(Fig. 1). The unique feature of resorcinarenes as molecular platform is the presence of four pairs of proximal phenolic OHs at the
upper rim, which can be “bridged” using appropriate bifunctional reactants. The choice of the bridging units is fundamental to
define shapes and dimensions of the concave surface, to modulate the degree of conformational rigidity of the resulting cavitand,
and to introduce convergent binding groups. The selective binding of a guest by a cavitand receptor to form a complex requires,
beside shape complementarity, the presence of specific weak interactions such as hydrogen bonding,4 p–p stacking,5 CH–p,6 and
cation–p.7 The lower rim functionalization of resorcinarenes and cavitands has been mostly used to impart solubility in a broad
range of solvents, spanning from apolar organic solvents to water. Alternatively, the lower rim functionalization was employed for
surface grafting, copolymerization, and for the assembly of ditopic/multitopic receptors connected either via covalent linkers of
via coordinative bonds.
Following the basic rules delineated earlier, the chemical ingenuity of the active researchers in the field has led to the synthesis of
a large variety of cavitands, to the point that the original dream of Cram of a truly programmable class of abiotic receptors is nowa-
days largely realized. The focus has therefore shifted to the function side, designing the cavitand structure according to the desired

Figure 1 Molecular sketch of a generic resorcinarene-based cavitand. X, bridging groups; R1, upper rim substituents; R, lower rim substituents.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12512-0 87

88 Cavitands

property. This paradigmatic shift has led to totally new, unprecedented approaches to the preparation, organization, and use of cav-
itands, widening at the same time the pool of potential users.
According to this emerging scenario, we believe that time is ripe for reviewing the cavitand chemistry with this new mindset. In
this chapter, we discuss some examples where the molecular recognition properties of cavitands have been adapted to fulfill specific
requirements, from analytical applications to materials science. These examples are by far not exhaustive, but sufficiently indicative
to highlight the appeal of cavitands as modular receptors.

3.05.2 Gas-Phase Preconcentrators and Sensors

The key issue for this application is mastering molecular recognition at the gas–solid interface, where solvation is absent. This is not
a trivial task, due to the competing presence of nonspecific dispersion interactions in the solid layer, which very often override the
specific ones. In the liquid phase, nonspecific dispersion interactions mainly cancel out upon complexation, due to concomitant
solvent release in the bulk. The situation is totally different at the gas–solid interface. Any given analyte, upon moving from the
vapor to the solid phase, experiences a dramatic increase in nonspecific dispersion interactions, which tend to override any specific
complexation event responsible for the selective responses. Upon entering the solid layer, the analyte can position itself not only
into the cavity but also between the host structures, having a higher probability in the last case in the absence of energetically favor-
able interactions. The extra- versus intracavity positioning of the guest is often exacerbated by the presence of long alkyl chains in
peripheral positions of the receptors, necessary to improve solid layer permeability. The main structural requirement to minimize
nonspecific physisorption is therefore the presence of a preorganized noncollapsible cavity. This preorganized free volume in the
solid provides an energetically favorable site, since it eliminates the necessity to generate a void in the lattice for the incoming ana-
lyte. The second structural requirement is the presence of multiple, synergistic weak interactions at the cavity site to impart selectivity
toward the desired analytes. This can be obtained by positioning appropriate functional group in the correct arrangement to match
the complementary ones of the analyte. Finally, the selection of the transduction mechanism is crucial: ideally it should be turned
on exclusively by the desired complexation mode with the analyte. The following examples will highlight how the combination of
these approaches led to highly selective supramolecular sensors for organic vapors.

3.05.2.1 Preconcentrators
The achievement at the same time of molecular-level selectivity and ppb sensitivity requires an innovative approach that departs
from the usual design of sensor devices. The exploitation of molecular receptors as preconcentration materials is particularly attrac-
tive to address the selectivity issue, while the sensitivity issue can be solved using a suitable detection mode. By a molecular-level
understanding of the receptor–analyte interactions at the gas–solid interface, selective receptors can be rationally designed as a func-
tion of the analytes to be detected and the interfering agents to be excluded.
The use of selective preconcentrators has been successfully exploited by Dalcanale et al. for the detection of BTEX (benzene,
toluene, ethylbenzene, xylenes) in air8–11 and nitroaromatic explosives, both in air and in soil. 12 The methodology proposed relies
on the disconnection of the recognition event from the detection mode, by assigning the former to specific molecular receptors
capable of selectively trapping organic vapors at the gas–solid interface and release them afterward to the detector upon thermal
stimuli. In 2007,8 they reported an innovative approach to sub-ppb level benzene detection in air. A miniaturized system was
proposed, composed of a selective supramolecular concentration unit, a Si-micromachined GC column and a Si-integrated Metal
Oxide (MOX) sensor. The recognition event was assigned to a quinoxaline cavitand receptor (QxCav), capable of selectively trap-
ping aromatic vapors at the gas–solid interface, acting as preconcentrator unit. QxCav is well-known to bind aromatic guests both in
solution and in the gas phase.13,14 The noncovalent CH–p and p–p interactions established between the receptor and the included
aromatic compound constitute the main driving forces responsible for the formation of inclusion complexes.15 QxCav completely
engulfs aromatic guests while the most relevant interferents, namely aliphatic compounds and water vapor, are not retained. The
selective concentration component was interfaced to a miniaturized Si GC column, necessary for the separation of the different
aromatic compounds released by the trapping unit by thermal desorption, which are then individually channeled to the MOX
detector, constituted by an array of four metal oxide gas sensor arrays. With this setup it was possible to achieve a detection limit
for benzene of 0.1 ppb. This compact, low consumption device was also successfully tested on the field and it is now commercially
available.
Owing to its simplicity and low cost, solid-phase microextraction (SPME) 16 is an attractive alternative to most of the conven-
tional sampling technologies. Recently, a novel SPME coating based on a conformationally rigid cavitand receptor characterized by
four methylenoxy connecting units among the quinoxaline bridges was presented (Fig. 2).10 With respect to the reported class of
QxCav used for benzene detection, in this study the authors introduced a novel cavitand, the MeQxBox (1), designed to achieve the
highest selectivity and sensitivity for benzene detection. Cavitand 1 presents a blocked conformational mobility with respect to the
QxCav, with a dual scope: (i) gain sensitivity by strengthening the host–guest interactions through cavity rigidification and (ii)
improve selectivity by reducing the cavity opening at the upper rim to hamper the uptake of the bulkier substituted aromatics
(mainly toluene and xylenes).
1, which presents excellent thermal stability, was used as selective coating for SPME fibers. The BTEX enrichment properties of
these cavitand-coated fibers were tested by sampling an air mixture containing BTEX (385–473 ng m
3) and aliphatic hydrocarbons
 Cavitands 89

Figure 2 (A) Molecular structure of cavitand 1. (B) Crystal structure of benzene,1 complex crystallized from chloroform. The guest is shown in
space-filling mode. Adapted from Riboni, N.; Trzcinski, J. W.; Bianchi, F.; Massera, C.; Pinalli, R.; Sidisky, L.; Dalcanale, E.; Careri, M. Anal. Chim.
Acta 2016, 905, 79–84.

(38–56 mg m
3). Consecutive desorption experiments at different temperatures showed that aliphatic hydrocarbons are completely
desorbed between 50 C and 100 C, whereas BTEX desorption begins at 200 C and is exhaustive only at 250 C. These different
desorption temperatures were explained by the authors as a consequence of the different binding mode of the two classes of ana-
lytes: BTEX are complexed by 1 in the cavity, while aliphatic hydrocarbons are physisorbed by the organic coating. The enrichment
factors (EFs) were calculated for each analyte as the ratio of the concentration of the analyte in the fiber after the extraction to that of
the analyte in the gas-standard mixture. The EFs resulted to be: benzene (700  51  103), toluene (410  26  103), ethylbenzene
(550  45  103), m-xylene (360  30  103), p-xylene (570  35  103), and o-xylene (360  25  103). The highest EF calculated for
benzene proves that the reduction in the cavity opening by the methylenedioxy bridges facilitate the entrance of benzene with
respect to the other aromatic analytes. It was also demonstrated that the cavitand-coated fiber extracted up to 42 times as much
analytes compared to the commercial ones. In terms of sensitivity, excellent results with limit of detection (LOD) values at the
low ng m
3 level were achieved by using 1 for all the target aromatic analytes (BTEX).
As discussed earlier, the rational design of QxCav molecular structures offers the possibility to further improve both the sensi-
tivity and the selectivity of the preconcentrator. Diederich and coworkers 17,18 demonstrated that quinone-based cavitands function-
alized with bulky triptycene units at the upper rim are able to completely sterically encapsulate various guests in their closed “vase”
conformation, increasing association constants and reducing guest-exchange rates owing to steric congestion.19 Upon exposure to
air, the hydroquinones oxidize to quinones, promoting the switching process from the closed vase to the open “kite” conforma-
tion,20 which is not suitable for guest encapsulation within the shallow cavity. These materials, although interesting, have reduced
performance in oxygenated atmosphere.
In order to take advantage of the presence of bulky triptycene units at the upper rim of the cavitand, avoiding the oxidation draw-
backs presented by the Diederich’s cavitands, in 2016 Dalcanale and Swager exploited the ability of two novel triptycene quinoxa-
line cavitands for the supramolecular detection of BTEX in air. 11 In particular, they designed a new class of triptycene
tetraquinoxaline “roofed cavitands,” MonoTriptyQxCav (2, Fig. 3) and DiTriptyQxCav (3, Fig. 3) with one and two triptycene units,
respectively, at the upper rim.
The crystal structure of 2 showed that, despite the presence of a bulky triptycene group at the upper rim, the four quinoxaline
substituents are almost orthogonal to the mean plane defined by the eight oxygen atoms of the cavitand and the cavity assumes
a pseudo-fourfold-symmetric vase conformation ( Fig. 4A and B, top). In the case of 3, the presence of two encumbering triptycene
groups at the upper rim gives rise to large distortions in the structure of the receptor and the cavity assumes a pseudo-twofold-
symmetric vase conformation (Fig. 4A and B, bottom). The solid state studies of the complexes benzene,2 and benzene,3 high-
lighted that the benzene is well inserted in the cavity, forming specific p–p stacking interactions. In the benzene,3 complex, the two
triptycene substituents act as a “roof,” locking the entrapped benzene molecule inside the cavity, covering almost completely the
cavity (Fig. 4D, bottom).
The inclusion properties in the solid state of 2 and 3 were exploited using the receptor as coating for SPME fibers and tested
sampling BTEX at trace levels in air.
The extraction capabilities of both cavitand receptors were evaluated in terms of EFs. Cavitand 3 showed excellent enrichment
capabilities, with EF values up to nine times higher than those achieved by 2. The calculated EF for benzene was the highest of the
entire series of BTEX, and resulted to be 22 times higher with respect to the one obtained with commercial coating. Cavitand 2 and 3
coatings resulted to be highly selective versus BTEX with respect to aliphatic hydrocarbons. Aliphatic hydrocarbons were released at
90 Cavitands

Figure 3 (A) Molecular structure of MonoTriptyQxCav (2) and (B) DiTriptyQxCav (3). Adapted from Bertani, F.; Riboni, N.; Bianchi, F.; Brancatelli,
G.; Sterner, E. S.; Pinalli, R.; Geremia, S.; Swager, T. M.; Dalcanale, E. Chem. Eur. J. 2016, 22, 3312–3319.

Figure 4 Side views (A,B), top views (C), and space-filling models (D) of crystal structures of complexes benzene,2 (top) and benzene,3 (bottom).
The surface of the void volume available inside the cavity is represented in yellow. In all the structures, solvent molecules, lower rim chains, and
hydrogen atoms are omitted for clarity. Adapted from Bertani, F.; Riboni, N.; Bianchi, F.; Brancatelli, G.; Sterner, E. S.; Pinalli, R.; Geremia, S.;
Swager, T. M.; Dalcanale, E. Chem. Eur. J. 2016, 22, 3312–3319.

lower temperatures (up to 70 C) with respect to BTEX, which release temperature began at 200 C and was complete at 250 C. This
behavior is due to the much higher affinity of the aromatic hydrocarbons for the receptor cavity with respect to the aliphatic ones.
The aromatic molecules are inserted inside the cavity through synergistic p–p and CH–p interactions with the walls and the bottom
of the cavity, 21 while aliphatic hydrocarbons are only physisorbed in the solid layer. The capabilities of 3 as sorbent for the deter-
mination of BTEX in air at trace levels were proved by calculation of the LOD and limit of quantitation (LOQ) which resulted to be
at ng m
3 levels (Table 1), three times lower than those achieved by using 2 as sorbent.
Finally, to test the capability material as alternative to the commercial coatings for BTEX monitoring, an environmental air
sample taken at noon near a traffic fixed-site air monitoring station was analyzed using 3 as coating for the SPME-GC–MS analysis.
The BTEX concentration levels obtained were in the 1.1–5.4 mg m
3 range in agreement with the data provided by the nearby fixed-
site station.
The importance of the supramolecular analytical chemistry 22 as approach to solve complex analytical problems was demon-
strated by Careri and coworkers, developing a cavitand-based SPME for the detection of nitroaromatic explosive taggants in air
and contaminated soil.12 To this purpose, the authors synthesized a quinoxaline cavitand equipped at the upper rim with a carboxyl
group (4, Fig. 5) to enhance the selectivity of this receptors toward nitroaromatic volatile compounds. The presence of a carboxylic
group strengthened the multiple p–p and CH–p interactions, responsible for the aromatic inclusion within the cavity, adding
 Cavitands 91

Table 1 LOD and LOQ of the DiTriptyQxCav 3 obtained via the SPME-GC–MS method

LOD (ng m3) LOQ (ng m3)

Benzene 1.7 5.5

Toluene 3.1 10.0
Ethylbenzene 1.3 4.3
m-Xylene 2.0 6.6
p-Xylene 1.3 4.5
o-Xylene 2.2 7.3

Figure 5 Sketch of cavitand 4–6.

a synergistic H-bonding interaction with one NO2 group of the aromatic guest. The performances of the new receptor as selective
preconcentrator for the enrichment of nitroaromatic explosives and taggants were tested through both dynamic head space (DHS)
and SPME analysis, using the cavitand as adsorbent for DHS cartridge and coating for SPME fiber. The ability of 4 in sampling nitro-
aromatic volatile compounds at the trace levels in real world air and soil samples was compared toward: a commercial fiber
(TenaxÓ), a classical quinoxaline cavitand (5, Fig. 5) not functionalized at the upper rim with a carboxylic group, and a quinoxaline
cavitand with only three quinoxaline walls (6, Fig. 5).
Cavitand 4 showed the highest extraction efficiency with GC responses 20 times higher than those achieved using TenaxÓ as
commercial adsorbent, thus proving that the synergistic presence of p–p, CH–p, and H-bonding interactions is able to selectively
target nitroaromatic vapors. In the case of 6, the open cavity did not allow the complete engulfment of the analytes, thus reducing
the adsorption of the investigated compounds ( Fig. 6).
Through SPME experiments, the authors calculated the EFs, which resulted high for NB, 4-NT, 3-NT, 2-NT, and 3,4-DNT. Lower
values were obtained for TNT, 2,6- and 2,4-DNT, and toluene; this last one used as reference compound to assess the complexation
capabilities of the cavitand toward analytes lacking NO2 substituents. The low EF values calculated for TNT, 2,6- and 2,4-DNT are
ascribable to steric hindrance that affects cavity inclusion, while for toluene, the low EF is ascribable to the lack of one interaction,
the hydrogen bond between the COOH substituent at the upper rim of the receptor and the nitro group absent in the case of the
toluene.
LOD values in the low ppbv and ng kg
1 range, respectively, for air and soil samples were achieved for the selective sampling of
nitroaromatic explosives using the developed coatings. To verify the applicability of the developed method to real samples, two
debris samples collected on two different explosion scenes were analyzed. The developed method allowed us to assess the different
origin of the explosive present in the two blind samples. The absence of TNT and the high amount of di- and mono-nitrotoluenes
present in one sample indicated the use of a propelling charge, while the presence in the second sample of a high amount of TNT
and DNTs coupled to the detection of other compounds like paraffin proved the use of military explosive.

3.05.2.2 Gas Sensors

Moving from preconcentration to sensing requires the effective coupling of the receptor to a suitable transduction unit. Two
different approaches are highlighted as examples of different strategies. Ballester and coworkers 23 proposed the use of multiwall
carbon nanotubes (MWCNTs) functionalized with thioether-legged QxCav as conductimetric sensor for benzene in air. In the
92 Cavitands

Figure 6 DHS sampling of air containing a mixture of mononitroaromatic compounds each at 10 ppbv followed by GC–(SIM)–MS analysis. NB,
nitrobenzene; NT, nitrotoluene. Adapted from Bianchi, F.; Bedini, A.; Riboni, N.; Pinalli, R.; Gregori, A.; Sidisky, L.; Dalcanale, E.; Careri, M. Anal.
Chem. 2014, 86, 10646
10652.

device, the QxCav is self-assembled onto gold nanoparticles (Au-NP) which in turn are grafted on MWCNTs, previously treated with
oxygen plasma, and referred to as cav-Au-MWCNT (Fig. 7B).
The functionalization of carbon nanotubes (CNTs) with metal-NPs enhanced the sensitivity of the material for benzene sensing,
reaching an experimental detection of 2.5 ppb and a theoretical calculated LOD of about 600 ppt in dry air. The metal-NP-CNT
system acts as the transduction unit of the adsorption event in the resistive gas sensor, and the interaction of the material with mole-
cules of benzene in the gas phase results in an electronic charge-transfer process between the organic molecule and the metal-NP-
CNT nanomaterial. Cav-Au-MWCNTs were exposed to different pollutant vapors, like benzene, toluene, o-xylene, ethanol, and
carbon monoxide. The sensor responses showed significantly higher sensitivity to benzene than to the other tested pollutants,
and it resulted to be partially selective toward benzene. Moreover, even at very low benzene levels, the response of the sensor
was highly reproducible. Both the detection and the recovery of the baseline were performed at room temperature, which implies
that these sensors can operate at very low power consumption and that they can be integrated in hand-held portable analyzers and
wearable detectors. Two main drawbacks are highlighted by the authors: (i) the significant cross-sensitivity of the sensor to NO2, and
(ii) the response dependence to humidity, since the sensor response toward aromatic VOCs diminishes as the relative humidity in
the gas flow increases. The first one can be compensated combining the QxCav-Au-MWCNT sensor with a bare Au-MWCNT sensor,
since the latter is more responsive to NO2 and insensitive to benzene levels below 60 ppb. To avoid the effect of moisture, the
authors propose the dehumidification of the gas flow by employing an inexpensive filter.
A different approach has been undertaken for the selective detection of volatile alcohols. Mono, 24,25 di-,26 and tetraphospho-
nate27–29 cavitands were successfully used as molecular receptors for supramolecular sensing of short-chain alcohols at the gas–solid
interface using quartz crystal microbalances (QCMs) as transducers. A synergistic two-point interaction was identified in phospho-
nate cavitands for the complexation of short-chain alcohols, namely H-bond between the P]O and the alcoholic OH and CH–p
interactions between the methyl residue of the alcohol and the p-basic cavity of the receptor.24

Figure 7 (A) Energy-minimized (MM3 as implemented in Scigress v3.0) structure of a general quinoxaline cavitand in vase conformation. (B)
Sketch of the cav-Au-MWCNT material. The cavitand is presented as complex with benzene. Adapted from Clément, P.; Korom, S.; Struzzi, C.; Parra,
E. J.; Bittencourt, C.; Ballester, P.; Llobet, E. Adv. Funct. Mater. 2015, 25, 4011–4020.
 Cavitands 93

Figure 8 Mono phosphonate cavitands 7 and 8.

The well-defined spatial orientation of the P]O group with respect to the cavity determines the complexation properties of these
cavitands. The P]O group can be oriented inward the cavity (7, Fig. 8) or outward the cavity (8, Fig. 8). The synergistic two-point
interaction with an alcohol is possible only for the 7 cavitand, while in the 8 isomer the two interactions are disconnected. The
introduction of more inward-facing P]O groups does not change this pattern, but it only stabilizes entropically the complex by
increasing the number of energetically equivalent H-bonding options available to the alcohol.
The unavoidable presence of extra cavity physisorption in the solid layer coated on the mass sensors has detrimental effects on
the sensor selectivity, since being the transducer unselective, these adsorptions dilute or, even worse, override the specific ones due
to complexation. A suitable strategy to avoid these nonspecific interactions is to introduce a transduction mode activated exclusively
by the molecular recognition event.
Following this approach, Dalcanale and coworkers designed a monophosphonate cavitand bearing at the upper rim a fluoro-
phore directly connected to the P]O bridge ( Fig. 9).25 As fluorophore, a derivative of 2-anilinonaphthalene-6-sulfonic acid
(2,6-ANS) was chosen, because of the charge-transfer character of its excited state.
The measurements were made exposing 9/10-functionalized glass substrates, where PVC thin films containing 0.2% w/w of cav-
itands 9 and 10 were deposited, to different short alcohols vapors, under nitrogen atmosphere. Upon excitation at 350 nm, the 9
film showed an intense band emission with a maximum at 414 nm. In presence of C1–C4 alcohols this band was red-shifted and
intensity changes were comparable for the whole C1–C4 alcohol series with the exception of 1-butanol and 1-pentanol, which
caused lower responses. Under the same conditions, films of 10 showed negligible changes in the emission maximum, as expected
being the two interaction modes disconnected. The fluorescent responses nicely reflect the intrinsic molecular recognition properties
of phosphonate cavitands toward alcohols. The very low responses registered by exposing the 9 layer to high concentrations of
acetone, n-pentane, and n-heptane demonstrate the remarkable selectivity of the sensor. The authors also performed competition
experiments between ethanol and water, showing that in the presence of ethanol vapors, the low responses of the 9 layer to water are
totally suppressed.
These results demonstrate that it is possible to achieve molecular-level resolution in chemical vapor sensing by harnessing the
binding specificity of a cavitand receptor. The key requirement for transferring the molecular recognition properties from the solid
state to the gas–solid interface is the selection of the transduction mechanism, which must be turned on exclusively by the desired
complexation mode with the analyte.

Figure 9 Structure of the fluorescent phosphonate cavitands 9 and 10. Adapted from Maffei, F.; Betti, P.; Genovese, D.; Montalti, M.; Prodi, L.;
De Zorzi, R.; Geremia, S.; Dalcanale, E. Angew. Chem. Int. Ed. 2011, 50, 4654–4657.
94 Cavitands

3.05.3 Liquid-Phase Sensors

Molecular recognition at the solid–liquid interface is solvent dependent. Since most applications are in the environmental and
biomedical fields, the key requirement is selectivity in water and/or water-based physiological fluids. Therefore, the interacting
groups to be introduced on the cavitands must not only complement those of the analytes, but also be operative in water. From
the material side, monolayers on inorganic surfaces are preferred because they eliminate the requirement of water solubility for
the receptor and reduce nonspecific physisorption. Gold, silicon, and glass are the most used inorganic supports, dictating the
choice of the functionalities to be introduced on the cavitands feet. Self-assembled monolayers on gold have the advantage of being
highly ordered and the drawback of reduced stability over time. Monolayers covalently grafted on silicon and glass are less ordered,
but more robust. Silicon is a particularly attractive inorganic platform, as it offers the possibility to make robust and durable devices
by forming thermally and hydrolytically stable SieC bonds. In this section, we highlight three examples of sensing of biologically
relevant substances with cavitands using different transduction modes.

3.05.3.1 Detection of Sarcosine in Urine

Early stage detection of aggressive prostate cancer has been recently linked to the presence of sarcosine in urine. 30 The challenges of
detecting sarcosine in urine are twofold: (i) the presence of overwhelming amounts of glycine and other potential interferents such
as ammonium, sodium, potassium, magnesium, and calcium salts; (ii) operation in aqueous environment, where the H-bonding
between host and guest can be severely weakened.
Tetraphosphonate cavitands (Tiiii) 31 demonstrated remarkable molecular recognition properties toward N-methyl ammonium
salts both in liquid32–34 and in solid states.35,36 The origin of the receptor selectivity toward N-methyl ammonium salts is attributed
to the presence of three synergistic interaction modes: (i) Nþ/O]P cation–dipole interactions; (ii) cation–p interactions of the
acidic þNeCH3 group with the p basic cavity7; (iii) two simultaneous hydrogen bonds between two adjacent P]O bridges and
the two nitrogen protons (Fig. 10). Within the ammonium salt series, the bias toward the mono-methylated species over di-
and trimethylated ones is determined by the number of H-bonds formed with Tiiii, while nonmethylated ammonium ions are
less favored by the lack of cation–p interactions.36 This particular affinity of tetraphosphonate cavitands toward the H2NþeCH3
group makes this receptor a valuable candidate for the detection of a broad range of biologically active compounds containing
this residue, like synthetic drugs37,38 and biomarkers.39
A comprehensive study on the molecular recognition properties of Tiiii toward amino acids 40 revealed that, upon moving from
methanol to water, the complex formation changes from an enthalpy–entropy driven process to an enthalpy driven–entropy
opposed process. The thermodynamic profile of complex formation in water is typical of a nonclassical hydrophobic effect. The
entropy loss experienced in moving from methanol to water leads to a drop of three orders of magnitude in Ka (from 106 to
103M
1). However, this drop is associated with a dramatic increase in selectivity, since in aqueous solutions only N-methylated
amino acids are complexed, while pristine amino acids are not.

3.05.3.1.1 The Conductimetric Sensor

In 2012, Dalcanale and Swager reported one significant example concerning single-walled carbon nanotubes (SWCNTs) function-
alized with tetraphosphonate cavitand receptors for the binding of charged N-methyl ammonium species. 41 CNTs are a versatile
platform for sensor engineering, thanks to their electrical properties and quasi-one-dimensional structure.42 They are very sensitive
to a wide variety of chemical signals, but pristine CNTs lack selectivity.43,44 The authors attached covalently the tetraphosphonate
cavitands onto SWCNTs (Tiiii@SWCNTs) in order to couple the ability of tetraphosphonate cavitands in complexing small ammo-
nium salts in liquid phase together with the high sensitivity offered by CNTs. Firstly, to evaluate the molecular recognition capa-
bilities of Tiiii@SWCNTs, a dichloromethane suspension of the functionalized SWCNTs was exposed to 4-bromo-N-methyl

Figure 10 Crystal structure of the Tiiii@sarcosine hydrochloride showing the three synergistic interaction modes. Adapted from Biavardi, E.;
Tudisco, C.; Maffei, F.; Motta, A.; Massera, C.; Condorelli, G. G.; Dalcanale, E. Proc. Natl. Acad. Sci. 2012, 109, 2263–2268.
 Cavitands 95

Figure 11 (A) Reversible binding of 4-bromo-N-methylbutylammonium bromide guest 11; (B) XPS analysis of Tiiii@SWCNTs before exposure to 11
(blue), after exposure to 11 (red), and after subsequent washing with DBU (green). Si signals are due to the utilized Si substrate. Adapted from
Dionisio, M.; Schnorr, J. M.; Michaelis, V. K.; Griffin, R. G.; Swager, T. M.; Dalcanale, E. J. Am. Chem. Soc. 2012, 134, 6540–6543.

butyl ammonium bromide (11, Fig. 11), which binds as a guest. The Ka calculated for the complex between Tiiii and N-methyl butyl
ammonium bromide in methanol was  4  105M
1.36 The binding was confirmed via XPS as bromide shows an XPS diagnostic
signal (Fig. 11), and through 31P MS NMR, to further confirm that the guest binds directly to the cavitand on the CNTs.
The reversibility of the process was tested by washing the sample with 1,8-diazabicyclo[5.4.0]undec-7ene (DBU), since in
previous experiments it has been shown that DBU deprotonates the guest, thereby breaking the cavitand–guest complex. 45 31P
MAS NMR of the product after this washing step showed a spectrum similar to the pristine Tiiii@SWCNTs, confirming the successful
removal of the guest. The covalent functionalization of the cavitand onto the SWCNTs led to a Tiiii@SWCNTs-based device with
high stability and allowed for the formation of a robust liquid sensing device. As a proof of concept experiment, the authors demon-
strated the selective detection of sarcosine ethyl ester hydrochloride (guest 12), at concentrations as low as 0.02 mM. In aqueous
environments, Tiiii binds sarcosine over glycine with complete selectivity. To prepare the sensor, an aliquot of the reaction solution
of Tiiii@SWCNTs was drop casted onto a glass slide decorated with two Au electrodes. The obtained device was alternatively
exposed to Milli-Q water and an analyte solution (1–0.22 mM) at pH 5 to ensure protonation of the amine, while the current
through the CNT network (at Vapp ¼ 50 mV) was measured. As controls, the weaker binding glycine ethyl ester hydrochloride 13
and tetraethyl ammonium chloride 14, too bulky to be complexed,36 were chosen. Exposing the device to guest 12 at pH 5 resulted
in an increase in current, while exposure to guests 13 and 14 led to a current decrease (Fig. 12B and D). This change in the current
upon exposure to the analytes (positive in one case and opposite for the controls) allows selective detection of the analytes, regard-
less of their concentration.
The covalent functionalization resulted in a Tiiii@SWCNTs-based device that showed high stability, in fact no significant change
in sensitivity was observed over several months of regular operation, and sensitivity, as the detection limit for 12 was determined to
be 0.02 mM ( Fig. 12C). However, the device failed to detect exclusively sarcosine upon moving from water to urine. The inorganic
cations present in urine interact directly with the SWCNTs, leading to a current change which covers the sarcosine response.

Figure 12 Measurements at pH 5. (A) Tiiii@SWCNTs and pristine SWCNTs show opposite responses upon exposure to a 1 mM solution of 12.
(B) Comparison of the current change upon exposure of Tiiii@SWCNT and pristine SWCNT devices to guests 12–14; error bars are based on three
consecutive measurements. (C) Response of Tiiii@SWCNT devices to different concentrations of 12; error bars are based on three consecutive
measurements. (D) Response of Tiiii@SWCNT devices to alternating exposure to 12 and 13. Adapted from Dionisio, M.; Schnorr, J. M.; Michaelis,
V. K.; Griffin, R. G.; Swager, T. M.; Dalcanale, E. J. Am. Chem. Soc. 2012, 134, 6540–6543.
96 Cavitands

3.05.3.1.2 The Electroluminescent Sensor

To overcome the problem of sarcosine detection in urine, electrochemiluminescence (ECL) was chosen as an effective transduction
mode. 46,47 Analytical techniques based on ECL show several advantages over photoluminescence and chemiluminescence, since
the electrochemical way to generate luminescence allows to obtain sensors with very low background and high sensitivity, good
temporal and spatial resolution, robustness, versatility, and low fabrication costs. In ECL applications, the combination of polypyr-
idine ruthenium complexes, like RuðbpyÞ3 2þ (15), and amines is the most used labels/coreactant couple. Sarcosine, being
a secondary amine, possesses the energy requirements for generating the excited state of the fluorophore and it is therefore
a good candidate to act as an ECL coreactant.
To couple the supramolecular recognition properties of the Tiiii cavitands with the ECL transduction, the cavitand receptor was
equipped with an azide group at the lower rim and reacted with propargylamine coated magnetic microbeads (MMBs) via click
chemistry. The resulting MMBs decorated with the tetraphosphonate cavitand (Tiiii@MMB) were tested for the selective capture
of sarcosine hydrochloride in urine. 48 The analytical protocol consisted of three main steps, as depicted in Scheme 1: (1) capturing:
at pH 5 ( sarcosine pKa) the protonated form of sarcosine is recognized and complexed by Tiiii@MMB (Inset 1); (2) separation:
the beads are captured and separated from the matrix by means of a magnetic field, separating the sarcosine hydrochloride–Tiiii
complex from unbound amines and interferents (Inset 2); (3) release and detection: sarcosine is released as free base in the
measuring solution by increasing the pH to 12 ([ sarcosine pKa) (Inset 3). Luminophore 15 was then added, and the resulting
solution deposited on disposable screen-printed electrode for ECL generation (Fig. 13).
The final analytical tool is able to measure sarcosine in the mM–mM window, a concentration range that encompasses the diag-
nostic urinary value of sarcosine in healthy subject and PCa patients, respectively. In particular, the calculated LOD and LOQ were
30 and 50 mM, respectively. These results indicate that this ECL-supramolecular approach is extremely promising for the detection of
sarcosine and for early stage prostate cancer diagnosis and monitoring.

Scheme 1 Schematic representation of the three steps in the protocol analysis. The complex between tetraphosphonate cavitand and sarcosine is
represented through the crystal structure. C, gray; O, red; P, orange; N, blue; Cl, green; H, white; H-bonds, black dotted lines. H are omitted for clarity.
Reproduced with permission from Valenti, G.; Rampazzo, E.; Biavardi, E.; Villani, E.; Fracasso, G.; Marcaccio, M.; Bertani, F.; Ramarli, D.; Dalcanale,
E.; Paolucci, F.; Prodi, L. Faraday Discuss. 2015, 185, 299–309.

Figure 13 Structure of luminophore 15 and schematic representation of ECL coreactant “oxidative-reduction” mechanism. Adapted from Valenti, G.;
Rampazzo, E.; Biavardi, E.; Villani, E.; Fracasso, G.; Marcaccio, M.; Bertani, F.; Ramarli, D.; Dalcanale, E.; Paolucci, F.; Prodi, L. Faraday Discuss. 2015,
185, 299–309.
 Cavitands 97

3.05.3.2 Detection of Drugs in Water

Another innovative route to translate surface molecular recognition at the interface is the use of microcantilevers (MC). 49 MC are
able to translate surface molecular recognition into nanomechanical work with high fidelity, reproducibility, and robustness. The
free energy released by a host–guest interaction confined at a solid–solution interface splits into chemical and mechanical surface
work; the latter determined by the work that the host performs to “accommodate” the guest at the solid–solution interface.50 This
work appears as a variation of the surface stress (surface pressure) that the MC balances by bending. MC nanomechanical transduc-
tion is therefore “energy-based” and occurs regardless of the analyte mass in a label-free fashion.
Once again, the decoration of the cavitand feet with suitable reactive groups for grafting is pivotal for harnessing the molecular
recognition properties of the receptor. For this purpose, the Tiiii cavitand bearing u-decylenic feet was covalently grafted on the H-
terminated Si(100) face of Si–MC by photochemical hydrosilylation of the double bonds. The resulting Tiiii–Si–MC assay was able
to detect the whole class of methamphetamine, the fastest growing synthetic illicit drugs, independently of the type of residue
attached to the þNH2eCH3 moiety. 37 This is the first example of a sensor capable to single out the entire methamphetamine class
and for the recognition of the so-called “designer drugs.” A designer drug is the result of minor modifications in the chemical
structure of an existing drug, but shows pharmacological effects similar to its archetype. Analogues of amphetamine and metham-
phetamine are among the most commonly known types of designer drugs and pose serious challenges to the current lab- and
on-site-detection technologies, which are optimized for identification of a specific drug or substance rather than for the recognition
of the entire drug family.
As in the case of the sarcosine, the interaction modes responsible for the drug complexation by Tiiii were disclosed by the molec-
ular structures of the corresponding complexes in the solid state, obtained by X-ray diffraction analysis on single crystals and re-
ported in Fig. 14.
In all the structures, one or two strong hydrogen bonds between the ammonium þNeH and the P]O of the cavitand are
present. Further stabilization is given by cation–p and CH–p interactions between the aromatic cavity of the host and the avail-
able methyl groups of the drugs. 3,4-Methylenedioxymethamphetamine (MDMA) and 3-Fluoromethamphetamine (FMA)
behave exactly in the same way despite their different aromatic substituents ( Fig. 14C and D). In these two cases, the methyl
group draws its parent nitrogen atom deeper inside the cavity, thus enhancing the strength of charge–dipole interactions. An
array of four functionalized MCs was exposed to a 1  10
4 M water solution of MDMA, cocaine, amphetamine, and caffeine,
which is a known excipient. In the case of drugs, the interaction with the Tiiii-grafted MC drives a significant downward deflec-
tion of the MC, while for caffeine no significant deflection is observed, despite the presence of three potentially interacting
N-methyl groups in the molecule. The nominal detection limit of the employed Tiiii–Si–MC system for ammine-based drugs
in water was calculated to tenths of ppm, one order of magnitude lower than the one obtained with molecular imprinted poly-
mer coated QCM. The authors completed the study by testing the specificity of the Tiiii–Si–MC for MDMA and cocaine with
respect to lactose and glucose, which are common excipients used in drug formulations, and by testing it against a real “street”
sample. All these experiments were performed in 1  10
4 M water solution. Both MDMA and cocaine were recognized with
high fidelity in the presence of the excipients. Lactose caused no signal when pure and does not interfere with cocaine, but
showed some interference to the MDMA signal. Glucose instead interfered with the signals of both drugs in a similar and addi-
tive fashion. These effects arise from competitive nonspecific adsorption of the excipients on the functionalized MC. These
results consistently replicate for the real seized “street” sample, whose excipient turned out to be glucose. All the results were
confirmed by the authors performing control experiments with Si–MC decorated with the parent cavitand Tiiii, which is ineffec-
tive in complexing methylammonium salts.

Figure 14 Molecular structures of the complexes: (A) Tiiii amphetamine, (B) Tiiii cocaine, (C) Tiiii MDMA, and (D) Tiiii 3-FMA hydrochlorides. C,
gray; O, red; P, orange; N, blue; Cl and F, green; H, white; H-bonds, blue-dotted lines. For clarity, the H atoms of the Tiiii have been omitted. Adapted
from Biavardi, E.; Federici, S.; Tudisco, C.; Menozzi, D.; Massera, C.; Sottini, A.; Condorelli, G. G.; Bergese, P.; Dalcanale, E. Angew. Chem. Int. Ed.,
2014, 53, 9183–9188.
98 Cavitands

3.05.3.3 Detection of Acetylcholine in Water

Acetylcholine is very important neurotransmitter and neuromodulator. Synthetic receptors capable of binding and detecting its
presence are relevant in the biomedical field. Rebek et al. reported the use of a fluorescent deep cavitand as sensor for small-
charged molecules, including acetylcholine. 51 Chemosensors that used photoluminescence as readout are very appealing, because
they are sensitive, easy-to-use, low cost, and versatile. Photophysical properties of luminescent molecules can be fine-tuned through
a number of different interactions such as electron-, proton-, and energy-transfer processes; destabilization of excited states; heavy
atom effects; changes in electron density.52,53 These interactions can quench (“turn-off”) or enhance (“turn-on”) the intensity of the
fluorescent emission. The strategy used here complements the one used for gas sensing: the fluorescent probe is in direct contact
with the analyte, being part of the receptor cavity, instead of being perturbed by the interaction of the guest with the binding
unit. Whenever possible, this approach is very effective because it eliminates any intermediation between the guest and the analyte.
The authors designed and synthetized a deep cavitand (16, Fig. 15) where the fluorescent functionality, a benzoquinoxaline
group, is one of the walls of the cavitand host. The other three walls are hexa-amide groups, which form intramolecular hydrogen
bonds, stabilizing the cavitand vase conformation. Once bound, the guest analyte is placed in direct contact with the fluorophore
causing a bathochromic shift of the fluorescence, that is, also influenced by the nature of the anion.
1
H-NMR spectra in CDCl3 revealed that cavitand 16 has a fluxional behavior (broadened signals, Fig. 16A), resulting from the
presence of the extended benzoquinoxaline wall and the absence of two amide substituents. The addition of a guest molecule such

Figure 15 Cavitand 16, control, and guest molecules used in the work. Adapted from Berryman, O. B.; Sather, A. C.; Rebek, J., Jr. Org. Lett. 2011,
13, 5232–5235.

Figure 16 Select portions of the 1H NMR spectrum of the host fluorescent cavitand 16 (down left inset) in CDCl3 at 300 K (A) and in the presence
of acetylcholine chloride (B). A CAChe MM3 minimized model of cavitand and acetylcholine is provided in the upper left inset. Adapted from Berry-
man, O. B.; Sather, A. C.; Rebek, J., Jr. Org. Lett. 2011, 13, 5232–5235.
 Cavitands 99

as acetylcholine chloride results in sharper signals characteristic of a kinetically stable complex, where the cavitand is in the vase
form (Fig. 16B).
The characteristic blue fluorescence of the benzoquinoxaline wall was used to probe the host–guest interactions of cavitand 16
with alkyl ammonium salts small enough to complement the receptor cavity ( Fig. 16). In particular, the addition of acetylcholine
chloride 18 to a CHCl3 solution of cavitand produced a bathochromic shift and an increase in fluorescence. The change in emission
was attributed to the proximity of the cation and anion to the fluorophore. Molecule 17 was used as control and it was demon-
strated that its fluorescence was not altered by addition of guest, highlighting the necessity of a preorganized cavity to induce
the bathochromic effect.
The authors demonstrated also that the guest binding and emission of 16 are dependent on the guest counterion. In particular,
they observed that the chloride counterion of (19) produced an increase in fluorescence, while the bromide counterion of guest (20)
led only to a smaller increase. Iodide is well-known to quench fluorescence, 54 and the iodide guest (21) resulted in a significant
decrease in fluorescence probably due to a collisional quenching process of the excited state. The binding constant values of the
complexes follow the same trend; higher for the chloride salt, and lower for the iodide one. This trend is attributed to the different
hydrogen bond strength between the amide protons at the upper rim of 16 and the anions which is in the order Cl
> Br
> I
.

3.05.4 Molecular Grippers

The study of molecular-level machines, discrete assemblies of molecules designed to perform mechanical-like movements (output)
as a consequence of external stimuli (input), 55 is boosted by the idea that macroscopic tools can be transferred to the nanoscale. In
recent years, microscopic analogues of everyday objects, such as turnstiles,56 ratchets,57 motors,58 muscles,59 tweezers,60 rotors,61
shuttles,62 balances,63 and cars,64 have been successfully synthesized and tested, while the development of molecular grippers65
is still challenging. To act as a gripper, a molecule should close and open upon external stimulation to grab and release molecular
objects. Applications of this gripper-like function range from the construction of smart cantilever tips for atomic force microscopy
(AFM) to drug delivery.
In this field, cavitands play a prominent role as they not only possess a preorganized cavity suitable for the incorporation guest
molecule, but they can also be engineered to change their conformation in response to external stimuli. 66 In particular, the confor-
mational switching of properly functionalized quinoxaline cavitands resembles the movement of a mechanical gripper. In fact,
these systems are able to reversibly interconvert between a closed vase conformation and an open extended kite one.67 This switching
highly affects the binding properties since the cavity is no longer present in the open form and guests are inevitably released. Placed
on a substrate, these cavitands can be designed to capture molecules in vase form, hold them during translocation, and finally release
them as a consequence of a stimulus that changes their conformation. To date, changes of temperature,68,69 pH,70,71 metal-ion
concentration,72 and light73 have been found to successfully alter cavitand conformations and binding properties.
The main activities related to molecular grippers have been carried out in the group of Diederich at ETH. In 2007, they reported
initial studies on gripper-like molecular systems based on pH-driven quinoxaline cavitands vase–kite interconversion. 70 They
prepared two switchable container molecules, basket 22 and tube 23, that can respectively form stable 1:1 and 1:2 host–guest
complexes with suitably sized cycloalkanes, such as cyclohexane, in their closed conformation (Fig. 17A). The addition of deuter-
ated trifluoroacetic acid (CF3COOD) to a solution of 22 or 23 in [D12]mesitylene converts these molecules into open-portal
conformers unable to complex guest molecules, while neutralization with base induces the re-uptake of the guests. Both cavitand
opening/closing and guest uptake/release can be followed by 1H NMR spectroscopy. Upon acid-triggered vase to kite conversion,
methine protons of the resorcinarene scaffold experienced an diagnostic upfield shift from 5.6 to 3.6 ppm (except for rigid structures
like basket 22, where the effect is by far less pronounced), while the strongly upfield shifted resonance for complexed cyclohexane
disappeared (Fig. 17C).
However, pH-triggered switching in solution is hardly applicable to the realization of an operating molecular gripper. In order to
be used in electronic applications via interfacing with electroactive metal surfaces, redox-switchable cavitands are highly desirable.
Initial efforts in this direction were made via decoration of cavitand walls with tetrathiafulvalene (TTF) 74 or ferrocene75 units as
redox-active components. In 2012, the Diederich group reported the synthesis of a new family of cavitands containing quinone
moieties as redox-active wall components.17 To induce vase–kite conformational change by redox interconversion between quinone
and hydroquinone states, the introduction of H-bonding interactions as driving forces was strictly required. In particular, they
designed N,N-di(n-alkyl)carboxamides as H-bond accepting groups on the quinoxaline walls of diquinone–diquinoxaline cavi-
tands.18 The strong intramolecular interactions between the hydroquinone OH groups and the carboxamide C]O groups specif-
ically stabilize the vase conformation in one redox state.
While N,N-dioctyl-substituted oxidized cavitand (ox-24) is present in the kite form in CDCl3 and [D12]mesitylene, its reduced
form (red-24) switch to a rigid, hydrogen bond-stabilized vase form in the same solvents ( Fig. 18). Even if cavitand ox-24 undergoes
a guest-induced kite to vase switching in mesitylene-d12, the Ka values for cycloalkane complexations are in the range 10
1–101 M
1
(Table 2). Instead, for its preorganized vase form, cavitand red-24 is capable to complex the same guests with higher association
constants (102–104 M
1).
As a result, the molecular gripper behavior of diquinone–diquinoxaline cavitands is not related to the opening/closing of the
structure, but to the redox-driven modulation of their association constants by a factor of 102–103. 19 Hydrogen bond stabilization
of the vase form, coupled with the steric hindrance of triptycene moieties, highly affects also guest uptake and release kinetics.20
100 Cavitands

Figure 17 Molecular models (Spartan ’04, AM1) of basket 22 (A) and tube 23 (B) in the closed and open forms; 1H NMR experiments (500 MHz,
298 K, [D12]mesitylene) proving the reversible switching of guest complexation for 22 (C) and 23 (D). Adapted from Gottschalk, T.; Jaun, B.;
Diederich, F. Angew. Chem. Int. Ed. 2007, 46, 260–264.

Figure 18 Conformational properties of cavitands ox/red-24 in the absence and presence of guests: (A) H2, Pd/C, THF (degassed), 25 C, 30 min,
quantitative; (B) air, quantitative. Adapted from Pochorovski, I.; Diederich, F. Acc. Chem. Res. 2014, 47, 2096–2105.
 Cavitands 101

Table 2 Association constants (Ka) for the complexation of cavitands ox/red-24 with various guest
molecules in mesitylene-d12 19

Guest Ka (ox-24,guest) (M
1) Ka (red-24,guest) (M
1)

Cyclopentane 0.2 160

Cyclohexane 2.6 300
Cycloheptane 8 330
Cyclooctane 2 5300
Tetrahydroquinone 40 8700

The comparison between cavitand red-24 (kout ¼ (5.3  0.2)  10
5 s
1, cyclohexane) and the top-closed but not hydrogen bond-
stabilized basket 22 (kout ¼ 2.5  10
3 s
1, cyclohexane) evidenced that the additional rigidity caused by hydrogen bonds is capable
to reduce the guest-release rate by a factor of 102.
Future prospects in this field are related to the extension of cavitand wall to trap larger guest molecules as well as to the devel-
opment of redox-switchable cavitands that does not require an external proton source for the switching process. The functionaliza-
tion of the lower rim to graft these molecules on metal surfaces will enable the application of cavitands as molecular grippers.

3.05.5 Supramolecular Catalysts

Initial efforts to design synthetic abiotic receptors capable to complex substrates enhancing reaction rates have been inspired by the
lock-and-key principle typical of enzymes. Covalent or noncovalent hosts with catalytic functions have been engineered to
mimicking the molecular recognition properties of enzymes without copying their structure. 76 For their high versatility and superior
recognition proprieties,2 cavitands played an active role in opening new frontiers in supramolecular catalysis.77 Similar structures,
such as metallocavitands,78 in which the metal participates in the construction of the cavity or cavitand-based capsules79 and
cages,80,81 will not be treated in this chapter.
To be truly efficient, cavitand-catalyzed reactions must be driven by substrate ground state destabilization, transition state stabi-
lization, and/or optimal orientation of the substrate (Pauling’s principles). 82 In their initial designs, catalytically active functional
groups have been attached at the cavitand upper rim to complement reactant transition states, leading to large increases in reaction
rates. Similarly to enzymes, which not only exhibit a proper orientation of active acids and bases but also fold around the targets
isolating them from the solvent, cavitands combine the effect of the optimal positioning of the active center with solvophobic inter-
actions within the cavity. Since reactant motions along a reaction coordinate are intimately related to the behavior of the
surrounding molecules, solvent must respond to reactant changes in shape, volume, polarity, and charge distribution (energy-
demanding process). For cavitand-complexed reactants, part of this energy has been already spent in the desolvation process during
the complexation event, and their transition states do not require solvent molecule reorganization. This confined environment can
also lead to unusual selectivity; the specific orientation of the substrates inside the host can promote reaction pathways different
from those of the same reaction in solution, while spatial factors may induce regioselectivity.83
Rebek’s group developed a series of receptors bearing catalytically active functionalities that descend from octamide cavitand 25
( Fig. 19). Receptor 25 exhibits catalytic properties even in the absence of additional active functionalities since the secondary
amides at the rim play a noninnocent role and can be involved in hydrogen bond interactions with the reactant or reaction
intermediates.

Figure 19 Rebek’s deep cavitand 25 and its derivatives 26 and 27. Parts of structures have been removed to show the positioning of the active
functional groups. Adapted from Purse, B. W.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 10777–10782.
102 Cavitands

Remarkable acceleration of a,b-unsaturated ketone deuteration, 84 Diels–Alder reaction,85 and Menschutkin reaction86 has been
observed with 25. It is interesting to note that, in the case of the Diels–Alder reaction, no product inhibition was observed since the
cavitand can host the dienophile but has low affinity for the diene and the product. The same cavitand has been used by Ballester
and coworkers to encapsulate bisnorbornadiene rhodium(I) cation acting as a second-sphere ligand, modifying the stability, selec-
tivity, and reactivity of the organometallic complex.87 While the free rhodium(I) complex promotes the dimerization of norborna-
diene, the cavitand complex catalyzes the formation of norbornene as the major reaction product.
Among cavitand 25 derivatives, 77 salen cavitand 26, metallated with zinc(II), has been successfully used to promote the hydro-
lysis of p-nitrophenyl choline carbonate.88 Cavitand affinity for alkylammonium ions, coupled with the coordination of the
carbonate group to the zinc, results in the positioning of the reactive groups near the catalytic site at the upper rim. With a stoichio-
metric amount of catalyst, a 50-fold acceleration was observed (first-order reaction), but the metallated cavitand is only fivefold
more efficient compared to the corresponding bare Zn(II) salen. Cavitand 26 has also been used as template for the esterification
of choline with acetic anhydride to form the biologically relevant acetylcholine.89
Cavitand 27 is decorated at the upper rim with an inwardly directed Kemp’s triacid derivative that has a twofold role: (i) it stabi-
lizes the host–guest complex through hydrogen bonding interactions; 90 (ii) it provides a source of Brønsted acidity–basicity. Rebek
and coworkers demonstrated that cavitand 27 promotes highly regioselective epoxide ring-opening cyclization reaction.91 Upon
binding 1,5-epoxyalcohol 28, the receptor catalyzed the formation of the five-membered ring ether 29 as the exclusive product
of the reaction (Scheme 2). Binding studies indicated that the complexation is mainly enthalpy driven and it benefits for the forma-
tion of hydrogen bonding interactions between the inwardly directed acid and the hydroxyl group of the guest.92 Based on the NMR
experiments corroborated by in silico modeling, the following mechanism was proposed: the epoxide is complexed by the cavity
thanks to the hydrogen bonding interactions described earlier; the mobility within the receptor allows the epoxide terminus to react
with the acid function of the host (Scheme 2, species A); the resulting epoxide ring-opening cyclization (rate-determining step)
forms a protonated ether (Scheme 2, species B); the ether function in intermediate B is readily deprotonated by the carboxylate
group of the host, leading to a kinetically unstable host-product complex that quickly dissociates allowing a new epoxide molecule
to access the cavity.

Scheme 2 Equation and proposed mechanism of the regioselective epoxide ring-opening cyclization reaction of 1,5-epoxyalcohol 28 catalyzed by
cavitand 27. Adapted from Pinacho Crisóstomo, F. R.; Lledó, A.; Shenoy, S. R.; Iwasawa, T.; Rebek, J., Jr. J. Am. Chem. Soc. 2009, 131, 7402–7410.
 Cavitands 103

The lack of product inhibition in this system, ascribable to a lack in shape complementarity between the cavitand 27 and the
cyclic ether product 29, suggests that this system might follow Michaelis–Menten kinetics of enzymes. Surprisingly, the rate of reac-
tion was found to diminish as a function of substrate concentration, indicating that this system experiences substrate inhibition. The
hydroxyl group on the substrate, which was crucial for host–guest complexation, plays also an important role in disrupting the
hydrogen bond seam stabilizing the active vase-like confirmation of the cavitand. This unfolding results in the deactivation of
the cavitand and in the consequent suppression of its catalytic efficiency ( Fig. 20).
Recently, Rebek and coworkers focused their attention on cavitand-catalyzed reaction in water. In this solvent, hydrophobic
pocket capability to bring reactive centers and reactants in close proximity is well-known. 93 However, the template effect of
water-soluble cavitands 30–32 on bola-amphiphilic molecule is nonclassical: guests assume a U-shaped conformation that buries
their hydrophobic part and solvates the cavity while exposing polar groups to the bulk solvent. Moreover, after the first reaction, the
cavity exerts a protective action on guest remaining polar functionality hampering intermolecular reactions (oligomerization). For
long aliphatic guests, octamethylation of the host is necessary to prevent the formation of capsules, while bola-amphiphiles can
form 1,1 complexes also with the receptor 32, which shows a superior solubility in water among the series.94 This approach has
been successfully applied to 12- and 13-membered rings lactamization reactions of u-amino acids,95 efficient synthesis of mono-
functionalized products from Staudinger reduction of diazides,96 macrocyclization of di-isocyanates to ureas,97 and macrocycliza-
tion of folded long-chain a,u-diamines (C11–C18) with activated diesters of succinic acid and glutaric acid.98 The potential of these
cavitands to desymmetrize reactions through the protection of buried functions has been emphasized by the promoted mono-
hydrolysis of long-chain diesters.99 In all these cases, however, a stoichiometric amount of cavitand is necessary to reach the
enhancement of rate constants and catalyst recovery steps must be taken into account.
The possibility to fine tuning cavitand structures open the way for the development of more complex systems, such as photo-
switchable catalysts. An analogous of cavitand 25, carrying a cis–trans diaryldiazene group at the upper rim (cavitand 33, Fig. 21),
was found to accelerate the Knoevenagel reaction between various aromatic aldehydes and malonitrile in the presence of piperidi-
nium acetate as co-catalyst.100 The decrease in the degrees of freedom of the piperidinium, that is bound in the cavity, combined

Figure 20 (A) Rebek’s water-soluble cavitands 30–32; (B) cyclization of folded amino acid complexes in cavitand 32; (C) macrocyclization of folded
long-chain a,u-diamines with activated diesters. Adapted from Shi, Q.; Masseroni, D.; Rebek, J., Jr. J. Am. Chem. Soc. 2016, 138, 10846–10848.

Figure 21 (A) Light-responsive cavitand 33. (B) light-induced uptake/release of the catalyst. Adapted from Berryman, O. B.; Sather, A. C.; Lledó, A.;
Rebek, J., Jr. Angew. Chem. Int. Ed. 2011, 50, 9400–9403.
104 Cavitands

with the presence of the secondary amides, facilitates the deprotonation of malonitrile that reacts with the aromatic aldehydes
outside the host. Being the complexation of the piperidinium possible only when the cavitand is in its trans-conformation, the
light-induces isomerization of the diaryldiazene group to the cis form and the subsequent release of the catalyst from the cavity
lead to reduced reaction rates.

3.05.6 Supramolecular Polymers

The merging of polymer science with supramolecular chemistry has generated a new, thriving research field, broadly defined as
supramolecular polymer chemistry. The positive fallout of this merging is demonstrated by the appearance of supramolecular poly-
mers, presenting unique mechanical, electronic, biological, and self-healing properties. 101 The supramolecular approach is very
attractive for the design of functional polymeric materials featuring reversibility and responsiveness to external stimuli. Molecular
recognition, resulting from a delicate balance of shape, size, and functional complementarity, is a fascinating tool to assembly indi-
vidual entities into complex multicomponent aggregates with desirable connectivities and designs.102–104 For polymer science, the
macroscopic expression of molecular recognition is the next step necessary to harness its full potential.
Among the variety of supramolecular interactions from which to choose, to obtain truly polymeric materials there is the need of
relatively high association constants (> 105M
1). So far, few classes of molecular receptors have been turned into supramolecular
host–guest polymers: cyclodextrins, cucurbiturils, calixarenes, crown ethers, and cavitands. 105 In the first two cases, hydrophobicity
is the driving force for polymerization, while in the others specific host–guest interactions are operating. In order to assure the poly-
mer growth by the reversible association of their end-groups, the monomers are requested to be ditopic or polytopic. Ditopic
species, bearing two self-assembly efficient moieties connected through suitable linkers, can be homoditopic monomers (the
two moieties are identical) or heteroditopic monomers (the two moieties are different from each other).
Early attempts to turn cavitands into polymeric materials relied on solvophobic interactions (p–p stacking) present between
quinoxaline cavitands in the kite form 106 either as heteroditopic or homoditopic monomers. In the first case, the second interaction
mode was a metal coordination between pyridines inserted at the lower rim of the kite cavitand and suitable Pd complexes precur-
sors.107,108 In the second case, two kite quinoxaline cavitands were covalently linked to form a homoditopic monomer.109 In both
the cases, the interaction strength was sufficient to generate oligomers, but not polymers.
Another early example of polymeric arrangement of cavitands in the solid state was given by Aakerӧy and coworkers. The authors
reported the use of cavitands as monomers for the assembly of a polymeric network in the solid state via hydrogen bonding with
suitable guests. In particular, they reported the use of cavitands functionalized at the upper rim with four amino-pyridine groups
able to form hydrogen bonds with glutaric acids. 110 The existence of the polymeric network was proved through X-ray single-crystal
diffraction. Recently, they reversed the H-bonding scheme by introducing four carboxylic groups at the upper rim of an ethylene-
bridged cavitand and using 4,40 -bipyridine as ditopic linker.111 The co-crystallization of the cavitand with 4,40 -bipyridine produced
an infinite polymer network, whose structure was determined via X-ray diffraction.
The design of cavitand monomers requires to consider several factors, like number and type of the noncovalent interaction
modes, the synthetic strategy to introduce the effective end-groups on the cavitand scaffold, and the structural requirements needed
to maximize the efficiency of the selected binding motifs. The preorganization of the monomeric units results pivotal in the deter-
mination of the final assembled objects. Many factors can be controlled by acting on the rigidity and on the preorganization of the
building block, like the equilibrium between cyclic and linear polymers, which is often observed during supramolecular polymer-
ization. Also the thermodynamic contributions can be tuned, thus achieving enthalpy and entropy favorable polymerizations.
For their outstanding and versatile molecular recognition properties, tetraphosphonate cavitands are appealing monomers for
the formation of supramolecular polymers via host–guest interactions. The possibility to functionalize these receptors both at the
upper rim and at the lower rim with specific functions makes them suitable molds to create a preorganized pattern, and to induce
geometrical spatial arrangements in the solid state.
Dalcanale and coworkers synthesized a heterotopic monomer introducing both host and guest units in the same cavitand to
induce the self-assembly of supramolecular polymers. 112 The desired monomer presented a single methylpyridinium unit
(Fig. 22) at the lower rim of a tetraphosphonate cavitand, connected to the macrocycle with a short tether to exclude the possibility
of self-association. Tetraphosphonate cavitands fulfill the requirement of high association constants between the host and suitable
guests.45 By inclusion of the methylpyridinium unit in the cavity of an adjacent cavitand, a linear homopolymer was formed, self-
assembled via multiple ion–dipole interactions between the P]O groups and the positively charged methylpyridinium moiety,
and cation–p interactions between the acidic methyl group and the p-basic cavity, as demonstrated by solid state studies. In the
crystal, the polymer assumes a straight and extended (all-trans pyridinium linker) conformation (Fig. 23).
In solution, the presence of the supramolecular polymer was confirmed through static light scattering (SLS) measurements,
which revealed an average of 18 monomers units linked together. A progressive, linear decrease of the molecular weight (Mw)
was obtained by addition of the stopper suitable to be complexed but unable to complex. The stopper, acting as a monotopic impu-
rity, produced a detrimental effect on the polymer growth. On the contrary, the addition of a tetratopic porphyrin guest led to
a substantial increase in Mw, since the porphyrin derivative acted as a template molecule, ordering the preformed, linear polymer
chains into a star-branched overstructure ( Fig. 24), as confirmed by SLS measurements.
The addition of a competitive guest caused the complete and reversible disassembly of the supramolecular polymer. The N,N-
methyl butyl ammonium iodide is complexed by tetraphosphonate cavitand with association constant higher than the methyl
 Cavitands 105

Figure 22 (A) Heteroditopic monomer A employed for the polymerization process. (B) Polymerization mode of cavitand A. Adapted from Harada, A.
Supramolecular Polymer Chemistry; Wiley-VCH: Weinheim, 2012.

Figure 23 Crystal structure of the linear homopolymer, showing two independent chains (blue and yellow). The triflate counterion is depicted in
green. Reproduced with permission from Yebeutchou, R. M.; Tancini, F.; Demitri, N.; Geremia, S.; Mendichi, R.; Dalcanale, E. Angew. Chem. Int. Ed.
2008, 47, 4504–4508.

Figure 24 Switching from linear to star-branched architectures induced by tetratopic porphyrin guest. Reproduced with permission from Harada, A.
Supramolecular Polymer Chemistry; Wiley-VCH: Weinheim, 2012.

pyridinium (> 108 M
1), thanks to its capability to establish additional H-bonding between its NH protons and the P]O groups of
the host molecule. The reversibility of the process was demonstrated through subsequent addition of a hindered base such as DBU.
DBU, too large to be engulfed in the cavity, is able to deprotonate the ammonium salt, lowering its affinity for the cavitand and
restoring the initial complex with the pyridinium guest and, consequently, the homopolymer. The whole process was monitored
by 1H and 31P NMR spectroscopy using CDCl3, where the polymer is soluble, and visually in acetonitrile, where it is insoluble
( Fig. 25).
An alternative approach to obtain the formation of supramolecular copolymers is the use of homoditopic monomers that
requires the distribution of the self-assembling functionalities in two different species. The designed homoditopic complementary
106 Cavitands

Figure 25 Reversibility of the polymerization process. Reproduced with permission from Harada, A. Supramolecular Polymer Chemistry; Wiley-VCH:
Weinheim, 2012.

partner molecules are: homoditopic hosts (A–A), presenting two tetraphosphonate cavitands covalently attached at their lower rim,
and homoditopic guests (B–B), in which flexible alkyl or ethylene oxide chains of different length are functionalized with two
N-methylpyridinium end-groups ( Fig. 26).113
By mixing the two co-monomers in equimolar amount, both linear and cyclic copolymers were obtained, whose distribution is
temperature and concentration dependent. The structure of the copolymers and MW determination were obtained via X-ray analysis
and viscosity measurements, respectively. The formation of rigid systems was obtained via self-assembly of A–A monomer bearing
an aromatic unit as linker between the two cavitand units and methyl viologen as ditopic guest. In this case, the X-ray analysis
provided a physical evidence of the formation of a linear structure ( Fig. 27). Flexible polymers were obtained by mixing the

Figure 26 Homoditopic host A–A and homoditopic guest B–B leading to A–A:B–B alternating copolymer formation. Adapted from Harada, A. Supra-
molecular Polymer Chemistry; Wiley-VCH: Weinheim, 2012.
 Cavitands 107

Figure 27 Crystal structure of the copolymer AA:BB obtained by self-assembly of the rigid ditopic cavitand host and the methyl viologen ditopic
guest. Reproduced with permission from Tancini, F.; Yebeutchou, R. M.; Pirondini, L.; De Zorzi, R.; Geremia, S.; Sherman, O. A.; Dalcanale, E. Chem.
Eur. J. 2010, 16, 14313–14321.

A–A monomer featuring the adipic spacer and the B–B monomer bearing a polyethylene glycol (PEG) linker. This second case is
more intriguing, since viscosimetry studies revealed the presence of a ring-chain equilibrium, shifted to the formation of linear poly-
meric species at high concentrations. The temperature dependence of this equilibrium is shown in Fig. 28. This behavior is in line
with the thermodynamic signature of host–guest polymerization, obtained by ITC studies. A clear trend is seen for the entropic
contribution by increasing the flexibility of the guest linker in the homoditopic B–B monomer: upon moving from the short meth-
ylene linker to the longer and flexible ones, the negative TDS term first becomes almost neutral and then positive. The high flexibility
of the PEG spacer imparts conformational freedom in the final complex, which reduces the entropy loss that generally occurs during
self-association and leads to a process that is both enthalpy and entropy-driven.
Enthalpy is more effective at 25 C, so that in the low-temperature regime heating negatively affects polymerization by inducing
reversible formation of smaller oligomeric and cyclic species, and accounts for the observed viscosity decrease. Nevertheless, because
entropy also plays a favorable role in the complexation, a critical temperature should exist above which the entropic contribution
becomes dominant. At this temperature, sufficient energy is provided to the system to break small rings, and consequently elonga-
tion of the PEG chains is allowed. This occurs by exposing “reactive end-groups” on the different oligomers, causing their assembly
into long polymeric species that are responsible for the recorded viscosity increase.
Supramolecular cross-linking was also demonstrated, thanks to a suitable engineering of the host spacer. The metal-directed
conversion of linear polymeric chains into cross-linked supramolecular architectures was achieved via coordination of the pyridine
units embedded in the spacer of ditopic host A–A 35c. In this case, neutral metal complex (CH3CN)2PdCl2 was selected as orthog-
onal curing agent, since it easily exchanges its trans acetonitrile ligands for the pyridine ligands of the host spacer, without interfering
with the host–guest complex.

Figure 28 Specific viscosity of a solution of homoditopic host A–A 35b and homoditopic guest B–B 36c in tetrachloroethane as a function of
temperature. The structures of the corresponding linear polymer and cyclic oligomer are referred to 35c and methyl viologen for clarity reasons.
Adapted from Tancini, F.; Yebeutchou, R. M.; Pirondini, L.; De Zorzi, R.; Geremia, S.; Sherman, O. A.; Dalcanale, E. Chem. Eur. J. 2010, 16,
14313–14321.
108 Cavitands

3.05.6.1 Polymer Blending

Polymer blending is a long-standing issue in polymer science, 114 with relevant practical implications. The blending of polymers is
an economically attractive route to develop new materials combining the desirable properties of two or more polymers. The cova-
lent introduction of compatibilizers or reactive functional groups in the side chain of the polymers are usually employed to mini-
mize the interfacial energy and, in turn, the phase segregation. Supramolecular interactions have been used to increase the
compatibility between different polymers, yielding uniform blends between otherwise incompatible polymers.115–118 By using
a stimuli-responsive, supramolecular host–guest system as compatibilizer for otherwise immiscible polymers, those interactions
can be turned off, leading to a controlled disassembly of the blend. Tetraphosphonate cavitands have been proposed as host
and N-methylpyridinium as guest to obtain switchable host–guest polymer blends. The complex formed by these receptors and
N-methylpyridinium presents a high association constant (Ka ¼ 5.8  106 M
1 in chlorinated solvents)34 and it can be dissociated
both chemically45 and electrochemically.119
At first, the molecular recognition properties of tetraphosphonate cavitands were exploited to introduce supramolecular cross-
links and, consequently, to induce the compatibilization between polystyrene (PS) and poly(butylmethacrylate) (PBMA), which are
known immiscible polymers. A slight modification of the two immiscible polymers was performed with the introduction of the two
recognition groups, tetraphosphonate cavitand (37) and methylpyridinium (38) ( Fig. 29).
The resulting copolymers PS–HOST and PBMA–GUEST resulted to be fully miscible in the solid state in a wide molar ratio, as
demonstrated by the presence of a single Tg in the Differential Scanning Calorimetry (DSC) thermograms of the mixtures and by
AFM topography of the corresponding films, which showed a homogeneous texture at the surface level. The energetically favorable
host–guest interactions among polymeric chains overcome their repulsive interfacial energy, leading to the suppression of phase
segregation at the level of material.
The exhaustive formation of the host–guest complexes among the polymeric chains was proven through 31P NMR in solution
and through a control experiment with nonmethylated PBMA–GUEST in the solid state. In this last case, the polymer blending
resulted suppressed because the presence of the N-methyl group is necessary for the complexation with the tetraphosphonate
unit. The authors demonstrated also that the complexation between PS–HOST and PBMA–GUEST is reversible, by the action of
a specific external stimulus in the form of guest exchange with the competitive N-methyl butyl ammonium chloride. N-methyl
ammonium salts are known to complex tetraphosphonate cavitands with higher Ka with respect to N-methyl pyridinium salts. 45
The monotopic guest replaced PBMA–GUEST in the interaction with PS–HOST, restoring the original polymer immiscibility.

Figure 29 Styrene-footed tetraphosphonate cavitand 37 and its (6-methacryloyloxy)hexyl isonicotinate (38) counterpart. PS-HOST obtained incorpo-
rating 4% mol/mol of 1 into PS and its counterpart PBMA–guest. Nonmethylated PBMA–GUEST for the control experiment and butyl methyl ammo-
nium chloride used in the guest-exchange experiment. Adapted from Dionisio, M.; Ricci, L.; Pecchini, G.; Masseroni, D.; Ruggeri, G.; Cristofolini, L.;
Rampazzo, E.; Dalcanale, E. Macromolecules 2014, 47, 632–638.
 Cavitands 109

Figure 30 (A) PS–Host; (B) PBMA–Sarc. Reproduced with permission from Masseroni, D.; Rampazzo, E.; Rastrelli, F.; Orsi, D.; Ricci, L.; Ruggeri,
G.; Dalcanale, E. RSC Adv. 2015, 5, 11334–11342.

A related pH-responsive host–guest polymerization and blending was reported. 120 In this case, sarcosine hydrochloride (Sarc)
was inserted in the PBMA as recognition unit, obtaining the PBMA–Sarc as guest polymer (Fig. 30).
As in the previous case, the use of PS–HOST and PBMA-Sarc led to the mixing of the two otherwise immiscible polymers thanks
to the energetically favorable host–guest interactions between the polymer chains. The polymer blending was verified by the pres-
ence of a single glass transition temperature (Tg) and showed its homogeneous morphology by AFM. The polymer assembly was
controlled by means of acid–base treatment, demonstrating the reversibility of the system. In the presence of a base, the sarcosine
moiety of the PBMA–guest is deprotonated and once deprotonated it leaves the cavity. The subsequent protonation of the guest
restores the polymer blend.
In the two cases discussed earlier, the disassembly required dissolution of the blend in a suitable solvent. The procedure results
unfeasible for practical applications, for which the stimuli-responsive decompatibilization must work on the polymers in the solid
state, either bulk or thin films. Recently, the phase-separation directly in the solid phase by means of electrochemistry on supported
films was reported. 121 Films of mixtures composed of the PS–host and the PBMA–guest (Fig. 29) were deposited on electrodes
using spin coating and Langmuir–Schaefer (LS) deposition techniques. PS–host and the PBMA–guest were synthesized incorpo-
rating 2.5 and 8 mol% of the tetraphosphonate cavitand host and N-methyl pyridinium guests, respectively. It is known that in
solution it is possible to break apart electrochemically the complexes between N-methyl pyridinium salts and phosphonate cavi-
tands.119 The one-electron reduction of the guest leads to a radical species with no affinity for the host, as shown in Fig. 31.
This approach resulted appropriate to trigger polymer blend segregation in the solid state. The electrochemical stimulus effect
on PS–host/PBMA–guest segregation was investigated by AFM microscopy on the treated electrodes. Starting from a previously
homogeneous and flat morphology, after the electrochemical stimulus a long-range migration of the polymers resulted in the
formation of retreats and accumulations, both for the LS films and the spin coated ones. The former films showed a more
pronounced effect than the spin coated ones, which need to be heated above the Tg to show segregation. Due to the layered depo-
sition process, the LS films are typical 2D structures, homogeneous only in the lateral direction, with little or no entanglements
between polymer chains belonging to different stacks. On the contrary, spin cast films are supposed to be homogeneous in all
the directions, and the polymer chains are entangled to form 3D structures as in the bulk. In the LS films, morphology rearrange-
ment is triggered by the electrochemical stimulus alone, with no need for the subsequent temperature treatment above the Tg,
which is needed for the latter.

3.05.7 Membrane Functionalization for Protein Recognition and Polymer Growth

The decoration of membranes with cavitands shows convincingly that the applications of cavitand chemistry are limited only by the
ingenuity of the researchers. The embedding of synthetic receptors into membranes brings in abiotic molecular recognition features,

Figure 31 Schematic representation of the electrochemical disassembly of the complex between a phosphonate cavitand (schematically drawn as
a trapezoid) and N-methyl pyridinium. Reproduced with permission from Orsi, D.; Frϋh, A. E.; Giannetto, M.; Cristofolini, L.; Dalcanale, E. Soft Matter
2016, 12, 5353–5358.
110 Cavitands

which can be harnessed to impart new properties to the receiving membrane. The key issue of this application is the correct orien-
tation of the cavities toward the exterior of the membrane. This is typically obtained by introducing hydrophilic charged groups on
top of the cavity rim, leaving the hydrophobic body of the cavitand surrounded by the lipid membrane. Amphiphilic cavitands are
preferred for membrane incorporation, in which the exterior of most of the cavitand surface is hydrophobic, with few charged polar
groups strategically positioned at one side of the molecule.
The bacterial cell structure presents an outer polysaccharide cell wall surrounding a fluid membrane. 122 This polymeric cell wall
provides protection to the sensitive membrane structure, as well as incorporating molecular recognition motifs for cell signaling,
transport, and adhesion processes.123,124 Approaches that foreseen the creation of synthetic equivalent with preformed polymers
covalently attached to cells or bilayers are limited by the solubility of the polymers,125–129 while methods that grow polymeric
coatings onto a biomimetic supported lipid bilayer (SLB) are limited by the poor tolerance of the lipid bilayer to polymer growth
conditions. Atom-transfer radical polymerization (ATRP) is tolerant to aqueous media, can be performed under very mild condi-
tions,130–132 and can be used to graft polymers on surfaces and materials.133–137 To grow a tailored polymeric coating from indi-
vidual monomers at the water–bilayer interface, the polymerization initiator must be incorporated in the bilayer itself. To prevent
the destruction of the lipid bilayer, the reaction conditions must be mild, and the reactive species must be tolerant to the buffered
aqueous conditions necessary for bilayer formation. The polymerization must be compatible with the bilayer environment, allow-
ing successful, robust reaction while maintaining the integrity of the membrane. The synthesis of species that are capable of both
selective membrane incorporation and reaction promotion or catalysis is challenging. In 2012, Hooley and coworkers presented the
use of the selective molecular recognition capabilities of the water-soluble deep cavitand 40 (Fig. 32) for the synthesis and setting up
of a functionalized polymeric surface at interface of a SLB.138
The tetracarboxylate cavitand 40, able to recognize trimethylammonium-tagged substrates through cation–p interactions
between the faces of aromatic cavitand walls and the charged guest, was incorporated in a supported bilayer. Long guests hosted
by the cavitands can extend out of the cavity, presenting large functional groups into the exterior milieu, allowing immobilization
of a number of species at the membrane surface. 139 Hooley and coworkers explored the incorporation of the reactive initiator
species 41 capable of initiating ATRP of methacrylate monomers (42, 43, and 45) under mild conditions in aqueous solutions,
as depicted in Fig. 33A.
The authors demonstrated that displaying the initiator at the membrane surface, it is possible to create polymers that are non-
covalently attached to the top of the bilayer to form a flexible coating. Both hydrophobic and hydrophilic polymers, as well as bio-
adhesive polymers, can be synthesized by simple alteration of the monomer ( Fig. 33B). The displaying of the initiator at the
membrane surface lead to the synthesis of polymers that are noncovalently attached to the top of the bilayer to form a flexible
coating. The polymethylmethacrylate (PMMA) was obtained at the membrane surface at room temperature using as monomer
MMA 42. The attached polymer resulted to be resistant to washings; in fact neither water nor Phosphate buffered saline (PBS) solu-
tions caused the removal of the polymer from the membrane. The living nature of the polymerization was tested by repeating poly-
mer growth after removing the excess monomer by washing. Polymer growth was restarted after removal of monomer by simple
reinjection of monomer and catalyst mixture. Control experiments were performed in the absence of the cavitand, to demonstrate
that the anchoring of the initiator in the membrane is essential for polymer growth. Without the cavitand present, no incorporation
of initiator 41 into the membrane was observed, and no growth of polymer upon addition of monomer and catalyst occurred. Not
only hydrophobic polymers, but also hydrophilic as well as bioadhesive polymers, can be synthesized by simple alteration of the
monomer. For hydrophilic poly(HEMA), 2-hydroxyethyl methacrylate (HEMA) 43 was used as monomer. The obtained polymer
was not removed from the bilayer interface upon washing with water, but a PBS buffer washing was needed. After the removal of the

Figure 32 (Left) Tetracarboxylate deep cavitand 40 and (center) the minimized conformation (SPARTAN) of the complex between 40 and the initi-
ator41. (Right) Guests and monomers used in the studies. Adapted from Liu, Y.; Young, M. C.; Moshe, O.; Cheng, Q.; Hooley, R. J. Angew. Chem. Int.
Ed. 2012, 51, 7748–7751.
 Cavitands 111

Figure 33 (A) Representation of the ATRP process. (A) Adapted from Pochorovski, I.; Boudon, C.; Gisselbrecht, J.-P.; Ebert, M.-O.; Schweizer, W.
B.; Diederich, F. Angew. Chem. Int. Ed. 2012, 51, 262–266; Angew. Chem. 2012, 124, 269–273. (B) Representation of polymer growth at supported
lipid bilayer functionalized with cavitand 40.Adapted from Liu, Y.; Young, M. C.; Moshe, O.; Cheng, Q.; Hooley, R. J. Angew. Chem. Int. Ed. 2012, 51,
7748–7751 and Perez, L.; Ghang, Y.-J.; Williams, P. B.; Wang, Y.; Cheng, Q.; Hooley, R. J. Langmuir 2015, 31, 11152–11157.

polymer, the membrane was still intact and cavitand 40 still present inside the membrane and fully functional, ready for refilling
with new reactants. The polymerization reaction can be repeated several times after polymer removal by simple washing, without
further addition of initiator molecules. This is due to the fact that not all bound initiator molecules are used up in the initial poly-
merization, and remain intact, bound in the cavitands underneath the growing polymer, while the “used” initiators are removed
from the cavitand along with the polymer. Bioadhesive, functional polymers were synthesized using 2-aminoethylmethacrylate
hydrochloride (AEMA) as monomer (44). The poly(biotin-AEMA), obtained using 45 as monomer, resulted to be resistant to
removal from the surface by PBS washing, indicating its relative insolubility in water. The ability of the poly(biotin-AEMA) surface
to capture a selected protein at the polymer surface was proved using fluorescently tagged avidin by confocal fluorescence
microscopy.
The next step of Cheng and Hooley was to apply the “in situ cavitand-mediated polymer growth” protocol to promote the poly-
merization of functionalized monomers, like AEMA 44. 140 Primary amines are unsuited to ATRP, as they show strong coordination
to metal ions, leaching the catalyst from the reaction mixture and causing low turnovers, poor polydispersities, and the formation of
somewhat random polymer sizes.130,141 Since a small, reactive polymer patch is perfectly sufficient to allow in situ reactivity at the
bilayer, narrow polydispersities are unimportant to this aim, allowing the optimization of the catalyst system for ATRP effectiveness.
The selected one was the combination of three ligands, 2,2 bipyridyl (bipy), 9,10-phenanthroline (phen), and tris(benzimidazole)-
triethyleneamine (tbte), and two metal salts (FeCl2 and CuBr) in the presence of ascorbic acid as reductant.130 Phen and bipy are
bidentate ligands more weakly coordinating, whereas tbte can occupy up to four sites on the metal center, potentially limiting
AEMA coordination and catalyst inactivation. The polymerization of AEMA was conducted at the bilayer interface, where water-
soluble tetracarboxylate cavitand 40 was incorporated and the ATRP initiator 41 bound via shape-fitting noncovalent interactions
with the membrane-bound cavities (Fig. 34).
This membrane was able to promote the polymerization of primary amine containing monomers at a supported bilayer inter-
face, allowing functionalized polymers to be formed. The resulting polymer did not display living characteristics at the bilayer inter-
face, as observed in the case of HEMA. 138 After reaction, the amine groups inactivate the catalyst mixture and terminate the process,
limiting the polymerization to the formation of small microscale polymer patches. The obtained polymer patches display multiple
primary amine groups at the surface that can be reacted in situ to allow display of fluorescent reporters or epitopes for protein
immobilization, as well as acting as “molecular glue” by displaying a cationic surface for the soft immobilization of nonadherent
cells at the bilayer. For protein recognition, the poly(AEMA) surface was derivatized with biotin groups and the recognition of avidin
by the functionalized membrane proved. The authors demonstrated that only specific biotin:avidin interactions allowed immobi-
lization of the protein at the bilayer interface providing selective biorecognition via the cavitand-mediated polymer synthesis. The
performed control experiment evidenced that the naked poly(AEMA) surface shows no affinity for biotin. Finally, the authors
demonstrated also that the thin layer of polymer at the bilayer is able to act as the “glue” required for cell adhesion between the
bilayer and living cell. The cell recognition properties of the functionalized construct were tested using human monocytic THP-1
112 Cavitands

Figure 34 In situ cavitand-mediated polymer growth at a bilayer interface and application to protein recognition and cell adhesion. Adapted from
Perez, L.; Ghang, Y.-J.; Williams, P. B.; Wang, Y.; Cheng, Q.; Hooley, R. J. Langmuir 2015, 31, 11152
11157.

cells, which are nonadherent. After introduction and incubation of THP-1 cells to the freshly grown poly(AEMA) surface, a substan-
tial, retained resonance angle change was observed, indicating immobilization of cells at the cationic polymer interface. THP-1 cells
are quite small, and the polymer patches are large enough to provide a cationic surface area sufficient to allow adhesion of the cells.
The cell attachment proved to be robust, as the cells were not removed from the surface after washing with water or PBS buffer. The
developed method to support ATRP polymerization on the bilayer surface resulted to be suitable not only to promote functional
polymer growth bilayer–water interface but also to promote cell and protein recognition, as well as in situ reactivity.
In 2014, the same authors demonstrated that the anionic tetracarboxylate self-folding deep cavitand 40 is capable of immobi-
lizing unmodified proteins and enzymes at a SLB interface, providing a simple, soft bioreactive surface that allows enzymatic func-
tion under mild conditions. 142 Cheng and Hooley demonstrated that the adhesion was not based on the usual cavity-based
recognition properties of similar host molecules, but rather on complementary charge interactions. This was proved to perform
two tests. First, an excess of choline chloride (a strongly binding guest)143,144 was added to the functionalized cavitand
40:POPC (palmitoyl-oleyl-phosphocholine) membrane (Fig. 35) to prevent a suitably sized group from fitting inside the cavity.
The bound choline does not protrude above the cavitand rim once bound, and has no effect on interactions with the external
carboxylates. Alternatively, carboxylate-depleted cavitand 46 was synthesized (Fig. 35).
Cavitand 46 displays an identical cavity size and similar host properties to 40 but no charged groups at the upper rim. 145 The
lack of charged, hydrophilic species at the cavity external rim has little effect on its orientation in the upper leaflet of the bilayer. The
benzimidazole groups, while only slightly more polar than the base, are still capable of providing some orientational preference in
the upper leaflet.145 As target protein, bovine serum albumin (BSA), which has no obvious motif that can be recognized by the
cavity of both 40 and 46, was selected. BSA showed no affinity for the SLB constructed from a mixture of POPC lipids and 2% cav-
itand 46, while the protein was retained at the surface of the cavitand 40–bilayer system, even when the cavity of 40 was occupied by
the choline. This is extremely unusual for self-folding deep cavitands, since the recognition process is always controlled by size and
shape complementarity between guest and the host cavity.
The potential of the system to bind macromolecules was further examined with proteins that differ from BSA in overall size and
charge, like cytochrome c (cyt c) that is by far smaller (12.4 kDa with respect to 66.4 kDa of BSA), and has a higher isoelectric point
(pI ¼ 10.5, with respect to pI ¼ 4.8 for BSA). Cyt c is positively charged in pH 7.4 PBS buffer, whereas the cavitand maintains

Figure 35 Protein binding at the cavitand 40:POPC membrane by charge matching interactions. Adapted from Ghang, Y.-J.; Perez, L.; Morgan, M.
A.; Si, F.; Hamdy, O. M.; Beecher, C. N.; Larive, C. K.; Julian, R. R.; Zhong, W.; Cheng Q.; Hooley, R. J. Soft Matter 2014, 10, 9651–9656.
 Cavitands 113

a negative charge. 143,144 The ability of the membrane-bound cavitand 40 to bind cyt c was already demonstrated by the authors.145
The POPC:40 bilayer showed high affinity for cyt c under a variety of salt conditions, with the strongest affinity experienced for low
salt conditions. The presence of multiple cavitands in the bilayer environment aids the persistence of the bound proteins on the
surface, since they can easily shuttle from one position to another on the surface, rather than dissociate completely. The most robust
binding occurred for proteins with high isoelectric point, which can be immobilized under high salt concentration, while less posi-
tive proteins require lower ionic strength conditions for recognition. This system can selectively discriminate proteins displaying
different charge.
The recognition event is promoted by the interfacial nature of the system: cavitand 40 shows no affinity for proteins or positively
charged amino acids in aqueous solution. The introduction of negatively charged lipids to the POPC bilayer has a somewhat similar
effect to that of cavitand 40, but in a far less effective way. The ability of sodium palmitate to bind proteins, however weak, suggests
that disruption of the bilayer surface has an effect on the recognition. The recognition event could be due to the fact that water at the
interface solvates the host poorly with respect to free water. In this system, cavitand 40 is so surrounded by hydrophobic lipids that
may restrain the conformational freedom of nearby water molecules. Positively charged side chains may provide a stronger inter-
action by combination of hydrogen bonding and Coulomb attraction in the slightly hydrophobic pocket, sufficient to allow
binding.
Finally, the authors explored the possibility to use this system to create a soft, bioreactive surface ( Fig. 35). To test the ability of
the system to perform reactions, trypsin was selected as target enzyme, since it has the correct charge matching properties to bind at
the POPC:40 bilayer. The recognition event is mild, and even enzymes can be attached via this method. The reactivity of the adhered
enzyme was tested using insulin B as substrate for trypsin cleavage. Insulin B is a 30-mer oligopeptide with two sites susceptible to
trypsin cleavage: an arginine group at position 22 and a lysine at position 29. The bound trypsin showed almost full functionality at
the surface, in contrast to bioreactive surfaces formed by covalent catalyst attachment. When insulin B was incubated with the
POPC:40 bilayer in the presence of adhered trypsin, the presence of the 1–22 and 23–29 fragments, indicating C terminal cleavage
at both the arginine and lysine residues, were observed as expected, as well as the 23–30 fragment, indicating incomplete cleavage at
the lysine 29 site. This is due to the fact that trypsin cleavage at arginine residues is much more faster than at lysine under similar
conditions.146,147 No unreacted insulin B and no fragments for incomplete arginine cleavage were observed. In the absence of
adhered trypsin, no reaction or decomposition of insulin B was observed with the POPC:40 bilayer. The enzymatic process was
easily interrupted washing away insulin B, and, as the trypsin was not washed away from the surface, the bioreactive surface was
reusable. The process resulted to be fully repeatable and the activity of the immobilized enzyme is undiminished. The system forms
a reusable bioreactive surface with minimal catalyst loss, even though the individual enzyme surface contacts are “weak” forces.

3.05.8 Conclusions and Outlook

Cavitands have undergone to two development stages and are now entering the third one. The first two, deeply intertwined, deals
with synthesis and molecular recognition. The synthetic stage brought in a whole set of synthetic procedures for the upper and lower
rim functionalization of cavitands, including the bridging reactions of four pairs of resorcinarenes of phenolic OHs. In most of the
cases, standard synthetic procedures were adapted to the specific resorcinarene/cavitand substrate, often inspired by the cognate cal-
ixarenes field, which developed earlier. After the initial synthetic burst, the focus drifted toward the molecular recognition properties
of cavitands. In this stage, cavitand chemistry contributed, together with many other synthetic receptors, to define, weight, and
orchestrate the interaction modes responsible for molecular recognition. The most significant legacy of this stage is a set of rules
for the molecular-level engineering of multiple synergistic interactions, necessary to boost selectivity in recognition. Having the
synthetic and molecular recognition toolboxes filled, the focus has now shifted to the function side, in which the required property
defines the cavitand structure. Here is where the ingenuity of the researchers active in the field should focus to bring the cavitand
field to the next level. The selected examples reported in this chapter demonstrate the almost unlimited possibilities of cavitands to
offer innovative solutions in many different fields, spanning from biology to materials science.

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 3.06 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors
PK Bharadwaj, Indian Institute of Technology Kanpur, Kanpur, India
Ó 2017 Elsevier Ltd. All rights reserved.

3.06.1 Introduction 117

3.06.2 Synthesis 118
3.06.2.1 Methodology 118
3.06.2.2 Strategy 119
3.06.3 Metal Complexation 120
3.06.3.1 Cryptands With N and O as Donors 120
3.06.3.2 Cryptands With N, S, and O as Donors 131
3.06.3.3 Complexation by Anions 135
3.06.3.4 New Class of Unsymmetrical Cryptands 138
3.06.4 Cryptand-Based Amphiphiles 140
3.06.4.1 Formation of Vesicular Structures 140
3.06.4.2 Amphiphiles at the Air–Water Interface 144
3.06.4.3 Molecular Recognition 147
3.06.5 Fluorescence Signaling With Cryptand-Based Systems 148
3.06.5.1 Cryptands in Fabricating Logic Gates 157
3.06.5.2 Reversible Fluorescence Signaling 158
3.06.6 Förster Resonance Energy Transfer 165
3.06.6.1 Single-Step FRET 165
3.06.6.2 Multi-Step FRET 166
3.06.7 Cryptands as Nonlinear Optically Active Materials 170
3.06.7.1 Third-Order Optical Nonlinearity 171
Acknowledgments 176
References 176

3.06.1 Introduction

Cryptands are molecules with varied structures, although in the present article, the term “cryptand” will be reserved for macrobi-
cyclic compounds where two bridgehead atoms are connected by three bridges. It is also possible to build these molecules with
benzene or multiaromatic systems as bridgeheads. A few cryptands with mixed bridgeheads are also reported. Cryptands have struc-
tural features that make them an important component in supramolecular chemistry with wide ranging applications in chemical,
biological, and material sciences. These molecules are characterized by a number of donor atoms in its architecture whose nature as
well as topology can be designed to accommodate guests such as cations, anions, or neutral molecules inside the cavity to form
inclusion complexes. The number, as well as the nature, of the donor atoms and their strategic positions greatly affect the binding
characteristics of a cryptand. The selectivity of a cryptand toward a guest depends upon the number as well as nature of the donor
atoms and their spatial positions besides several external parameters such as pH of the medium, temperature, nature of the solvent,
and so on. The rigidity of the framework also greatly influences the binding characteristics of a cryptand. When the three bridges are
made up of saturated aliphatic chains, the cavity exhibits greater flexibility whereas unsaturation present in the chains can lead to
steric constraint and a rigid cavity. Introduction of aryl groups tend to stiffen the macrocyclic rings and can rigidify the cavity. Func-
tional groups like amide, ester, etc. facilitate organic polar group binding and additional ligand stiffening. In general, the more rigid
the cavity, the greater will be its discriminatory power against the substrates that are either smaller or larger than the cavity, as it will
require severe deformation of the cryptand. An ideal situation for substrate binding will arise if the donor set and shaping groups are
preorganized to accommodate a substrate with minimum deformation of the cryptand cavity. However, the desired selectivity
toward a particular guest in the presence of several others remains an elusive goal and cryptands usually exhibit plateau selectivity.1
It is also possible to influence the binding characteristics of a cryptand through chemical modifications so that a guest can bind from
outside, further extending the scopes for guest binding.
Broadly, macrobicyclic cryptands can be divided into two groups considering the donor atoms present. They can be laterally
symmetric (Fig. 1A) or laterally nonsymmetric (Fig. 1B).
Also, cryptands can be considered nonsymmetric, if the three bridges are not identical in terms of length. Such cryptands are
important members of the cryptand family.
Since its discovery,2,3 the literature on cryptands has witnessed an explosive growth. An overwhelming majority of the cryptands
synthesized are laterally symmetric in nature although a substantial number of laterally nonsymmetric ones are also known. The
present article is restricted to laterally nonsymmetric cryptands. These molecules can be modified to have quite interesting systems.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12513-2 117

118 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 1 Examples of laterally (A) symmetric and (B) nonsymmetric cryptands.

However, the literature covered is not exhaustive and if there is any omission of an important article, it is not intentional. A number
of books and review articles have been devoted4–12 to the chemistry of laterally symmetric cryptands.

3.06.2 Synthesis

There are two aspects13 of synthesis of these molecules: (i) methodology and (ii) strategy. The commonly adopted methodology
includes high dilution, use of templates, inclusion of rigid groups and low temperature while major strategies14 can be termed
as (a) stepwise, (b) tripodal coupling, (c) tripodal capping, and (d) single or double capping.

3.06.2.1 Methodology
Allowing reactions to proceed under high dilution is the most extensively used technique and is accomplished by simultaneous
addition of the reactants in a flask having a large amount of the solvent. The appropriate concentration level for the cyclization
step is, however, determined empirically. Under high dilution conditions, the reactions should be facile to reduce the scope of
forming undesired side products and also to maintain a very low stationary concentration of the reactants. In addition, the
desired product must be stable under the prevailing reaction conditions. An apparatus for the high dilution synthesis has
been described.15,16 This apparatus consists of motorized burets, which can add measured quantities of the reactants to the reac-
tion vessel at a very slow rate. Although this technique has been known17 for a long time, it was Ziegler who developed18 and
widely used this method for macrocyclization reactions. Detailed theoretical studies19 regarding the factors that influence a mac-
rocyclization process and practical hints20,21 are available. As a high dilution synthesis takes a long time to complete and requires
a large volume of solvents, other methods like use of a template or allowing the reaction to proceed at low temperature have
been used wherever possible. A template can organize22 the reactants with respect to each other so that they undergo reaction
in a particular linking to form the desired compound or can stabilize a particular product out of many.23 When a kinetically inert
metal ion is used, the final isolated product contains a metal ion in the cavity whose removal might sometimes become diffi-
cult.24 Introduction of rigid groups in the reactants should lower the conformational mobility25 to aid in the preorganization of
the reactive fragments to react in a directed fashion and reduce the possibility of unwanted oligomerization. In cases where a reac-
tion can proceed at a reasonable rate at low temperature (
5 C), macrocylization can be achieved without any significant
polymerization.26
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 119

3.06.2.2 Strategy
Some major strategies27 developed for the synthesis of cryptands are termed as (1) stepwise, (2) tripodal coupling, (3) single
capping, and (4) double capping. In the case of laterally nonsymmetric cryptands as defined earlier (hereafter only cryptands),
the popular synthetic strategies are (i) tripodal coupling and (ii) single capping.
In tripodal coupling, [1 þ 1] condensation of two tripodal units is carried out in a one-pot synthesis.28 A number of cryptands
have been synthesized by Schiff base condensation of tripodal amines with tripodal trialdehydes, followed by reduction of the
imine groups formed with NaBH4 in one-pot synthesis. An alkali metal ion such as Rb (I) or Cs (I) is used29 at
40 C as a kinetic
template to organize the reactants with respect to each other. The entire operation requires < 12 h and the yields are usually quite
satisfactory (range,
40–55%). The cryptands are isolated as crystalline solids through fractional crystallization. The Schiff base
condensation involves initial attack on the carbonyl carbon by the lone-pair of nitrogen; hence, availability of this lone-pair is
important. When a transition metal ion is used as the template, it coordinates strongly to the lone-pair of amino nitrogen attenu-
ating its nucleophilicity. So, the reaction does not proceed in the desired direction even when the temperature is raised to a higher
value using a different solvent.
Comparable yields of the products are also obtained when these reactions are carried out at a low temperature (
5 C) without
employing any templating ion (Fig. 2). However, choice of solvent, although empirically determined, is crucial for the success of
this method. For the condensation of the podant with three terminal aldehydes with a podand amine, methanol has been found to
be the solvent of choice. The trialdehyde is taken in methanol in a round bottom flask and the solution of the amine in methanol is
added dropwise at a very slow rate. The podand aldehyde is slightly soluble in methanol at low temperature and with the progress of
the reaction, more and more of the aldehyde comes into the solution phase. This condition keeps the amount of the reactants in
solution low, mimicking a high dilution reaction condition. In this method, the product is obtained in satisfactory yields with only
small amounts side products from which the desired product can be easily separated through fractional crystallization. Simple
modification of the two podand partners can lead to the synthesis of a large number of cryptands by this method. However, if
the two tripodal units are mismatched in size, the [1 þ 1] product is not formed. Instead, the [2 þ 2] product is formed30 along
with a number of side products. This tripodal coupling strategy can afford a dynamic combinatorial library of laterally nonsym-
metric cryptands.31 Two such cryptands are shown in Fig. 3 where the substitutions on the aromatic rings can be exploited to
generate interesting chemistry.
Two other cryptands (Fig. 4) with a small cavity have been synthesized by adopting the tripodal coupling strategy. Interestingly,
chemistry with these molecules is waiting to be explored.
In the tripodal capping strategy, the Co(III) ion is used as a template in bringing about the reaction to the desired cage
compound (Fig. 5). Sargeson and coworkers used Co(III) as the template because of its kinetically inert nature.32 However, in

Figure 2 Low-temperature bulk synthesis of a cryptand by tripodal coupling.

Figure 3 Two cryptands with scopes for further derivatization through the aromatic groups.
120 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 4 Cryptands with small cavity.

Figure 5 Synthesis of a cage molecule using Co(III) as a template.

case of laterally nonsymmetric cryptands like the one shown in Fig. 5, only moderate yields are achieved. The presence of thioethers
in the podand leads to reduction of Co(III) to kinetically labile Co(II). In addition, a thioether is a poor donor to Co(III) compared
to an amine. Both these factors lead to the loss of the cobalt ion from the podand under the capping conditions and results in a poor
yield of the desired product. This synthetic strategy can be applied to obtain macrobicyclic compounds with a contracted cavity33
(Fig. 6) and also provides an easy access to functionalized cage molecules34 (Fig. 7). However, after the reaction is complete, the
Co(III) ion being both kinetically inert as well as thermodynamically stable is held inside the cavity and its removal poses problems.
The encapsulated Co(III) is first reduced to Co(II) by means of a strong reducing agent like Zn dust followed by complexation with
cyanide ion or concentrated boiling HBr.

3.06.3 Metal Complexation

3.06.3.1 Cryptands With N and O as Donors
Metal complexation abilities of the cryptands shown in Fig. 8 have been probed in solution as well as in the solid state. Each crypt-
and has a large cavity with two distinct binding sites: a tetraamine moiety and an ethereal moiety at the two ends of the cavity. In
order to determine the coordination properties of these ligands in aqueous solution, the complexation behavior of various metal
ions such as Ni(II), Cu(II), Zn(II), Cd(II), Tl(I), Ag(I), and Pb(II) as well as of alkali and alkaline earth cations toward these crypt-
ands have been investigated. While the tetramine moiety is suitable to bind transition as well as main-group metal ions, the hard
ethereal moiety is expected to favor an alkali/alkaline earth metal ion. The protonation behavior of the cryptands 9–11 have been
probed35 since they form stable protonated species as well as metal cryptates that have been X-ray crystallographically characterized.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 121

Figure 6 A cage molecule with a contracted cavity.

Figure 7 Synthesis of a cage molecule with a functionalized group.

122 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 8 Cryptands incorporating N and O donors.

 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 123

The protonation constants were determined in 0.10 mol dm 3 (Me4N)NO3 at 298.1 K and the values are listed in Table 1. In the
case of 11, the first protonation constant could not be determined due to precipitation in the pH region where the [H11]þ species is
expected to form.
In the pH range, 2.5–10.5, both 10 and 11 form the fully protonated species, that is, [H510]5 þ and [H511]5 þ, while cryptand 9
forms the fully protonated species [H59]5 þ only at pH lower than 2.5. Its existence is confirmed by the crystal structure of the
species, [(H59)(ClO4)5]·4H2O. This suggests higher basicity for 10 and 11 compared to 9. A look at Table 1 also suggests that
for 9, the first two protonation constants are significantly higher compared to those of 10 and 11. In contrast, the third and fourth
protonation constants are significantly lower in 9. Such abnormal protonation behavior is not unprecedented and possibly due to
solvent molecules inside the cavity that can stabilize intermediate protonated species.36 In fact, the crystal structure of the diproto-
nated cryptands [H29]2 þ and [H210]2 þ show the presence of one H2O molecule37 included inside 9 and two H2O molecules38
included inside 10 that are involved in significant hydrogen-bonding interactions with the ammonium groups.
Surprisingly, cryptand 16 which is the para-analog of cryptand 9, dimerizes upon protonation39 with hydrochloric acid in
aqueous methanol (Fig. 9). The crystal structure of the hydrochloride salt of this dimer has also been reported with the presence
of highly disordered water molecules in the cavity.
Since the cryptands 9–11 are sparingly soluble in water, their complexation properties toward Cu(II), Zn(II), Ni(II), Co(II),
Cd(II), Ag(I), Tl(I), and Pb(II), as well as alkali and alkaline earth metal ions in aqueous media, have been studied. Other metal
ions could not be studied due to extensive precipitation of indefinite composition. From the results of this study, it is clear that
the three cryptands do not show any tendency to form complexes with alkali or alkaline earth cations, while they are capable of
forming stable complexes with the remaining metal ions. Nevertheless, the ethereal moieties of these ligands display a poor propen-
sity to remain vacant; indeed, as shown by crystal structure determinations, they are well suited for strong hydrogen-bonding inter-
actions with water molecules inside the ligand cavity.
Although the set of stability constants is not complete, some interesting conclusions regarding the coordination properties of
these ligands can be drawn. In the case of the metal ions Zn(II), Cd(II), and Pb(II) for which no ligand-field stabilization is possible,
the complex stability increases with increasing metal ion size. Such coordination tendency is evidently connected with the macro-
bicyclic nature of the ligands since an opposite stability trend is observed40 for Zn(II) and Cd(II) complexes with the podand tris(2-
aminoethyl)amine (tren) which can be considered as the acyclic analog of these molecules. Cryptands are more rigid compared to
acyclic molecules and, consequently, are less prone to modification of the donor atoms’ topology to satisfy the metal ion coordi-
nation requirements. In the present cases, cryptands 9–11 are too large to give a good fitting with all the studied metal ions, justi-
fying the increase of stability with increasing the cation size. Accordingly, the difference in stability between the complexes of tren
and those of the cryptands diminishes with increasing cation size. The complexation ability has been found to be highly dependent
on the ligand structure. Compared to 9 and 10, cryptand 11 shows lower tendency to form complexes in spite of being most flexible
among the three. This is expected due to the formation of six-membered chelate rings rather than the more stable five-membered

Table 1 Logarithms of protonation constants for 9–11

log K a
9 10 11

L þ Hþ ¼ HLþ 10.45(7) 9.74(6)

HLþþHþ ¼ H2L2 þ 21 10.44(2) 8.68(6) 8.9(1)
H2L2 þþHþ ¼ H3L3 þ 5.56(6) 7.47(8) 8.8(1)
H3L3 þþHþ ¼ H4L4 þ 3.46(6) 5.6(1) 4.6(1)
H4L4 þþHþ ¼ H5L5 þ 2.4(1) 2.9(1)
a
Values in parentheses are standard deviations in the significant figure.

Figure 9 Dimerization of cryptand 16 under low pH.

124 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

ones formed in case of 9 and 10. Surprisingly, all complexes formed with 9 are more stable than those with 10; this difference in
stability amounted to more than three orders of magnitude for the Cd(II) and Pb(II) complexes. The more rigid framework in 10
does not allow the entering metal ion to adjust the coordination geometry to its liking. Indeed, the solid-state structure of the Cd(II)
complex with 9 shows that its more flexible structure allows all the donor atoms including ethereal oxygens to get bonded to the
metal ion41 without stretching any of the bond lengths to a significant extent in the cryptand (Fig. 10). This binding brings the two
bridgehead N atoms to 4.978(4) Å, which is much closer compared to the distance of 6.249(5) Å found in the metal-free cryptand.
The Pb(II) ion, on the other hand, prefers42 to bind at the tren-end without any noticeable distortion of the metal-free structure
of the cryptand 9 (Fig. 11).
The Tl(I) ion exhibits a “4 þ 3” coordination43 mode with 9 having four normal TleN bonds [2.788(8)–2.869(9) Å] with the
donors at the tren-end and three long interactions [3.07(9)–3.14(9) Å] with the ethereal O atoms (Fig. 12). Since the TleN
bond lengths are at the long end of the range observed for other complexes of the metal ion, the bonds are regarded as quite ionic
in character.44,45
The effect of such loose binding leads to complete replacement43 of the metal by Ag(I) when an acetonitrile solution of the Tl(I)-
cryptate is treated with a AgNO3 solution at RT. The Ag(I) ion is bonded to four nitrogens at the tren-end of the cryptand in a very
distorted fashion (Fig. 13).
When the secondary amino nitrogens in 9 are derivatized with the electron, withdrawing acetonitrile groups to afford cryptand
17 its binding characteristics toward Tl(I) and Ag(I) changes drastically. Now, Tl(I) exhibits “3 þ 5” coordination comprising three
normal TleN bonds and five long interactions with the remaining donor atoms (Fig. 14).

In contrast, an Ag(I) ion binds only the two bridgehead nitrogens showing a linear two coordination structure (Fig. 15).
In the 17 3 Ag cryptate (Fig. 15), the bond lengths and bond angles of the cryptand moiety are within the normal statistical
errors. However, the two bridgehead N atoms are significantly pulled inside by the Ag(I) ion; the distance between them is found
to be 4.687(2) compared to 4.903 (4) Å in the previous Ag-cryptate. With 17, Cu(II) forms a 1:1 complex but here two out of the
three cyano groups are hydrolyzed to carboxylic acids and the metal ion is bonded to 17 from outside near the tren-end of the cavity
(Fig. 16). It is speculated that the metal ion initially binds the cryptand outside the cavity and activates the cyano group, which is
then attacked by H2O. Many metal-mediated processes of cyano group hydrolysis are known46 in the literature.

Figure 10 A perspective view showing a Cd(II) ion bonded to all donor atoms of 9.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 125

Figure 11 A perspective view of the Pb(II) cryptate of 9.

Figure 12 A perspective view showing a Tl(I) ion included in the cavity of 9.

Figure 13 A view of the Ag(I)-cryptate of 9.

126 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 14 A Tl(I) ion bound inside the cavity of 17. Hydrogen atoms are omitted for clarity.

Figure 15 A view showing a Ag(I) ion bonded to the two bridgehead nitrogens of 17.

Figure 16 A Cu(II) ion bonded to 17 from outside. Hydrogens are not shown.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 127

On the other hand, the secondary amines in cryptand 10 can be methylated to give 18. It readily forms a Cu(II) inclusion
complex when treated with cupric acetate. Here, the metal ion is bonded47 to two methylated and the bridgehead N donors besides
an acetate and a methanol molecule in a square pyramidal geometry (Fig. 17). Reaction of this cryptate with basic hydrogen
peroxide in methanol causes decomposition of the complex with concomitant transfer of an oxygen atom to the cryptand.
Stopped-flow experiments carried out at  90 C support the formation of the species CuOOH before ligand oxygenation thus
mimicking the enzyme, dopamine-b-hydroxylase.
The inclusion complexes of 9–11 with a number of first-row transition metal ions have been characterized in the solid state.
While the N4 moiety is suitable to bind a transition metal ion, the number of donor atoms is insufficient to saturate the coordina-
tion sphere of many metal ions. Besides, in both cases of 9 and 10, the tren moiety pushes the metal ion out of the plane described
by the three secondary amines away from the bridgehead nitrogen exposing the metal ion to further attack by other ligands,
including solvent molecules. These ligands/solvent molecules are constrained to occupy coordination sites located in the vicinity
of the hydrophobic region defined by the aromatic rings. For example, a mononuclear complex of Ni(II) cryptate of 10 is formed37
where the Ni(II) ion inducts a Cl anion to adopt a trigonal bipyramidal coordination geometry (Fig. 18). However, with 9 in the
absence of a coordinating anion, the metal attains48 octahedral coordination through bonding to a water molecule and a MeCN

Figure 17 An illustration showing the binding mode of a Cu(II) ion with 18.

Figure 18 A perspective view showing a Ni(II) ion bonded to a chloride anion inside the cavity of 10.
128 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

molecule. The H atoms of the water molecule are hydrogen-bonded to the two nearest ethereal oxygen atoms at the upper deck of
the cryptand (Fig. 19).
In case of the cryptand 10, however, its top part tilts away upon binding of an anion to the Cu(II) ion49 anchored at the tren-end
to avoid hydrophobic aromatic spacers (Fig. 20), such that a part of the anion is outside the cavity. However, a neutral molecule, like
water, bound to the Cu(II) ion inside the cavity cannot come closer to the ethereal oxygens and instead38 its hydrogen atoms take
part in hydrogen bonding interactions with the aromatic groups (Fig. 21).
Metal cryptates have been suggested to be effective as homogeneous catalysts50,51 because of their increased kinetic and thermo-
dynamic stability. Transition metal catalyzed oxidation of organic substrates with dioxygen is closely related to important biological
processes like enzymatic oxygenation and therefore, can serve as biomimetic models.52 Also, with effective oxygenation, such
systems can be potentially useful as the next-generation low-temperature bleaching agents.53 The cryptand 10 readily forms the
mononuclear complex [10 3 Co(II)](picrate)2 when it is treated with 1 equiv of Co(II)-picrate. While the solid-state structure of
this species is not known, it affords crystals in the presence of SCN anion whose structure is found to be the same as that of
Cu(II) (Fig. 24). In absence of the SCN anion, the coordination site can either be vacant or be occupied by a solvent molecule.
Both the Co(II) and Cu(II) cryptates and their perchlorate salts behave as homogeneous catalysts54 in converting olefinic substrates
to epoxides and benzylic substrates to the corresponding ketones in excellent yields in the presence of 2-methylpropanal and molec-
ular oxygen at ambient temperature and pressure (Table 2). The catalyst can be reused many times without loss of activity since the
metal ion is tightly held inside the cavity. It will be interesting to synthesize chiral cryptands that can form stable transition metal
cryptates for chiral epoxidation as well as other chiral organic transformation reactions.
Cryptand 11, with a tris(3-aminopropyl)amine (trpn) unit in place of tren and ortho-substituted benzene groups in the three
bridges, has a collapsible cavity that can enlarge upon metal binding. The trpn unit can wrap around an ion like Zn(II) in such
a way that the metal can adopt a tetrahedral coordination geometry (Fig. 22).

Figure 19 A view showing a Ni(II) ion inside the cavity of 9. The metal ion is also bonded to a water and a MeCN molecule. Hydrogens are
omitted.

Figure 20 A Cu(II) ion inside the cavity of 10 is also bonded to a SCN anion. The anion is directed outside the cavity while the cryptand is tilted
in the opposite direction. Hydrogens are not shown.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 129

Figure 21 A perspective view of Cu(II) cryptate of 10. The metal ion is also bonded to a water molecule. Hydrogen atoms of 10 are not shown.

Table 2 Summary of Co(III) cryptate catalyzed oxidation of olefinic and benzylic substrates

Yield%
Entry Substrate Product A B

1 Quant. Quant.

2 82 60

3 50 36

4 Quant (3:1) 75(2:1)

5 91

6 70 54

7 49 35

A ¼ 10 3 Co(II)](CIO4)2; B ¼ 10 3 Cu(II)](CIO4)2
130 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 22 A Zn(II) ion bound at the N4-end of 11 showing tetrahedral coordination. Hydrogen atoms are omitted.

Various nonbonding distances in the free ligands and in the complexes (Table 3) suggest that the donor atoms do not move
from each other to a significant extent upon complexation in the cases of 9 and 10, while in case of 11 they move significantly.
However, the X-ray structures of the cryptates of 9–11 show that out of four nitrogens at the tren(trpn) end, three bind a metal
ion with normal metal–nitrogen distances (range, 1.94–2.10 Å) while the fourth metal–nitrogen distance is much longer
(
2.40 Å). Thus, these cryptands not only impose a low coordination symmetry onto the metal ion but make the ligand field
around the bound metal weak as well. Consequently, the cryptates exhibit low-energy ligand-field bands in the UV–vis spectra
and small AII values in the EPR signals for the Cu(II) cryptates. For the cryptands 12–14, no cryptate could be isolated in the solid
state. However, electronic spectral studies indicate that these cryptands also form 1:1 complexes with first-row transition metal ions
showing low-energy ligand-field bands.
Synthesis of the laterally nonsymmetric cryptand 19 (Fig. 23) has been achieved55 in high yields by Cu(II)-catalyzed alkyne to
azide cycloaddition followed by tripodal coupling reaction using La(III) as the templating metal ion. The cryptand has two distinct
binding sites that are well separated. However, only mononuclear cryptates of Zn(II) and Ag(I) ions have been isolated and

Table 3 Selected nonbonded distances (Å) in free and metal cryptates of 9–11

9 [93Ni(MeCN)(H2O)]2ClO4$MeCN

N(1)/N(3) 6.249 6.410

N(2)/N(4) 4.036 3.082
N(2)/N(5) 4.336 4.295
N(4)/N(5) 3.536 3.354
O(1)/O(2) 4.862 4.603
O(1)/O(3) 5.365 5.450
O(2)/O(3) 3.992 3.602
10 [103Cu(H2O)]$2picrate$H2O
N(1)/N(3) 9.904 9.221
N(2)/N(4) 3.738 3.452
N(2)/N(5) 3.684 4.102
N(4)/N(5) 3.717 3.284
O(1)/O(2) 3.672 4.491
O(1)/O(3) 3.579 5.332
O(2)/O(3) 3.520 3.632
11 [11 3 Zn]2ClO4$2H2O
N(1)/N(3) 5.291 7.263
N(2)/N(4) 4.960 3.342
N(2)/N(5) 6.526 3.350
N(4)/N(5) 6.410 3.336
O(1)/O(3) 4.974 4.589
O(1)/O(3) 5.321 4.309
O(2)/O(3) 5.805 4.346
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 131

CHO CHO OHC

O
N O O O

N3 N3 N3 N N N

OHC N N N N
N N

CHO CHO OHC

N O O O
+

NH2 NH2H2N N N N

N N N N
N N
N

NH NH HN

O O O

N N N

N N N N N
N
N

Figure 23 Synthesis of a cryptand incorporating triazole moieties.

characterized by X-ray crystallography. The Ag(I) ion binds at the tren-end forming a distorted trigonal pyramidal coordination
geometry where the metal ion sits above the plane of the three amines away from the bridgehead nitrogen. The other end of the
cavity remains empty with the cryptand assuming an endo–endo conformation. Likewise, a Zn(II) ion also occupies the tren-end
of the cavity when the cryptand is allowed to react with ZnCl2. In this case, however, the metal ion is bonded to a Cl anion inside
the cavity forming a trigonal bipyramidal geometry with equatorial ligation from three secondary amino N atoms and two axial
ligations from the bridgehead N and the Cl anion. Another Cl ion occupies the other end and is involved in multiple H-
bonding interactions. Thus, this cryptand acts like a ditopic receptor. Perhaps para-substituted trialdehyde would provide a rigid
ditopic cryptand for favorable formation of cascade complexes opening up new, interesting chemistry.

3.06.3.2 Cryptands With N, S, and O as Donors

The cage molecules 20–25 known as sarcophagines (Fig. 24) were synthesized by the tripodal capping strategy. These molecules are
much more rigid compared to the cryptands described earlier. Since their structural characteristics are similar to cryptands they are
discussed here. All these cage molecules readily form mononuclear inclusion complexes with a number of transition metal ions.
Replacement of secondary amines in the original nitrogen cage molecules24,32 by softer thioether S has a profound effect on the
spectroscopic, as well as the electrochemical properties of the metal complexes. The Co(III) complexes of all these cage ligands
132 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

NH S
NH S

H C NH S C Me
N NH S C Me
NH S
NH S

21
20

NH S NH NH

Me C NH S C Me H2N C NH S C Me

NH S NH S

22 23

NH NH NH S

NH C Me Me C NH S C Me
H 2N C NH

NH S NH S

24 25

Figure 24 Laterally nonsymmetric cage molecules.

are known, making structure/property correlation possible for these complexes. In the electronic spectra, two spin-allowed ligand
field bands (1A1g / 1T1g and 1A1g / 1T2g) characteristic of low spin octahedral Co(III) are observed.56–58
However, in case of the ligand 24, the coordination symmetry around the metal ion will be lower giving rise to two spin
forbidden transitions (1A1g / 3T1g and 1A1g / 3T2g). In the case of 25 that has a contracted cage, the metal–ligand bond is very
strong and the corresponding spin-allowed ligand-field transitions to shift33 to higher energy by
750 cm 1 each. As expected,
the band positions are insensitive to the nature of the apical atom (i.e., whether C or N) as they do not take part in coordination.
Assuming an approximate octahedral coordination symmetry around Co(III) for the complexes with N3S3, N4S2, and N5S donors
(Fig. 25), the ligand-field parameters have been calculated based on the two spin-allowed transitions, to find a possible correlation
between the number of thioether sulfur donors and the parameters 10Dq and Racah B. The data reveal that on going from N6 to S6
donor, the value of 10Dq reduces by
400 cm 1 initially, that is, from N6 to N5S complex. Thereafter, the reduction is much less

Figure 25 Perspective views of the Co(III) complexes of the cage molecules. Hydrogen atoms are omitted.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 133

and is only
300 cm 1 from the N5S to S6 complex. These data indicate that the ligand-field strength of thioether sulfur is only
slightly weaker compared to that of amino nitrogen in these complexes. This could be due to the fact that as the number of thioether
S increases, the cavity becomes larger leading to weaker metal–ligand bonds. The Racah B parameter, on the other hand, is reduced
by
30 cm 1 on introduction of a thioether sulfur in place of an amino nitrogen.
It is no surprise that these cage molecules do not allow normal substitution chemistry of kinetically labile Co(II) ion. Moreover,
the metal ion is prevented from relaxing to its preferred geometry upon change in its oxidation state. Both these factors contribute59
to the chemical as well as electrochemical reversibility of the Co(III)/Co(II) couple. However, the potential values are found to be
sensitive to (1) the number of thioether donors, (2) the nature of the apical atom and its substituents, and (3) the size of the
cavity.32,59 The redox potential moves to the positive direction as the number of thioether S increases. Replacement of amine by
a thioether causes (1) an increase of the cavity size due to longer CeS bond distance and (2) a greater shift of electron density
from the metal to the more covalent MeS bond. Both of these factors make the Co(II) state more stable inside a NxS6 -x cage
compared to that in the N6 cage. Keeping the donor set as well as the cavity size unchanged, the potential depends on the nature
of the substituents when the bridgehead is carbon. If the substitutent has a negative inductive effect (like a bound chloride), the
potential shifts to the positive direction. On the other hand, a substituent like a methyl group with a positive inductive effect causes
the potential to shift to the negative direction. However, manipulating the donor atoms as well as substituents does not allow reduc-
tion of the Co(II) to the Co(I) state. The cavity in any case is not large enough to accommodate a Co(I) ion and hence leads to the
rupture of the cage.
The high chemical stability of the cobalt cages allows the Co(III)/Co(II) redox states to be cycled repeatedly without decompo-
sition. Besides, these compounds are soluble in water. Thus, Co(III) complexes with N3S3 donors can be used as electron relay
compounds for the photoinduced H2 production (Scheme 1).
As Eqs. (3), (4) indicate, electron transfer from the excited sensitizer (S*) to Co(III) will be favored if the Co(III)/Co(II) potential
is less negative, whereas a more negative potential will favor H2 production. These two opposing influences are optimized in N3S3
donors with different apical substituents and they have been used for dihydrogen production from water at modest rates.60–62
These cage molecules have been used to coordinate other metal ions as well. Cu(II) forms a distorted tetragonal complex with 23
(Fig. 26) where one thioether and one nitrogen occupy the axial positions63 forcing a significant distortion of the pseudo-threefold
symmetry of the molecule. Low-temperature electronic and EPR spectral data of this complex in solution is consistent with its solid-
state structure. Cage 21 incorporating three N and three S donors forms a stable Ru(II) inclusion complex.64 The presence of three

Scheme 1 Co(III) cage compound for photoinduced H2 generation.

Figure 26 A view showing a Cu(II) ion inside the cavity of a cage molecule with very nonsymmetrical donor set. Hydrogen atoms are omitted.
134 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Scheme 2 Step-wise dehydrogenation upon oxidation of the metal centre.

thioether S helps in stabilizing the Ru(II) state by þ 0.9 V compared to the situation where all six donors in the cage are nitrogens.
The increase in the reduction potential is believed to be mainly a function of donor (and acceptor) properties of the sulfur atom,
which forms a more covalent Ru–S bond rather than differences in the cavity size from N6 to N3S3. Since the metal is tightly held
inside the cage, oxidation of the metal center causes the ligand to undergo stepwise dehydrogenation of the (Scheme 2) coordinated
amine to form coordinated imine. Similar behavior has been observed with the cage where all donors are amino nitrogens (N6
cage). The cage molecule 24 has a very unsymmetrical donor set and hence it can enforce a distorted octahedral geometry onto
the Cr(III) ion both in the solid state and in solution.65
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 135

Cryptands 26–28 contain three different types of donors: S, N, and O making the cavity quite large. Several first-row transition
metals were used for complex formation but only Cu(II) and Ni(II) cryptates could be isolated as pure solids. The UV–vis spectro-
scopic data of these cryptates are consistent66,67 with a distorted octahedral geometry around the metal ion with coordination from
three amino nitrogens and three thioether sulfurs. The Cu(II) cryptates show only a broad EPR signal at g z 2.15 in the solid-state, as
well as in acetonitrile glass, typical of magnetically concentrated Cu(II) complexes. They also show quasi-reversible Cu(II)/Cu(I)
coupling (DEp ¼ 140–180 mV at 100 mV s 1 scan rate) at E1/2 of about 0.5–0.6 V versus Ag/AgCl. Upon addition of a further equiv-
alent of [Cu(H2O)6](ClO4)2 in acetonitrile, the solution turns dark green and within hours, colorless crystals of [Cu(MeCN)4]ClO4
deposit.
Cryptands can interact with DNA or RNA in a number of ways like the intercalation68–71 of planar aromatic groups between the
base pairs, electrostatic interaction between the metal cryptate cation, the negatively charged phospodiester backbone, etc. Both 9
and 10 were studied72 for their possible binding abilities toward DNA, RNA, and oligonucleotides in addition to their phosphoes-
terase activity in the presence of lanthanide ions. Once a metal ion enters the cavity of a cryptand, it shows extra thermodynamic and
kinetic stability and, hence it can offer a starting point for the attachment of rate-enhancing cofactors. Experiments with oligonu-
cleotides, DNA, and RNA reveal that both 9 and 10 can destabilize the double strands. However, they have limited scope especially
with lanthanide ions as they form rather weak complexes. In contrast, the water soluble Co(III) inclusion complex of the cage mole-
cule shown in Fig. 27 exhibits73 limited nuclease activity when irradiated with 254 nm light. More metal cryptates should be probed
for their nuclease activity before their efficacy can be established.
It is quite understandable from the foregoing discussions that the chemistry of metal cryptates is interesting from the points of
view of their novel structure and bonding and the associated spectroscopic properties. Suitably designed cryptands can impose low
coordination symmetry around the metal ion in the cavity and thus can be excellent candidates to serve as electronic structural
analogs of intrinsic active sites74 of several metalloproteins.

3.06.3.3 Complexation by Anions

Complexation of anions by cryptands is also an area of intense research activity75–77 because anions are essential in several func-
tions of biological processes. Cryptands can include a monoatomic anion inside the cavity provided size of the cavity is big enough.
Both the cryptands 9 and 10 were probed for complexation with spherical halide anions.
The fluoride anion being the smallest in size in the series can be encapsulated78 by both cryptands 9 and 10. In 9, the amine
groups in the bridges are protonated along with the bridgehead N atom at the oxa end. All these four H atoms are directed toward
the cavity to “coordinate” to the internal fluoride in a tetrahedral manner (Fig. 28). In case of the bigger cryptand 10, all N atoms at
the “aza” end are protonated and a fluoride anion is bonded78 to all four hydrogens of the protonated amines. Three additional
aromatic CeH protons are also bonded to the fluoride anion giving it a seven-coordination geometry (Fig. 29).

Figure 27 A Co(III) complex that shows nuclease activity.

Figure 28 A perspective view showing a fluoride anion bound inside the cavity of 9.
136 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 29 A fluoride anion with bonding interactions inside the cavity of 10. Some of the hydrogen atoms are omitted.

Cryptand 9 accomodates one chloride anion within the cavity78 where the anion sits exactly on the C3 axis joining the two
bridgehead N atoms. The chloride anion is bonded to the three hydrogens of the protonated amines in a trigonal planar coordi-
nation geometry (Fig. 30).
In case of 10, the chloride anion is again located on the threefold axis passing through the two bridgehead N atoms and shows
hepta-coordination (Fig. 31).
A bromide anion being much larger in size cannot be accommodated inside 9 but is placed between the same side-directed two
arms of the cryptand (Fig. 32).
However, cryptand 10 with a substantially larger cavity can include79 a Br anion inside the cavity via H-bonding with the three
protonated secondary amines and H atoms of the aromatic groups in the three bridges showing hexa-coordination (Fig. 33). Other
bromide anions are bound to cryptand molecules from outside involving an intricate array of H-bonding interactions also including
several water molecules. The water molecules present in the lattice form adamantanoid structure and six such units form a 3D cage-
like supramolecular network. The bromide-encapsulated cryptand lies within this cage in a host-within-a-host-like structure
(Fig. 34) resembling the Russian nesting doll.80–82

Figure 30 A perspective view along the two bridgehead nitrogen atoms of 9 showing a chloride anion inside the cavity.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 137

Figure 31 A chloride anion with bonding interactions inside the cavity of 10.

Figure 32 A bromide anion between two arms of 9. Also shown a space-filling model.

Figure 33 A perspective view showing a Br anion inside the cavity of 10.
138 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 34 A host within a hostlike structure.

Figure 35 A nitrate anion bound inside the cavity of 10. Most of the hydrogen atoms are omitted.

The iodide anion is so big that it is not accommodated inside any of the cryptands. The cryptand cavity in 10 can even include
a NO 83
3 anion inside which resides closer to the tren-end of the cavity showing H-bonding interactions with the H atoms of the
protonated secondary amines as well as with nearby H atoms of the aromatic groups (Fig. 35). Other anions collect several cryptand
molecules around and bind them from outside with an intricate array of H-bonding interactions involving protonated amines and
aromatic protons.
The secondary amino groups in the three bridges can be easily derivatized to give new receptors leading to new areas of research.
In one such example, the cryptand 9 has been attached84 to the lower rim of calix[4]arene via spacers to generate a new type of
receptor molecule (Fig. 36). However, the calixarene-cryptand hybrid shown here is yet to be explored for ion or neutral guest
binding.

3.06.3.4 New Class of Unsymmetrical Cryptands

Another type of unsymmetrical cryptands would result when the three bridges are not identical. Although these molecules are not
covered here, a brief mention of their existence should be in order. X-ray crystallographic studies on cryptand 29 to probe its utility
in binding halides and polyatomic anions inside the cavity reveal85 that the cryptand holds a chloride ion in the pocket of the
smaller 24-membered macrocyclic unit, while in the case of a dihydrogen phosphate anion it lies within the larger arm. In the nick-
el(II) structure, the metal ion also resides in the larger chain. More such systems should be synthesized and probed for having crypt-
ates of different ions as well as neutral molecules.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 139

Figure 36 A cryptand-calixarene hybrid structure.

Another unsymmetrical cryptand 30 is found86 to include alkali metal ions inside its cavity, which is proved by spectroscopic
techniques. However, no selectivity of binding a particular ion is observed.
140 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 37 An illustration showing a number of nonsymmetric cryptands.

A series of unsymmetrical cryptands has been synthesized by several groups that are collected87 in Fig. 37. These cryptands have
large cavities and are able to host large organic guest molecules. Besides molecular recognition of large organic guests, these crypt-
ands have been extensively used as hosts for different types of guest molecules for potential uses in diverse areas of supramolecular
chemistry that include fabrication of topochemical structures, molecular switches, polymeric structures, and so on. Extensive
descriptions of their chemistry are available.88–92

3.06.4 Cryptand-Based Amphiphiles

Amphiphilic molecules are one of the most important93 structural units essential to life starting from forming cell walls to trans-
location of biomolecules in vivo. Synthetic amphiphiles are known to form a great variety of supramolecular structures such as
micelles, vesicles, monolayers, bilayers, multilayer rods, and so on. Naturally, a large number of synthetic amphiphiles with
both acyclic as well as cyclic headgroups and one or more hydrophobic tails with different chemical structures have been re-
ported.94–101 Such amphiphiles can be important as model systems for membrane structure as well as functional102,95 studies.
They can also be useful in drug delivery and targeting, medical imaging, catalysis, energy conversion, and separation.103–107
Synthetic surfactants with a cryptand headgroup offer several design options: a cryptand has (i) a preformed cavity whose topology
can be designed to recognize an ion/molecule of interest, (ii) the rigidity of the macrobicyclic structure favor ordered structures, and
(iii) the possibility to have amphiphilic molecules with different chemical structures by selective derivatization of the amino groups.
The first surfactant molecule, with a macrobicyclic sarcophagine headgroup, was reported by Sargeson and coworkers.108 They were
able to attach alkyl chains to the N6 macrobicycle either by reductive alkylation or by diazotization reaction (Fig. 38). Presence of
high charge in the form of a Co(III) ion inside the cage and the alkyl chain make these amphiphiles capable of very close approach
to the cell walls of the tapeworm, Hymenolepis Diminuta and burst the walls by detergent action. Such studies are possible when the
amphiphilic molecules are soluble in water. The secondary amino groups in laterally nonsymmetric aza cryptands can be derivat-
ized easily with acid chlorides to form a new generation of surfactant molecules (Fig. 39).

3.06.4.1 Formation of Vesicular Structures

Vesicles are of immense importance in different areas of science and technology. In basic research, they serve as models for cell
membranes and their fusion, transport studies, and investigations of membrane proteins that can be reconstituted in vesicles.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 141

Figure 38 Amphiphiles with a cage molecule as the headgroup.

Figure 39 Cryptand-based triple-tailed amphiphiles.

They also serve as delivery vehicles for drugs, genetic materials, enzymes, and other molecules into living cells and through other
hydrophobic barriers in pharmacology, medicine, genetic engineering, and the cosmetic and food industries. Therefore, the process
of vesicle formation via self-assembly is an important event that has attracted wide attention. Amphiphiles can self-organize into
vesicular aggregates depending on several factors such as solubility, alignment of hydrophobic tails, hygrophilic/hydrophobic ratio,
intermolecular packing of rigid segments, hydrogen bonding among neighboring amphiphiles, and so on. Cryptand-based amphi-
philes shown in Fig. 39 represent a class of neutral amphiphiles having a single headgroup and three hydrophobic tails.109,110 The
cryptand headgroup can accommodate a Cu(II) ion forming a new class of synthetic surfactants. Both these free as well as Cu(II)
complexed amphiphiles can self-organize into vesicular structures when an ethanolic solution of an amphiphile is dispersed in
water. In biosystems, vesicles form spontaneously in vivo in the existing biological environment. Synthetic amphiphiles on the
other hand require considerable mechanical energy like sonication, extrusion, or chemical treatments like detergent dialysis,
reverse-phase evaporation, and so on, for vesicle formation.93 Few systems are also known,111,112 however, that spontaneously
form vesicles in solution. The surfactants shown in Fig. 39 spontaneously form mostly unilamellar113 vesicular aggregates when
an ethanolic solution of any of the compound is added to water (Fig. 40). This is presumably due to the special topology of the
142 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 40 A perspective view of the amphiphile, 36.

cryptand architecture and the presence of carbonyl units as spacers between the headgroup and the hydrophobic tails that allow
compact chain packing without conformational constraint on the headgroup (Fig. 39). The threefold symmetry of the headgroup
prevents the alkyl chains from aligning in intermolecular digitizing fashion. The chains are curved in one direction114,115 and the
carbonyl linkages do not allow the hydrophobic tails to spread laterally out of the cryptand. Besides, the alkyl chains favor curvature.
The copper(II) complexes of these amphiphiles behave in a similar manner. These surfactants pack in the lattice in an intermolec-
ular digitizing and nondigitizing fashion (Fig. 41) in the crystal lattice, which is not common with amphiphilic molecules.116–118

Figure 41 A perspective view showing the packing pattern of 36.

 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 143

Figure 42 Representative negative-stain transmission electron micrographs of spontaneously made vesicles of 36 (A) magnification, 10000
(B) its Cu(II) inclusion complex; magnification  12000; micrographs of vesicles made by extrusion method of 36 (C) magnification  20000 (D) its
Cu(II) inclusion complex, magnification  20000.

Both tunneling electron microscopy (Fig. 42) and dynamic light scattering studies of 36–39 show the average diameter of these
vesicles lie within the range, 250–350 nm. In 100 m mol dm 3 NaCl/sucrose medium, the vesicular suspensions are stable for 5–
10 h and the stability increases with the increase of the hydrophobic chain length. However, vesicular dispersions made by the extru-
sion method are found to be stable for 15 days under similar conditions. Changing the cryptand headgroup from 9 to 10 does not
affect the stability of vesicular dispersions to any noticeable extent. With time, the vesicles fuse, they form clusters, and finally coag-
ulate. Lowering the temperature to 278 from 298 K increases the stability of the dispersions due to slowing down of the fusion
process. A TEM micrograph of a vesicular dispersion taken after a week clearly shows (Fig. 43) fusion of vesicles prior to coagulation.
When one or two alkyl chains are attached to a cryptand (Fig. 44), the resulting amphiphiles also form unilamellar vesicular
aggregates spontaneously. However, unlike the previous cases, the vesicular dispersions are not stable and within hours, they coag-
ulate, underlining the need for an optimum hydrophilic/hydrophobic balance to make stable vesicles. Two cryptand headgroups
can be covalently connected where each cryptand is derivatized with a single long chain acid chloride to form what is known as
a bola-amphiphile,119 the noun “bola” relates to the shape of a South American missile weapon.120 The bola-amphiphiles form
vesicular structures with diameter in the range 500–600 nm that are stable for almost a week at 298 K.
Unsymmetrical derivatization of a cryptand can afford yet another class of amphiphiles121 known as gemini-amphiphiles
(Fig. 45). However, vesicles from these surfactant molecules are not stable for more than 1 h at 298 K. Amphiphiles with covalently
connected three cryptand headgroups and six hydrophobic tails have also been synthesized (Fig. 46).
These amphiphiles can also form vesicular aggregates (Fig. 47) of about 900 nm average diameter although they coagulate after
2 h at 298 K.
144 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 43 Negative-stain transmission electron micrograph of the spontaneously made vesicles of 36 (magnification 10000) taken after a week.

Figure 44 Cryptand-based amphiphiles with different numbers of hydrophobic tails.

3.06.4.2 Amphiphiles at the Air–Water Interface

The Langmuir–Blodgett (LB) technique122 is one of the most effective ways of depositing extremely thin films on to substrates. This
technique has assumed greater importance in recent times123–126 with the demand for materials with tailored interfacial properties.
Besides, organized molecular layers provide unique environments for molecular interactions and consequently for molecular recog-
nition.127 These supramolecular systems should be important in applications, such as chemical sensors, in understanding molecular
interactions on biological cell surfaces, and in developing novel 2D molecular assemblies composed of multiple chemical
species.128 Cryptand-based amphiphiles have been probed at the air–water interface as these molecules can accommodate a metal
ion/molecular guest to impart potentially important properties on to the thin film. Since these aza cryptands can be selectively deriv-
atized, their recognition properties can be enhanced as well. The pattern of the isotherms obtained with the amphiphiles 34–39 is
illustrated in Fig. 48.
In every case, behavior of the monolayer is reproducible without any hysteresis. Thus, these amphiphiles are capable of forming
robust monolayers, which can withstand reversible compression and expansion without any major change in the monolayer struc-
ture. Several generalizations can be made on the nature of the isotherms vis a vis the amphiphiles. For a particular amphiphile, the
area per molecule shrinks as one goes from the metal-free amphiphile to the corresponding Cu(II) complexed one which is
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 145

Figure 45 (A) A bola-amphiphile with cryptand headgroups (B) gemini-amphiphiles with cryptand headgroups.

Figure 46 Amphiphiles with multi-headgroups.

consistent with the crystal structure of the free and Cu(II) complexed headgroup. Also, the extent of shrinkage is more for amphi-
philes with long hydrophobic tails. Thus, complexed amphiphiles with long hydrophobic tails pack better, sustain higher surface
pressure, and form more stable monolayers. As a matter of fact, within each series, the stability of the monolayers decreases mono-
tonically with the decrease in the length of the hydrophobic chains. The molecular radii of the amphiphiles are calculated to be in
the range, 6.4–7.0 Å which are slightly larger compared to the average radius of the cryptand headgroup as determined from X-ray
crystallography, suggesting that the cryptand headgroups are slightly tilted with respect to the water surface reflecting the association
tendencies and orientations of the hydrocarbon chains. It is also found that when a monolayer is compressed at a slow speed of 20–
50 cm2 min 1, the isotherms are slightly steeper compared to the situation when the barrier speed is 250 cm2 min 1. This suggests
that when barrier speed is slow, the individual molecules get time to undergo reorganization and pack more effectively. With
concentrated spreading solutions, there is always a chance of formation of multi-layers especially under high surface pressures.
146 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 47 A TEM photograph of 68.

Figure 48 Behavior of Langmuir Isotherms at the air–water interface for the amphiphiles 34–39 shown in Fig. 39A.

In the present cases, however, no multilayer film formation on the water surface has been observed apparently owing to the lack of
extensive cohesive forces among the amphiphilic molecules. These surfactants are found to form stable mixed monolayers with stea-
ric acid (SA) with the following characteristics: (1) when mixed with SA, maximum pressure sustained by the monolayer increases,
(2) the shape of the isotherm becomes steeper, and (3) with increasing SA concentration in the spreading solution, limiting area/
molecule decreases monotonically. All these observations can be rationalized by the fact that no attractive interactions exist between
the two types of amphiphiles. Other amphiphiles afford quite similar isotherms with similar properties.
The LB films of the monolayers can be transferred onto substrates such as glass, quartz, indium-tin oxide (ITO) coated glass and
fluorite with a Y-type deposition.122 The transfer ratio varies from 65% to 80% when the glass plate is untreated. However, when the
plate is precoated with SA, the transfer ratio can reach up to 95%. Typically, 50 layers can be transferred without encountering any
problem. The scanning electron micrographs of the LB films deposited onto ITO-coated glass plates of free amphiphiles appear
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 147

Figure 49 Scanning electron micrographs of the LB films of (A) 34, (B) 34 after 12 months exposed to air, (C) Cu(II) inclusion complex of 34,
(D) after 12 months exposed to air.

inhomogeneous and remain so after a year exposed to air (Fig. 49A and B). The Cu(II) complexed amphiphiles, on the other hand,
show a distinct plate-like appearance with sharp edges attributable129 to ordered aggregates in the film that disappears and becomes
inhomogeneous after 1 year at RT and exposed to air (Fig. 49C and D). In triple-tailed amphiphiles the three hydrophobic tails
cannot pack in a parallel fashion due to which they cannot sustain > 25 m Nm 1 surface pressure. Sustenance of high surface pres-
sure by a monolayer signifies large attractive interactions between the amphiphiles with the formation of rigid films. It also indicates
that the individual amphiphilic molecules pack effectively in the monolayer that is important for its eventual use(s) as materials. In
case of the mono- and bis-substituted amphiphiles (Fig. 47), the sustenance pressure is
45 m Nm 1, which is significantly higher
compared to the triple-tailed amphiphiles due to better packing ability of the former. In these cases also no hysteresis is observed on
repeated expansion and compression experiments. However, the big headgroup with a single hydrophobic tail reduces the stability
of the monolayers and they can sustain a pressure of 40 m Nm 1 for only
10 min. This instability reduces the transferability of the
films to ITO-coated glass plates to
60% in a Y-type deposition. With triple-headed, hexa-tailed amphiphiles (Fig. 46), the Lang-
muir isotherms are not well-defined.130 It is therefore important that a balance should be achieved between the headgroup and the
tails in terms of size. However, a mono-substituted cryptand-based amphiphile offers other possibilities; it can be a starting point
for the attachment of fluorophoric or donor/acceptor groups that can lead to thin films with either sensing or nonlinear optical
(NLO) capabilities.

3.06.4.3 Molecular Recognition

Molecular recognition relies upon the complementarity of size, shape, and intermolecular forces.131 It explores and exploits inter-
molecular forces, the weak attractions that act over short distances between molecules. Hydrogen bonding is a highly directional
secondary valence force compared with other noncovalent interactions such as electrostatic, van der Waals, and hydrophobic forces.
Intensive effort has been made recently to develop organic host molecules that specifically bind substrates by complementary
hydrogen bonding. It plays decisive roles in biological molecular recognition such as replication of nucleic acids, maintenance
148 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

of the tertiary structure of proteins, and substrate recognition of enzymes. Studies of molecular recognition of most of the abiolog-
ical systems are not effective in the aqueous medium due to strong interference from water. To circumvent the problems associated
with probing hydrogen bonding interactions in water, several strategies have been applied for effective hydrogen bonding interac-
tions in aqueous media.132–135 Molecules at the air–water interface behave differently than those in bulk water. The interface intro-
duces directionality in the molecular interactions and causes a particular orientation of the molecules. Besides, the average distance
between molecules at the interface is much smaller compared to their distances in the bulk medium under dilute condition. This
high local concentration increases the probability of forming desired entities via intermolecular bonds. Shimomura and
coworkers136 have investigated the binding of aqueous nucleosides to a cytosine-functionalized monolayer. Fluorescence micro-
scopic observation revealed that the monolayer produced spiral domains on aqueous guanosine. Hydrogen-bond based recognition
systems other than the nucleic acid mimics have also been found effective at the air–water interface.137–139 Since the pioneering
work on the base pair mimic at the air–water interface by Kitano and Ringsdorf,140 several studies have been carried out. These
studies concern investigation of pressure–area isotherms of an adenine-functionalized amphiphile on aqueous nucleosides and
proposed141 that larger expansion of the isotherm on aqueous thymidine is ascribable to formation of the complementary A–T
type pair at the interface. Cryptand 9 has been mono-derivatized first with a thymine group followed by attachment of two long
chain alkyl groups to afford the amphiphile 74 shown in Fig. 50.
It gives a well-behaved isotherm in pure water as the subphase. The isotherm is expanded142 by
20% when adenine is present
in the subphase (Fig. 51) due to the formation of A–T base pair at the interface. Such an expansion does not take place if any other
nucleic acid base is present in the subphase.

3.06.5 Fluorescence Signaling With Cryptand-Based Systems

Binding of an analyte to a receptor is an event at the microscopic level that can be conveniently transmitted to the macroscopic
world when such an event is accompanied by a perceptible change of the system that is measurable. It is perhaps the changes in
the photochemical/photophysical properties of the system that can be conveniently monitored in such cases and indeed are of great

Figure 50 Amphiphile 74 showing two hydrophobic tails and one thymine group attached.

Figure 51 Pressure–area isotherms of 74 (1) in pure water as the subphase and (2) 0.1 M adenine in pure water as the subphase at 298 K.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 149

demand in designing chemosensors143–147 and molecular information processing.148,149 It should be noted that the ubiquitous
nature of fluorescence quenching reduces its sensitivity as well as practical utility. Besides, compared to a weak fluorescence, the
detection of a strong fluorescence is analytically favored because of high signal-to-noise ratio and appearance of a characteristic
new and longer-lived fluorescence decay component. Therefore, choice of fluorophores also plays a significant role. Mainly two
arrangements can be envisaged for the signal transduction process with cryptands as receptors (Scheme 3). Both designs have
been adopted for cryptand receptors.
The design (a) where the receptor and the fluorophore are connected through a spacer is modular in design and easier to synthe-
size with cryptand receptors. It should be understood that the spacer plays a crucial role(s) in the signal transduction process. The
fluorophore can be varied for higher quantum efficiency, lower energy of excitation, high photostability, and so on, while the
receptor can be changed to bind a cation or an anion or a neutral molecule. Signal transduction upon analyte binding can be real-
ized via any one of the processes: (1) electron transfer, (2) charge transfer, (3) energy transfer, and (4) excimer and/or exciplex
formation or disappearance. Of course, more than one process can be operative concurrently. The emphasis has been on the trans-
duction of discrete and stoichiometric recognition events into fluorescence signals. The photophysical changes can be in terms of (1)
appearance of the spectrum, (2) emission quantum yield, and (3) excited-state lifetime. Knowledge of the concentration of the guest
can be understood from the fluorescence quantum yield.
In case of cryptand receptors, photoinduced electron transfer (PET) can be one of the most conveniently used signal transduction
mechanism for the design of chemosensors as well as molecular photonic logic gates. If the PET between fluorophore and receptor
groups is to control the sensory action of the system, the photo energy contained within the electronically excited fluorophore must
be (in the first instance) thermodynamically capable of driving the electron transfer process. The quantitative relationship is given
by Weller150 as:

DGET ¼ Es  Ered:fluorophore þ Eox:receptor  e2 3 r (1)

where DGET is the thermodynamic driving force for PET, ES is singlet-state energy of the fluorophore, Ered.fluorophor is the reduction
potential of the fluorophore, while Eox.receptor is the oxidation potential of the receptor and e2/3 r is the attractive potential between
the radical ion-pair. The signaling possibilities arise when the “fluorophore-spacer-receptor” system in the guest-free situation has
been chosen such that its fluorescence is “switched off” by the PET process (Fig. 52A). The PET process, in turn, can be suppressed by
the entry of a guest into the receptor causing increase of the ionization/oxidation potential of the receptor so that PET is inhibited.
Other ways of inhibiting PET include conformational changes, local polarity modulations, and hydrogen bonding. Suppression of
the PET process means that fluorescence again becomes the dominant decay channel of the excited fluorophore (Fig. 52B) that is, its
fluorescence is “switched on.” The entire situation is illustrated in terms of frontier orbital energy diagrams depicted on the right side
of Fig. 52. While Weller’s pioneering work provides the thermodynamic basis of PET, the intramolecular PET kinetics are best
described following Marcus.151
Transition metal ions effectively quench152,153 fluorescence, and a number of mechanisms have been forwarded to rationalize
such behavior. These are conversions of electronic energy to kinetic via collisions, heavy atom effects, magnetic perturbations,
formations of charge-transfer complexes, electronic energy transfers from/to the metal ion, etc. Design of efficient sensors/device
systems for these ions, therefore, demands special molecular architecture that should fulfill certain important criteria: (i) PET should
be fast in the metal-free molecule, (ii) PET should be effectively stopped once the guest is bonded to the receptor, (iii) the distance
and orientation of the metal ion in the receptor should be such that the spin–orbit coupling which facilitates the S / T intersystem
crossing would be minimum, and (iv) the compound should be photochemically stable. In other words, for efficient fluorescence
sensing with cryptand receptors, the metal ion–fluorophore communication should be much less than the metal–receptor interac-
tion. When a cryptand receptor is used, it binds the metal ion inside the cavity very strongly due to the cryptate effect.36 Once the
metal ion enters the cavity, it is largely shielded from outside influence. Both these factors weaken metal–fluorophore communi-
cation while at the same time increase metal–receptor interactions.154
Cryptands 9–11 have been covalently linked to anthryl groups155,156 as fluorophores to afford PET sensors, 75–77 (Fig. 53).

Scheme 3 Designs of fluorescence signaling systems.

150 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

PET
LUMO
E
Spacer PET
Fluorophore Receptor
HOMO

HOMO

Photon Fluorescemce Fluorophore Free Receptor

A

PET

LUMO
Spacer
Fluorophore Receptor
E
Fluorescemce

Photon Fluorescemce HOMO

HOMO
Analyte bonded to receptor
B

Figure 52 The simplified frontier orbital picture for the PET process in signaling.

Figure 53 Tris-anthryl derivatives of cryptands 9–11.

In the metal-free state, compounds 75–77 give UV–vis absorption spectra reminiscent of 9-monoalkyl-substituted anthracene157
with well-resolved vibrational structures. This indicates no interaction between the N lone-pairs of the receptor and the anthracene
ring in the ground state. Both 75 and 77, however, exhibit slight bathochromic shifts (2–5 nm) of the peak positions upon metal
complexation at room temperature. On the other hand, 76 does not show any detectable shift of the band positions. This is consis-
tent with the X-ray crystallographic studies discussed earlier which reveal that the cryptand receptors accept a transition metal ion at
the tren-end of the cavity with slight conformational changes as the receptors are mostly preorganized. In the metal-free state, 75–77
exhibit extremely low but well-resolved anthracene monomer emission155,156 along with a structureless broad band centering
around 550 nm. Intensity of this 550 nm band increases with concomitant decrease of the monomer emission as the concentration
is raised (Fig. 54). Emission experiments carried out in different solvents of low polarity show that position of the maximum of the
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 151

Figure 54 Emission of metal-free 75 in dry THF illustrating the effect of concentration on the exciplex: (1) 5  10 5 M, (2) 2  10 5 M, and (3)
1  10 5 M.

band make red-shift with increasing polarity of the solvent showing the charge-transfer character158 of the emitting complex. A
linear relationship between nmax and solvent polarity parameter consistent with the Weller equation159 is obtained (Fig. 55).
This is consistent158,160 with the formation of intramolecular exciplex formation between the N lone-pair and the anthracene
moiety (Fig. 56).
The quantum yields of monomer emission (FFM) are very low (Table 4) for metal-free systems due to efficient intramolecular
PET from the N lone-pair to the anthracene p system. The FFM increases greatly when a first-row transition metal ion is used as the
input and as expected, the exciplex band disappears (Fig. 57). A transition metal ion occupies the N4-end of the cavity engaging the
lone-pairs on the N atoms thereby stopping both the PET and the exciplex formation. The extent of emission enhancement depends
upon the nature of the metal ion used as input and the receptor as well. Very high fluorescence recovery can be effected with metal
ions such as Co(II), Cu(II), or Zn(II) that prefers tetra-coordination and strong bonding with N. Even metal ions like Mn(II), Ni(II),
or Fe(III) that prefers hexa-coordination give high emission enhancement because these metal ions can accept solvent molecules to
achieve greater than four coordination. Compound 75 affords highest FFM value for any particular transition metal ion as its cavity
is flexible and smallest among the three and so can adjust to have the strongest bonds with a metal ion. Alkali or alkaline earth metal
ions do not show any enhancement, as they tend to bind to ethereal O atoms at the other end of the cavity.

Figure 55 Wavenumber of the exciplex emission maximum at 298 K of 75 as a function of solvent polarity parameter, f-1/2f’. Solvent (f-1/2f’):
(A) dichloromethane (0.319); (B) THF (0.306); (C) cyclohexane (0.100); (D) n-hexane (0.092).
152 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 56 An illustration showing intramolecular exciplex formation.

Table 4 Fluorescence output of 75, 76, and 77 with different cation inputsa

Fluorescence output quantum yield (VF)

Fluorophore Ionic input (0, 0) Band position (nm) VFM VFE VFT

75 Nil 394.8 0.0005 0.0005 0.001

Mn(II) 405.0 0.301 – 0.301
Fe(III) 404.0 0.226 – 0.226
Co(II) 405.6 0.215 – 0.215
Ni(II) 403.2 0.210 – 0.210
Cu(II) 405.0 0.280 – 0.280
Zn(II) 405.8 0.310 – 0.310
Pb(II) 405.0 0.180 – 0.180
Eu(III) 394.8 0.077 – 0.077
Tb(III) 395.0 0.100 – 0.100
76 Nil 395.5 0.001 0.0005 0.0015
Mn(II) 401.0 0.136 – 0.136
Fe(III) 403.0 0.156 – 0.156
Co(II) 397.0 0.131 – 0.131
Ni(II) 395.5 0.080 – 0.080
Cu(II) 403.0 0.110 – 0.110
Zn(II) 396.0 0.150 – 0.150
Pb(II) 395.6 0.148 – 0.148
Eu(III) 395.8 0.024 – 0.024
Tb(III) 395.8 0.036 – 0.036
77 Nil 394.6 0.001 0.001 0.002
Mn(II) 403.6 0.370 – 0.370
Fe(III) 404.2 0.289 – 0.289
Co(II) 403.4 0.512 – 0.512
Ni(II) 404.4 0.309 – 0.309
Cu(II) 403.2 0.266 – 0.266
Zn(II) 403.4 0.603 – 0.603
Pb(II) 404.4 0.420 – 0.420
Eu(III) 394.4 0.005 0.001 0.006
Tb(III) 394.8 0.007 – 0.007
a
Experimental conditions: medium, dry THF; concentration of 75 and 76, 10 5 M; concentration of 75, 5  10 3 M; concentration of ionic input, 10 3 M; excitation at iso-
sbestic point 370 nm with excitation band pass of 5 nm; emission band pass, 5 nm; temperature, 298 K; VF calculated by comparison of corrected spectrum with that of
anthracene (VF ¼ 0.297) taking the area under the total emission. The error in VF is within 10% in each case, except free ligands, where the error in VF is within 15%.

The emission signal undergoes drastic enhancement also in presence of heavy metal ions like Pb(II) or Hg(II) although other
heavy metal ions like Tl(I) or Ag(I) do not show any appreciable enhancement although they are known to form inclusion
complexes with these receptors. Presumably, the solvated Tl(I) or Ag(I) cannot enter the cavity under high dilution conditions.
Lanthanide ions such as Eu(III) and Tb(III) show fluorescence enhancement in 75 and 76 but not in 77. This is due to much
less metal–receptor interactions between 77 and Eu(III)/Tb(III) ions which cannot attenuate communication between the fluoro-
phore and the lone-pairs on nitrogens. Lanthanide ions prefer higher coordination161 compared to transition metal ions. Therefore,
they would like to occupy middle of the cavity to bind all available donor atoms of the receptor. The receptor unit in 75 or 76 has
smaller cavity and is able to bind a lanthanide metal relatively strongly but not in 77 as the cavity is much bigger. Further, upon
binding of a lanthanide metal, the exciplex is not observed in 75 and 76 but 77 gives exciplex emission (Fig. 58).
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 153

Figure 57 Corrected emission spectrum of metal-free 75 and of 75 in the presence of 10 equiv. of Cu(II) ion in dry THF at 298 K.

Figure 58 Corrected emission spectra of (i) metal-free 75 (ii) of 75 in the presence of Tb(III) and (iii) of 75 in the presence of Cu(II) in the dry THF
medium.

The energy of the lowest triplet state of anthracene is lower than the emitting states of Eu(III) and Tb(III) ions. The lower FFT
observed in case of lanthanide ions with 75 compared to that of any of the transition metal ions is presumably due to nonradiative
decay of the excited state of anthracene to the lowest triplet state through the rare-earth (III) ion states. In all cases, the emission
spectra show slight red-shifts with broadening of the (0,0) as well as other vibrational bands, and a different intensity ratio of
the (0,0) and the first vibrational band compared to those of the metal-free 75–77. Fluorophores are known to show emission
bands, which are solvatochromic in nature. Therefore, a possible mechanism for such a red-shift can be due to a metal ion induced
change in polarity around the fluorophore. Excited-state lifetime measurements carried out with these systems do not show any
distinct behavior.
Metal salts used in these studies are hydrated and they are known to generate protons in dry organic solvents. These protons can
engage the N lone-pairs through protonation causing enhancement as well. Participation of metal ions rather than protons has been
established155,156 through a number of control experiments.
154 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

The three secondary amino groups in the unsubstituted cryptands exhibit different pKa values and can be selectively function-
alized. This allows synthesis of mono- and bis-derivatives of the cryptands 9 and 10 besides attachment of two cryptands to one
anthracene group (Fig. 59). Like before, metal-free 78–82 gives very low monomer emission in dry THF at 298 K due to PET being
operational. This emission intensity decreases with increasing concentration like the tris-derivatives with an exciplex band around
545 nm for the bis-derivatives. However, none of the mono-derivatives exhibits any exciplex presumably due to distortion of the
cryptand core disallowing interaction of the nitrogen lone-pair with the anthracene p-cloud and/or interference from the solvent
molecules,162,163 which will have more access for the nitrogen atom attached to the anthryl group. In the presence of a transition
or a lanthanide metal ion, 78–82 show fluorescence enhancement to a lesser extent compared to the value obtained with the tri-
anthryl derivatives. However, no apparent relation can be established between the number of anthryl groups and the extent of fluo-
rescence enhancement due to wide differences in the binding abilities of the cryptand derivatives toward a metal ion.
A better understanding of the PET process in these systems can be made164 by varying the length, as well as the nature of the
spacer, and the fluorophore keeping the receptor the same (Fig. 60). The idea is to observe the effects of (a) flexibility of the fluo-
rophore unit with respect to the cryptand moiety (b) orientation of the fluorophores with respect to each other depending on the
nature of the spacer and (c) the communication (interaction) between the fluorophore and the receptor moieties. Varying distance,
as well as flexibility of the systems, also allows investigation of the possibility of intramolecular exciplex and excimer formation.
Metal-free 83 and 84 exhibit locally excited emission with the (0,0) band at 327 nm for the naphthalene moiety and an exciplex
at 415 nm. Compared to 84 the PET is more efficient in 83; however, both are much less efficient compared to the trianthryl cases.
As a result, with a transition metal ion as an input, the maximum emission enhancement does not go beyond a factor of 10. On the
other hand, metal-free 85 and 86 shows significantly less efficient PET and with a transition metal ion as input, the emission
enhancement is barely noticeable. Compound 87 is structurally different from the others; here, the fluorophore moiety is integrated
with the receptor. In this case, the PET is also inefficient and it shows quenching of emission in presence of a transition metal ion,
suggesting much greater interaction between a metal ion and the fluorophore. The most important criterion for any PET process is
the orbital overlap factor.165 In addition to the extent of separation, the spatial orientations of the donor and acceptor orbitals are
vital for effective orbital overlap. Calculations performed on the orientation dependence of the overlap integral for some aromatic
molecules revealed that for a constant edge-to-edge separation distance, overlap is larger for reactants in face-to-face orientation
whereas for a constant center-to-center distance, the electronic interaction is larger for end-to-end orientation. In the present cases,
the orbital overlap is less effective compared to the case of the trianthryl derivative, 75.
For further probing of the PET process in cryptand-based fluorescence signaling systems, cryptand 9 has been derivatized to have
88 and 90 (Fig. 61). Metal-free 88 shows166 a well-resolved anthracene monomer emission similar to that of 75 without showing
any exciplex emission. The emission spectra of carbonyl substituted anthracenes have been found to be greatly influenced by the

Figure 59 Bis- and mono-anthryl derivatives of cryptands.

 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 155

Figure 60 Cryptand 9 derivatized with different fluorophores and spacers.

Figure 61 Two fluorescence signaling systems with different spacers.

nature of the carbonyl substituent.167 The presence of the carbonyl group causes restricted rotation of the anthracene group with
respect to the cryptand moiety. This restriction has two significant effects: (1) 88 does not show any exciplex like 75 and (2) the
PET process in 88 is much less efficient compared to that in 75 due to unfavorable donor–acceptor orientation165 in 88. Conse-
quently, the quantum yield of monomer emission FFM increases only slightly upon addition of a metal ion as input. Similarly,
89 also shows168 inefficient PET although it exhibits an exciplex band centered at
520 nm. Among the metal ions studied as input,
the FFM increases marginally, that is, by a factor of
10 in presence of Zn(II), Co(II), or Mn(II) while binding of Ni(II) or Cu(II)
does not elicit any enhancement. In the presence of protons, the molecule exhibits an intramolecular excimer169 emission with
156 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

concomitant decrease in the monomer emission due to close approach of two pyrene moieties in the excited state when the nitrogen
lone-pairs are engaged to protons. This system is thus one of the rare examples showing monomeric, excimeric, and exciplex emis-
sions depending on the environment and can have important implications as proton-induced fluorescence “ON–OFF” switching
where a red-shifted new emission is switched “on” while the monomer emission is switched “off” simultaneously. In order to char-
acterize these three emissions, time-resolved fluorescence measurements were carried out in various environments.170 The mono-
mer region showed a lifetime of 11 ns, which is shorter compared to that of free pyrene indicative of PET from the cryptand N atom
to the pyrene moiety.171 The presence of a longer lifetime component of
55 ns (only
4% contribution) is attributed to a different
conformation of the cryptand. The major component of the lifetime of the exciplex emission is 2.9 ns for the metal-free system. This
value is of the same order as that of systems where tertiary amino groups are semirigidly attached to polycyclic aromatic hydrocar-
bons.172 In presence of protons, the system switches over to a conformer that favors excimer formation. The lifetime of the excimer
as well as that of the monomer in the presence of Hþ are, however, shorter compared to that of other pyrene-based systems,171
indicating all the N atoms in the cryptand are not protonated so that the process of PET is not totally blocked.
A convenient way of making the PET process highly efficient is to use fluorophores that are electron withdrawing in nature. It is
expected that in such cases, the recovery of fluorescence will be quite high. With this idea in mind, the compound 90 has been
synthesized.173 However, the ethylene spacer in 90 makes the PET inefficient and hence, the fluorescence enhancement is only
marginal.

From the foregoing discussions, it is now clear that laterally nonsymmetric cryptands are ideal receptors for transition metal
induced fluorescence signaling and with properly designed fluorophores and spacer, fluorescence “ON” systems can be built
with significantly high quantum yields. Cryptand receptors considered here are poor chemoselectors and efforts should be made
to synthesize cryptands that can discriminate a metal ion in presence of many others.
As a fluorophore and chromophore probe, rhodamine derivatives have attracted considerable interest from chemists on account
of its excellent photophysical properties.174 Perhaps the largest number of fluorogenic chemosemsors for the detection of metal ions
has been reported with rhodamine derivatives.175 As a fluorophore, its mechanism of action is simple and elegant (Scheme 4).
Rhodamine derivatives are nonfluorescent and colorless, whereas upon spirolactum ring-opening in presence of a Lewis acid,
the resulting compound gives a strong fluorescence emission and a red or pink color.

Scheme 4 Mechanism of action of a rhodamine derivative in the presence of a Lewis acid.

 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 157

N N
O O O O O O

N N N N N Hg2+
N N N N N
N N
O O Hg(II)
O
N O Hg(II) N
N O N N °O
Hg(II)
°
N O O N ° O N
N O
O ° °
O

N
°N
91
Fluorescence-OFF Fluorescence-ON

Figure 62 A chromogenic and fluorogenic sensor for the Hg(II) ion.

Among the commonly occurring heavy metal pollutants, mercury is considered to be one of the most dangerous. Some
mercury salts (such as HgCl2) are sufficiently volatile to exist as an atmospheric gas.176 Mercury in different forms can be released
through natural events as well as human activities and it exhibits profound genotoxic, neurotoxic, and immunotoxic effects.
Microorganisms such as sulfate-reducing bacteria produce177 methyl mercury, a dangerous neurotoxin, from other forms of
mercury, that permeates through the skin, respiratory, and gastrointestinal systems of the human body damaging the central
nervous and endocrine systems, leading to many cognitive and motion disorders.178–180 It can spread through air, food, water,
etc. and persists in the environment with subsequent bioaccumulation through the food chain. The Environmental Protection
Agency (EPA) standard181 for the maximum allowable level of Hg(II) in drinking water is 2 ppb. Therefore, there is a high
demand for the determination of trace quantities of Hg(II) ion in the environment as well as in industrial waste. A crypt-
and–rhodamine hybrid has been synthesized182 as the chemodosimeter 91 (Fig. 62). Presence of three rhodamine groups
increases its solubility in aqueous medium necessary for better cell permeability and intracellular fluorescence imaging studies.
The corresponding mono- and bis-derivatives lack the essential requirements for a successful in vivo imaging. Compound 92
shows a dual chromo- and fluorogenic response toward Hg(II) ion in a selective and sensitive manner at ppb level even in
the presence of huge excess of biologically as well as environmentally relevant metal ions. Besides, the dye is not cytotoxic as
per its MTT assay and it is water soluble. Hence, it can be a useful probe for detecting traces of mercury in presence of a host
other metal ions in live cell imaging (Fig. 63).

3.06.5.1 Cryptands in Fabricating Logic Gates

Modulation of the fluorescence signal by two simultaneous ionic inputs can emulate the behavior of an [AND] logic gate.183–187
Cryptands being excellent receptors for transition metals can be used188 in fabricating a fluorescence PET-based logic gate.
Compound 92 mimics the function of a molecular [AND] logic gate. While the cryptand receptor binds a transition metal ion inside
the cavity, an alkali metal ion such as Na(I)

occupies the azacrown cavity. In presence of either a Na(I) ion or a transition metal ion alone, the quantum yield of the system is
very low. When both transition and alkali metal ions are added, the PET is blocked from both ends leading to significant recovery of
fluorescence and thus emulates the Truth Table for the [AND] logic gate.
The compound 92 can be modified further through attachment of two electron-withdrawing groups to the cryptand to afford
93189 which acts like an [INHIBIT] logic gate. An [INHIBIT] logic gate190 is built with a [NOT] gate stopping the input signal
158 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 63 Confocal fluorescence images of Hg(II) in HEK 293 cells (Zeiss LSM 510 META confocal microscope X40 objective lens). (A) Bright-field
transmission image and (B) fluorescence image of HEK 293 cells incubated with 91 (1.0 mM). Further incubation with the addition of Hg(ClO4)2 gives
images (C)–(E): (C) 1, (D) 3, and (E) 5 equiv., respectively, and (F) an overlay image of (A) and (E).

before it can reach the [AND] gate. In MeCN solvent, 93 gives a low emission in the metal-free as well as in presence of Cu(II) but
gives an enhanced emission in presence of Hþ ion. However, when both Cu(II) and Hþ are present as inputs, the fluorescence is
quenched (Fig. 64) emulating a two-input INHIBIT logic operation. Since cryptands can be selectively derivatized, it is expected that
more number of logic gates will be fabricated in the near future.

3.06.5.2 Reversible Fluorescence Signaling

Translocation of a metal ion between inside and outside a cryptand cavity is highly desirable as it can lead to the development of
paradigms for a new class of molecular systems, adding a new dimension to the kinetic, thermodynamic, and a multitude of
other properties in these systems. A system with fluorescence on/off capability can potentially act as a molecular photonic switch,
which is the most important component of any true photonic device. Many problems remain with crafting and operating such
a device. The immediately realizable objective is, however, to build molecular systems exhibiting useful photonic properties that
can be modulated. A pertinent question, therefore, would be when can such a cryptand be forced to bind a metal ion from
outside the cavity overcoming the cryptate effect? For the laterally nonsymmetric cryptands, the easiest way this can be achieved
would
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 159

Figure 64 Fluorescence spectral behavior of 93 alone and in the presence of Cu(II) and Hþ ion in MeCN.

be to alter the donor characteristics of the amino nitrogens in the three bridges by directly attaching191 rigid electron-
withdrawing 1,4-dinitrobenzene groups to the amines to get 94–96. Although cryptate effect favors a metal ion to enter the
cryptand cavity, influential factors such as lower metal-ligand kinetics, larger size of the metal ion than the cavity, structural
rigidity of the covalent architecture, availability of lesser number of donor atoms favoring inclusion complexes and reduction of
their coordinating tendencies, etc. may compel the metal ion to bind the cryptand from outside. The efficient and reversible
metal ion translocation “in and out” of the cryptand cavity comes into action through exploration of the coordination properties
and the compound 94 is found to be favorable for such studies. Presence of a 2,4-dinitrobenzene group in 94 provides a steric
rigidity to the cavity creating a thermodynamically unfavorable condition for the metal ion entering the cavity besides the lone-
pair of the amino N being in conjugation with the p-acceptor group reduces its availability inside the cavity. Thus, although the
donating ability of functionalized amino group is modulated and it may or may not participate in metal ion coordination, other
two unfunctionalized bridging amino groups are still available to form inclusion complexes and also provides a basis for the
metal ion to translocate under the influence of external agents. The 2,4-dinitrobenzene moiety is chosen because it shows an
intense ICT band at 380 nm due to transition from the donor N atom to the acceptor dinitrobenzene moiety. This ICT transition
can be used to monitor in solution the inclusion of a transition metal ion inside the cavity as the metal ion will bind the N donor
stabilizing the ground state and cause blue-shift of the ICT band. Thus, addition of a perchlorate salt of a transition metal ion
induces antiauxochromic shift of the ICT band arising from direct communication between the metal ion inside the cavity and
the D–p–A system (Fig. 65). On gradual addition of cupric perchlorate salt to the cryptand in THF, a clear isosbestic point is
observed signifying formation of an inclusion complex with 1:1 stoichiometry. Upon addition of Cl, SCN, or N 3 ion to any of
the metal perchlorate and 94 mixture, the ICT band position as well as its intensity is restored to the values obtained with metal-
free 94 indicating the metal ion coming out of the cavity. Single crystal structure of some of the complexes191 indeed show the
metal ion bound to the cryptand from outside (Fig. 66).
Putting these ideas together, the fluorophore 7-nitrobenz-2-oxa-1,3-diazole (hereafter, only diazole) with electron-withdrawing
ability has been attached41 to the cryptand to have 97.
160 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 65 The ICT band of 94 in metal-free state and metal included in the cavity.

Figure 66 Crystal structures showing Cu(II), Zn(II), and Cd(II) ion coordinated to 94 from outside the cavity.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 161

Metal-free 97 gives a weak emission at 525 nm in the THF medium which enhances upon addition of a transition metal ion.
Heavy metal ions such as Ag(I), Cd(II), and Pb(II) give appreciable enhancement when a perchlorate/tetrafluoroborate salt is added
to 97 in dry THF. Among all the metal ions studied, Cd(II) gives the maximum enhancement of about 240 times in dry THF
compared to the metal-free 97 (Table 5). Since Cd(II) ion afforded maximum fluorescence enhancement, it was tested for a possible
reversibility of emission through translocation. Fluorescence titration with Cd(II) indicate that it forms a very stable 1:1 inclusion
complex, in consistent with the solution and solid-state studies of the parent cryptand 9 with the same metal ion. When coordi-
nating anions such as Cl, SCN or N 3 are added, the metal ion comes out of the cavity and prefers to bind the receptor from
outside away from the fluorophore causing restoration of PET and quenching of the fluorescence. The extent of quenching depends
upon the coordinating ability of the counter anion toward Cd(II). The addition of SCN exhibits the lowest fluorescence quantum
yield (fF ¼ 0.006, THF), lowering the emission almost to the level of metal-free 97. The metal ion can be put back into the cavity
upon addition of AgBF4 with the fluorescence mostly recovered (fF ¼ 0.333, THF). Of course, the quantum yield is much higher
compared to the situation when AgBF4 is added to 97, confirming that the enhancement is due to Cd(II) and not due to Ag(I).
The excess Ag(I) present in the solution can be removed by adding NaCl in aqueous THF. A schematic representation of this
ON–OFF switchability through metal ion translocation is shown in Scheme 5.
Binding of a metal ion to a cryptand from outside the cavity affords one to design a molecule192 showing reversible controlled
movements of its parts. Such controlled movement due to an external stimulus enables the system to act as a molecular
machine.193–197 Exploiting the somewhat flexible nature of the three bridges of the cryptand 9 including its ability to bind a metal
ion within and outside the cavity, molecule 98 has been designed198 for possible movement of the bridges and its understanding
through fluorescence.

Absorptions observed in the 340–400 nm region in metal-free ligands are due to two operative processesd(i) anthracene
S0 / S1 transition with p–p* nature and (ii) the ICT from the N donor to the p-acceptor moiety. The ICT overlaps with the anthra-
cence transitions and both are nonsolvatochromic in nature. Complexation with a transition metal ion in MeCN results in a small
shift of the (0,0) band retaining the spectral pattern, except in the presence of Cu(II) where the Frank–Condon vibrational structures
of ligand absorption transitions are modulated with the decrease in molar extinction coefficient. This is indicative of a different
binding mode of 98 with Cu(II) in the ground state in contrast to other metal ions.
The metal-free 98 gives a low emission typical of 9-substituted anthracence as the ICT is nonemissive. Interestingly, in the pres-
ence of Cu(II) perchlorate in MeCN, the monomer emission selectively exhibits 80–180-fold increase due to blockade of the PET
along with a red-shifted emission centering at
540 nm (Fig. 67). With protons, the fluorescence enhancement is about 100-fold
although other transition metal ions do not give more than
20-fold enhancement. The lower stability constant values obtained
compared to that of the parent cryptand 9 suggests that Cu(II) binds to these systems from outside the cavity staying farthest away
from the electron-withdrawing groups attached to these systems. The emission band at
540 nm is attributable to an exciplex emis-
sion originating from the intramolecular interaction between the anthracence and one of the aromatic side arms. This exciplex is
162 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Table 5 Fluorescence quantum yield of L9 in the presence of different ionic inputa

Ionic input Solvent Quantum yield (fF) Fluorescence enhancement

– THF 0.00189 1 (standard)

– THF:H2O::9.5:0.5 0.00192
1
Mn(II) THF 0.1387 74
Fe(II) THF 0.1200 64
Co(II) THF 0.0842 45
Ni(II) THF 0.04538 24
Cu(II) THF 0.05791 31
Zn(II) THF 0.18008 95
Ag(I) THF 0.1503 80
Pb(II) THF 0.2088 111
Cd(II) THF 0.4567 242
Hþ THF 0.02784 14
2, 6-di tert. butyl pyridine (DBP) THF 0.0019
1
Cd(II) þ KSCN THF 0.00576 3
Cd(II) þ KSCN THF:H2O::9.5:0.5 0.00559 3
Cd(II) þ NaN3 THF:H2O::9.5:0.5 0.01751 9
Cd(II) þ NH4PF6 THF 0.32459 172
Cd(II) þ NaCl THF:H2O::9.5:0.5 0.0536 28
Cd(II) þ KSCN þ Ag(I) THF 0.3326 175
Cd(II) þ KSCN þ Ag(I) þ NaCl THF: H2O::9.5:0.5 0.3497 185
Cd(II) þ KSCN þ Ag(I) þ DBP THF 0.38178 202
Cd(II) þ KSCN þ Ag(I) þ DBP þ NaCl THF: H2O::9.5:0.5 0.442 234
a
Experimental conditions: medium, dry THF; concentration of free ligand: 3.2  10 6 M; concentration of ionic input, 3  10 5 M; lex ¼ 338 nm; excitation
band pass: 5 nm; emission band pass: 5 nm; temperature, 298 K; fF is calculated by comparison of corrected fluorescence spectrum with that of quinine
sulfate in 1 N H2SO4ðf ¼ 0:54Þ by taking the area under the total emission.

Scheme 5 Translocation of a Cd(II) ion between inside and outside of the cavity of 97.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 163

Figure 67 Emission spectra of 98 alone (close to the baseline) and in presence of Cu(II) ion in MeCN (1  10 6 M, 298 K).

specifically resulted in a coordinating solvent like acetonitrile which usually quenches exciplex emission, and is not observed in
other less coordinating solvents like THF, CH2Cl2, etc. From the correlation of the photoluminescence spectra and the X-ray crystal
structures (Fig. 68) of [98.H]$ClO4$2MeCN, it is evident that one of the 2,4-dinitrobenzene groups moves on protonation and
aligns parallel to the anthracene plane showing p–p stacking interactions leading to exciplex formation. The intensity of exciplex
emission in the presence of Cu(II) in MeCN is higher compared to the corresponding protonated species, indicating a stronger p–p
stacking interaction in the former.
Induction of reversibility can be achieved, in this case, by simply varying the solvent. With Cu(H2O)6$2ClO4, no significant fluo-
rescence enhancement of these systems is observed in a less coordinating solvent such as THF or CH2Cl2. However, on adding
MeCN, monomer emission of 98 increases
130-fold along with the exciplex at
540 nm, suggesting participation of MeCN in
binding Cu(II) to these systems. Alternatively, when a coordinating counter anion like SCN is added in the THF medium, the
fluorescence is enhanced (
160-fold) to a similar extent. When AgBF4 is added to the solution of 98 containing Cu(II) and
SCN, the fluorescence is quenched, almost to the level of metal-free compound due to preferential binding of Ag(I) to SCN
leaving the Cu(II) with BF 4 anion when Cu(II) does not bind to 98 and allows PET to restore. Thus, a reversibility in Cu(II) binding
to the systems can be induced with the coordinating tendencies of the counter anions. However, further addition of SCN to the
solution results in fluorescence enhancement up to
40-fold, a much lesser extent in comparison with the earlier SCN to the
Cu(II) 3 98 (
160-fold, MeCN), possibly due to the change in the ionic strength of the solution. When the Cu(II) chloride salt
is used as the input, the dual emission with comparable enhancement is observed in THF as well.

Figure 68 Perspective views of the X-ray structures of (A) 98 and (B) [98.H]þ showing p–p interaction between a dinitobenezene group and
anthracene to give exciplex.
164 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Scheme 6 Dual monomer and exciplex emission in the presence of Cu(II) in MeCN.

The movements of the side arms take place here in a reversible manner in association with the Cu(II)-binding/detachment. A
schematic sketch of controlled movements of the side arms of 98 and its detection by dual emissions is illustrated in Scheme 6.
An exciting possibility will be translocation of a metal ion inside the cavity exploiting the readily accessible variable oxidation
states of a transition metal ion. Two new cryptand

receptors with trianthryl derivatives 99 and 100 have been designed that provide NS3 and N4 donor sets at the two ends.199 A Cu(I)
ion being a soft Lewis acid prefers to bind to soft S donors while Cu(II) ion being hard prefers hard N donors. Therefore, depending
upon its oxidation state, copper ion can be either at the NS3 or the N4 end of the cavity (Scheme 7). Since PET is blocked when
Cu(II) occupies the N4-end, it leads to a strong emission enhancement. Upon reduction with a mild reducing agent like NaCNBH3
to the Cu(I) state, it moves to the NS3-end of the cavity allowing PET to be operational again leading to fluorescence disappearance.
In air, Cu(I) is oxidized to Cu(II) and moves once again to the N4-end of the cavity resulting in fluorescence enhancement (Fig. 69).
The time taken by the metal ion for this movement from one end of the cavity to the other critically depends upon the rigidity of the
cryptand backbone. In case of 100, which has a more rigid cavity, the time taken is about 5 h as the fluorescence quantum yield
attains the original value by this time. For 99, however, the cavity is less rigid and it takes about 12 h for the movement of the metal
ion from one end to the other. However, this process is reversible because the metal ion stays inside the cavity (Scheme 6). The time
taken for translocation can be further reduced with receptors having high p surface that can make the cavity rigid making the
movement faster.

Scheme 7 A schematic view of the translocation of a redox-active metal ion within a cryptand cavity.
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 165

Figure 69 Emission quantum yield values with change in the oxidation state of copper.

Scheme 8 Illustration of the situation in one-step FRET process.

3.06.6 Förster Resonance Energy Transfer

The use of Förster resonance energy transfer (FRET) as a spectroscopic technique has been in practice for well over 50 years.200 FRET
is a nonradiative process where an excited-state donor (usually a fluorophore) transfers energy to a proximal ground state acceptor
through long range. The rate of energy transfer is highly dependent on many factors such as the extent of spectral overlap, the relative
orientation of the transition dipoles, and most importantly the distance between the donor and acceptor molecules.152 The process
of FRET usually occurs over distances comparable to the dimensions of biological macromolecules, that is,
10–100 Å.

3.06.6.1 Single-Step FRET

Systems of particular interest are bichromophoric molecules separated by spacers where the emission spectrum of one overlaps with
the absorption spectrum of the other, substantial FRET201 can take place (Scheme 8).
Such single-step FRET processes allow for ratiometric fluorescence signaling202 and offers a new generation of fluorescence
sensors besides being an important biological tool to monitor enzyme activity and conformational analysis of protein struc-
tures.203,204 Two-step FRET offers several advantages over one-step FRET: higher efficiency of long-range energy transfer, larger
Stokes shift and better detection sensitivity for the acceptor fluorophore.
With the possibility of partial derivatization of the secondary amino groups in the cryptand 9, it is a simple procedure to sequen-
tially derivatize with different fluorophores205 where the emission spectrum of one overlaps with the absorption spectrum of the
other to make resonance energy transfer possible. This has been achieved in the two systems 101 and 102.
166 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 70 Emission spectra of 101 and 102 in MeCN at RT with different inputs as indicated.

Both compounds show dual emissions, the exact nature of which depends upon the wavelength of light used for excitation. In the
MeCN medium, on excitation at 344 nm, where anthracene absorbs significantly, emissions due to both the anthracene and the diaz-
ole fluorophores appear albeit with low intensity due to PET being operational. However, appearance of both emissions suggests
a small amount of resonance energy transfer from the anthracene to the diazole moiety. When excited at 483 nm, emission due
to the diazole moiety alone is observed. When a metal ion is added as the input, substantial enhancement of diazole emission takes
place with either excitation wavelengths, (344 or 483 nm) with concomitant reduction in the intensity of anthracene emission
(Fig. 70). Here, the metal ion inside the cavity serves dual roles: it blocks the PET and helps as a conduit of fluorescence resonance
energy transfer from excited anthracene to the diazole upon excitation at 344 nm. In the solid state, both compounds in the metal-
free as well as in presence of metal ion or proton exhibit only anthracene monomer emission when excited at the anthryl absorption
maximum without showing any emission from diazole. When the metal complexes are dissolved in MeCN, quantum yields for the
fluorophores are restored and become equal to the values in solution. This shows FRET to be operational only in the solution phase
because it allows movement of the receptor arms as well as the fluorophores for optimum mutual orientation.
The energy transfer efficiency (E) can be determined by the enhancement of acceptor (here, diazole) fluorescence by utilizing the
following equation:
 
Am ðlD Þ FAb ðlD Þ
E ¼ Am  1 (2)
AD ðlD Þ FAm ðlD Þ

where Am A (lD) is the absorbance of the acceptor in model acceptor (diazole) bound cryptand molecule at the lmax wavelength
corresponding to the donor moiety of the bichromophore, Am D (lD) is the absorbance of the donor in model donor (anthracene)
bound cryptand molecule at the lmax wavelength corresponding to the donor moiety of the bichromophore, FbA(lD) is the fluo-
rescence emission of the acceptor in bichromphoric cryptand molecules (101 and 102) at the lmax wavelength corresponding to the
donor moiety of the bichromophore, and Fm A (lD) is the fluorescence emission of the acceptor in model acceptor bound cryptand
molecule, that is, 9 with mono-substituted diazole at the lmax wavelength corresponding to the donor moiety of the bichromo-
phore. The detail of the mathematical derivation is available in the literature.206
The interchromophoric distances can be estimated through fluorescence anisotropy measurements of donor and acceptor and
following a protocol provided207 by Valeur and coworkers:


E ¼ R60 R60 þ R6 (3)

1=6
R0 ¼ 9:78  103 h4 Fd k2 J

A (4)

The interchromophoric distance (R) due to dipole–dipole interaction depends upon the orientational factor (k; Eq. 4). The limits
on k2 are obtained by measurements of fluorescence anisotropy208 of the donor and the acceptor to minimize the uncertainties in
the calculated interchromophoric distances in the solution state. In the present case, the interchromophoric distances estimated to
be in the range of
18 Å that are larger than the distances observed in the cases of metal-free 101 and 102. The changes in the inter-
chromophoric distances in the metal complexes tune them to be specific in the involved fluorescence resonance energy transfer
processes. Thus, the cryptand 9 is attractive for studying FRET as it acts as a perfect skeleton to sequentially add different fluoro-
phores, Besides, it can undergo structural changes to enable partial movement of one of the side arms with respect to another
that changes the distance as well as orientation of the fluorophores with implications on the FRET efficiency.

3.06.6.2 Multi-Step FRET

A two-step FRET209–211 takes place between the first (donor D) and the third chromophores (acceptor A) via the second chromo-
phore (transmitter T) (Scheme 9). Transfer of the adsorbed radiation energy by many chromophores is achieved in a multi-step
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 167

Scheme 9 Approximate energy diagram in a two-step FRET process.

FRET mechanism. Three different fluorophores can be attached to a cryptand for two-step FRET processes. Compound 103 has been
synthesized212 by sequential addition of one 7-nitrobenz-2-oxa-1,3-diazole (diazole, A), one anthracene group (T), and one quin-
oline (D) group to the cryptand, 9.

This PET compound (103) exhibits three emission bands in MeCN upon excitation at 316 nm, where the band due to quinoline
absorbs213 predominantly, emissions due to quinoline (
345 nm) as well as anthracene (
420 nm) and diazole (
520 nm)
appear with low intensity. This suggests a small amount of multiple FRET from quinoline to the diazole via anthracene. When
excited at 345 nm, low emission due to anthracene and diazole are found while excitation at 475 nm gives only diazole emission.
In the presence of a first-row transition metal ion, exciting 103 at 316 nm does not elicit quinoline emission as before. Instead, two
strong emission bands at
420 and
520 nm, assignable to the anthracene and diazole moieties, respectively (Fig. 71), are

Figure 71 Fluorescence spectra of 103 with different inputs as shown.

168 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

observed. The characteristic vibrational structure of anthracene is absent presumably due to interactions between fluorophores. This
result suggests a significant amount of FRET from the excited quinoline (D) to the diazole (A) via anthracene (T) where the metal
ion acts as a conduit. To probe further, compounds 104 have

been synthesized. In this case, no emission is observed due to the diazole moiety when 104 is excited with 316 nm light indicating
that FRET from the quinoline to the diazole moiety is not possible in the absence of the anthracene chromophore. Cu(II) shows the
highest diazole emission in a two-step FRET process in 103 providing the first example of a two-step FRET in the presence of a para-
magnetic metal ion. The energy transfer rate resolves the time for the excitation energy to circulate from the quinoline end to the
diazole part and it involves several energy transfer steps. Fluorescence decays have been measured at the wavelengths dominated by
the anthracene (Fig. 72) and diazole (Fig. 73) moieties to estimate the time required for the excitation energy to arrive at the diazole.
The fluorescence decays can be fitted to a three-exponential expression with three positive amplitudes (Tables 6 and 7). All three
lifetimes are found to increase significantly, thereby lending support to our contention that PET is responsible for the low quantum
yield of the free ligand. The fact that no rise time is observed, even in a femtosecond fluorescence upconversion setup, indicates that
the energy transfer is too fast, even for the best resolution of the available instrument. The interchromophoric distances are esti-
mated by steady-state energy transfer experiments following the protocol described earlier and the value is about
13 Å.
For probing the two-step FRET further, the compound 105 has been designed214 and synthesized. As in the case of 103,
compound 105 exhibits triple emissions depending upon the wavelength of emission applied. When a first-row transition metal
ion is used as an input, no quinoline emission is observed upon excitation at 316 nm (for quinoline). Instead, significant amount
of emission from anthracene and diazole groups is observed due to FRET from quinoline to diazole via anthracene. Time-resolved
fluorescence measurements at wavelengths dominated by anthracene and diazole were carried out to find out the rate of transfer of
the excitation energy to arrive at the diazole. The fluorescence decay at 518 nm can be fitted to a two-exponential expression with
two positive amplitudes.

Figure 72 Time-resolved emission spectra of 103 in the presence of different ionic input in MeCN (lex ¼ 295 nm; lem ¼ 418 nm).
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 169

Figure 73 Time-resolved emission spectra of 103 in the presence of different ionic input in MeCN (lex ¼ 295 nm; lem ¼ 518 nm).

Table 6 Time-resolved fluorescence decay analysis (lex ¼ 295 nm; lem ¼ 418 nm)

Sample A1 T1 A2 T2 A3 T3

103 0.53 0.20 0.10 1.36 0.37 3.89

103 þ Ag(I) 0.58 0.56 0.13 4.47 0.29 27.19
103 þ Cu(II) 0.49 0.95 0.09 6.77 0.43 31.29
103 þ Zn(II) 0.55 0.59 0.12 5.30 0.33 30.93
103 þ Hþ 0.46 0.97 0.13 6.36 0.41 31.04

Table 7 Time-resolved fluorescence decay analysis (lex ¼ 295 nm; lem ¼ 518 nm)

Sample A1 T1 A2 T2 A3 T3

103 0.42 0.57 0.42 2.81 0.15 9.62

103 þ Ag(I) 0.54 2.25 0.34 6.77 0.11 24.8
103 þ Cu(II) 0.55 1.2 0.34 5.71 0.11 27.08
103 þ Zn(II) 0.50 2.27 0.36 7.7 0.14 27.95
103 þ Hþ 0.45 1.79 0.40 6.38 0.15 24.52

The fact that no rise time is observed even in a femtosecond upconversion setup indicates that the energy transfer is too fast. The
interchromophoric distances are estimated by steady-state energy transfer experiments following the protocol described earlier. The
distances between quinoline and anthracene, in the case of Hg(II) and Cu(II) complexes of 105, afford values of
11 and
15 Å,
respectively. On the other hand, the distances between anthracene and diazole, in the case of Hg(II) and Cu(II) complexes of 105,
afford values of
13 and
10 Å, respectively.
170 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

3.06.7 Cryptands as Nonlinear Optically Active Materials

Design and synthesis of organic molecules exhibiting second-order NLO properties have been motivated by their potential appli-
cations215–219 in emerging technologies of optoelectronics and photonic devices such as telecommunications, optical computing,
data storage, and so on. Advantages of using organic molecules as NLO materials stem from the fact that they can be designed to
optimize the desired NLO property. At the molecular level, compounds likely to exhibit large values of molecular hyperpolariz-
ability, b must have polarizable electrons (e.g., p-electrons) spread over a large distance. The most important manifestation of
second-order bulk nonlinearity is frequency doubling also known as second harmonic generation (SHG). Detailed mathematical
explanations of the nature and origins of NLO effects are available. Second-order NLO effects, including SHG and electrooptic
modulation, are important parameters for interfacing electronic data to wide-band optical communication.
Although b in a molecule is closely related to bulk nonlinearity c2 in the solid state, large values of b do not ensure that when
crystallized, it will show a high value of c2. For this to happen, the molecule must crystallize in a noncentrosymmetric space group.
It has been a belief for a long time that linear extended p systems with a considerable molecular dipole character are most promising
candidates as second-order NLO materials. A major problem216 of traditional dipolar chromophores is the nonlinearity/transpar-
ency trade-off, where the desirable increase in second-order polarizability is accompanied by a bathochromic shift220 of the elec-
tronic transition, leading to reabsorption of the second harmonic light making them ineffective in frequency doubling
applications. Moreover, these molecules are difficult to crystallize in noncentrosymmetric space groups.
At the microscopic level, strategies have been developed during the past decade in order to circumvent these eventual drawbacks
by extending the CT dimension from one to two or even to three. These two- and three-dimensional (2D and 3D) chromophores
with C3, D3, or T symmetries have several advantages: (1) they are more transparent as the lack of a permanent dipole moment
results in negligible solvatochromism, (2) enhanced nonlinearity due to coupling of the excited states at no cost of transparency,
and (3) greater probability of crystallization in a noncentrosymmetric space group due to very low dipole moment.
Laterally nonsymmetric cryptands incorporating secondary amino nitrogens can serve as excellent skeletons onto which acceptor
groups can be added for having trigonal nonlinear materials. The cryptands 9 and 10 were derivatized221,222 with different acceptor
units (p-A) to have 3D NLO chromophores with pseudo-threefold symmetry (Fig. 74).
The central core or the cryptand has been varied (Fig. 75) to alter the donating ability of the nitrogen atoms and also to probe any
effect of rigidity of the cryptand has on the NLO behavior. The nitrogen atoms give the cryptand its donor (D) character and the p-A
units were grafted by simple aromatic nucleophilic substitution (ArSN) reactions.
As each cryptand core inherits threefold symmetry, there arises two possibilities by which these trigonal molecules can crystallize
(Scheme 10): a planar centrosymmetric hexagonal lattice formed by the interactions between identical groups resulting in SHG
inactive molecules or noncentrosymmetric trigonal lattice formed by the interaction between different groups leading to the
SHG active form. Until now, crystal structures of three of the compounds shown in Figs. 74 and 75 are available. These compounds
are numbered 106–108 and shown in Fig. 76.
Compound 106 crystallizes in the centrosymmetric orthorhombic space group Pbca while 107 crystallizes in the noncentrosym-
metric trigonal space group P3 and 108 crystallizes in the triclinic crystal system.223 All three maintain a pseudo-threefold symmetry
along the two bridgehead N atoms of the cryptand. None of the compounds shown in Figs. 74 and 75 fluoresce at room temper-
ature and are essentially transparent at 532 nm for nonresonant HRS measurements at l ¼ 1064 nm. Besides, a plot of I(2u)/I(u2)
(where u is 532 nm) against the number density of any of the chromophores show a perfectly linear dependence as expected from
a system of independent scatterers. This finding again confirms the suitability of these cryptand derivatives as NLO materials.
The nonlinearity of 106–108 as well as other compounds (Figs. 74 and 75) are comparable to the classical para-nitroaniline
(pNA) molecule,224 with O < b2 > (0) ¼ 10  10 30 esu as measured in CHCL3 under similar experimental conditions. Compara-
tively, the nonlinearity of the compounds with the more rigid cryptand 10 show a slightly higher value compared to pNA.
Compound 107 gives a SHG powder signal that is 0.6 times that of urea in conformity with its acentric crystallization.
Compound 106, in spite of being crystallized in a centrosymmetric space group, shows a very weak SHG powder signal efficiency
of 0.05 times that of urea, which points out some defect sites in the crystal. Although the molecules crystallize in a centrosymmetric
space group, there may be regions or zones having defects. In fact, such defects are known in organic molecules. The X-ray crystal-
lographic data pertaining to the macroscopic ordered region of the crystal say nothing about the molecular packing in the defect
region. The structure of 106 is stabilized by hydrogen bonding and stacking interactions in a different fashion compared to the other
two cases. Perhaps this is the reason why it adopted a centrosymmetric packing. In other words, stacking interactions between the
molecules in a unit cell seems necessary for adopting a noncentrosymmetric crystal structure in the solid state and, hence, for effi-
cient macroscopic SHG. Surprisingly, compound 108 in spite of being crystallized in the triclinic centrosymmetric space group
exhibits a SHG powder signal of 0.36 times that of urea. This could be due to polymorphism of the crystalline structure or due
to a slight difference in the molecular orientations along one of the axes. However, this result is not unprecedented and was earlier
observed in case of 2,4,6-triamino-1,3,5-trinitrobenzene (TATB) that crystallizes in a centrosymmetric space group but shows
substantial SHG activity.225
Using a cryptand as the skeleton has other added advantages. The cryptand can include a redox-active metal ion in the cavity that
can act as a signal transducer offering switching possibilities226 or it can include a paramagnetic transition metal ion that might be
useful in aligning in strong fields. The ability to switch the NLO response of a molecule “ON” and “OFF” reversibly should add
significant utility to NLO molecules. Interestingly, the use of metals in altering the properties of nonlinear materials has not
been explored extensively.227–229
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 171

Figure 74 Mono-, bis-, and tris-derivatives of cryptand 9.

3.06.7.1 Third-Order Optical Nonlinearity

While second-order nonlinearity is observed in bulk samples only when they crystallize in the noncentrosymmetric space groups,
no such restriction is necessary for observing third-order optical nonlinearity effects. The two-photon absorption process is a third-
order NLO process which involves the excitation of molecular species from the ground state (So) to the first singlet excited state (S1)
or to the second singlet excited state (S2) by absorption of two photons. The efficiency of this process is determined by measuring
two-photon absorption cross-section (s(2)) value, which is related to the imaginary part of the second hyperpolarizability, g. The
design and synthesis of materials exhibiting large s(2) values have been motivated by their tremendous potential for applications in
several areas of bio-photonics and materials science such as two-photon fluorescence excitation spectroscopy, optical power
limiting, three-dimensional optical data storage, two-photon upconversion lasing, photodynamic therapy, and so on. At the molec-
ular level, compounds likely to exhibit large s(2) values must have polarizable electrons (i.e., p electrons) spread over a large
distance. Both experimental results and theoretical calculations suggest that donor–acceptor strength, conjugation length, and
dimensionality of charge-transfer symmetry are the most important molecular parameters affecting TPA activity. Thus, the most
extensively investigated basic structural motifs for appreciable TPA cross-sections are D–p–A, D–p–D, A–p–A, D–p–A–p–D,
and A–p–D–p–A (D ¼ donor, A ¼ acceptor, p ¼ conjugated spacer).230,229,231 Strategies have been evolved to arrange various
D–p–A fragments around suitable skeletons to afford dipoles,232,233 octupoles,234,235 quadrupoles,236 and multi-branched
172 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Figure 75 Mono-, bis-, and tris-derivatives of cryptand 10.

Scheme 10 View of a trigonal lattice (left) and a hexagonal lattice (right).

 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 173

Figure 76 Crystal structures of the above compounds are available.

structures.237 Macrobicyclic cryptands can serve as skeletons for the attachment of different electroactive groups for multidimen-
sional charge-transfer possibilities. Besides, they can accommodate one or more metal ions, anions, or neutral molecules inside
the cavity to act as mediator(s) for cooperative interaction among the individual arms leading to enhanced nonlinear responses.238
Apart from tuning the TPA activity, a cryptand can act as a suitable host for the switching of optical properties through translocation
of the metal ion. Different numbers of donor groups have been attached239 to the cryptand 9 to have the following systems:
174 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Here, 4-(dimethylamino)benzene is a strong donor and the ferrocene moiety is a very good electron transfer group.240 The TPA
cross-sections s(2) were measured at 800 nm laser by the Z-scan technique for each metal-free system and also in the presence of
Zn(II) ion that is known to occupy the cavity of the cryptand. A look at (Table 8) suggests that some generalizations can be made.
There is a gradual increasing trend of TPA cross-section values when one goes from the singly branched system to the triply
branched one, both for free chromophores and their metal complexes. The TPA cross-section values increase monotonously
with the number of substituents for each type. Furthermore, in the presence of metal ions as input, the s(2) value increases in
each case due to the enhanced acceptor strength. Especially, compared with 109–111, the s(2) values of 112–114 are more
enhanced. This is commensurate with the fact that while 4-(dimethylamino)benzene is a strong donor, ferrocene is a good electron
transfer group. The maximum value of s(2) is found with the Zn(II) complex of 114. There is a similar trend for the Cd(II)
complexes. When the TPA measurements were carried out in the available wavelength range of 740–900 nm, it revealed that the
maximum s(2) value in the wavelength range was not exactly double the lmax in the one-photon absorption spectra. Deriving
the multi-photon excitation wavelength maximum is not as simple as doubling the single-photon excitation wavelength maximum,
although in some cases this can be a good place to start. Anyway, the results are shown graphically in Fig. 77.
Theoretical calculations using the B3LYP functional241 with a 6–31G* basis set showed that the substituents in the metal-free
chromophores are tilted and become much more planar when a Zn(II) ion enters the cavity. This demonstrates an interesting point
that the most regular arrangement of these kinds of macrobicyclic compounds has a marked influence upon their electronic

Table 8 Photophysical data for 109–114 and their corresponding Zn(II) and Cd(II) complexes

Compounds lmax (nm) 3  10

4
(mol L 1 cm 1) s(2) (GM) in 800 nm

109 382, 319 3.891, 2.281 450

109 þ Zn(ClO4)2$6H2O 484, 371 5.207, 1.005 1220
109 þ Cd(ClO4)2$6H2O 487, 369 4.903, 0.996 1340
110 374, 318 8.915, 4.815 940
110 þ Zn(ClO4)2$6H2O 454 12.487 2860
110 þ Cd(ClO4)2$6H2O 460 11.459 2750
111 375, 322 13.587, 7.468 1640
111 þ Zn(ClO4)2$6H2O 456 19.783 4640
111þ Cd(ClO4)2$6H2O 462 17.98 4990
112 370, 467 4.109, 0.437 910
112 þ Zn(ClO4)2$6H2O 401, 533 4.877, 1.955 2700
112 þ Cd(ClO4)2$6H2O 407, 543 3.851, 1.524 2560
113 357, 456 4.819, 1.266 1940
113 þ Zn(ClO4)2$6H2O 384, 537 10.334, 3.323 7490
113 þ Cd(ClO4)2$6H2O 386, 544 8.345, 2.66 6750
114 352, 460 7.136, 0.814 3050
114 þ Zn(ClO4)2$6H2O 387, 540 13.951, 5.141 11200
114 þ Cd(ClO4)2$6H2O 393, 547 12.751, 4.753 10660
 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors 175

Figure 77 Plot of TPA cross-section values for the Zn(II) complex of 109 to 114 at different wavelengths in 10 5 (M) CH3CN solution. The solid
lines are shown as guides for the eye.

properties. The contour surface diagrams239 of the metal complexes clearly indicate a strong communication among the side arms
through the metal ion. Especially, the electron density is more delocalized from one side arm to another two side arms inducing
large enhancement of the TPA cross-section value.
Two symmetrical dipolar NLO-phores 115–116 have also been studied242 for evaluating their TPA activity. When compared with
109–114, these two systems exhibit larger s(2) values (Table 9).

Larger TPA cross-section has been achieved due to lengthening of the conjugation. However, more such studies are required
before a structure/property correlation can be made.
Laterally nonsymmetric cryptands containing amine groups in the bridges constitute a special type of macrobicyclic cryptands
that can be synthesized easily in bulk quantities. The amino groups in the bridges can be selectively derivatized with different groups
to have molecules that have been found to be useful in different contemporary areas of research. Synthesis of such cryptands with
176 Macrobicyclic Cryptands With Laterally Nonsymmetric Donors

Table 9 Photophysical data for 115–116 and their corresponding metal complexes

Compounds lmax (nm) 3  10

4
(mol L 1 cm 1) Max s(2) (GM) at 800 nm

115 341, 403 3.5, 5.92 4000

115 þ Zn(II) 400, 496 3.326, 4.309 6600
116 333, 415 2.949, 6.652 6100
116 þ Zn(II) 382, 528 2.332, 7.411 11,100

larger cavities should be attempted where larger anions as well as neutral molecules can enter forming inclusion complexes. Selec-
tive derivatization of the amine groups should be explored further for making cryptand-based dendritic structures opening up yet
another exciting possibilities.

Acknowledgments

Partial financial support from the Department of Science and Technology, New Delhi, India is gratefully acknowledged. The author wishes to express
his sincere thanks to all his students and co-workers over the years whose names appear in the references.

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236. Werts, M. H. V.; Gmouh, S.; Mongin, O.; Pons, T.; Blanchard-Desce, M. J. Am. Chem. Soc. 2004, 126, 16294–16295.
237. Drobizhev, M.; Karotki, A.; Dzenis, Y.; Rebane, A.; Suo, Z.; Spangler, C. W. J. Phys. Chem. B 2003, 107, 7540–7543.
238. Chung, S.-J.; Kim, K. S.; Lin, T. C.; He, G. S.; Swiatkiewicz, J.; Prasad, P. N. J. Phys. Chem. B 1999, 103, 10741–10745.
239. Jana, A.; Jang, S. Y.; Shin, J.-Y.; De, A. K.; Goswami, D.; Dongho Kim, D.; Bharadwaj, P. K. Chem. Eur. J. 2008, 14, 10628–10638.
240. Barlow, S.; Marder, S. R. Chem. Commun. 2000, 1555–1562.
241. Becke, A. D. J. Chem. Phys. 1993, 998, 5648–5652.
242. Jana, A.; Lin, J. M.; Park, S. W.; Kim, D.; Bharadwaj, P. K. Indian J. Chem., Sect. A 2011, 50A, 511–518.
 3.07 Synthetic Lectins
AP Davis, University of Bristol, Bristol, United Kingdom
Ó 2017 Elsevier Ltd. All rights reserved.

3.07.1 Introduction 181

3.07.2 General Principles 181
3.07.3 Carbohydrate Recognition by Calixarenes and Related Macrocycles 183
3.07.4 Platforms With Polar Peripheries 184
3.07.5 “Temple” Receptors I: Biphenyl-Based Cages 185
3.07.6 “Temple” Receptors II: Terphenyl-Based Cages 189
3.07.7 “Temple” Receptors III: Macrocycles Based on Condensed Aromatics 190
3.07.8 Receptors Based on Peptide Chains 195
3.07.9 Oligoaryl Foldamers 196
3.07.10 Porphyrin-Based Systems 197
3.07.11 Metal Complexes as Synthetic Lectins 198
3.07.12 Cucurbit[7]uril as a Synthetic Lectin 199
3.07.13 Beyond Binding: Implications and Applications of Synthetic Lectins 199
3.07.14 Conclusions 200
References 201

3.07.1 Introduction

Carbohydrates are important substrates for supramolecular chemists. On the one hand, they are clearly significant. They constitute
one of the three major chemical components of the living world and play a wide variety of roles ranging from fuels (e.g., starch) and
building materials (e.g., cellulose) to the storage of biological information in complex oligosaccharides. 1,2 At the same time, they
are unusually challenging. They are, of course, quite complex molecules with irregular three-dimensional shapes that may differ
quite subtly from each other (see Fig. 1). However, the major difficulty is that their natural environment is water; they should there-
fore be bound from water, but they are closely similar to water. A carbohydrate receptor designed to operate in aqueous solution
must distinguish between the water molecules occupying the binding site and a target that features largely the same functional
groups. There are indications that even nature finds this problematic. Although some protein–carbohydrate interactions are strong,
reaching 106–107 M
1 for glucose þ bacterial periplasmic proteins,3 a great many are far weaker. The largest class of carbohydrate-
binding proteins, the lectins, are notorious for their low affinities.4 This applies especially to monosaccharide substrates, for which
binding constants rarely seem to exceed 104 M
1.5
Supramolecular chemists have been addressing the problem of carbohydrate recognition for nearly four decades. Many have
exploited the well-known (reversible) reaction of carbohydrates with boronic acids, designing scaffolds that promote the reaction
and, in some cases, bring multiple boronic units to bear on a substrate. 6,7 Other work has focused on binding carbohydrates in
organic solvents,8,9 an easier challenge that can yield interesting results but is less relevant to biology. This article, entitled “Synthetic
Lectins,” covers a third group of studies that face the problem head on. The systems described herein bind carbohydrates in water
and rely purely on noncovalent interactions (as opposed to covalent B–O bond formation). They are therefore directly comparable
to lectins and able to inform on the principles that underlie carbohydrate recognition by proteins. Although much of the work has
served mainly to highlight the difficulty of the problem, some recent results have shown that a good level of success is possible, at
least in some cases. Indeed, some synthetic lectins show affinities and selectivities that compare remarkably well with their natural
counterparts. Ongoing research is motivated by the prospect of complementing lectins as biological research tools and addressing
other important issues such as carbohydrate sensing. Progress toward these goals, and toward developing an understanding of
carbohydrate recognition in water, is outlined in the following sections.

3.07.2 General Principles

As mentioned earlier, binding carbohydrates in water is expected to be difficult and appears to be so in practice. The fact that
proteins succeed (albeit often weakly) has engendered much discussion. Crystal structures of protein–carbohydrate complexes
reveal complementary polar and apolar contacts. Polar groups on the carbohydrate typically form hydrogen bonds with polar
groups in the binding site, while apolar regions within the substrates (formed from clusters of CH groups) make contact with hydro-
phobic units in the protein (see Fig. 2). Interestingly, the hydrophobic surfaces employed by the proteins are almost exclusively
aromatic, suggesting that CH–p interactions make an important contribution.10,11 The controversial issue is the driving force for
complexation, especially the role of water. One view is that the major factor is the network of hydrogen bonds formed on binding.3

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12525-9 181

182 Synthetic Lectins

Figure 1 Carbohydrates commonly employed as substrates in studies of synthetic lectins. Protonation states at pH 7 are shown where relevant.

Despite the requirement to desolvate both partners before H-bond formation, it is thought that the network is so precisely engi-
neered that high affinities can be achieved. The alternative suggestion is that the driving force is largely hydrophobic, that is, result-
ing from the release of high-energy water molecules on binding. There is little doubt that hydrophobic effects play some role in
respect of the CH–p contacts mentioned earlier, but the surfaces involved are small and (arguably) insufficient to supply the
main impetus for binding. Instead, it was proposed by Lemieux that the whole interior surface of a carbohydrate-binding protein
may be inhospitable to water.12 Although these binding sites will contain many polar units, the fact that they are dispersed among
apolar groups might interfere with solvation. The water in contact with these polyamphiphilic regions might thus be relatively high
energy and capable of driving binding through release into bulk. Lemieux suggested that this effect be termed “hydraphobic” to
distinguish it from the classical hydrophobic effect.
From the viewpoint of the practical supramolecular chemist, this debate is intriguing but probably has marginal relevance. What-
ever the driving force for carbohydrate recognition by proteins, the structural requirements for a binding site are fairly clear. As is
often the case in supramolecular chemistry, the guiding principle is complementarity. Apolar patches on the carbohydrate substrate
should be paired with aromatic surfaces in the receptor, to take advantage of whatever hydrophobic/CH–p forces are available.
Polar groups on the carbohydrate should be matched with complementary H-bonding units. Even if the H-bonds formed contribute
little to the binding energy (due to desolvation), at least the meeting of polar moieties will do no harm. If polar groups are not
 Synthetic Lectins 183

Figure 2 Crystal structure of glucose in the active site of the E. coli galactose chemoreceptor protein (see Ref. 3). Hydrophobic patches on the
substrate make contact with two aromatic side chains (phenylalanine and tryptophan, shown in green), a water molecule (purple), and eight polar
amino acid residues (3  aspartate, blue; 3  asparagine, orange; 1  histidine, cyan; and 1  arginine, magenta).

matched, they must desolvate without forming new H-bonds and binding will be strongly inhibited. Thus, the great majority of
synthetic lectins feature aromatic units combined with polar groups of some type. Importantly, the polar groups must include units
capable of mobilizing the system in water. Indeed, water solubility is not enoughdthe receptor should be monomeric in water, or
full characterization of the system (e.g., the measurement of binding constants) will be virtually impossible.
While the nature of the driving force for binding may not affect design strategies, it does provide opportunities for supramolec-
ular chemistry. Synthetic lectins can serve as models for natural lectins but are amenable to studies that cannot be carried out on
proteins. As discussed later (section “ Beyond Binding: Implications and Applications of Synthetic Lectins”), work of this type has
made a useful contribution to resolving the controversy.
Finally, it should be noted that carbohydrates are highly variable and may present quite different challenges. For example, oligo-
saccharides possess larger surface areas than monosaccharides and more functional groups. One might therefore expect that they
would be easier to bind, and this is borne out in practice (although achieving selectivity is another matter). Charged substrates
(e.g., aminosugars and sulfated or phosphorylated carbohydrates) are also less difficult targetsdelectrostatic interactions are moder-
ated by water but can still be quite powerful. Any modification that adds hydrophobic surface (e.g., conversion to a methyl glyco-
side) will also reduce the challenge. The most difficult substrates are probably the simple monosaccharides (e.g., glucose, galactose,
and mannose) that are small, hydrophilic, and hydromimetic (water-like). As shall be seen, good solutions for most of these targets
are still awaited.

3.07.3 Carbohydrate Recognition by Calixarenes and Related Macrocycles

In any discussion of synthetic carbohydrate receptors, the calixarenes 22 ( Fig. 3) serve as a natural starting point. These molecules
may be prepared from resorcinol and aldehydes and were studied from the late 1980s onward by the group of Aoyama. Early vari-
ants were organic-soluble,13 but in 1992, they reported the water-soluble tetrasulfonates 22a–c.14 1H NMR titrations produced
evidence of binding to some carbohydrates in water, though affinities were very low and the most hydrophilic substrates (e.g.,
glucose and mannose) gave no sign of complexation. The most significant results were obtained with fucose 6, a deoxysugar
and somewhat more hydrophobic than the common monosaccharides. Even with 6, the binding constants Ka measured for
22a-c were just 2, 6, and 8 M
1, respectively. A later study showed that deprotonating 22a could raise the affinity for 6 as far as
26 M
1, possibly by enhancing CH–p interactions.15 These studies were important in setting a benchmark for subsequent work
and confirming that carbohydrate recognition in water did indeed represent an exceptional challenge.
Promising results were also reported for a second calixarene-type system, the cyclotetrachromotropylene 23 synthesized and
studied by Poh and coworkers. This naphthalene-based macrocycle did not appear to bind simple monosaccharides such as glucose
1 or xylose 12, but was quite effective for methyl glycosides. The preferred substrate was methyl a-D-mannoside 24 that was bound
with Ka ¼ 75 M
1, as measured by 1H NMR titration. 16
184 Synthetic Lectins

Figure 3 Calixarene-type receptors for carbohydrate recognition in water.

3.07.4 Platforms With Polar Peripheries

The calixarenes in Fig. 3 set the tone for a range of other systems in which aromatic cores are surrounded by polar functional groups.
The easiest way to access such structures is to start with a planar aromatic platform with two or more reactive centers and then elab-
orate side chains as required. Some examples are shown in Fig. 4. Receptors 25 and 28 provide good illustrations of the principle,
mentioned earlier, that large and charged substrates are relatively easy to bind. Neither is reported to bind simple carbohydrates, but
25 forms complexes with sialylated oligosaccharides such as sialyl Lewis X (26) and GM3 (27) with Ka  100 M
1 (1H NMR titra-
tion),17 while pentacationic 28 associates strongly with polyanionic heparin 29 (as revealed by ultraviolet (UV)/visible spectros-
copy).18 Hexa-anionic 30, studied as a mixture of stereoisomers, was ineffective for uncharged substrates but showed
Ka ¼ 90 M
1 for protonated glucosamine 19.19 Bis-carboxylate 31 was studied as a receptor for the neutral carbohydrates methyl
b-D-glucoside 4 and cellobiose 14, again by 1H NMR titration. In this case, there were clear signs of binding, despite the absence
of electrostatic attraction. Quantitative analysis of binding was complicated by multiple stoichiometries; the studies suggested

Figure 4 Receptors based on aromatic central platforms.

 Synthetic Lectins 185

that both 1:1 and 1:2 receptor/substrate complexes were formed for both 4 and 14. In such cases, the fitting of titration data involves
variation of three independent parameters, with the result that fits are easy to obtain but not necessarily definitive. With this note of
caution, the affinities measured for 31 were promising, with sequential Ka values of 2 M
1 (1:1) and 72 M
1 (1:2) for monosac-
charide 4 and 305 M
1 (1:1) and 66 M
1 (1:2) for disaccharide 14.

3.07.5 “Temple” Receptors I: Biphenyl-Based Cages

To bind a molecule powerfully and selectively, it is usually advantageous to employ an enclosed binding site. This is illustrated by
natural carbohydrate recognition, where lectins possess relatively open clefts or cavities and bind rather weakly, whereas the
stronger-binding bacterial periplasmic proteins fully surround their substrates (see Fig. 2). The first successful attempts to build
rationally designed, carbohydrate-binding cavities employed the “temple” approach illustrated in Fig. 5. The aim was to bind
substrates with all-equatorial substitution patterns, such as the b-glucosyl unit (as in b-glucose, methyl b-D-glucoside 4, etc.) and
b-N-acetylglucosaminyl (b-GlcNAc, as in 7 and 10). Despite their lack of strict symmetry, these structures possess some regularity.
Top and bottom faces are similarly hydrophobic, while the substituents form an evenly distributed ring of polar functionality. As
indicated in Fig. 5, the resulting arrangement is loosely approximated by a squat cylinder with hydrophobic ends and polar circum-
ference. This may be complemented by symmetrical structures in which apolar (aromatic) surfaces are separated by apolar spacers. A
cartoon depiction of the design resembles a classical temple, hence the name chosen for this family of receptors.
The temple design concept was first realized in the form of 32 ( Fig. 6).20 Biphenyl units were chosen as roof and floor, partly to
achieve the correct dimensions for binding a monosaccharide and also because functionalized biphenyls may be synthesized readily
via the Suzuki–Miyaura methodology. The isophthalamide spacers provided polar units to hydrogen bond with substrate func-
tional groups, while externally directed tricarboxylate units ensured water solubility. Initial binding studies included simple hexoses
such as glucose 1, galactose 2, and mannose 3. Affinities were very low, for example, just 9 M
1 for glucose (the primary target).
However, this represented the first case of measurable binding to glucose by a biomimetic receptor in water. Moreover, the predicted
selectivity was observed in that galactose and mannose were bound even more weakly. Binding constants to methyl b-D-glucoside 4
and cellobiose 14 were somewhat higher at 28 and 17 M
1, respectively, as might be expected for larger substrates with additional
hydrophobic surface area. However, these values were eclipsed quite dramatically in a later study that considered GlcNAc 7 and its
derivatives as substrates.21 This later work benefited from the discovery that, for some pairings, the exchange between free and
bound carbohydrates was slow on the NMR timescale. This allowed the direct observation of the spectra of the complexes and
thus more detailed interpretations. For example, while the Ka for GlcNAc itself was initially measured at 56 M
1, it was possible
to show that the b-anomer was bound predominantly and that the affinity for this species was  150 M
1. The methyl b-glycoside
of GlcNAc, 10, was bound even more strongly at 630 M
1. This pairing also showed slow exchange on the NMR timescale, permit-
ting a nuclear Overhauser effect spectroscopy (NOESY) study that yielded a detailed structure for the complex (Fig. 6). The structure
confirmed that the theory behind the temple design was correct, that is, that the all-equatorial substrate slides between the biphenyl
units forming CH–p interactions and allowing H-bonding to the isophthalamide spacers.

Figure 5 The “temple” approach to synthetic lectins for all-equatorial carbohydrates.

186 Synthetic Lectins

Figure 6 Biphenyl-based 32, the first temple synthetic lectin, and the NMR structure of its complex with GlcNAcb-OMe 10 (side chains omitted,
NOE connections shown as red and green dotted lines).

A list of affinities of receptor 32 for various carbohydrates is given in Table 1. Essentially, it positions 32 as a highly selective and
relatively strong receptor for the b-O-GlcNAc unit, with some interference from b-glucosyl but almost none from other types of
substrate. In terms of strength, one might require higher affinities for widespread applications, but it is notable that the natural lectin
most commonly used to bind GlcNAc, wheat germ agglutinin (WGA), shows similar affinities. This is illustrated in Table 1, which
includes a column listing binding constants to WGA obtained from the literature. While the affinities of WGA and 32 to 10 are
almost identical, it can be seen that, remarkably, the synthetic receptor is more discriminatory. It should be said that WGA is clearly
not optimized for b-O-GlcNAcdin fact, its natural targets seem to be GlcNAc oligomers (chitin fragments, e.g., 17). However, the
comparability between 32 and WGA was highly encouraging and represented a breakthrough in the area.
Although the b-O-GlcNAc unit in 10 might seem obscure (compared, e.g., to glucose), it possesses particular significance as
a dynamic posttranslational modification of proteins. 22 Molecules that can bind the unit are required as tools to help elucidate
its role in biology, which is still not fully clear. Receptor 32 was therefore tested with a number of more realistic models in which
the GlcNAc was attached to serine or threonine oxygens. Results were mixed. On the one hand, the decapeptide 33 (Fig. 7) was quite
strongly bound, with Ka ¼ 1040 M
1.21 Less encouragingly, the simple derivatives 34 and 35 showed much lower affinities, at 91
and 13 M
1, respectively.23 The data implied that binding is quite strongly affected by interactions to the peptidic portions of the
substrates. This may suggest that molecules related to 32 are unlikely to serve as general O-GlcNAc receptors, but that binding to
subsets of the modification in particular environments may be a realistic proposition (see also section “Temple” Receptors III: Mac-
rocycles Based on Condensed Aromatics).
Following the success of 32, a number of variations were explored with the aim of increasing affinities or altering selectivities.
The most intensively studied involved replacing the hydrogen atoms para to the biphenyl bonds with other groups designed to
affect the steric or electronic environment of the binding site ( Fig. 8).24,25 Because these changes would not greatly affect the confor-
mation of the tricyclic receptor core, it seemed likely that the binding properties would be moderated but not destroyed. To avoid
steric congestion, the investigation was restricted to F- and O-based substituents, as in 36–42. Binding results are gathered in Table 2.
Some aspects of the data are surprising. If, as seems likely, binding is partially driven by CH–p interactions, reducing the surface
charge of the biphenyl units should lower affinities.26 Against this expectation, fluoro-substituted 36 is generally a stronger receptor
 Synthetic Lectins 187

Table 1 Association constants (Ka) for binding of carbohydrates in water to temple

receptor 10, in order of descending affinity

Ka (M
1) for Ka (M
1) for binding to

Substrate a
binding to 32 b wheat germ agglutinin c

GlcNAc-b-OMe 10 630 d 730

GlcNAc 7 (a:b ¼ 64:36) 56 410
Methyl b-D-glucoside 4 28
GlcNAc-a-OMe 11 24 e 480
D-Cellobiose 14 17
D-Glucose 1 9
Methyl a-D-glucoside 5 7
D-Xylose 12 5
D-Ribose 13 3
D-Galactose 2 2
L-Fucose 6 2
N-Acetyl-D-galactosamine 8 2 60
N-Acetyl-D-mannosamine 9 2 60
D-Mannose 3 2
D-Maltose 16 2
D-Lactose 15 2
N-Acetyl-D-neuraminic acid 18 0f 560
N,N0 -Diacetylchitobiose 17 0f 5300

Values for the natural lectin wheat germ agglutinin are also given.
a
See Fig. 1.
b
Measured by 1H NMR titration in D2O unless otherwise indicated. Data from Refs. 20,21
c
For more information, see Ref. 21
d
Confirmed by isothermal titration calorimetry (ITC; Ka ¼ 635 M
1).
e
Measured by induced circular dichroism (ICD).
f
No change in spectrum on addition of carbohydrate.

Figure 7 GlcNAc-derivatized peptides used as substrates for 32.

Figure 8 Biphenyl-based temple receptors with para substituents.

188 Synthetic Lectins

Table 2 Association constants (Ka) for binding of carbohydrates in water to temple receptors 36–42 (values for 32 are included for comparison)

Ka (M
1) b
Carbohydrate a 32 (Y ¼ H) 36 c (Y ¼ F) 37 c (Y ¼ OH) 38 c (Y ¼ O
) 39 d (Y ¼ OMe) 40 d (Y ¼ OEt) 41 d (Y ¼ OPr) 42 d (Y ¼ OBu)

D-Glucose 1 9 20 43 18 35 41 60 47
D-Galactose 2 2 9 8 4 4 3 3 2
D-Mannose 3 0 2 3 7 2 0 0 2
Methyl b-D-glucoside 4 27 66 155 83 70 81 130 82
Methyl a-D-glucoside 5 7 16 26 17 11 11 15 8
N-Acetyl-D-glucosamine 7 56 41 10 7 3
GlcNAc-b-OMe 10 630 730 43
a
See Fig. 1.
b
Measured by 1H NMR titration in D2O.
c
See Ref. 24
d
See Ref. 25

than 32. Replacing F with OH (to 37) yields a further enhancement, this time in line with theory, but deprotonation of the OH to 38
inhibits binding despite a large increase in biphenyl electron density. The results may suggest that increasing electron density may be
helpful in some cases (e.g., 36 / 37) but that the effect is small and easily overwhelmed by other factors (e.g., changes in receptor
hydration).24 In practice, oxygen substituents appear to favor binding, as observed for 37 and also for the alkoxy series 39–42.25
Variations within the alkoxy receptors are also curious, as it is not obvious why a remote alkyl group should affect affinity or
why the most favorable chain length should be C3.
Whatever the explanation, the binding constant of 41 for glucose, at 60 M
1, represented a significant advance on 32. A major
potential application of these receptors is in glucose monitoring. As for any substrate–receptor combination, glucose concentrations
may be followed in principle by determining the level of receptor occupancy (provided this can be measured). This could provide an
important service to diabetics, possibly as part of an “artificial pancreas.” 27,28 As shown in Fig. 9, a binding constant of 60 M
1 is
well suited to monitoring glucose in the range 0–30 mM, and this corresponds to the range of medical interest. For further discus-
sion of this area, see also section “Temple” Receptors III: Macrocycles Based on Condensed Aromatics.
Other variations to the biphenyl-based temple structure are represented by 43–45 ( Fig. 10). Tetra-amine 43 was prepared to
investigate the effect of changing the polar interactions.29 The pyrrolo-diamine spacers had been successful in organic-soluble carbo-
hydrate receptors30 and provided clearly different H-bonding functionality when compared to the isophthalamides. The results
were not especially dramatic. The binding constant to glucose 1 was raised to 16 M
1 (as opposed to 9 M
1 for 32), while affinities
to GlcNAc 7 and methyl b-D-glucoside 4 were lowered, probably for steric reasons. The increase for glucose is more significant than it
appears, because the reduced symmetry in 43 should lower binding constants for statistical reasons.31 Nonetheless, the marginal
effect of so large a change may have strategic implications for synthetic lectin design. Arguably, it will always be difficult to raise
affinities by manipulating polar interactions, as improved binding to substrate may be counterbalanced by improved binding to
water. In the short term at least, it may therefore be more productive to focus on the hydrophobic/CH–p interactions by optimizing
the roof and floor of the temple (see, e.g., section “Temple” Receptors III: Macrocycles Based on Condensed Aromatics).

Figure 9 Variation of receptor occupancy with glucose concentration assuming a binding constant of 60 M
1. The graph is color-coded according
to the medical implications of these concentrations in blood (blue ¼ normal). Large changes are observed across the range of interest.
 Synthetic Lectins 189

Figure 10 Changing spacers and connectivity in biphenyl-based temple receptors.

Receptors 44 and 45 were synthesized to test whether the tricyclic cage structure of 32 is necessary or whether a simpler bicyclic
framework would suffice. 32 The bicyclic structure is advantageous synthetically, requiring just one macrocyclization, and thus facil-
itates variations. Tests on 44 revealed that the receptor was effective but, perhaps unsurprisingly, showed reduced affinities for
monosaccharides (e.g., Ka ¼ 4 M
1 for glucose). On the other hand, affinities for disaccharides were increased relative to 32,
presumably due to the more open, less sterically crowded structure. Pyridine-containing 45 was prepared to demonstrate the vari-
ability of the system, but proved a generally weaker receptor.

3.07.6 “Temple” Receptors II: Terphenyl-Based Cages

If a biphenyl-based temple accommodates a monosaccharide, then a terphenyl-based analog should be appropriate for a disaccha-
ride. This possibility was investigated using two types of receptor framework: a tetracyclic structure based on meta-terphenyl units as
in 46 33 and a tricyclic structure based on para-terphenyl units as in 47 and 4834(Fig. 11). The tetracyclic design 46 was studied first,
due to fears that the tricyclic system was too flexible and would suffer from cavity collapse. 46 was synthesized via a series of the
Suzuki–Miyaura couplings and macrocyclizations and tested against di- and monosaccharide substrates (Table 3). Nuclear
magnetic resonance (NMR) titration could not be used in all cases due to intermediate exchange rates, but fluorescence and induced
circular dichroism (ICD) could also be applied. 46 was expected to bind all-equatorial disaccharides such as cellobiose 14, methyl b-
0
D-cellobioside 49, xylobiose 50, and N,N -diacetylchitobiose 17(Fig. 12). As shown in Table 3, this proved to be the case. Affinities
for these substrates were encouraging (e.g., Ka z 600 M
1 for cellobiose) and selectivities were very high (e.g., 50:1 for cellobiose vs.
lactose). This system was published in 2007, before the results on 32 þ GlcNAc were available, and provided the first indication that
lectin-like behavior was possible for small nonprotein organic molecules.
As mentioned earlier, the tricyclic framework of 47/48 was originally ignored because of its conformational freedom. Specifi-
cally, a motion in which one end of the molecule twists relative to the other, around the long axis of the system, brings together
the two central aromatic rings of the terphenyl units. The movement closes the cavity and should be favored due to improved hydro-
phobic interactions. However, when 47 and 48 were eventually synthesized, they proved surprisingly effective. Results are

Figure 11 Terphenyl-based temple receptors targeting all-equatorial disaccharides.

190 Synthetic Lectins

Table 3 Association constants (Ka, M
1) for binding of carbohydrates in water to tetracyclic receptor
46, as measured by 1H NMR, induced circular dichroism (ICD), and fluorescence titrations a

Substrate b 1
H NMR ICD Fluorescence

Methyl b-D-cellobioside 49 c
910 850
D-Cellobiose 14 600 d 580 560
c
D-Xylobiose 50 250 270
N,N0 -Diacetyl-D-chitobiose 17 120 d 120
c
D-Lactose 15 11 14
c
D-Mannobiose 51 13 9
c
D-Maltose 16 15 11
D-Gentiobiose 52 12 5
D-Trehalose 53 0e 0e
D-Sucrose 54 0e 0e
D-Glucose 1 11 f 12 0c
D-Ribose 13 0e 0e
N-Acetyl-D-glucosamine 7 24 f 19
a
Data from Ref. 33
b
See Figs. 1 and 12.
c
Spectra broadened, presumably due to intermediate rates of exchange on the 1H NMR timescale.
d
Slow exchange on the NMR timescale.
e
No change in spectrum on addition of carbohydrate.
f
Fast exchange on the NMR timescale.

Figure 12 Disaccharide substrates tested with receptors 46–48.

summarized in Table 4. Tetramethoxy tricycle 48, which was subjected to the more complete study, was found to bind cellobiose 14
with Ka ¼ 3330 M
1, around six times more strongly than 46. Selectivity over other disaccharides was less impressive (e.g., 13:1 for
cellobiose 14 vs. lactose 15), but discrimination between di- and monosaccharides was remarkable (e.g., 1000:1 for cellobiose vs.
glucose). Although unexpected, the success of 47 and 48 can be rationalized by assuming that (a) cavity collapse is less problematic
than intuition might suggest and (b) the linear geometry of the para-terphenyl-based framework is better suited to these substrates
than the angled shape of meta-terphenyl-based 46.

3.07.7 “Temple” Receptors III: Macrocycles Based on Condensed Aromatics

Although bi- and terphenyls can clearly provide effective hydrophobic surfaces for synthetic lectins, they are probably not ideal. As
shown in Fig. 13, they prefer to adopt twisted conformations even when lacking ortho-substituents. This may interfere with the
formation of CH–p interactions to axial CH groups and is likely to impede the movement of a bound carbohydrate so that other
contacts cannot be optimized. By contrast, a condensed aromatic unit can provide a continuous, smooth, electron-rich surface, able
to form multiple CH–p contacts without trapping the substrate in a particular position. It is notable that the indole unit in tryp-
tophan, a natural condensed aromatic, is especially prevalent in the binding sites of lectins.11
Accordingly, there is a strong argument for employing condensed aromatics as the roof/floor units of temple synthetic lectins.
This strategy has only been explored recently but has proved very effective. As the first step, the simple monocyclic design 56 was
synthesized and studied ( Fig. 14).35 This structure could be prepared in approximately five steps from the commercially available
anthracenediamine 55 and is thus a great deal more accessible than any of the systems described in the previous two sections.
 Synthetic Lectins 191

Table 4 Selected association constants for binding of carbohydrates in water to tricyclic

receptors 47 and 48 Values for tetracyclic receptor 46 are repeated for easy comparison. a

Ka (M
1)
Carbohydrate b 46 47 c
48 d

Methyl b-D-cellobioside 49 850 – 4500

D-Cellobiose 14 580 3100 3330
N,N0 -Diacetyl-D-chitobiose 17 120 – 910
D-Lactose 15 14 230 260
D-Maltose 16 11 67 76
D-Glucose 1 11 – 3
a
Data from Ref. 34
b
See Figs. 1 and 11.
c
Measured by fluorescence titration in H2O. 1H NMR titrations were unhelpful, apparently due to solubility/
aggregation issues.
d
Average of values from fluorescence and 1H NMR titrations.

Figure 13 b-D-Glucose forming CH–p interactions with (left) biphenyl and (right) a condensed aromatic unit.

Figure 14 Anthracene-based monocyclic temple receptors.

Nonetheless, as shown in the table, its affinity for glucose (Ka ¼ 56 M
1) effectively matched that of tricycle 41. This binding
constant is in the correct range for monitoring physiological glucose levels (see Fig. 9), and 56 provides the added advantage of
a fluorescence response; binding to glucose causes an  2.5-fold increase in anthracene emission. Notably, the success of 56 comes
despite indications that the shape of the cavity is not ideal. Modeling and nuclear Overhauser effect (NOE) studies suggest a binding
geometry in which the substrate does not penetrate to the center of the macrocycle, implying that the framework is slightly too small
to encapsulate a monosaccharide.
192 Synthetic Lectins

Table 5 Selected association constants (Ka) for binding of carbohydrates in water to

anthracene-based monocycles 56–58 (values for 41 are included for comparison)

Ka (M
1) b
Carbohydrate a 41 56 57 58

D-Glucose 1 60 56 90 70
D-Galactose 2 3 4 7 3
D-Mannose 3 0 0 0 0
Methyl b-D-glucoside 4 130 96 115 92
Methyl a-D-glucoside 5 15 6
N-Acetyl-D-glucosamine 7 7 9 31 33
D-Glucosamine 19 160 2400 7000
a
See Fig. 1.
b
Measured by 1H NMR titration in D2O.

The structural simplicity of 56 permits some quite straightforward variations that could be used to tune binding properties. The
solubilizing side chains are especially easy to modify. It might be thought that these units would have little influence on complex
stability. However, the use of dendrimers with their branched, spreading structures tends to place polar functional groups at the
entrance to the cavity, positioned to bind with equatorial functionality on the substrate. Moreover, while individual polar groups
can move away, each will automatically be replaced by another. The system thus benefits from “preorganization by degeneracy.”
Analogs of 56 with various dendrimeric solubilizing groups have been prepared and tested, with promising results. 36 For example,
receptor 57, with second-generation (G2) dendrimers, showed a small but significant increase in affinity for glucose, when
compared to 56 (see Table 5). Moreover, receptor 57 and especially the G3 analog 58 were remarkably effective for glucosamine
19, the affinity rising to 7000 M
1 in the latter case (Table 5).
As mentioned earlier, there are indications that the cavities in these monocyclic anthracene-based systems may be slightly too
small for ideal complementarity to saccharide units. This is not true for the biphenyl-based systems such as 32, so designing
condensed aromatic analogs of these latter systems might seem a promising strategy. The condensed aromatic system most closely
related to biphenyl is pyrene, and this consideration has recently led to a number of pyrene-based synthetic lectins. The first to be
reported was 60 ( Fig. 15), in which the two aromatic surfaces are separated by three spacer units.37 60 could be assembled in a fully
directed fashion from bis-protected triamine 59, via a linear intermediate in which two pyrenes are linked through the free amino
groups. As illustrated in Table 6, affinities to monosaccharides such as glucose and methyl glucoside showed modest improvements
on previous values, but were not outstanding. However, especially significant results were obtained for oligosaccharides. The cel-
lodextrins 61 (n ¼ 0–4) were bound with affinities  3900 M
1, peaking at 12,000 M
1 for cellotetraose 61 (n ¼ 2). These high
affinities for such large substrates suggested an unprecedented binding mode, in which the substrate threads through the receptor
cavity. This pseudorotaxane geometry was confirmed by NOE data for 60þ cellopentaose (61, n ¼ 3) (see Fig. 16 for a model of this

Figure 15 Pyrene-based bicyclic receptor 60 and oligosaccharide substrates.

 Synthetic Lectins 193

Table 6 Selected association constants (Ka) for binding of carbohydrates

in water to pyrene-based bicyclic receptor 60

Carbohydrate a Ka (M
1) b

D-Glucose 1 120
D-Galactose 2 18
D-Mannose 3 0
Methyl b-D-glucoside 4 240
Methyl a-D-glucoside 5 15
GlcNAc-b-OMe 10 270
D-Cellobiose 14/61 (n ¼ 0) 3900
D-Cellotriose 61 (n ¼ 1) 5200
D-Cellotetraose 61 (n ¼ 2) 12,000 c
D-Cellopentaose 61 (n ¼ 3) 8800 c
D-Cellohexaose 61 (n ¼ 4) 8700 c
D-Chitobiose (62, n ¼ 0) 19,000
a
See Figs. 1 and 15.
b
Measured by 1H NMR titration in D2O unless otherwise indicated.
c
Measured by ITC in H2O.

Figure 16 Model of receptor 60 þ cellopentaose 61 (n ¼ 3) in the pseudorotaxane geometry indicated by NOE data. Water-solubilizing side chains
are omitted for clarity; isophthalamide spacers are colored gold.

complex). It was also shown by atomic force microscopy (AFM) that 60 could form a multiply threaded complex (polypseudoro-
taxane) with cellulose. This discovery points to an important potential application for synthetic lectins. Though exceptionally plen-
tiful, cellulose is hard to utilize due to its insolubility. A threading receptor, if sufficiently powerful, might be able to promote
dissolution of the polymer under mild aqueous conditions, opening up new methods of exploitation. Receptor 60 did not seem
to dissolve crystalline cellulosedthe solvent used to form the polypseudorotaxane was strong aqueous base, in which the polymer
can be dissolved. However, there are various means by which affinities could be improved so that solubilization can be achieved.
Receptor 60 was also found to bind the cationic disaccharide chitobiose (62, n ¼ 0) with Ka ¼ 19,000 M
1 and to form a polypseu-
dorotaxane with chitosan (62, n ¼ large). Chitosan is an important material in areas such as tissue engineering, and the formation of
threaded complexes could provide a novel method for modifying its properties.
The synthetic route to 60 allows scope to vary the structure by changing one of the aromatic surfaces. This possibility was realized
in the synthesis of 64 from pyrene 59 and biaryls 63 ( Fig. 17).38 Neither of receptors 64 showed exceptional binding properties, but
the approach may be used for a diverse range of structures and seems a promising route to receptors with alternative selectivities.

Figure 17 Asymmetrical temple receptors 64. For X, see Fig. 15.

194 Synthetic Lectins

Figure 18 Top: Pyrene-based tricyclic receptors 66 and 67 and precursor tetra-amine 65. For X, see Fig. 15. Bottom: NOE-based structure of the
complex between 67 and GlcNAc-b-OMe 10.

Given the initial success of prototype synthetic lectin 32, the bis-pyrenyl analog 66 might seem an especially attractive design
( Fig. 18). However, attempts to synthesize this cage were delayed because of perceived difficulties. A directed route that might
give 66 in a controlled fashion would require a pyrenyl intermediate in which free NH2 groups could be revealed sequentially
(cf. 59): a major, perhaps impossible, synthetic challenge. On the other hand, routes via unprotected tetra-amine 65 (Fig. 18) would
be expected to give complex mixtures of products including a second cage 67. In the event, the approach in Fig. 18 did prove work-
able, and both “eclipsed” 66 and 67 could be isolated after an high performance liquid chromatography (HPLC) separation.39 Slow
conformational motions limited the binding studies which could be performed by 1H NMR, but for some substrates, the exchange
between bound and unbound states was slow on the NMR timescale. In these cases, the spectra of the complexes could be observed
clearly and affinities could be measured with confidence. Supporting values were obtained with ITC, and as these were very similar
to the NMR-based binding constants, ITC was also used alone for some substrates. The results are summarized in Table 7. Both 66
and 67 are considerably more powerful than 32, especially for methyl b-glycosides 4 and 10. The affinity of 67 for GlcNAc b-OMe
10, at nearly 20,000 M
1, is especially notable. At the time of writing, this is the highest well-characterized binding constant for
a synthetic lectin paired with a small, electrically neutral monosaccharide derivative in water. As the spectrum of this complex could
be observed directly (due to slow exchange), it was possible to obtain an NOE-based structure. As shown in Fig. 18, the substrate
adopts the predicted geometry, sliding between the pyrene units to form CH–p interactions involving axial hydrogens and appear-
ing to participate in at least four hydrogen bonds with the isophthalamide spacers.
As discussed earlier, the b-O-GlcNAc unit is an important target, being a dynamic posttranslational modification of proteins.
Receptors 66 and 67 were also tested against glycopeptide 33 (see Fig. 7) to establish whether they could be used to bind b-OGlc-
NAc when attached to a peptide chain. Binding of 33 to 67 could not be quantified, but the affinity of 66 for the glycopeptide was
found to be 67,000 M
1. This impressive value presumably reflects some binding between the peptidic portion of 33 and the exte-
rior of receptor 66 (given that Ka for 66 þ 10 is only 2100 M
1). However, this need not provide a barrier to applications. NOE data
 Synthetic Lectins 195

Table 7 Association constants (Ka) for binding of carbohydrates in water to pyrene-based tricyclic
receptors 66 and 67, measured by ITC and 1H NMR titrations (values for 32 are included for comparison)

Ka (M
1) b
Carbohydrate a 32 66 67

D-Glucose 1 9b 120 c 190 c

Methyl b-D-glucoside 4 27 b 1440 c 1180, b 1230 c
N-Acetyl-D-glucosamine 7 56 b –d 520, b 520 c
GlcNAc-b-OMe 10 630 b 2100, b 2200 c 18,200, b 16,600 c
GlcNAc-a-OMe 11 24 b –d 1550, b 1520 c
a
See Fig. 1.
b
Measured by 1H NMR titration in D2O.
c
Measured by ITC in H2O.
d
Could not be determined accurately.

confirmed a specific binding mode in which the saccharide unit enters the receptor cavity, so it seems that 66 is indeed recognizing
the GlcNAc unit in 33. If further interactions are required for strong binding, this can be turned to the advantage of glycobiology.
Indeed, by varying the receptor side chains, it seems likely that complementary receptors could be made for OGlcNAc in a range of
situations, providing a suite of useful glycobiological research tools. Affinities approaching 105 M
1, as found for 66 þ 33, could be
sufficient for practical applications such the selective staining of OGlcNAcylated proteins in western blots.40

3.07.8 Receptors Based on Peptide Chains

If one wishes to mimic a protein, such as a lectin, the use of a peptidic scaffold has obvious attractions. Peptides are readily synthe-
sized, so that variations are easily made. Moreover, the results may throw light on aspects of biological carbohydrate recognition.
This approach was explored initially by Aoyama and coworkers, who prepared the simple dipeptide Trp–Trp 68 ( Fig. 19) and tested
it as a receptor for carbohydrates using fluorescence spectroscopy.41 Weak binding was detected to maltose 16 (Ka ¼ 1 M
1) and
maltotriose 69 (Ka ¼ 8 M
1), which were thought to intercalate between the tryptophan indole units. The discovery of preferential
binding to the longer substrate, with the larger surface area, is not surprising and generally mirrors later developments (see earlier).
Perhaps the main conclusion of this early work is that simple, flexible peptides are unlikely to form complexes with carbohydrates in
water, even when they possess side chains known to favor binding.10,11 More recently, the bowl-shaped receptor 70 was designed by
Meldal and coworkers to present a lectin-like binding site to carbohydrates.42 Again, the binding studies tended to emphasize the
difficulty of the problem, the only positive result being an affinity of 8 M
1 for cellobiose 14.
Other works have sought to exploit the methods of combinatorial chemistry, for which peptidic structures are well adapted. For
example, Hall and coworkers investigated a library of boron-containing peptides as receptors for the Thomsen–Friedenreich antigen
73 and discovered a promising structure in variant 71 43 (Fig. 20). Although this system falls outside the scope of the present article,
it is notable that the unborylated analog 72 was tested as a control and was found to be quite effective (Ka for 73 z 400 M
1).
Peptide 72 was not studied by the usual methods of supramolecular chemistry (the affinity was measured by competitive
enzyme-linked immunosorbent assay (ELISA)), so it is difficult to compare with other systems. However, the synthesis and
screening of peptidic structures, which may or may not employ unnatural components, seem to be a promising approach.

Figure 19 Designed peptide-based carbohydrate receptors.

196 Synthetic Lectins

Figure 20 Peptide-based synthetic lectin 72 and boron-containing analog 71, with target substrate 73. 71 was discovered through combinatorial
chemistry and 72 was studied as a control.

The use of dynamic combinatorial chemistry has also been explored in a study employing cyclic peptides of general form 74 and
76 ( Fig. 21). Bis-cysteinyl starting materials of general form Cys-X-Cys (X ¼ various amino acids) were allowed to oxidize to form
the macrocycles in the presence and absence of carbohydrate substrates. Combinations that were enhanced by the presence of carbo-
hydrate were identified and further investigated.44 In the original work, the macrocycles could only be studied as head–head þ -
head–tail mixtures(74 þ 76), but it was later found possible to synthesize and study the isomers independently.45 ITC
measurements on these systems produced some remarkably high binding constants. For example, variant 75 was found to bind
trehalose 53 with Ka ¼ 1200 M
1, while 77 was reported to bind methyl b-D-galactoside 78 with Ka ¼ 8000 M
1.45 However, these
values were not supported by other techniques such as NMR titrations (although NMR did provide evidence of binding), and no
structural information was obtained for the complexes. In the absence of this information, these systems appear promising but
probably require further investigation.

3.07.9 Oligoaryl Foldamers

A further approach to synthetic lectins is the construction of linear oligomers based largely on aryl components, with limited
options for folding. In aqueous solution (provided that they are soluble), such chains will tend to fold in well-defined ways, which
can create binding surfaces or clefts. The binding sites will generally not be optimized for the most challenging monosaccharide
substrates, but can be effective for oligosaccharides. For example, the hexacationic receptor 79 ( Fig. 22) binds to low-molecular-
weight heparin 29 with Ka ¼ 5  105 M
1.46 Heparin, also bound by 28, is an important target because of its use in surgical proce-
dures as an anticoagulant. Another example is the oligoresorcinol 80, which forms a double-helical structure in water but can
disassemble and bind to a number of oligosaccharide substrates. The strongest complex was formed with isomaltoheptaose
(81), which achieved half-saturation of 80 at  10 mM (due to complex stoichiometry, a simple 1:1 affinity could not be esti-
mated).47 Complexation was readily detected through a strong circular dichroism (CD) effect, the receptor itself being optically
inactive. Water-soluble poly(ethynylpyridine)s 82 also gave altered CD spectra on exposure to oligomeric substrates, in this case

Figure 21 Peptide-based carbohydrate receptors discovered through dynamic combinatorial chemistry.

 Synthetic Lectins 197

Figure 22 Oligoaryl foldamer carbohydrate receptors and isomaltoheptaose 81, the main substrate for 80.

the polysaccharides glycogen, pullulan, and hyaluronic acid.48 This system was also studied with monosaccharides, but estimated
affinities were low (Ka ¼ 4 M
1 for mannose and 2 M
1 for glucose).

3.07.10 Porphyrin-Based Systems

The study of porphyrin-based synthetic lectins constitutes a substantial body of work. Structures that have been investigated include
platforms 83–649–51 as well as macrocycles 87 and 88 52 (Fig. 23). As illustrated in Table 8, some of the affinities reported have been

Figure 23 Porphyrins reported to act as carbohydrate receptors in water.

198 Synthetic Lectins

Table 8 Association constants (Ka) reported for binding of carbohydrates in aqueous solvent to porphyrins 61–66,
measured by UV–Vis titrations (however, see text for discussion)

Ka (M
1)
Carbohydrate a 83 b 84 c 85 d 86 d 87 e 88 e

D-Glucose 1 120 17,600 60 110 4300 1200

D-Galactose 2 135 19,700 50 100 3300 2100
Methyl b-D-glucoside 4 <10 20 2300 1100
Methyl a-D-glucoside 5 20 50 7800 5900
a
See Fig. 1.
b
In H2O-MeOH, 95:5. Data from Ref. 49
c
In H2O-MeOH, 95:5. Data from Ref. 49,50
d
In H2O-CH3CN, 50:50. Data from Ref. 51
e
In H2O-MeOH, 95:5. Data from Ref. 52

extraordinary. For example, the Ka of  20,000 M
1 for glucose þ 84 greatly surpasses all others measured for this challenging
substrate. Moreover, most of the structures are remarkably simple; 83 is even commercially available. It is, however, curious that
molecules that are not obviously complementary to carbohydrates can achieve such high affinitiesdfor example, the polar groups
in 84 are too widely spaced to cooperate in binding a monosaccharide. Also, the binding studies have relied on UV–visible or fluo-
rescence spectroscopy, rather than NMR that generally gives more structural information. In order to address these issues, a recent
investigation reexamined the interaction of 83 with glucose in water.53 It was found (a) that addition of 83 to glucose caused no
movement of carbohydrate 1H NMR signals, indicating that the two components do not form a closely associated complex, and
(b) that the UV–visible absorbance spectrum of pure 83 can change significantly over a timescale of hours, presumably due to
slow reorganization of aggregates that form even at very low concentrations. Although UV–visible titrations of glucose into 83
did indeed give curved plots, these were best explained by changes in aggregation occurring during the course of the experiments.
It was therefore concluded that UV–visible titrations could not be used to measure binding constants to 83 and that no clear
evidence was available for binding of the porphyrin to glucose. While this may not apply to 84–88, it is clearly necessary to proceed
with care when studying porphyrin-based receptors in aqueous solvent systems and unwise to rely solely on optical methods.

3.07.11 Metal Complexes as Synthetic Lectins

Although one would normally exclude boron-based receptors from a discussion of synthetic lectins, given their reliance on covalent
bonding, other systems containing inorganic elements may reasonably be included. Indeed, there is a family of natural lectins (the
C-type lectins) that depend on Ca2 þ ions for their activity. 54 Thus far, synthetic systems have tended not to use calcium, presumably
because it is less easy to harness than some other metal cations. However, Cu2 þ ions can be immobilized in water by employing soft
ligand atoms (e.g., nitrogen), and this has been exploited in systems such as 8955 (Fig. 24). As indicated, this binuclear complex
shows a particular affinity for mannose, which is bound with Ka z 104 M
1 in water at pH 12.4. While this affinity is impressive,
the use of such basic conditions (presumably to deprotonate sugar hydroxyls) must limit applicability. Lanthanide ions have also
been employed, as in 90. This complex showed a strong increase in fluorescence when exposed to certain sialylated oligosaccharides,
including the ganglioside GM1.56
There is one group of Ca2 þ-dependent carbohydrate receptors that, though not synthetic lectins, may be discussed in similar
terms. They are the pradimicin and benanomycin natural products, exemplified by pradimicin A 91 ( Fig. 25), produced as
secondary metabolites by actinomycetes.57,58 In the presence of Ca2 þ, pradimicin A has been shown by ITC to bind methyl a-D-
mannoside 24 with Ka ¼ 10,000 M
1, with weaker binding of 260 M
1 at a secondary site. Unfortunately, this system is difficult
to study because of a tendency to aggregate, but good progress has been made by using solid-state NMR spectroscopy.58,59 It seems

Figure 24 Metal complexes that bind carbohydrates in water.

 Synthetic Lectins 199

Figure 25 Pradimicin A, a calcium-dependent carbohydrate-binding natural product.

that the mannoside occupies a pocket formed by the D-alanine residue and carbons C14, C4, C5, and C3-Me (see Fig. 25), presum-
ably mediated by Ca2 þ coordinated to the D-alanine carboxylate. Mannosides are important targets due to their role in immu-
nology, so natural product 91 and its relatives could serve as valuable lead compounds for supramolecular chemists.

3.07.12 Cucurbit[7]uril as a Synthetic Lectin

One final water-soluble carbohydrate receptor that stands alone, being essentially unrelated to any other, is the toroidal macrocycle
cucurbit[7]uril 92 ( Fig. 26). This molecule possesses a cavity that is capable of remarkable affinities for protonated amines in water,
especially when the substrate is a good fit for the cavity.60,61 To give one example, cyclo-octylammonium 93 is bound with
Ka ¼ 3  1011 M
1.61 Thermodynamic studies have established that the release of high-energy water is a major driving force for
binding,62 and as the affinities are so extreme (up to 1017 M
1), it seems that the interior of 92 is exceptionally unfriendly to water.
A recent investigation has shown that, among its other amino substrates, receptor 92 is capable of binding glucosamine 19, galac-
tosamine 20, and mannosamine 21 with affinities of 4400, 16,000, and 1900 M
1, respectively. It is notable that these binding
constants are lower than those of 92 for many other amines, and it could be said that the results illustrate the power and versatility
of the macrocycle as an amine receptor rather than a carbohydrate receptor. Nonetheless, the affinities compare well with the best
obtained by other systems for monosaccharide substrates, and it will be interesting to see if this system can be developed further.

3.07.13 Beyond Binding: Implications and Applications of Synthetic Lectins

Although workers in this area naturally focus on the optimization of affinities and selectivities, it is important to consider how
synthetic lectins can be exploited, either in studies designed to throw light on natural carbohydrate recognition or in systems
with practical relevance to healthcare. Thus far, there are no well-established practical applications of these molecules, although
some of the systems described earlier seem to have genuine potential. For example, the anthracene-based macrocycles 56–58
show useful affinities and selectivities for glucose as well as provide a readily detectable optical response on binding (section
“Temple” Receptors III: Macrocycles Based on Condensed Aromatics”). It is not unreasonable to hope that they can be employed
in devices for monitoring glucose concentrations in real-life samples, and work toward this end is currently under way. One may
also hope that continuing work on receptors for O-GlcNAc, building on the success of 66 and 67, may lead to probes for detecting
this modification in proteins (see section “Temple” Receptors III: Macrocycles Based on Condensed Aromatics).
While synthetic lectins have yet to be exploited in a practical context, they have made a definite contribution to the theoretical
understanding of biological carbohydrate recognition. As discussed earlier (section “ General Principles”), there has been debate
concerning the role of water in carbohydrate binding by lectins. A useful method for probing this question is to study the effect
of solvent variation on binding constants.63,64 If affinities correlate simply with solvent polarity, one might conclude that binding
is essentially polar in nature. In this case, water, the most polar solvent, should prove the least favorable medium for carbohydrate
binding. However, if the displacement of water helps to drive binding, through either hydrophobic or hydraphobic effects,

Figure 26 Toroidal macrocycle cucurbit[7]uril 92 and typical guest 93.

200 Synthetic Lectins

Figure 27 Solvent dependence of synthetic lectin binding, employing 46 and its O-protected precursor. The graph on the left shows binding
constants measured by fluorescence titration in chloroform–methanol mixtures for the O-protected receptor þ octyl cellobioside. The graph on the
right shows corresponding values in methanol–water mixtures, using water-soluble 46 and cellobiose.

a different order may prevail. Nonaqueous solvents should be less able to promote binding through solvophobic effects, due to the
exceptional cohesive properties of water. Binding in pure water may thus be stronger than in some other, less polar media. Although
this argument should apply to all lectin-like binding sites, studying lectins themselves in a range of solvents is impractical. As
proteins, they are subject to denaturing, or at least conformational changes, in solvents other than water. However, synthetic lectins
with controlled binding site geometries can be far more versatile, especially as solubilizing groups can be changed without affecting
the core structure.
This approach was taken using two of the synthetic lectins from the “temple” family, the monosaccharide-binding prototype 32
and the disaccharide-binding 46, along with their organic-soluble precursors. 65 Some of the results obtained with the disaccharide-
binding system are shown in Fig. 27. In organic media, the system shows the expected sensitivity to solvent polarity; addition of
methanol causes affinities to decrease. However, for the water-soluble system, the effect is reversed; for the methanol–water
mixtures, increasing the proportion of water (the more polar solvent) increases affinities. These and other results from the same
study provide unambiguous evidence for a hydrophobic component to biological carbohydrate recognition.

3.07.14 Conclusions

The design and development of synthetic lectins have made notable progress over the past 1–2 decades. In the early years of the
twentieth century, it was widely felt that biomimetic carbohydrate recognition might prove excessively difficult. Even proteins
seemed to find the problem challenging, and early studies with synthetic systems had not proved encouraging. Indeed, the first
report on the temple receptors was remarkable for the single-digit binding constants, a rarity in supramolecular publications. 20
However, since this paper appeared in 2005, perceptions have changed. Binding carbohydrates in water is still seen as an exceptional
challenge for supramolecular chemists, but not an impossible one. Affinities for glucose have risen to  200 M
1, while some
methyl glycosides and oligosaccharides are bound with Ka > 10,000 M
1. Some systems also show excellent selectivity, especially
those that target the all-equatorial family of saccharides. It is true that the best-performing systems are limited in scope. Substrates
outside the all-equatorial family are less well-served, and we still lack effective, designed binding sites for most monosaccharide
units. Nonetheless, having achieved success in one area, it is reasonable to hope that other substrates will eventually be addressed.
A key question is whether the problems will be solved by rational design based on model building, following the approach used for
the temple receptors, or whether combinatorial chemistry is more likely to provide the answers. On the one hand, it will certainly be
difficult to find designed solutions to all targets of interest, if only because there are so many. On the other hand, if carbohydrate
recognition is intrinsically challenging, most randomly generated structures may show no activity whatsoever. Some combination
of the approaches may well prove most productive, and it will be interesting to see what strategies emerge as the field develops in
future years.
 Synthetic Lectins 201

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 3.08 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and
Nomenclature
R Aav, S Kaabel, and M Fomitsenko, Tallinn University of Technology, Tallinn, Estonia
Ó 2017 Elsevier Ltd. All rights reserved.

3.08.1 Introduction 203

3.08.2 Nomenclature of Cucurbiturils 204
3.08.3 Unsubstituted Cucurbiturils 204
3.08.3.1 Cucurbituril Homologues 204
3.08.3.2 Inverted and nor-Seco-Cucurbiturils 206
3.08.4 Mechanism of Cucurbituril Formation 206
3.08.5 Substituted Cucurbiturils 208
3.08.5.1 Fully Substituted Cucurbiturils From Glycoluril Derivatives 208
3.08.5.2 Partially Substituted Cucurbiturils From Variable Starting Material 209
3.08.5.3 Cucurbiturils Substituted at the Bridges 212
3.08.5.4 Postfunctionalization of Cucurbiturils 212
3.08.6 Structural Parameters and Water Solubility of Cucurbiturils 214
3.08.7 Summary and Perspectives 217
References 218

3.08.1 Introduction

The first synthesis of macrocyclic urea was already reported by Behrend et al. in 1905. 1 Over 70 years later, in 1981, Mock et al.
repeated the experiment and observed the formation of a very symmetric product, which was unambiguously characterized by
X-ray crystallography as a hexameric macropolycyclic compound.2 As its systematic name requires at least three lines of text and
symbols, a trivial namedcucurbituril (CB)dwas given due to the shape of the macrocycle resembling a pumpkin (Cucurbitaceae
in Latin).
The Cucurbituril chapter in the first edition of Comprehensive Supramolecular Chemistry included the only two members of the
cucurbituril family known at that time, the 6-membered cucurbit[6]uril (CB[6]) and 5-membered decamethylcucurbit[5]uril
(all1,5-Me10CB[5]). 3 Mock covered, in this article, his studies on the properties of the cucurbituril as a host and a catalyst. Since
then, the cucurbituril family has enlarged significantly and is still expanding. The family of cucurbiturils has grown not only through
the ring size of homologues, which differ in the number of monomers in the macrocycle, but also through the synthesis of new
relatives. The main subdivisions of the cucurbituril family are the normal or core CBs, hemiCBs, and acyclic CBs (Fig. 1).
This article focuses only on normal CBs, excluding acyclic cucurbiturils4–10 and hemicucurbiturils.11–22 The functionalization of
selected positions with different substituents in the CB core introduced the need to express the differences between regioisomers and

Figure 1 Cucurbituril family tree.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12514-4 203

204 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

analogs. Due to the fast growth of the CB family, a unified approach to the naming of cucurbiturils is attempted in the cucurbituril
nomenclature section. The synthesis of cucurbiturils is then presented, based on the current understanding of the CB formation
mechanism. Last, the structural and known physical properties of CB family members are summarized. This article does not focus
on the complexation properties of CBs, nor on their application. One could find reviews on the synthesis,23–27 properties of CB
homologues and derivatives, 23,26,28–46 their formation mechanisms,24,25 and applications.26,30,46–61

3.08.2 Nomenclature of Cucurbiturils

Mock composed two systematic names for a 6-membered cucurbituril. First, dodecahydro-1H, 4H, 14H, 17H-2, 16:3,
15-dimethano-5H, 6H, 7H, 8H, 9H, 10H, 11H, 12H, 13H, 18H, 19H, 20H, 21H, 22H, 23H, 24H, 25H, 26H-2, 3, 4a, 5a, 6a, 7a,
8a, 9a, 10a, 11a, 12a, 13a, 15, 16, 17a, 18a, 19a, 20a, 21a, 22a, 23a, 24a, 25a, 26a-tetracosaazabispentaleno [1000 ,6000 :500 , 600 , 700 ]cyclo-
octa[100 , 200 , 300 :30 , 40 ]pentaleno(10 , 60 :5, 6, 7)cycloocta(1, 2, 3-gh:10 , 20 , 30 -g0 h0 )cycloocta(1, 2, 3-cd:5, 6, 7-c0 d0 )dipentalene-1, 4, 6, 8,
10, 12, 14, 17, 19, 21, 23, 25-dodecone and second, 1, 3, 5, 7, 10, 12, 14, 16, 19, 21, 23, 25, 28, 30, 32, 34, 37, 39, 41, 43, 46, 48, 50,
52-tetracosaaza-nonadecacyclo[41.11.1.17,19.110,52.116,28.125,37.134,46.03,53.05,9.08,12.014,18.017,21.023,27.026,30.032,36.035,39.041,45
.044,48.050,54]hexacontane-2, 6, 11, 15, 20, 24, 29, 33, 38, 42, 47, 51-dodecone. 62 It is clear that such names are not practical, so,
following the trends in the literature published on CBs and discussions in the cucurbituril community, we proceed to use the trivial
namedcucurbiturildas a parent structure for all derivatives. The core structure of normal cucurbit[n]urils consists of repeating gly-
coluril monomers connected by two methylene bridges, where n is the number of monomers (Fig. 2).
Each monomer is designated with a small Greek letter, 63 starting from the superior substituent and preferring alphabetical
ordering. If there are reoccurring substitutions in all monomers, then instead of listing letters for all monomers, the prefix all is
used. The numeration within a monomer should be started from the fused 5-membered cycles at the CH position, moving toward
the heteroatom and looking from the outside of the cycle. The methylene bridges are given the highest atom numbers in the mono-
mer. Following the IUPAC nomenclature of fused and bridged fused ring systems,64 the names of the substituents in the parent CB
structure are placed as prefixes just after the respective Greek letters with the substituted atom number(s) in superscript following it.
Such prefixes include seco for a missing bond, nor for a missing atom, and the letter i for an inverted monomer. A similar nomen-
clature may be used for hemicucurbiturils, where the parent structure is a single-bridged hemicucurbituril core structure. All cucur-
biturils covered in this article will be named accordingly.

3.08.3 Unsubstituted Cucurbiturils

3.08.3.1 Cucurbituril Homologues
The first isolated and characterized cucurbituril was the 6-membered CB[6]. Mock et al. showed that CB[6] is very easily accessible
and produced in 40–70% yield ( Scheme 1). Mock was a pioneer in working with CBs, and his group was the only one studying its
synthesis and properties for over a decade.2,65–72 The main drawback of CB[6] was its very poor solubility in organic solvents and
water. Only in the presence of acids, either inorganic or organic, its solubility in water was sufficient for applications.
Mock used a formic acid and water mixture as a “standard” solvent. In this solvent mixture, it was showed that CB[6] binds alky-
lammonium compounds with high affinity, with the highest binding ability observed for diammonium compounds and especially
for 1,5-pentanediammonium salt (Ka > 106 mol L 1). 73 Understanding that organic molecules are held within the cavity of CB[6]
encouraged Mock et al. to take advantage of the inner space of this macrocyclic receptor. They showed that 1,3-dipolar cycloaddi-
tion, which is currently known as a “click” reaction between an azide and alkyne, both of which contain ammonium binding sites
for CB[6], can be accelerated 1000 times and proceeds regioselectively.66 These studies proved that CB[6] is a selective synthetic
molecular receptor with very intriguing properties. It is exceedingly stable toward many potent reagents, it can form complexes

Figure 2 Line and schematic structure of cucurbit[6]uril with numeration.

 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature 205

Scheme 1 Synthesis of the first cucurbituril.

with metal salts and inclusion complexes with organic compounds, and it can even act as a catalyst. Nevertheless, only after CB[6]
was noticed by the Anthony Day and Kimoon Kim groups, the chemistry of cucurbiturils started to flourish. Understanding that CB
formation proceeds through a polymerization reaction encouraged the search for homologues of CB[6]. In 2000, Kim et al.17
reported the isolation of the new CB family members CB[5], CB[7], and CB[8] (Fig. 3) as by-products in the synthesis of CB[6],
in 2–3% yield for each homologue. The synthesis was conducted in a single step, heating glycoluril and an excess of formaldehyde
first at 75 C and then at 100 C in 9 M sulfuric acid without the isolation of intermediate polymers.
Despite the observation that CB[6] and CB[7] were formed in the 3:1 ratio, the low isolated yields of the new homologues reflect
the difficulties in their separation by crystallization. 74,78 Nevertheless, pure CB[5], CB[7], and CB[8] were isolated, and their crystal
structures were reported. In this early research, Kim et al. observed that CB[8] can accommodate within its cavity two aromatic
guests, which later led to a completely new way to control supramolecular networks.46,59,79
In the same year, 2000, Buschmann et al. 80 filed a report on the isolation of CB[5], and Day filed a patent81 for the synthesis of
CB homologues and in 2001 published results explaining the formation mechanism of CBs.82 The influences of the form of form-
aldehyde, the mineral and organic acids, concentration, temperature, and additives were tested, and the following conditions for the
large-scale synthesis were chosen: 1.4 kg of a mixture of glycoluril and formaldehyde in a 1:2 ratio, without any excess of aldehyde,
was heated at 100 C in concentrated HCl. These conditions and the optimized crystallization protocol afforded CB[5] in 8%, CB[6]
in 46%, CB[7] in 24%, CB[8] in 12%, and, as a surprise, a CB[5]@CB[10] inclusion complex75 in 5% isolated yield. The separation
of CB[10] from the CB[5]@CB[10] inclusion complex was later achieved by Isaacs et al. via the exchange of the CB[5] with a dia-
mmonium guest and further guest removal.76 The best yield for CB[5], 28–32%, was achieved by starting from preformed oligomers
and using KCl as an additive.83
Most recently, Ni and Tao et al. 77 isolated the largest known 14-membered cucurbituril, CB[14]. The synthesis of CB[14] was
conducted at 100 C in concentrated HCl, analogously to the previously described procedures, and a new homologue was success-
fully separated by very careful ion-exchange chromatography, which lasted 3 months. The authors used the prefix t in the CB[14]
name as an abbreviation for twisted because it adopts a twisted belt conformation upon complexation with Eu3 þ in its crystal struc-
ture. However, in aqueous solution, without any guests, it behaves like normal cucurbituril, having only three signals in its 1H-NMR,
which reflects that all monomers of CB[14] are equal. Complexation studies of CB[14] showed that it binds 1,8-octyldiammonium

Figure 3 X-Ray structures of unsubstituted CB[5] (Ref. 74), CB[6] (Ref.2), CB[7], and CB[8] (both from Ref.74). CB[10] and CB[14] are visualized as
complexes: CB[5]@CB[10] (Ref.75), G2@CB[10] (Ref.76), and Eu3þ CB[14] (Ref.77). Highest yields are given, see main text for the references.
206 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

in a 1:1 manner similarly to CB[8], with a Ka of 7.9 $ 106, and the smaller 1,4-butyldiammonium guest in a 1:2 ratio, with Ka values
of 1.9 $ 108 and 2.9 $ 106, indicating that CB[14] can have two separate binding compartments.84
Considering the fact that the starting materials for the preparation of cucurbiturils are cheap and the synthesis is simple, new
research groups were attracted to start exploring the properties of CB family members.23–61 Currently, the most applied CBs are
CB[6], due to its cheapest price, and CB[7], due to its highest water solubility and up to attomolar 85 guest binding ability.

3.08.3.2 Inverted and nor-Seco-Cucurbiturils

The search for the holy grail of dynamic intermediates, which was so necessary for developing a better understanding of the mech-
anism of CB formation, paid off with the isolation of a completely new type of CB. The diastereomers of CB[6] and CB[7], the
inverted CB[6] or iCB[6] and its homologue iCB[7] ( Fig. 4A),86 were isolated in 2% and 0.4% yield, respectively. Confirmation
that iCBs are kinetic intermediates was provided by heating them in concentrated DCl, where iCB[6] was transformed into a mixture
of CB[5], CB[6], and CB[7] and iCB[7] to CB[6] and CB[7]. iCBs have smaller cavities and more open portals compared with their
normal diastereomers, and their binding affinity among ammonium ions is 2–6 orders of magnitude lower.
The Isaacs group was also able to isolate another type of kinetic intermediatesdnor-seco-CBs ( Fig. 4B–D). Achiral nor-seco-CB
[10] or a9,10,z9,10-tetranor-a2b4,a8b6,z2h4,z8h6-tetraseco-a8b4,z2h6-dimethyleneCB[10] (nsCB[10]) was isolated in 15% yield.87
Further, it was showed that nonbridged urea functional groups in nsCB[10] can be capped with ethyleneurea cycles, which are
able to act as valves within the prolonged cavity of the 10-membered CB, and through the formation of clipped-nsCB[10], the
[3]rotaxane derivative can be formed.88 The rearrangement of methylene bridges may generate chiral centers in the CB structure
as in the racemic ()-a9,10, d9,10-tetranor-a2b4,a8b6,d234,d836-tetraseco-a2b6,d238-dimethyleneCB[6] (()-nsCB[6]), isolated in
5% yield.89 Isaacs et al. showed that nsCBs can be useful starting materials for substituted CBs. The missing methylene bridge in
a10-nor-a2b4-seco-CB[6] (nsCB[6])90 was filled by a reaction with o-phthalaldehyde, creating a10-nor-a2b4-seco-(10 ,30 -dihydroiso-
benzofuran-10 ,30 -diyl)CB[6], which opened a new way to access the substitution at the bridge of the CB (See Section “Cucurbiturils
substituted at the bridges”).

3.08.4 Mechanism of Cucurbituril Formation

The formation of cucurbiturils proceeds first via the condensation of formaldehyde and the functional groups of cyclic urea
( Scheme 2). As nitrogen atoms are the best nucleophiles in the reaction media, the methylene groups are captured between
them. Day et al. showed that CBs can also be formed from oligomers83 and that the formation and dissociation of bridges are

Figure 4 (A) schematic structures of i CB[6] and i CB[7] and line structures of (B) ()-ns CB[6] and (C) ns CB[6]; (D) scheme of synthesis of clip-
ped-ns CB[10] from ns CB[10].
 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature 207

Scheme 2 Proposed mechanism of CB formation through dynamic covalent chemistry.

reversible not only in oligomers but also in the thermodynamically less stable larger CBs.82 To achieve full dissociation, it is neces-
sary to break both methylene bridges between neighboring monomers. Considering that these reactions are reversible, the occur-
rence of two simultaneous dissociations between the same monomers becomes statistically disfavored.
At a lower temperature and with deficiency of formaldehyde, the thermodynamically unstable intermediates have a longer life-
time and can therefore be isolated. In these conditions, Isaacs et al. 91 was able to isolate C-shaped linear oligomers containing 2–6
monomers and determine their crystal structures. Isaacs has also showed with substituted glycoluril dimers that the C-shaped
dimers are thermodynamically more stable by 1.55–3.25 kcal mol 1 compared with the S-shaped diastereomer (Scheme 2B).92
Therefore, it is clear that the conformation of the oligomers preorients the chain and brings the terminal groups closer to each other,
which leads finally to cyclization and CB formation.
Preformed methylene bridges in the starting material, such as oligomers or tetracyclic ethers 2 ( Scheme 2), generally result in
a higher yield of formed macrocycles.82 In preformed methylene bridges, the removal of water from the intermediate hemiaminal
has already occurred, and thereby faster entrance to the conditions of dynamic covalent chemistry93–98 is granted. Then, through an
equilibration of the same type of reversible reaction between the members of the dynamic combinatorial library, the most stable
product is formed.
The strength of the acid and its concentration regulate the chain-growth process. The reaction is faster when a stronger acid is
used, while a higher concentration promotes the formation of longer oligomers, leading to the highest fraction of larger CB homo-
logues. The high temperature necessary for the macrocycle formation reflects the thermodynamic control over the process. 82 CB[6]
is the thermodynamically most stable and is generally the major product when unsubstituted glycoluril is used as a starting material.
The thermodynamically higher energy products can be converted to lower ones.82,86 Isaacs has rationalized the preference for CB[6]
formation by the statistical distribution of the oligomeric building blocks available in the reaction media because compared with its
5- and 7- membered homologues, CB[6] is delivered by the highest number of oligomer combinations. Mock, however, has
proposed a templating effect of the oxonium ion during CB[6] formation,62 which was later supported by computational chemistry.
Theoretical studies at the quantum chemical level99 have explained the preference toward the formation of CB[6] and all1,5-Me10CB
[5] with their thermodynamic stability, if only compared with their homologues. On the other hand, a relatively small energy differ-
ence was observed between CB[6] and CB[7] and all1,5-Me10CB[5] and all1,5-Me12CB[6]; thus, to explain why CB[6] and Me10CB[5]
are formed in such high selectivities, the additional templating effect of the H3Oþ ion was investigated. Indeed, it was found that the
relatively small oxonium ion drives the equilibrium toward smaller cycles.99 Therefore, it can be concluded that the macrocycle
formation is directed by both the thermodynamic preference and the template effect.
Substitutions at the glycoluril monomer play an important role in directing the selectivity of the formed CB[n]. A change in the
angle of the methylene bridges of the oligomers upon the substitution of glycoluril could be the reason for the thermodynamically
preferred formation of 5-membered substituted CBs. 3 In CB[5], the corresponding angles at the methylene bridges are smaller
compared with those in CB[6], and comparing the angles in the dimers, it could be observed that the substituted dimer has an angle
2–7 degrees smaller100 compared with that of the unsubstituted dimer.91
The realization that the methylene bridges in CBs are dynamic encouraged Day et al. to search for alternative conditions and
templates to deliver besides CB[6] any other CB homologue as the major component. The influence of acids 82 and salts83 on
the ratio of the formed products was explored, and it was found that the addition of c. 60 mol% (based on monomer) of KCl
208 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

to the mixture of oligomers, which was heated in concentrated HCl, shifted the reaction toward the formation of the 5-membered
homologue. CB[5] was isolated in a 28–32% yield, which is much higher than the 8% collected from the reaction without this addi-
tive. Inspired by this positive influence of the potassium salt, Isaacs et al. also explored the influence of KI in CB synthesis. In a reac-
tion of the preformed glycoluril hexamer and tetracyclic methylchlorobutylglycoluril diether in HCl in the presence of KI, the
proportion of a1methyl- a5-chlorobutyl-CB[7] compared with CB[6] decreased, which confirms that the potassium cation stabilizes
smaller cycles.101 The addition of ammonium chloride to the reaction mixture in the synthesis of all1,5-Me10CB[5] helped to isolate
the product as an ammonium salt in higher yield, 36% versus 16% without NH4Cl. The yield was raised because the solubility of the
macrocycle was lowered, which allowed more efficient product isolation without affecting its formation.102 On the other hand, the
p-xylylenediammonium ion does affect the formation of kinetic products, slowing down the cyclization step in CB formation and
allowing the isolation of the glycoluril hexamer in a 10% yield103 compared with 1% from the nontemplated reaction.91 The effect
of neutral guests has not been comprehensively studied. The templating effect of CB[5] is proposed in the formation of the 10-
membered CB,75 and analogously, o-carborane, which forms an inclusion complex with CB[7], was tested as a template. Unfortu-
nately, the addition of c. 20 mol% (based on monomer) of o-carborane to the reaction mixture had small effect to the ratio of the
formed homologues.104
The available mechanistic studies have confirmed that the methylene bridges in CBs are dynamic, and their formation is affected
by the reaction conditions, the temperature, the acid strength, and the additives. Different from our experience with single-bridged
hemicucurbiturils, 21 to date, no template functionality has been uncovered that could efficiently direct the polymerization of
monomeric glycolurils to a single major product other than CB[6]. The CB formation goes through a large number of reaction steps,
containing single-bridged and double-bridged intermediate oligomers and macrocycles in equilibrium, all with different reactivity
abilities. It should especially be noted that when performing the reaction in water, in addition to reaction with urea nitrogen nucle-
ophiles, reactions with oxygen nucleophiles are also involved, which together generates a very complex kinetic profile of the reaction
mixture. Therefore, control over the products is challenging, and discoveries in this area are still forthcoming.

3.08.5 Substituted Cucurbiturils

The main motivation behind the development of new functional CBs is the studies on unsubstituted CBs that have showed a very
wide range of possible applications. The known homologues of CBs already cover a very broad range of guest sizes, but further func-
tionalization can offer new perspectives in the development of new hosts. The solubility of substituted CBs is generally higher than
that of their unsubstituted analogs. It is especially noteworthy that CBs with introduced lipophilic substituents are more soluble in
water than in organic solvents.
There are three main methodologies to insert substituents into the core CB structure. The first and most straightforward approach
is to start with a substituted glycoluril monomer, which preferentially arranges into 5-membered CBs. The second approach is to
mix monomers or oligomers with different substituents. This approach relies foremost on the nonequal thermodynamic stabilities
of isomeric CBs and may generate a very complex mixture of CB isomers. The third approach is to insert substituents into already
formed macrocycles in a postfunctionalization step, which has been successfully applied only via the hydroxylation of CB[n]s in
a first step.

3.08.5.1 Fully Substituted Cucurbiturils From Glycoluril Derivatives

As already noted, the first substituted CB was synthesized in the year 1992 by the Stoddart group, 3 where dimethylglycoluril
was condensed with formaldehyde and all1,5-decamethylCB[5] or all1,5-Me10CB[5] was obtained in 16% yield (Scheme 3A).
Day et al. showed later that the yield of this product can be significantly improved to 85% by using dimethylglycoluril
diether (Scheme 2, 2 R ¼ Me) as a starting material.82 Soon after that, the Kim group identified all1,5-pentacyclohexanoCB
[5] (all1,5CyHex5CB[5]) and all1,5-hexacyclohexanoCB[6] (all1,5CyHex6CB[6]) that were formed in 8:1 ratio and isolated in
16% and 2% yield, respectively105 (Scheme 3B). In an exploration of the effectiveness of affinity chromatography in CB puri-
fication, Keinan et al.106 enabled the isolation of, besides other substituted CB[6] derivatives, fully substituted all1,5Me12CB[6]
that was formed in very minor amount of 0.2% yield (Scheme 3A). The crystal structure of all1,5Me12CB[6] was reported some
years later by Tao et al.107 Day proposed that using a cyclopentano substituent in the monomer would keep the conformation
of the glycoluril similar to the unsubstituted monomer, favoring the formation of larger homologues. Indeed, the first fully
substituted 7-membered CB was made by Day et al.108 from a glycoluril tetraether derivative bearing a cyclopentane
substitution. The all1,5-heptacyclopentanoCB[7] (all1,5-CyPen7CB[7]) was isolated in a 9% yield, along with smaller homo-
logues all1,5-hexacyclopentanoCB[6] (all1,5-CyPen6CB[6]) and all1,5-pentacyclopentanoCB[5] (all1,5-CyPen5CB[5]) in 39%
and 21% yield, respectively (Scheme 3C).
The formation of larger homologues was directed with Li2CO3 using c. 30 mol% of Liþ in respect to the monomer. Besides the
Li cation, Csþ also shifted the equilibrium toward the formation of larger homologues. Starting from the glycoluril analog dime-
þ

thylpropanediurea, where a dimethylpropane group separates two urea functional groups, the new substituted CB was synthesized
almost simultaneously by the groups of Wang 109 and Sindelar110 (Scheme 3D). The product all1,5-pentaseco- all1,5-penta(dimethyl-
methylene)cucurbit[5]uril named by Sindelar as pressocucurbit[5]uril was isolated in 1–5% yield. The prefix presso is inspired by the
geometry of the new CB, where the clipped geometry of the monomers pushes the urea portals closer together and compresses the
 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature 209

Scheme 3 Synthesis of fully substituted cucurbiturils.

cavity of CB. This nice example demonstrates that a slight structural deviation of the glycoluril monomer does not disrupt the forma-
tion of CB but merely affects the shape of the resulting CB cavity. Substitution in the glycoluril affects the geometry of the monomer,
which translates to the preferred formation of 5-membered CBs.

3.08.5.2 Partially Substituted Cucurbiturils From Variable Starting Material

The formation of CBs from both substituted and unsubstituted glycolurils, based on their varying properties, such as solubility and
geometry, provides a perfect platform for exploring the richness of possibilities for the synthesis of CBs. The first partially substituted
CB, a1,5-diphenylCB[6], was synthesized by the group of Nakamura in 2002, 111 when glycoluril and diphenylglycoluril were
reacted in a 5:1 ratio in the presence of 3 equivalents of ammonium sulfate (Scheme 4). CB with one different monomer, a1,5-
Ph2CB[6], was isolated in 30% yield along with normal CB[6].
A year later, Day et al. published a synthesis of a1,5,g1,5,31,5-hexamethylCB[6] from a mixture of glycoluril and its methyl-
substituted diether derivative. The hexamethylCB[6] was produced in a 10% yield together with 5- and 7-membered CB isomers
( Scheme 5A).112 This article proposed the first additions to the CB nomenclature that would allow it to account for substituted
and unsubstituted monomers, but Day himself later abandoned it and proposed a new one that assigns a Greek letter to every
monomer.63 The latter system is taken as a base for the CB nomenclature in the current article.
The preferential formation of a1,5,g1,5,31,5-Me6CB[6] over the other 10 possible 6-membered CB isomers was encouraged by the
addition of LiCl to the reaction mixture. LiCl directed the reaction toward the formation of larger homologues than CB[5], and it
also influenced the distribution between the 6-membered isomers. When the same starting materials reacted without any salt addi-
tive, a mixture of 5-membered methyl-substituted CBs was isolated in a 30% yield, from which the crystal structures of a1,5,g1,5-
Me4CB[5] and a1,5,b1,5,d1,5-Me6CB[5] were obtained ( Scheme 5B).113
In templated conditions, with an excess of KCl, a dimer of glycoluril was reacted with a methylated diether of glycoluril, and as
a result, a1,5,d1,5-Me4CB[6] was isolated in a 30% yield ( Scheme 5C).114 On the other hand, when nontemplated conditions were
utilized, this reaction resulted in the formation of the tetramethylated a1,5,b1,5-Me4CB[6] in a low isolated yield of 4% (Scheme
5D)115 and octamethylated a1,5,b1,5,d1,5,31,5-Me8CB[6] in 2% yield (Scheme 5F).116
A mixture of partially substituted CBs can also be obtained from partially substituted monomers, such as methylglycoluril. Tao
et al. 117 showed that without any additive, a mixture of 5-, 6-, and 7-membered CBs was formed with very high diastereoselectivity
(Scheme 5E). As major products, only one 5-membered CB, a1,b1,g1,d5,35-Me5CB[5], only one 6-membered CB,
a1,b1,g5,d1,35,z5-Me6CB[6], and one 7-membered CB, a1,b5,g5,d1,31,z5-Me7CB[7], were isolated after very careful separation in

Scheme 4 Synthesis of the first partially substituted cucurbituril.

210 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

Scheme 5 Synthesis of methyl-substituted cucurbiturils.

40%, 35%, and 12% yields, respectively.117,118 On the other hand, if glycoluril was used alongside methylglycoluril in a ratio of 6:1,
monosubstituted a1-MeCB[6] was isolated in 14% yield along with CB[6] as a major product in a yield of 43% (Scheme 5G).119
Day et al. 63 used an excess of KCl, glycoluril dimer, and cyclohexanoglycoluril diether for the synthesis of a1,5,d1,5-dicyclohex-
anoCB[6], which was isolated in a 30% yield (Scheme 6A). The reaction proceeded very similarly to in the case of the methyl substi-
tution (Scheme 5C). Without the template, 40% of 5-membered a1,5,b1,5,d1,5-tricyclohexanoCB[5] (Scheme 6B) was isolated, and
it was mentioned that 6-membered CBs were also formed.120 Tao et al.121 reported isolation of 40% of a1,5,g1,5,31,5-tricyclohexa-
noCB[6] from the same conditions (Scheme 6B).
In nontemplated reaction conditions, Heck and Huber et al. 122 isolated a library of 6-membered cyclohexano-substituted CBs.
From a 1:1 mixture of glycoluril and substituted glycoluril diether 6, the monocyclohexano-substituted CB was isolated in a 32%
yield as a major product, and all other isomers were produced in much lower amounts (Scheme 6C and D). The scope of the iso-
lated products shows that the exchange of methylene bridges within the members of the dynamic combinatorial library proceeds
easily during the prolonged heating of the reaction mixture. In the same paper, the isolation of the new a1,5-seco-a1,5-methyleneCB
[6] (Scheme 6E) was also reported in a 7% yield.122 The conditions for the synthesis were the same as in Nakamura’s work111
(Scheme 4), but the yield remained much lower. Tao et al.123 reported that varying ratios of the starting glycoluril and substituted
diether 7 monomers and the number of cyclopentano substituents in CB can be controlled. Di-, tri-, and tetrasubstituted CB[6]s
were isolated by crystallization in 17%, 21%, and 14% yields (Scheme 6F–H).
In all presented examples of partially substituted CBs, 5- or 6-membered macrocycles were isolated with only one exception of
a1,b5,g5,d1,31,z5-Me7CB[7] ( Scheme 5E). The substitutions generally increase the solubility of the CBs, but their complexation
ability remained similar to that of their unsubstituted homologues. The isolated yields of all 6-membered substituted CBs remain
considerably lower than that for the unsubstituted CB[6] from glycoluril.
The 7-membered homologue has found the widest application among the CB family members, due to its solubility in water and
strong binding affinity. Likewise, a wide range of applications has been found suitable specifically for the 8-membered and larger
CBs. To tackle the evident lack of synthetic methods for 7- and 8-membered substituted homologues of CBs, Isaacs et al. started
employing the preformed glycoluril hexamer as a starting material ( Scheme 7). The hexamer can be isolated in a 10% yield
when glycoluril is condensed with 1.67 equivalents of formaldehyde in the presence of a para-xylylenediammonium template.
The latter forms a complex with the glycoluril hexamer and precipitates it out from the dynamic reaction media.103 Applying a short
reaction time, strong acid, and high temperature, the kinetic 7- and 8-membered products were trapped (Scheme 7).
Potassium iodide, used in excess, was applied to a 1:1 ratio of the hexamer and substituted glycoluril diether, resulting in the
formation of equal amounts of a1,5-dimethylCB[7] and CB[6]. The yield of the isolated a1,5-Me2CB[7] was 31%. In the same condi-
tions, the reactions with methyl-, phenyl-, and cyclohexano-substituted glycoluril ethers afforded a lower amount of monosubsti-
tuted CBs besides the major product CB[6]. 101 Upon substituting H2SO4 with HCl and increasing the ratio of the added substituted
diether, the 8-membered a1,5,b1,5-tetramethylCB[8] became the major CB formed, and it was isolated in 11% yield,124 alongside
 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature 211

Scheme 6 Synthesis of partially cyclohexano-, cyclopentano-, and methylene-substituted cucurbiturils.

Scheme 7 Synthesis of partially substituted 7- and 8-membered cucurbiturils.

212 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

a1,5-Me2CB[7] and CB[6] also formed. In a reaction performed under similar conditions, a1,5,b1,5-dicyclohexanoCB[8] was isolated
in a 4% yield, with a1,5-cyclohexanoCB[7] formed in a nearly equal amounts, while the major CB[6] was formed again.124
Having a general approach available for introducing a single substituted monomer into the CB core structure, Isaacs et al. chose
methylchlorobutylglycoluril diether for functionalization of CB[7], which allowed the introduction of new functionalities into CBs
( Scheme 8).101 Using the example of biotin-linked CB[7] (Scheme 8B), the targeted uptake of the leukemia drug oxaliplatin was
demonstrated.125 Triazolyl with a terminal ammonium linker (Scheme 8, 11) induced the self-aggregation of CB derivatives,101 and
the triazolylammonium compounds with long aliphatic chains (Scheme 8, 12) induced the formation of vesicle-type aggregates.126

3.08.5.3 Cucurbiturils Substituted at the Bridges

Attempts to fully substitute methylene bridges using allyl or aryl aldehydes instead of formaldehyde have failed. Glycoluril mono-
mers linked by a substituted methylene bridge preferentially form S-shaped oligomers, and therefore, the preorientation of the
terminal group for macrocyclization is disfavored. 127 To avoid the necessity of controlling the shape of the oligomers during the
introduction of the substituents, Isaacs et al. applied preformed nor-seco-CB derivatives as starting materials. As mentioned earlier,
the missing methylene bridge in a10-nor-a2b4-seco-CB[6] (nsCB[6]) can be filled. This approach was successfully applied in a reac-
tion with o-phthalaldehyde, creating a10-nor-a2b4-seco-(10 ,30 -dihydroisobenzofuran-10 ,30 -diyl)CB[6] (Scheme 9A).90 The possi-
bility of closing the two missing bridges in a hexamer with the dialdehyde is also feasible.103 In trifluoroacetic acid, the chiral
()-a9,10-dinor-a2b4,a8b6-diseco-a2b6-(10 ,30 -dihydroisobenzofuran-10 ,30 -diyl)CB[6] was formed in a 91% yield, while the same
reaction in sulfuric acid yielded a9,10-(10 ,20 -benzeno)CB[6] in a 72% (Scheme 9B).103 The scope of reacting aldehydes in this
reaction was screened (Scheme 9C), and additionally to that Isaacs and Anzenbacher, Jr, et al.103 demonstrated that
a9,10-(10 ,20 -naphtaleno)CB[6] coupled with Eu3 þ can be applied as fluorescent sensor. CB with a triazolammonium side chain
(Scheme 9C) was able to form cyclic assemblies through intramolecular self-complexation.128 Reacting two equivalents of a glyco-
luril hexamer with aromatic tetraaldehydes gives CBs with double 6-membered cavities. Such a rigidly coupled a9,10-10 ,20 -(a9,10-
cucurbit[6]urilo-40 ,50 -benzeno)CB[6] can be arranged into two- and three-ring supramolecular ladders through complexation
with guests containing one, two, and three hexanediammonium moieties connected by viologen units.129 As mentioned earlier,
the formation of the methylene bridges of CB from substituted aldehydes is sparse compared with formaldehyde. For example,
when formaldehyde and 3-phenylpropionaldehyde were used together in condensation with glycoluril, a9-(3-phenylpropyl)CB
[6] was isolated in only a 0.2% yield, whereas from hexameric glycoluril and substituted aldehyde, nearly 100 times more of
the same product was formed (Scheme 9D).130

3.08.5.4 Postfunctionalization of Cucurbiturils

The extraordinary stability of CB[6] was already noted by Behrend et al. when the first synthesized macrocycle was studied. This
chemical feature is good for the recycling of CBs, but on the other hand, it limits the possibility of modifying the macrocycle. Poly-
meric cycle formation reactions are in general difficult to control, so if one started from preformed CB, the yield loss from the equi-
librium between linear and cyclic oligomers could be avoided. The Kim group was the first to report the direct functionalization of
CBs ( Scheme 10A).131 They showed that heating the CBs in the presence of persulfate can deliver all1,5-(OH)10CB[5] in 42% and
all1,5-(OH)12CB[6] in 45% isolated yield. All1,5-(OH)14CB[7] and all1,5-(OH)16CB[8] were isolated in considerably lower yields
compared with their smaller homologues, probably due to their lower stability. Along with hydroxylation, Kim et al.131,132 also
showed that the further derivatization of the 6-membered hydroxylated CB can be performed (Scheme 10B). Allyl group addition

Scheme 8 Functionalized cucurbit[7]uril derivatives.

 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature 213

Scheme 9 Substitution at bridges of CBs.

followed by radical reaction with thiol-functionalized compounds proceeded well. The developed methodology established a reli-
able route for making new functional materials.48,56,61,133–141 Ritter et al.142 coupled all1,5-(propargyl)12CB[6] and azide-
functionalized b-cyclodextrin through the well-known 1,3-dipolar cycloaddition (Scheme 10B). The dual molecular receptor
formed was used in designing the properties of supramolecular polymers. It should be noted, though, that the derivatization of
all 12 hydroxy sites cannot always be controlled.
Nine years after the full hydroxylation of CBs was reported, the first publication on the monohydroxylation of CB[6]
appeared. 143 The reactivity of the starting CB compared to the hydroxylated product was enhanced by the formation of the
host–guest complex with a bisimidazolium guest, which increased the solubility of starting material. The overoxidation of the
hydroxylated product by ammonium persulfate was controlled by shortening the reaction time, which, on the other hand, entailed
214 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

Scheme 10 Hydroxylation of cucurbiturils and their further derivatization.

a penalty of the incomplete conversion of the starting CB. The difficulty of controlling the selectivity of the hydroxyl group insertions
could not be fully avoided, so a1-OHCB[6] was isolated in 12% yield. Scherman et al.143 also showed that the derivatization of
monohydroxylated CB can be easily achieved.
Bardelang and Ouari et al. 140 studied the monohydroxylation of CB homologues CB[5–8] (Scheme 10A) by peroxide, UV
radiation, and also an oxidation mechanism. Unfortunately, due to relying on the crystallization procedure and ambiguous
NMR and crystallographic data, the yield of the monohydroxylated CBs was reported incorrectly in the original paper. Nevertheless,
the separation procedure and correct yields for the purified products were published in a correction with new supporting informa-
tion, giving isolated yields of 10% for a1-OHCB[5], 37% for a1-OHCB[6], 20% for a1-OHCB[7], and 4.5% for a1-OHCB[8], starting
from their respective CB homologues.144 Latter example reflects the demand of the analytic methods to improve the identification
and purity assessment of CBs.

3.08.6 Structural Parameters and Water Solubility of Cucurbiturils

The dimensions of the CB[n] homologues and their derivatives are collected in Table 1 based upon the respective X-ray crystal
structures obtained from the Cambridge Structural Database.150Unsubstituted CB[5], CB[6], and CB[7] are symmetrical around
their central axis (a ¼ b, c ¼ d), resembling pumpkins, whereas their larger homologues CB[8] and CB[10] are inclined to adapt
a more ellipsoidal shape (a > b, c > d). Only small deviations are observed in the height (h) of CB[n] and its derivatives, while
its portals (a, b) and cavity (c, d), being slightly more flexible, are subject to deformations by the inclusion of a guest or
substitutions.
The substituted CB[n] species appear in a range of spherical to ellipsoidal shapes. The portal and cavity dimensions of the
substituted CB[5] derivatives remain symmetrical, whereas for the derivatives of CB[6], CB[7], and CB[8], these dimensions can
adopt a more pronounced ellipsoidal shape. In the case of CB[6], the deformations are subtle, with largest differences between
a and b and c and d seen for a1,5,b1,5-Me4CB[6] and a1,5,g1,5,31,5-Me6CB[6], 149 a1,5,d1,5-Me4CB[6],114 followed by Cyc2CB[6]148
and Me8CB[6].116 The very small sample of X-ray structures for substituted CB[7] is represented by a1,5-Me2CB[7]101 and
a1,b1,g5,d5,31,z1,h5-Me7CB[7].118 The deformation of a1,5-Me2CB[7] is notable only on the portals, while the cavities of both CB
[7] derivatives remained roughly symmetrical. The substituted CB[8] structures124 already show much larger deviations from spher-
ical, with a and c being approximately 30–40% larger than b and d, respectively. The marked deformation of CB[8] and its deriv-
atives, CB[10] and especially CB[14], illustrate the loosened rigidity of the larger homologues in the CB[n] family, which are
therefore more likely to adapt their shape to their respective environments, be it by guest inclusion or self-folding.37 The inverted
monomer creates a dent to one side of iCB[n], thus significantly reducing the diameter of the cavity in the direction d (Fig. 5A and B)
and giving the cavity a kidney-like shape. The two broken and two dislocated methylene bridges in the nsCB[n] give a degree of
freedom at the remaining single methylene bridges, so that the shape of the CB[n] in the solid state is largely affected by the encap-
sulated guest(s) (Fig. 5C and D).
Table 1 Structural parameters of CB[n] and derivatives

Cavity Portal
diameter a(Å) diameter b(Å) Height c(Å) Solubility in water d

CB[n] Year [Ref] CSD ref CCDC a b c d h mg mL 1 mol L1

all1,5Me10CB[5] 1992 3 LAHBAX 1202818 4.9 2.4 9.1 8 80

CB[5] 2000 74 LIRTEL 141408 4.7 2.6 9.2 <1 145 (1.7  0.5) $ 10 4
all1,5CyHex5CB[5] 2001 105 IDEBAU 164887 4.7 2.6 9.2 295 2.6 $ 10 1

Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

a1,b1,g1,d5,35-Me5CB[5] 2008 117 WIVDIP 638233 4.7 2.4 9.1 180 0.2
a1,5,g1,5-Me4CB[5] 2008 113 OFOLOL 642114 4.7 2.4 9.1 35 e
a1,5,b1,5,g1,5,d1,531-Me9CB[5] f 2008 113 OFOLUR 642115 4.7 2.4 9.1 28 e
a1,5,b1,5,d1,5-Me6CB[5] 2008 113 OFOMAY 655282 4.7 2.4 9.1 37 e
a1,5,b1,5,d1,5CyHex3CB[5] 2008 120 GOJRED 666616 4.8 2.3 9.1 Not reported
a1,5-Me2CB[5] g 2008 120 GOJRIH 684922 4.8 2.0 8.9 Not reported
all1,5-CyPen5CB[5] 2012 108 DATYEE 748653 4.8 2.3 9.1 Not reported
a1,5,g1,5CyHex2CB[5] 2013 146 WEXNOE 748650 4.8 2.3 9.1 Not reported
a1,5,b1,5,g1,5CyHex3CB[5] 2013 146 WEXNEU 748652 4.8 2.3 9.1 Not reported
a1-OHCB[5] h 2015 147 AHUPOK 1052401 4.8 2.2 9.0 Not reported
pressoCB[5] 2015 109 LUCDUK 1036915 5.0 1.9 8.5 12 1.15 $ 10 2
CB[6] 1981 2 BEBDOB 1107445 6.3 3.8 9.1 18 145 (1.8  0.7) $ 10 5
all1,5CyHex6CB[6] 2001 105 IDEBEY 164888 6.3 4.0 9.1 225 1.7 $ 10 1
all1,5-(OH)12CB[6] 2003 131 UKUQIA 205927 6.5 5.9 4.2 3.8 9.1 Not reported
a1,5,d1,5-Me4CB[6] 2004 114 ACIHOK 601920 6.9 5.5 4.3 2.5 9.1 Reported as soluble
a1,5,d1,5-CyHex2CB[6] 2005 148 KAXJUP 271400 6.5 5.7 4.4 3.6 9.1 Reported as soluble
all1,5Me12CB[6] 2007 107 XEZROK 633953 6.5 5.9 4.2 3.8 9.1 42 e
a1,b1,g5,d5,31,z5-Me6CB[6] 2008 117 WIVDOV 638455 6.1 4.0 9.1 160 0.11
a1,5,g1,5,31,5CyHex3CB[6] 2008 121 GIZKUW 647870 6.2 4.0 9.1 74.8 e
a1,5,b1,5-Me4CB[6] 2008 149 ROKFUT 655283 6.8 5.5 4.3 3.2 9.2 Moderately soluble
a1,5,b1,5,d1,5,31,5CyHex4CB[6] i 2008 149 ROKGAA 668849 6.4 5.9 4.2 3.8 9.1 Moderately soluble
a1,5,g1,5,31,5-Me6CB[6] f 2008 149 ROKGII 668851 6.7 5.6 4.5 3.7 9.2 Moderately soluble
a1,5g1,5-CyPen2CB[6] 2009 123 SOVJUJ 703159 6.2 4.1 9.2 178
a1,5g1,531,5-CyPen3CB[6] 2009 123 SOVKAQ 703160 6.5 5.8 4.2 3.6 9.1 167
a1,5b1,5d1,531,5-CyPen4CB[6] 2009 123 SOVKEU 703161 6.4 5.9 4.0 3.8 9.1 128
a1-OHCB[6] 2012 143 MAVRIM 855782 6.4 6.0 4.0 3.6 9.1 <1 <1 $ 10 5
all1,5-CyPen6CB[6] 2012 108 DATYOO 848924 6.5 5.9 4.2 3.5 9.1 Not reported
a1,5,b1,5,d1,5,31,5-Me8CB[6] 2014 116 NIZXUR 951713 6.5 5.7 4.5 3.3 8.9 Not reported
a1,5,b1,5-Me4CB[6] 2014 115 ROLBUR 986908 6.4 5.9 3.8 3.2 9.0 Not reported
CB[7] 2000 74 LIRTIP 141409 7.5 5.4 9.1 23-35 2–3 $ 10 2
a1,5-Me2CB[7] 2012 101 PEGJOC 913475 7.6 6.0 4.8 9.0 320 0.264

215
(Continued)
 216
Table 1 Structural parameters of CB[n] and derivativesdcont'd

Cavity Portal
diameter a(Å) diameter b(Å) Height c(Å) Solubility in water d

Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

CB[n] Year [Ref] CSD ref CCDC a b c d h mg mL 1 mol L1

a1,b1,g5,d5,31,z1,h5-Me7CB[7] 2015 118 QUWKAW 1407536 7.5 5.4 9.1 837 0.663
CB[8] 2000 74 LIRTOV 141410 9.2 8.8 6.3 5.9 9.1 <1 <10 5
a1-OHCB[8] h 2015 147 AHUQAX 1052403 9.3 8.9 7.1 6.7 9.1 Not reported
a1,5,b1,5-Me4CB[8] 2015 124 MURHUE 1432213 10.2 7.7 7.2 5.1 9.1 4 3.1 $ 10 3
a1,5,b1,5-CyHex2CB[8] 2015 124 MURJAM 1432214 10.5 7.2 8.1 5.2 9.1 1 0.9 $ 10 4
a1,5,31,5-Me4CB[8] f 2015 124 MURMIX 1432215 10.4 7.2 8.1 5.4 9.1 Not reported
CB[10] (CB[5]@CB[10]) 2002 75 IDIWEX 169807 12.9 11.1 10.8 9.2 9.1 Not applicable
CB[10] 2005 76 LAZPIM 293518 13.5 9.5 11.6 8.2 9.1 <1 <5 $ 10 5
CB[14] 2013 77 DEXHIZ 913620 10 4.1 $ 10 3
iCB[6] 2005 86 NEBDII 295128 6.5 3.9 5.5 3.0 9.1 Not reported
iCB[7] 2005 86 NEBDEE 295127 7.7 5.7 7.0 4.6 9.1 Not reported
nsCB[10] 2006 87 LETSUZ 632963 14.6 1.7 12.6 2.5 11.1 Poorly soluble
()-nsCB[6] 2007 89 TIKHOL 647413 6.4 5.6 5.4 2.4 10.9 Not reported
a10-nor-a2b4-seco-a2b4- 2008 90 ROBZIS 676703 7.1 6.3 5.0 9.1 Not reported
(1,3-dihydroisobenzofuran-1,
3-diyl)CB[6]
clipped-nsCB[10] 2011 88 UYAVUM 828943 6.3 5.8 3.8 14.3 j Poorly soluble
Bis-a9,10-(30 ,40 -benzeno)CB[6] 2013 129 BENWOI 918840 7.1 5.3 4.8 2.4 9.1 Not reported
a
Calculated from the radius of the cavity, measured as the distance between nitrogen atoms and the centroid of the cavity.
b
Calculated from the radius of the portal, measured as the distance between oxygen atoms and a portal centroid.
c
Calculated from the distance between the centroids of the opposite portals.
d
Derived from the reference given in column Ref., if not, otherwise stated.
e
Calculated from the crystallization conditions, where a solution in pure H2O is reported; saturation might not be achieved.
f
Synthesis is not described; only crystal structure is included.
g
It should be noted that the structure is deposited without refining any hydrogen atoms.
h
It should be noted that the hydroxyl group was severely disordered between multiple positions, and crystals were obtained from a mixture of non- and hydroxylated products.
i
Two of the four cyclohexyl groups appear as disordered between four sites.
j
A central plane was calculated from all the atoms in nsCB[n]; h is measured from the distance between this plane and furthest atoms on opposite sides.All measured dimensions take into account the van der Waals radii of the relevant atoms. Two
measures were taken for the ellipsoidal CB[n]: largest portal and cavity diameter are a and c, respectively; smallest are b and d, respectively (See Fig. 5).
 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature 217

Figure 5 X-Ray crystal structure of CB[6] (Ref. 2) with the dimensions in Table 1; X-Ray crystal structures of i CB[6] and i CB[7] and guest inclusion
complexes of ()-nsCB[6] and nsCB[10].

Available water solubilities of CBs that are characterized by X-ray crystal structures are listed in Table 1. Generally, CBs are poorly
soluble in water, with the exception of CB[7] and its derivatives, showing solubility up to 663 mM. The introduction of diammo-
nium salts to the aqueous solution increases the solubility through the formation of stable inclusion complexes.

3.08.7 Summary and Perspectives

The number of CB family members has grown exponentially in the past few decades. The syntheses of unsubstituted homologues,
such as CB[5,6,7,8,10,14], 5- to 8-membered fully or partially substituted derivatives of CBs, the inverted and nor-seco-isomers, and
additionally hemiCBS and acyclic CBs, have been demonstrated. To handle the differences between isomers, a nomenclature for
naming the substituted CBs is proposed herein. The search for advanced properties of CBs has progressed together with the synthesis
of new CB derivatives. The solubility, especially in water, of CBs is increased upon substitution, and in the case of CB[8], it increased
by as much as 1000 times. Substitution in CBs can be achieved through either monomeric or oligomeric building blocks; among
others, the glycoluril hexamer has been recognized as a useful starting material for 7- and 8-membered substituted CBs. Hexamer
and nor-seco derivatives offer opportunities for substitution at the CB bridges, and postfunctionalization of normal CBs has been
achieved only through hydroxylation. Utilizing glycoluril as a monomer, CB[6] can be prepared most efficiently due to its
thermodynamic stability. Substituents of glycoluril direct the thermodynamic preference toward 5-membered cycles, and
all1,5-decamethylCB[5] can also be isolated in high yield. All other CBs are isolated as by-products when starting from the mono-
mers, and only for some compounds can the yield be optimized to 20–40%.
Dynamic covalent chemistry is operative during the synthesis of CBs. The studied additives can influence the product compo-
sition of this polymerization reaction, but to date, no template has been found that would shift the equilibrium so that 7-membered
or larger CBs would be the major products.
All CB family members are capable of acting as hosts that form inclusion complexes, and their binding ability is directly related
to their shape. The 5-membered CBs are very rigid, and neither substitution at the equator nor guest binding affects their geometry.
The 6-membered CBs are almost as rigid, but depending on their substituents, their portal and subsequently cavity may be
deformed up to 15%. The geometry of inverted CB[6] deviates considerably from that of the other CB[6] derivatives, which is
also reflected in the weaker binding of guests. Despite the strongest ability of 7-membered CB to form host–guest complexes, to
the best of our knowledge, the crystal structures of only four different CB[7] isomers, CB[7], a1,5-Me2CB[7], a1,b1,g5,d5,31,z1,h5-
Me7CB[7], and iCB[7], are known. New isomers of this homologue are expected to be developed. The 8-membered cycle of CB
[8] derivatives is flexible, and substituted and unsubstituted macrocycles can adopt an ellipsoid conformation upon binding. Up
to a 2.5-fold increase in guest binding has been observed for substituted CB[8] compared with the unsubstituted. CB[10] adopts
the shape of the guest, and CB[14] is already so flexible that it can be folded, although in water and without any guests, all of
its monomers are equal.
The discoveries and new applications of CBs rely on the availability of the starting material. Therefore, improvements in the
synthetic methods that would take advantage of the dynamic character of the covalent bonds in CBs are awaited. This must, of
course, be accompanied by the development of useful analytic methods to improve the identification and purity assessment of
CBs and their intermediates. The steady growth in activity in the field of CB chemistry promises new and groundbreaking
discoveries.
The authors would like to thank Estonian Ministry of Education and Research (MER) for support through grant PUT692 and TUT
grant no. B25.
218 Cucurbiturils: Synthesis, Structures, Formation Mechanisms, and Nomenclature

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146. Li, Z.-F.; Liang, L.-L.; Wu, F.; Zhou, F.-G.; Ni, X.-L.; Feng, X.; Xiao, X.; Zhang, Y.-Q.; Zhu, Q.-J.; Clegg, J. K.; Tao, Z.; Lindoy, L. F.; Wei, G. Cryst. Eng. Comm. 2013, 15 (12),
1994–2001.
147. Ayhan, M. M.; Karoui, H.; Hardy, M.; Rockenbauer, A.; Charles, L.; Rosas, R.; Udachin, K.; Tordo, P.; Bardelang, D.; Ouari, O. J. Am. Chem. Soc. 2015, 137 (32),
10238–10245.
148. Zheng, L.-M.; Zhu, Q.-J.; Zhu, J.-N.; Zhang, Y.-Q.; Tao, Z.; Xue, S.-F.; Wei, Z.-B.; Long, L.-S. Wuji Huaxue Xuebao 2005, 21 (10), 1583–1588.
149. Yu, D. H.; Ni, X. L.; Tian, Z. C.; Zhang, Y. Q.; Xue, S. F.; Tao, Z.; Zhu, Q. J. J. Mol. Struct. 2008, 891 (1–3), 247–253.
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 3.09 Hemicucurbit[n]urils
M Lisbjerg and M Pittelkow, University of Copenhagen, Copenhagen, Denmark
Ó 2017 Elsevier Ltd. All rights reserved.

3.09.1 Introduction 221

3.09.2 En route to Hemicucurbit[n]urils 222
3.09.3 Hemicucurbit[n]uril 222
3.09.4 Cyclohexylhemicucurbit[6]uril 225
3.09.5 Bambus[6]uril 227
3.09.6 Biotin[6]uril 230
3.09.7 Outlook 235
References 236

3.09.1 Introduction

Hemicucurbit[n]urils (eg, hemicucurbit[6]uril, Fig. 1A) are macrocyclic structures synthesized from an acid-catalyzed condensation
reaction of an N,N0 -dialkylurea and formaldehyde (or other aldehydes, but only formaldehyde has been used to date).1 The name
“hemicucurbituril” is derived from the name of another type of macrocycle, the cucurbit[n]uril, which is a structure synthesized
from an acid-catalyzed condensation reaction of a glycoluril with formaldehyde (Fig. 1B).2 The “cucurbit[6]uril” was named by
Mock and coworkers due to the apparent structural resemblance between the 3D structure of the cucurbit[6]urils and the physical
appearance of a pumpkin family (Cucurbitaceae).3 In 2004, when Miyahara and coworkers described the first hemicucurbit[n]urils,

Figure 1 (A) Synthesis of hemicucurbit[6]uril by condensation of ethylene urea and formaldehyde. (B) Synthesis of cucurbit[7]uril by condensation
of glycoluril and formaldehyde. (C) Synthesis of biotin[6]uril by condensation of D-biotin and formaldehyde.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12515-6 221

222 Hemicucurbit[n]urils

Figure 2 The different building blocks ethylene urea, D-biotin, 2,4-dimethyl-glycouril, and (S,S)-cyclohexyl urea, all give the same general motif of
the hemicucurbit[6]uril, when using similar conditions.

they were named that way simply because the structure of one of the building blocks, ethylene urea, could be viewed, roughly, as
a half glycouril building block that is used to prepare cucurbit[n]urils.
In Miyahara’s pioneering work, a number of hemicucurbit[n]urils were prepared and a number of interesting observations and
trends observed. Almost all of the hexameric macrocycles in the hemicucurbit[n]uril family bind anions in the cavity through
CeH/anion interactions.1,4–6 This is in contrast to the cucurbit[n]urils that tend to bind cations largely through dipole cation inter-
actions.7–9 All the members of the hemicucurbit[6]uril family described so far have been synthesized through a templated conden-
sation reaction between the desired N,N0 -dialkyl urea monomer, formaldehyde, and the corresponding halide anion that works as
a template, yielding the macrocyclic structure (Fig. 2). New analogs include Sindelar and coworker’s bambus[6]uril,4 our own biotin
[6]uril,5 and the cyclohexylhemicucurbit[6]uril described by Aav and coworkers.6
Especially the anion-binding properties of the hemicucurbit[6]urils have achieved significant attention.10,11 The hexameric struc-
tures exhibit strong binding to anions, for example, iodide, both in water and in organic solvents depending on the specific hemi-
cucurbit[6]uril.4,12–14 These strong binding affinities have been obtained purely by CeH/anion interactions, and it has been
speculated that a chaotropic effect and/or the nonclassical hydrophobic effect is involved in achieving high binding affinities.13,15
The intriguing structures of the macrocycles have inspired their use as anionophores,14 catalysts,16 and oxidation vessels.17,18

3.09.2 En route to Hemicucurbit[n]urils

The first hemicucurbit[n]uril was described in 2004 by Miyahara and coworkers (Fig. 1). The original synthetic work was inspired by
the vast bulk of work describing the synthesis and properties of cucurbit[n]urils. When considering ethylene urea as “half” a glyco-
uril, the transfer of logic from the cucurbit[n]urils to the hemicucurbit[n]urils seems apparent, and initially the original expectations
were also that the supramolecular binding properties of the hemicucurbit[n]urils would be similar to those of the cucurbit[n]urils.
Glycouril was used as early as 1905 by Behrend et al. to prepare a polymer by reaction with formaldehyde, and it was much later
(1981) discovered that it was possible to prepare the corresponding macrocycles, the cucurbit[6]urils (eg, CB[6]), by a similar
synthetic procedure.
To fully appreciate the unique supramolecular chemistry of the cucurbit[n]urils, it is illustrative to consider the structural features
of the CB[6] (Fig. 3). CB[6] is a macrocycle composed of 6 glycourils connected by 12 methylene bridges. This gives CB[6] a hydro-
phobic cavity, and two polar entry portals. This construction is ideal for binding of, for example, the ammonium ions of a,u-alka-
nediamines, where the cations are located at the portals of the CBs, and the alkyl chain is situated inside the hydrophobic cavity.
When viewing each glycouril unit, they each have a convex side and a concave side, where the convex side has the two methine
protons. In CB[6], each glycouril has the convex side pointing outward from the cavity and the methine protons therefore point
away from the hydrophobic cavity.
The use of urea-containing molecules in supramolecular chemistry has been explored extensively in the past decades.19,20 The
cucurbit[n]uril family of macrocycles has gained significant popularity in recent years due to the possibility of preparing strong
binary and ternary complexes in water.8 The possibility to prepare ternary complexes with large binding affinities in water has
been used in a number of chemical biology applications.21,22 The chemistry of glycouril-containing structures has also been scru-
tinized by Nolte and coworkers in their elegant studies, which has led to many applications in biological and materials chemistry.19
In this book chapter, we discuss the recent progress of macrocycles prepared from condensation of N,N0 -dialkyl ureas, and their
thio analogs, with formaldehyde. The review is organized in a fashion such that each macrocycle is described first including the
synthesis followed by an analysis of their structures. Then an evaluation of the properties of the various macrocycles, for example,
anion binding or catalysis, is presented.

3.09.3 Hemicucurbit[n]uril

The original, and so far structurally most simple of these hemicucurbit[n]uril macrocycles is the hemicucurbit[6]uril (hmCB[6]),
which Miyahara and coworkers obtained by reacting ethylene urea and formalin in aqueous 4 M HCl at room temperature for
30 min (Fig. 4).1
 Hemicucurbit[n]urils 223

Figure 3 Top: Glycouril, the stippled line indicating the two “fused” ethylene ureas. Bottom: The main CB[6] macrocyclic products formed when
reacting glycouril in aqueous HCl. Key structural features are highlighted.

Figure 4 Synthesis of hemicucurbit[6]uril. Key structural features are highlighted.

From the reaction mixture, hmCB[6] precipitated as an HCl adduct, which was isolated in 94% yield. The hmCB[6] was the first
of the macrocycles with the alternating configuration of the urea moieties, which was seen from the single crystal X-ray structure
(Fig. 5). This alternating configuration is opposite of what has been observed in the CB[n]s, where the aligned carbonyls play an
important role in the host–guest chemistry. This alternating orientation makes metal–ion bonding nonfeasible, but the structure
does form a hydrophobic cavity that has been shown to interact favorably with anions through CeH/anion interactions.
The hmCB[6] can be viewed as a CB[6] cut in half at the equator, where the carbonyls of the ethylene urea units are arranged in
alternating fashion. This alternating structure is probably the reason that hmCB[6] has no significant interaction with the cations
224 Hemicucurbit[n]urils

Figure 5 Hemicucurbit[6]uril single crystal X-ray structure with alternating orientation of the ethylene urea subunits (left : side view, right : top
view). A chloride is situated in the cavity of the macrocycle, bound by CeH anion interactions.1 Hydrogens atoms and solvent molecules have been
removed for clarity.

like Naþ, Kþ, NH4 þ , Rbþ, or Csþ, but instead interacts with SCN and I and some transition metal ions like Co2 þ, UO2 þ, and
Ni2 þ.10,11 This is very different from the CB[6] that binds cations, but not anions.7,8
HmCB[6] has a low solubility in water, but taking advantage of the binding of, for example, thiocyanate, the solubility can be
increased from 0.03 to 250 mg L 1 in water, by the addition of excess thiocyanate.1,10
Furthermore, Miyahara and coworkers showed that it was possible to synthesize the hemicucurbit[12]uril (hmCB[12]) by
changing the concentration of HCl from 4 to 1 M, using either the same starting materials as for the hmCB[6] or a polymer of
ethylene urea and formaldehyde. The fact that the hmCB[12] can be formed either from the polymer or from the two components
of the polymer shows that the reaction between ethylene urea and formaldehyde is reversible under the acidic reaction conditions
used.
The hmCB[12] has a similar alternating orientation of the ethylene urea carbonyls as seen in the crystal structure of hmCB[6]
(Figs. 5 and 6). The cavity of the hmCB[12] is larger than the cavity of hmCB[6] and the orientation of the ethylene urea carbonyls
is not as strictly alternating as in the hmCB[6]. HmCB[12] has not been reported to bind anions.
In 2012, hmCB[6] was shown to catalyze the esterification of several conjugated carboxylic acids, but not simple alkyl carboxylic
acids (Fig. 7).16 The authors found that hmCB[6] caused more effective catalysis of the smaller conjugated systems than larger ones,
and they speculate that the mechanism of the reaction is a solvolysis.
Furthermore, they showed that the hmCB[12] did not have any catalytic effect, perhaps due to the larger size of the cavity. In
a later paper by Yamato and coworkers, it was shown that hmCB[6] was able to catalyze the oxidation of furan, 2-methylfuran,
and thiophene in water, using only the naturally occurring oxygen in the reaction mixture (Fig. 8).17
They also tested the hmCB[12], CB[6], and CB[7], but no catalysis of the oxidation reaction was observed. It was found that the
hmCB[6] oxidation is faster when the pH is lowered from 6.3 to 2.0, and the authors speculate that the reaction mechanism starts
with a protonation of the hmCB[6], which enables the macrocycle to bind furan within the cavity, and thereby enable the oxidation
with O2. It appears unlikely that a complex would form within the cavity of the neutral macrocycle, as this has only been reported to
bind anions. In 2013, hmCB[6] was shown to direct the oxidation of different hydroxybenzyl alcohols in the presence of
2-iodoxybenzoic acid (IBX) to the corresponding aldehyde without over oxidation (Fig. 9).18

Figure 6 Side view of the single crystal X-ray structure of hmCB[12] showing the alternating orientation of the ethylene ureas.1 Solvent molecules
and hydrogen have been removed for clarity.

Figure 7 Esterification of conjugated carboxylic acids, catalyzed by hemicucurbit[6]uril under neutral conditions. The hmCB[12] does not catalyze
the esterification, due to its larger size.
 Hemicucurbit[n]urils 225

Figure 8 Oxidation by hmCB[6] in water.

Figure 9 Oxidation by IBX in the presence of hmCB[6] which enables selective oxidation to the aldehyde of benzylic alcohols.

It was further shown that both steric and inductive effects affect the rate of oxidation, as 2-hydroxybenzyl alcohol reacts slowly
and gives lower yields than that of 3- and 4-hydroxybenzyl alcohol.
By expanding the hmCB[6] ability to bind ions, Yamato and coworkers showed that hmCB[6] is able to bind the phenazine-HCl
salt in a 1:1 ratio in a mixture of CHCl3/MeOH.23 Further, they showed that the hmCB[12] produces a 2:1 complex with phenazine-
HCl salt due to its larger cavity and more flexible structure than hmCB[6].

3.09.4 Cyclohexylhemicucurbit[6]uril

In 2009, Wu and coworkers mixed the urea of (R,S)-cyclohexane urea and 1 equivalent of paraformaldehyde in 4 M HCl followed
by heating at 70 C for 4 h (Fig. 10).24 The meso-cyclohexylhemicucurbit[6]uril (meso-cychmCB[6]) was isolated by column chro-
matography in 78% yield.
From the single crystal X-ray structure it was found that the meso-cychmCB[6] had the alternating orientation of carbonyl groups
(Fig. 11) just as hmCB[6] has, and that it could include CHCl3 or CCl4 in the cavity. If on the other hand the crystals were grown
from CH2Cl2, instead of CHCl3 or CCl4, the CH2Cl2 was located outside the cavity. Hydrogen bonding from methylene chloride to
the urea carbonyl groups dominated the crystal packing of this structure.

Figure 10 Synthesis of meso-cyclohexylhemicucurbit[6]uril.

Figure 11 Single crystal X-ray structure of the meso-cyclohexylhemicucurbit[6]uril with alternating orientation of the dialkyl N,N-ethylene ureas
(left : side view, right : top view).24 Hydrogens and solvent molecules have been omitted for clarity.
226 Hemicucurbit[n]urils

The first enantiomerically pure members of the hemicucurbit[n]uril family were described in 2013, when Aav and coworkers
produced the (all-S)-cyclohexylhemicucurbit[6]uril (all-S-cychmCB[6]) and (all-R)-cyclohexylhemicucurbit[6]uril (all-R-cychmCB
[6]) using the previously reported synthetic procedure, employing either 4 M HCl or 4 M HBr, from which yields of 85% and
64% were obtained, respectively.6 The products were isolated by filtration of the precipitate, and the product was the HCl or the
HBr complex depending on the acid used in the synthesis.
Again these structures had the alternating orientation of the cyclohexylurea monomeric units, and the macrocycles were shown
to bind halide anions and carboxylates in CHCl3 (Fig. 12). Unlike the meso-cychmCB[6] and the hmCB[6], which each have 12
methine groups where the hydrogen is pointing toward the cavity, (all-S)- and (all-R)-cychmCB[6] only has 6 of these hydrogens
pointing toward the cavity due to the identical configuration of the two methine groups in the monomeric unit.
The (all-S)- or (all-R)-cychmCB[6] bound planar conjugated carboxylic acids tighter than carboxylic acids that were branched at
the a position, probably due to steric congestion in the inclusion complex. Calculations, in gas phase, on the (all-S)-cychmCB[6]uril
showed that the anions preferred to be located inside the cavity of cyclohexylhemicucurbit[6]uril and that the binding affinity of the
anions in gas phase is Cl> Br> HCOO> I.25 This trend was also confirmed by ion-mobility mass spectrometry. In 2014, the
existence of even larger macrocycles of cyclohexylhemicucurbit[n]uril (n ¼ 7–10) were shown to exist by analyzing the reaction
mixture of (all-R)-cychmCB[6] by HPLC-MS.26 The authors were able to isolate the (all-R)-cyclohexylhemicucurbit[8]uril (all-R-
cychmCB[8]) in 11% yield by preparative HPLC. The all-R-cychmCB[8] was detected in negative-mode MS with either a chloride
or a formate anion, showing its ability to bind anions in the gas phase.
In 2015, Aav and coworkers further optimized the synthesis of the (all-R)-cychmCB[8] by employing different anions such as
HCO2  , CF3 CO2  , PF6  as the templates, and thereby increased the yield from 11% to 55–90% depending on the anion, and
conditions used (Fig. 13).27 The authors were able to synthesize the (all-R)-cychmCB[8] starting from either the (R,R)-cyclohexane
urea and paraformaldehyde or from the (all-R)-cychmCB[6], which again shows the reversibility of the aminal exchange reaction in
acidic conditions.
From the crystal structure in Fig. 14, it is again evident that the macrocycle had an alternating orientation of the monomeric
units, and that the cavity of the (all-R)-cychmCB[8] has a hydrophobic cavity. By diffusion (DOSY) NMR they showed that the mac-
rocycle was able to bind anions, such as HCO2  , CF3 CO2  , and CH3 CO2  in CDCl3 with similar affinities as the (all-R)-cyclohex-
ylhemicucurbit[6]uril.
Sindelar and Fiala synthesized the norbornahemi[6]cucurbiturils, which can be viewed as a cyclohexylhemicucurbit[6]uril with
a methylene bridge added to the cyclohexyl ring (Fig. 15).28 By MS they also detected the norbornahemicucurbit[4, 5, 7, and 8]urils.
The norbornahemicucurbit[6]uril macrocycle was prepared from 4 M HCl at 70 C in 9% yield. They furthermore tried to change
the reaction solvent to chloroform, but even with the addition of a template like iodide, they did not observe the desired macrocyclic
product. Unlike many of the hexameric macrocycles with alternating orientation of the ethylene urea groups, no anion binding has
been reported for the norbornahemicucurbit[6]uril.

Figure 12 Single crystal X-ray structure of the (all-S)-cyclohexylhemicucurbit[6]uril (left : side view, right : top view).6 Solvent molecules have been
omitted, and only methine hydrogens are shown for clarity.

Figure 13 Synthetic pathways for the (all-R)-cyclohexylhemicucurbit[8]uril starting from the (R,R)-cyclohexane urea or (all-R)-cyclo-
hexylhemicucurbit[6]uril.
 Hemicucurbit[n]urils 227

Figure 14 Single crystal X-ray structure of the (all-S)-cyclohexylhemicucurbit[8]uril (left : side view, right : top view).27 Solvent molecules and hydrogens
have been omitted for clarity.

Figure 15 Norbornahemicucurbit[6]uril synthesis.

3.09.5 Bambus[6]uril

A new family of macrocycles was described in 2010 by Sindelar and coworkers, when they presented their bambus[6]uril (bam[6]),
consisting of six glycouril monomers, which was capped with methyl groups at both nitrogen atoms on one of the urea groups, and
connected through methylene bridges at the other urea (Fig. 16).4
They reacted 2,4-dimethyl-glycouril with formaldehyde in 5.4 M HCl, which produced the hexameric macrocycle containing one
HCl molecule in 30% yield. The removal of HCl turned out to be tricky, but replacing the Cl with I, followed by oxidation of the
I to I3  caused the bam[6] to precipitate without guest.29 Removing the iodide from the bam[6] forces the macrocycle to precip-
itate anion-free, as the solubility of anion-free bam[6] is very low in common organic solvents. From single crystal X-ray analysis, it
was shown that the bam[6] had the alternating orientation of the dialkyl-N,N0 -ethylene urea groups, and it was shown that the mac-
rocycle could bind BF4  , I, Br, and Cl (Fig. 17).
Titration experiments showed that bam[6] binds halide anions in organic solvent mixtures (MeOD/CDCl3, 2:1) and in aqueous
media (D2O/CD3CN, 1:1), with the preference I> Br> Cl> F.4,29
In 2011, the family of bambus[n]uril was extended for three analogs, of which two methyl groups of bam[6] were changed to
benzyl or propyl groups, and for the third analog the macrocyclic ring only consisted of four glycouril monomers, the octabenzyl-
bambus[4]uril (Fig. 18).30
The propyl-bambus[6]uril (pro-bam[6]) showed similar binding affinities toward anions as the bam[6], whereas ben-bam[6]
showed stronger binding for the halide anions than bam[6] together with better solubility in organic solvents. The ben-bam[4]
did not show any binding to anions probably due the smaller cavity of the macrocycle. The ben-bam[6] crystallize with benzoates

Figure 16 General bambus[6]uril synthesis.

228 Hemicucurbit[n]urils

Figure 17 Single crystal X-ray structure of bambus[6]uril containing iodide (left : side view, right : top view).29 Hydrogens and solvent molecules
have been omitted for clarity.

Figure 18 Structures of (left to right) propyl-bambus[6]uril, benzyl-bambus[6]uril, and benzyl-bambus[4]uril.

(or tosylates) in a 1:2 fashion, whereas in chloroform solution both 1:1 and 1:2 complexes were detected (Fig. 19).31 The distribu-
tion between the 1:1 and 1:2 complexes in chloroform solution was affected by the amount of water. Increasing the amount of water
shifted the complex distribution toward the 1:2 complex (Fig. 19).
This observation fitted well with the single crystal X-ray structures as the two tosylates or benzoates are seen binding with
a hydrogen of one water molecule which is situated in the center of the cavity of bambus[6]uril.
In 2012, Heck and coworkers produced five new members of the bambus[n]uril family, the octa-allyl-bambus[4]uril, dodeca-
allyl-bambus[6]uril, octa-propen-bambus[4]uril, octa-propyl-bambus[4]uril, and a hepta-allyl-heptene-bambus[4]uril (selected
marcocycles are shown in Fig. 20). 32
Heck used Grubbs II catalyst on the octa-allyl-bambus[4]uril and 1-heptene to synthesize the hepta-allyl-heptene-bambus[4]uril
in 20% yield by metathesis (Fig. 21). Surprisingly, this reaction resulted in reaction of only one of the allyl groups to the heptane-yl
group, and in this way the first unsymmetrical dialkyl-N,N0 -ethyleneurea uril macrocycle was produced.
Heck also tried a ring closing metathesis of the octa-allyl-bambus[4]uril, using Hoveyda–Grubbs catalysts, but instead of the
desired ring closed product, they obtained the isomeric product the octa-propenyl-bambus[4]uril in quantitative yields. Further,
Heck and coworkers showed that the original bambus[6]uril synthesis by Sindelar could be improved from 65% to 90% yield
by employing microwave conditions instead of conventional heating.
Until 2015, no thio analogs of bam[n], hmCB[n], cychmCB[n], or even CB[n] had been prepared, even though calculations
proposed that thio-CB[6] should be a stable molecule.33 This was due to the fact that the thio-glycouril decomposes in acidic media,
which so far has been the reaction medium of choice to produce these hexameric structures.34 By methylation, and thereby protec-
tion of the nitrogens in the thio-urea part of the monothioglycoluril yielded a mono-thio-glycouril analog, which has an increased

Figure 19 The distribution of 1:1 and 1:2 complexes between benzoate and dodecabenzyl-bambus[6]uril (gray cylinder) which is shifted by addition
or removal of water.
 Hemicucurbit[n]urils 229

Figure 20 Schematic representation of selected bambus[6]uril analogs by Heck and coworkers (left to right) of the allyl-bambus[6]uril, propyl-
bambus[4]uril, and propen-bambus[6]uril.

Figure 21 Hecks synthesis of a unsymmetric hepta-allyl-heptene-bambus[4]uril.

stability in acidic media. Using this protected mono-thio-glycouril, Reany and coworkers were able to produce the first thio-analog
of bambus[4, 6]uril called semithiobambusurils (thio-bam[4, 6]), by employing Hecks reaction conditions (Fig. 22). 35
The thio-bam[6] was also rather insoluble in organic solvents but addition of suitable anions increased the solubility in DMSO.
The thio-bam[6] binds anions like the halides in the order Br> I> Cl in DMSO, which is a bit different from bam[6]. The thio-
bam[4] is able to bind soft thiophilic cations such as Hg2 þ and Pd2 þ as shown by 1H-NMR spectroscopy and by single crystal X-ray
structures (Fig. 23). Like for allyl-bambus[4]uril the cavity is too small to include anions (Fig. 24). The HgCl2 is bound by the thio-
bam[4] in linear chains of coordination polymers, where the sulfur is coordinating to the thiophilic Hg2 þ cation.
By comparing the structures in Figs. 23 and 24, it is observed that the cavity size and shape of the thio-bam[4] does not change
significantly, and that the cavity size prevents incorporations of even small anions such as Cl. The difference in the two crystal
structures is that the HgCl2 produces polymers with semithiobambus[4]uril, whereas no coordination polymers were seen when
HgCl2 is not present.

Figure 22 Synthetic pathway of the semithiobambus[4, 6]urils.

Figure 23 Part of the single crystal X-ray structure of the semithiobambus[4]uril HgCl2 complex (left: side view, right: top view).35 Hydrogens and
solvent molecules have been removed for clarity.
230 Hemicucurbit[n]urils

Figure 24 Single crystal X-ray structure of the semithiobambus[4]uril (left : side view, right : top view).35 Hydrogens and solvent molecules have
been removed for clarity.

Figure 25 Water soluble bambus[6]uril.

In 2014, Sindelar and coworkers expanded the bambus[n]uril family with the first water soluble analog.12 The benzyl groups on
benzyl-bambus[6]uril were changed to 4-carboxybenzyl to enable solubility in water (Fig. 25).
The binding interactions of the macrocycle spanned from 1.1  102 M 1 for F to impressive 1.0  107 M 1 for I in water at pH
7.1. These high binding affinities were obtained solely through CeH/anion interactions. Again the preference for anion binding
was I> Br> Cl> F, and as for the other bam[6]0 s no cation binding was detected, and a change in pH did not change the
binding interaction noticeably. The water soluble bambus[6]uril was later, in 2015, used to differentiate anions in water, by exploit-
ing that the water soluble bambus[6]uril makes 1:1 complexes with slow exchange on the NMR chemical shift time scale.36 Different
anions produce different bambus[6]uril I anion peaks in the 1H-NMR spectrum, and using these features it was possible to identify
nine different anions in the same sample of DMSO-D2O. Further, they were able to measure the concentration of the five different
anions simultaneously in the same NMR sample within a 5% error.
Later, in 2015, the ben-bam[6] was seen to bind anions in chloroform with Ka values of 2.8  1010 M 1 for iodide.37 Sindelar
and Havel further found that the binding was enthalpy driven and typically an unfavorable entropy was observed. Also they found
that in chloroform the ben-bam[6] makes 1:1 complexes with slow exchange, which again was used to identify different anions and
their concentration within a 10% margin of error.

3.09.6 Biotin[6]uril

In 2014, the first water soluble macrocycle of the N,N0 -ethylene urea family of receptors was presented by our group.5 Starting from
D-biotin, also known as vitamin B7, a natural compound from the natural chiral pool of vitamins, we were able to synthesize biotin
[6]uril (bio[6]).
The bio[6] was synthesized from a mixture of D-biotin and paraformaldehyde in 3.5 M H2SO4 with NaBr as a template, and was
isolated as a single isomer in 63% yield (Fig. 26). The bio[6] consists of six D-biotin monomers situated in an alternating orientation
of the carbonyl groups, which are connected through methylene bridges at the urea nitrogens. The alternating orientation produces
a hydrophobic cavity that has 12 CeH moieties pointing toward the cavity. The cavity of biotin[6]uril has been observed to include
molecules such as ethanol, water, and anions like iodide in the single crystal X-ray structures (Fig. 27).5,13
 Hemicucurbit[n]urils 231

Figure 26 Synthetic pathway of the biotin[6]uril.

Figure 27 Single crystal X-ray structure of the biotin[6]uril binding iodide.5 Hydrogens, cation, and solvent molecules are omitted for clarity.

The 6 þ 6 macrocycle has 18 chiral centers, 3 on each D-biotin monomer. Furthermore, the nonequivalence of the nitrogens in
the D-biotin monomers gives the possibility of nine different regioisomers for the biotin[6]uril. Considering all the possible combi-
nations of stereo- and regioisomers for the 6 þ 6 macrocycle makes it very intriguing that only one isomer is isolated.
We found that the synthesis of bio[6] could be carried out in both 7 M HCl or 3.5 M H2SO4 and that it was templated by halide
anions (Fig. 28). The isolated product contained the templated anion, for example, Cl or Br, and the chloride could be removed

Figure 28 Extracted HPLC ion chromatograms of both cyclic and linear oligomers employing different reaction conditions. (A) 7 M HCl, (B) 3.5 M
H2SO4, (C) 3.5 M H2SO4 þ 7 M NaCl, (D) 3.5 M H2SO4 þ 7 M NaBr, and (E) the isolated biotin[6]uril. All none marked peaks are smaller, linear, or
cyclic products.
232 Hemicucurbit[n]urils

using TlNO3 in alkaline solution followed by filtration and precipitation with acid. Later it was shown that the removal of Cl could
be obtained through a simple acid–base recrystallization.14
Bio[6] binds monovalent anions in water (pH 7.5) with the preference for softer anions over harder, which can be seen from the
preference SCN> I> Br> Cl.13 The stoichiometry of all the monovalent anions showed a 1:1 interaction as seen by studying the
complexation using Job’s method and by electrospray ionization mass spectrometry analysis. As many of the previously mentioned
macrocycles, the bio[6] shows no interaction with cations such as Naþ, Kþ, Csþ, and changing the pH, from pH ¼ 7.5 to pH ¼ 10.8
did not influence the binding isotherms. General for all the anion-binding interactions in water analyzed by isothermal calorimetry
titration (ITC) is that the enthalpic contribution is favorable and large, whereas the entropic contribution is small and unfavorable.
Like the bambus[6]uril macrocycles, the biotin[6]uril binds anions through CeH/anion interactions from the 12 hydrogens
pointing toward the cavity. The crystal structure of bio[6] containing either EtOH, water, or iodide showed that the radius of the
binding cavity is relatively constant as seen by solving the single crystal X-ray structure of a series of macrocycles-guest complexes
(Fig. 29). The height of the cavity of the macrocycle can change by a small rotation the biotin monomers, which influences the total
volume of the cavity. This small rotation will also change the orientation of the CeH interacting groups in the cavity, which thereby
is able to change the binding site in order to get the optimal fit of a potential guest.
In order to rationalize the reaction pathway of the macrocyclization, we followed the reaction by the LC–MS analysis, and found
that in the beginning of the reaction, mainly D-biotin and a linear dimer biotin[2]uril were observed (Fig. 30). After 2–4 h the
biotin[6]uril started to appear, and after approximately 24 h became the major product, by a decrease in the amount of both
the biotin monomer and the biotin[2]uril.

Figure 29 Overlay of the urea-part of the three crystal structures of biotin[6]uril showing that the diameter of the binding cavity only changes
marginally with the three different guest molecules (iodide, EtOH, and water).5,13

Figure 30 Evolution of the reaction between D-biotin and formaldehyde showing that biotin and the linear biotin[2]uril are consumed during the
reaction. The reaction was followed by LC–MS at 209 nm.
 Hemicucurbit[n]urils 233

Figure 31 Schematic representation of biotin[6]uril showing three identical parts of the macrocycle which resembles the linear biotin[2]uril (red,
blue, and green). The methylene bridges connecting the biotin[2]uril units are marked in black.

We were also able to isolate the linear biotin[2]uril from a mixture of D-biotin, a catalytic amount of H2SO4, and paraformal-
dehyde (Fig. 31). The two biotin moieties in biotin[2]uril were connected at the two nitrogens furthest away from the alkyl chain of
the D-biotin monomer. Due to the C3-symmetry of bio[6] it is possible to divide the macrocycle into three identical parts, where
each contains exactly the linear biotin[2]uril connected by methylene bridges (Fig. 32).
These facts lead us to believe that the biotin[2]uril would be able to trimerize to the hexameric macrocycle biotin[6]uril, as this
reaction pathway would also rationalize the high regioselectivity of the reaction. To test this hypothesis, the dimer was treated with
7 M HCl and paraformaldehyde. The result turned out to be the biotin[6]uril in similar yields as the synthesis starting from the
biotin monomer. This indicates that the reaction is thermodynamically driven, and that the biotin[6]uril is the most stable product
under the reaction conditions used.
In 2015, the bio[6] was made soluble in organic solvents by changing the carboxylic acids to the esters, methyl (bio[6]me), ethyl
(bio[6]et), and butyl (bio[6]bu), respectively, by employing Fishers ester synthesis strategy directly on the biotin[6]uril (Fig. 33).14
By 1H-NMR titrations and ITC experiments the binding interactions of the hexaesters to anions such as Cl, NO3  , HCO3  , and

SO4 2 were studied in acetonitrile. The biotin[6]uril hexaesters had comparable binding affinities whether the studies were done
using bio[6]me, bio[6]et, or bio[6]bu for both chloride and nitrate. The binding interaction for chloride was also measured by ITC
and it was found that both the enthalpy and entropy were favorable, which is different for bio[6] in water where the entropy was
unfavorable.
Chloride was bound two orders of magnitude stronger than NO3  and HCO3  , whereas no binding was seen for the SO4 2
anion. The selectivity for chloride over nitrate and bicarbonate is probably a consequence of hydrophilicity of the anions, as chlo-
ride is more hydrophilic than nitrate and bicarbonate.38 Both nitrate and bicarbonate have almost the same Ka, and this peaked our

Figure 32 Synthetic pathway of the biotin[6]uril, starting from either D-biotin or biotin[2]uril.
234 Hemicucurbit[n]urils

Figure 33 Synthetic strategy for the biotin[6]uril hexaesters.

hopes that the low affinities in none competitive medium would diminish the chances of extracting hydrophilic HCO3  from the
water phase. HCO3  is far more basic, and therefore the better acceptor for conventional hydrogen bonds (HNO3 pKa ¼  1.3;
H2CO3 pKa ¼ 3.6 and 10.3), so that NO3  and HCO3  having similar Ka values shows the difference between standard hydrogen
bonding and CeH/anion interactions.39
The anion transport capabilities of the biotin[6]uril hexaesters were tested using unilamellar vesicles consisting of POPC, choles-
terol (70/30), and bio[6] hexaester employing the “Lucigenin assay,” where the chloride influx and nitrate efflux are monitored by
a decrease in the emission from lucigenin due to the quenching by the increasing concentration of chloride within the vesicle cavity
(Fig. 34).40
When adding an external pulse of chloride, a decay in the emission at 535 nm was observed showing that the bio[6]esters were
indeed transporting chloride into the vesicles employing CeH/anion interactions. All three esters (bio[6]me, bio[6]et, and bio[6]
bu) showed transport, and increasing the lipophilicity by increasing the ester chain length showed enhanced transport rates with the
butyl ester being the fastest (Fig. 35). Leaching experiments showed that the transporters were solely located in the vesicle
membrane, and therefore the increased transport rate cannot be caused by a different distribution between the membrane and
the aqueous phases. The transport rate of the bio[6]esters is of modest rates, but compares well with other conventional systems
which employs NeH/X or OeH/X interactions for transport.41,42

Figure 34 Schematic representation of the Lucigenin assay employed in the study of anion transport by biotin[6]uril hexaesters. Transport of Cl
into the vesicles and NO3  out of the vesicles is monitored by the quenching of the lucigenin fluorescence caused by chloride inside the vesicle. In
the lower part of the vesicle membrane is illustrating the carrier mechanism employed by the biotin[6]uril hexaesters.
 Hemicucurbit[n]urils 235

Figure 35 Chloride/nitrate exchange by biotin[6]uril hexaesters (methyl, ethyl, and butyl) at a transporter-to-lipid ratio of 1:1000.

Changing from NO3  to SO4 2 in the lucigenin assay caused the transport to halt, which indicates that the biotin[6]uril hex-
aesters cannot transport intervesicular SO4 2 out of the vesicles when Cl is transported in, whereas NO3  is able to be transported
out of the vesicles in order to maintain electroneutrality. The change from nitrate to sulfate also shows that the biotin[6]uril hex-
aesters cannot transport Naþ. Changing the counter anion transported in the lucigenin assay to HCO3  resulted in an almost iden-
tical transport rate as seen in the sulfate experiment. Thus, the experiment shows high selectivity for chloride transport over
bicarbonate and sulfate transport.
The transport of anions using biotin[6]uril hexaesters was shown to occur via a carrier mechanism, by studying the system
employing the lucigenin assay with different amounts of cholesterol in the vesicle membrane. By changing the amount of choles-
terol the fluidity of the membrane should be changed, which in turn should affect carriers, whereas channels should be unaf-
fected.43 As expected for carriers, the transport rate was hampered when the cholesterol levels were increased. The transport
mechanism was further tested, still using the lucigenin assay, but by employing vesicles composed of DPPC which is a gel phase
at room temperature and a liquid crystalline phase above 41 C.44 A carrier would be expected to not show any transport at room
temperature but show transport at temperatures above 41 C, whereas channels should be unaffected by the temperature change.
Again the carrier mechanism of transport for the biotin[6]uril hexaesters was confirmed as transport was observed at 45 C and
not at 25 C.
The selectivity of biotin[6]uril hexaesters in both anion transport and anion binding could be a result of the “soft”
nature of the CeH hydrogen bond relative to other hydrogen bond donors, which favors softer anions over hard anions
(Cl over, eg, HCO3  ). Even though anion transporters have employed CeH/anion interactions in combination with
NeH hydrogen bonding before,45,46 the biotin[6]uril hexaesters are the first anion transporters that solely rely on
CeH/ anion interactions that enable selectivity. Furthermore, the CeH groups are not hydrophilic and therefore less
prone to promote aggregation.

3.09.7 Outlook

The intriguing world of macrocycles is growing at a rapid pace, and the hexameric macrocycles that bind anions have been growing
since the hemicucurbit[n]urils were first synthesized in 2004. Many of the macrocycles have the alternating orientation of the
monomers that enable them to bind anions instead of cations like the cucurbit[n]uril. The anions are bound by CeH/anion
interactions, which have been shown to be effective in binding anions in both organic and aqueous solutions. A factor that might
influence the strong binding affinities observed for the biotin[6]urils to the anions has recently been speculated to be the chaot-
ropic and the nonclassical hydrophobic effect.13,15,47 All the members in the hemicucurbit[6]uril feature neutral hydrophobic
binding pockets, and some members of the family have solubility in both water and organic solvents, which increase their appli-
cability in bioorganic applications. Furthermore, all of the hemicucurbit[6]uril family members are synthesized by templated
reactions typically with a halide as the template. The fact that the (all-R)-cychmCB[8] becomes the major product over the (all-
R)-cychmCB[6] by changing the template suggests that many new macrocycles of different sizes can be produced in the future
by changing the template, and thereby employing a dynamic combinatorial chemistry approach.48,49 A drawback of the hemicu-
curbit[6]uril family of macrocycles is the limit of direct functionalization; one exception is the transformation of biotin[6]uril to
the corresponding esters. In particular, for the biotin[6]uril systems the possibilities for direct functionalization appear very
attractive.
The possibility of chiral selectivity in molecular recognition could also be feasible, and initial efforts in this direction has been
made by the synthesis of the chiral cyclohexylhemicucurbit[n]urils and biotin[6]urils.
The hemicucurbit[6]uril family will probably grow both in numbers and in ring sizes in the future due to their interesting anion-
binding motifs. We predict that the use of these macrocyclic hosts will find applications in new areas such as biology, biochemistry,
and other areas of science.
236 Hemicucurbit[n]urils

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 3.10 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular
Chemistry
T Ogoshi, Kanazawa University, Kanazawa, Ishikawa, Japan; and Japan Science and Technology Agency, Kawaguchi, Saitama, Japan
T Kakuta and T Yamagishi, Kanazawa University, Kanazawa, Ishikawa, Japan
Ó 2017 Elsevier Ltd. All rights reserved.

3.10.1 Introduction 237

3.10.2 Synthesis and Structures of Pillar[n]arenes 238
3.10.3 Supramolecular Assemblies Based on Molecular Recognition of Simple Pillar[n]arenes 241
3.10.3.1 Molecular Recognition of Simple Pillar[5]arenes 242
3.10.3.2 Molecular Recognition of Simple Pillar[6]arenes 245
3.10.4 Supramolecular Assemblies Based on Functionalized Pillar[n]arenes 246
3.10.4.1 Monofunctionalized Pillar[n]arenes 246
3.10.4.2 Difunctionalized Pillar[n]arenes 252
3.10.4.3 Pentafunctionalized Pillar[n]arenes 255
3.10.4.4 Perfunctionalized Pillar[n]arenes 257
3.10.4.1 Perhydroxylated Pillar[n]arenes 257
3.10.4.2 Perfunctionalized Pillar[n]arenes by Etherification 259
3.10.4.3 Perfunctionalized Pillar[n]arenes by the CuAAC Reaction 261
3.10.5 Concluding Remarks 262
References 263

3.10.1 Introduction

Macrocyclic compounds have been key players in the field of supramolecular chemistry because they can capture various guest
molecules through physical interactions. The classical and most widely used macrocyclic host molecules are cyclodextrins (CDs),
whose structures were first reported by Schardinger in 1903.1–3 Crown ethers, which were reported by Pedersen in 1967, are the
first synthetic macrocyclic compounds.4 Calix[n]arenes, which consist of phenolic macrocyclic compounds, were popularized by
Gutsche et al. in 1978.5–7 Among cucurbit[n]urils, which are highly symmetrical pumpkin-shaped hexamers, cucurbit[6]uril was
first characterized by Mock et al. in 1981.8 Unfortunately, the low solubility of cucurbit[6]uril in solvents made the development
of cucurbit[n]uril chemistry slow until 2000. The synthesis of cucurbit[n]uril homologs (n ¼ 5–11), which were reported by Kim
et al. in 2000, was a big breakthrough because cucurbit[n]uril homologs, smaller or larger than cucurbit[6]uril, showed good solu-
bility in aqueous media.9–12
Against this historical backdrop, in 2008, we reported a new class of pillar-shaped macrocyclic host compounds, known as
“pillar[n]arenes.”13 Pillar[n]arenes combine several features of these macrocyclic compounds (Fig. 1).14–16 (i) Pillar[n]arenes
have highly symmetrical pillar-shaped structures that are similar to the highly symmetrical macrocyclic compounds cucurbit[n]urils.
The highly symmetrical pillar-shaped structures of pillar[n]arenes contribute to a highly electron-rich cavity. The electron-rich cavity

Figure 1 Structures and noteworthy points of pillar[n]arenes and typical host molecules.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12516-8 237

238 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

of pillar[n]arenes leads to the strong capture of not only electron-poor guest molecules but also neutral guest molecules in the cavity.
(ii) The constituent units of pillar[n]arenes are composed of phenolic units, and the constituent phenolic units are connected by
methylene bridges. Therefore, the chemical structures of pillar[n]arenes are similar to calix[n]arenes. (iii) The constituent units of
pillar[n]arenes are 1,4-dialkoxybenzene derivatives; thus, pillar[n]arenes have 2n substituents. For example, pillar[5]arenes and
pillar[6]arenes have 10 and 12 alkoxy substituents at both rims, respectively. The presence of the functional groups at both rims
is the same as for CDs. Among these three characteristics, the presence of the alkoxy groups at both rims of pillar[n]arenes is the
most important because deprotection of these alkoxy substituents results in the synthesis of reactive pillar[n]arenes with OH moie-
ties at both rims. Because of the good solubility of pillar[n]arenes containing OH moieties in various kinds of organic solvents,
various organic synthetic approaches can be applied for the functionalization of the reactive OH moieties. This point is a very
important advantage compared with the functionalization of native CDs, which is limited because of the low solubility of native
CDs in organic solvents. Introducing other reactive groups such as bromo, alkyne, and azido groups on both rims of pillar[n]arenes
can also be accomplished by various organic synthetic approaches. These pillar[n]arenes with reactive functional groups are impor-
tant key compounds for obtaining functionalized pillar[n]arenes. Furthermore, these reactive groups can be installed in targeted
numbers and positions of the pillar[n]arenes. The kind, number, and position of the substituents on the rims of pillar[n]arenes
largely effect various physical properties such as host ability, solubility, and self-assembly. Therefore, the versatile functionality
of pillar[n]arenes is definitely the most important feature among the various features of pillar[n]arenes.
In this article, we first describe the macrocyclization of 1,4-dimethoxybenzene to form pillar[n]arenes. So far, pillar[n]arene
homologs (n ¼ 5–14) have already been synthesized,17,18 but the cyclic pentamers, that is, pillar[5]arenes, and cyclic hexamers,
that is, pillar[6]arenes, have been the most widely used because they can be obtained in good yields. We discuss the driving force
for the high-yield synthesis of pillar[5]- and pillar[6]arenes. The synthesis of higher pillar[n]arene homologs (n  7) is also
described. Second, we provided a brief description of cavity-size-dependent host–guest properties of simple pillar[n]arenes. We
also show the synthesis of mechanically interlocked molecules (MIMs) using simple pillar[n]arenes as wheels based on the host
ability of simple pillar[n]arenes. Third, we examine the progress that has been made in the selective mono-, di-, penta-, and perfunc-
tionalization of pillar[n]arenes by various organic synthetic approaches. Various functionalized pillar[n]arene-based supramolec-
ular assemblies such as supramolecular dimers, polymers, sensors, photo- and thermoresponsive supramolecular assemblies, gas
and organic vapor adsorption materials, MIMs with unique topological and photophysical properties, and hybrid materials using
functionalized pillar[n]arenes are described.

3.10.2 Synthesis and Structures of Pillar[n]arenes

Historically, there have been many cases in which the synthesis of new macrocyclic compounds has occurred as a product of chance.
For example, the first synthetic macrocyclic compounds, crown ethers, were prepared as minor products by chance. Cucurbit[n]uril
homologs that are smaller or larger than cucurbit[6]uril were also prepared when attempting to control the reaction temperature. A
cyclic pentamer, the first pillar[5]arene, was prepared by chance when we were synthesizing new phenolic polymers by polymeri-
zation of featureless 1,4-dimethoxybenzene with paraformaldehyde in the presence of various kinds of Lewis acids (Scheme 1).13
When sulfuric acid, aluminum(III) chloride, iron(III) chloride (Fig. 2A), titanium chloride, and tin(IV) chloride (Fig. 2B) were used
as Lewis acids, the obtained products were a mixture of polymers and particular oligomers.
Conversely, when BF3,OEt2 was used as a Lewis acid, the major product was a particular oligomer (Fig. 2C). The structure of the
particular oligomer was completely characterized by single X-ray crystal structure analysis (Fig. 3).
The crystalline structure of the oligomer revealed a cyclic pentamer composed of five 1,4-dimethoxybenzene units (Fig. 3B). The
1,4-dimethoxybenzene units were connected by methylene bridges. Therefore, the structure of the macrocyclic pentamer was very
close to the well-known macrocyclic compounds, calix[n]arenes (Fig. 3A). However, the important difference between them is the
position of the methylene bridges. In calix[n]arenes, the phenolic units of the oligomer were bridged by methylene bridges at the
meta position. In contrast, the phenolic units in the macrocyclic pentamer were connected by methylene bridges at the para posi-
tion. The difference is reflected in the shape of the macrocyclic compounds. In calix[n]arenes, an open-ended calix-shaped structure
is formed as a result of the bridges at the meta position. Conversely, the cyclic pentamer forms a pillar-shaped structure from the side
view as a result of the bridge at the para position. From the top view, the cyclic pentamer forms a highly symmetrical pentagonal
structure. We named the highly symmetrical cyclic pentamer as “pillar[5]arene” (1[5]) because of their pillar-shaped structure.

Scheme 1 Reaction of 1,4-dimethoxybenzene and paraformaldehyde in the presence of Lewis acid.

 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 239

Figure 2 Size-exclusion chromatography (SEC) traces of the obtained products using (A) FeCl3, (B) SnCl4, and (C) BF3,OEt2 as a Lewis acid.
Reproduced with permission from Ogoshi, T.; Kanai, S.; Fujinami, S.; Yamagishi, T.; Nakamoto, Y. J. Am. Chem. Soc. 2008, 130(15), 5022–5023.
Copyright 2008 American Chemical Society.

Figure 3 X-ray crystal and chemical structures of (A) calix[5]arene and (B) pillar[5]arene.

The yield of pillar[5]arene 1[5] in our first report was 22%. We later optimized the synthesis to provide 1[5] in high yield
(71%).19 The feed ratio between 1,4-dimethoxybenzene and paraformaldehyde was the key to achieving a high-yield synthesis
of 1[5]. However, it remained unclear at this stage why the formation of a cyclic pentamer, pillar[5]arene, occurred in such
a high yield. Generally, selective synthesis of a particular macrocyclic compounds is difficult by kinetically controlled macrocycli-
zation process. The use of template compounds (thermodynamically controlled macrocyclization process) is necessary for the selec-
tive high-yield synthesis of particular macrocyclic compounds. Thus, we monitored the macrocyclization by size-exclusion
chromatography to clarify if the reaction takes place under kinetic or thermodynamic control (Fig. 4).19
At the beginning of the reaction (10–20 s), many peaks were observed at a retention volume of 20–23 mL, indicating the forma-
tion of linear oligomers. After 30 s, a clear peak at 22 mL appeared and increased in intensity with a concurrent decrease in intensity
of the other peaks from the linear oligomers. The clear peak at 22 mL was assigned as pillar[5]arene 1[5], indicating the conversion
of the linear oligomer to cyclic pentamer 1[5]. After 150 s, we only observed the clear peak at 22 mL. The monitoring strongly
suggests that the reaction proceeded under thermodynamic control and the thermally stable product in the reaction was the cyclic
pentamer pillar[5]arene. However, the remaining question was to determine what was acting as the template for the macrocycliza-
tion. Szumna et al. answered this question. They investigated the effect of different acids and solvents on the macrocyclization.20
They first replaced BF3, OEt2 with other acids. Pillar[5]arene 1[5] was obtained in high yield (up to 81% under the optimized condi-
tions) using trifluoroacetic acid, whereas 1[5] was not obtained using acetic acid and aqueous HCl and was obtained in low yield
(38%) using paratoluenesulfonic acid. These results indicate that the Lewis acids did not act as the template for the formation of
pillar[5]arene 1[5]. In contrast, the type of solvent had a big effect on the yields. When 1,2-dichloroethane was used as a solvent,
pillar[5]arene was produced as the major product (81%). In contrast, the yields were lower if other chlorinated solvents such as
dichloromethane (26%), chloroform (15%), or 1,1,2,2-tetrachloroethane (7%) were used as the solvents. The cavity size of
pillar[5]arenes ( 4.7 Å) fits linear alkyl chains, but not branched alkyl chains. Therefore, linear-shaped solvents such as 1,2-
dichloroethane act as templates for the synthesis of the cyclic pentamer 1[5], whereas bulky solvents, such as chloroform and
1,1,2,2-tetrachloroethane, do not act as a template for the synthesis of particular pillar[n]arene homologs. This explanation is
240 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 4 SEC traces of the obtained products after quenching of the reaction by addition of methanol. The feed ratio (1,4-dimethoxybenzene/para-
formaldehyde) is 1:1. Reproduced with permission from Ogoshi, T.; Aoki, T.; Kitajima, K.; Fujinami, S.; Yamagishi, T.; Nakamoto, Y. J. Org. Chem.
2011, 76(1), 328–331. Copyright 2011 American Chemical Society.

consistent with the macrocyclization in chloroform. Hou et al. reported the synthesis of higher pillar[n]arene homologs (n ¼ 6–10)
using chloroform as a solvent (Scheme 2).18
Chloroform does not act as a template solvent for the formation of pillar[n]arenes. Consequently, macrocyclization in chloro-
form proceeds under kinetic control. They obtained a mixture of pillar[n]arene homologs (n ¼ 5–10) by macrocyclization in the
nontemplate solvent chloroform and isolated higher pillar[n]arene homologs (n ¼ 6–10) by silica gel column chromatography.
The reaction proceeded under kinetic control; thus, the reaction time was one of the most important factors for the formation of
higher pillar[n]arene homologs. They concluded that the best reaction time for the formation of higher pillar[n]arene homologs
was 20 min. The reaction proceeded under kinetic control; thus, the major products were lower pillar[n]arene homologs (n ¼ 5:
yield 20%, n ¼ 6: yield 15%) with low-strain structures, whereas higher pillar[n]arene homologs (n ¼ 7: yield 3%, n ¼ 8: yield
1%, n ¼ 9: yield 2%, n ¼ 10: yield 2%) with high-strain structures were minor products even under optimized conditions. We
also found the formation of higher pillar[n]arene homologs (n ¼ 5–15) by the ring-opening/ring-closing reaction of the cyclic pen-
tamer with 10 ethoxy moieties 2[5] in the nontemplate solvent chloroform (Scheme 3).17
Heating of 2[5] at 50 C with BF3$ OEt2 resulted in the ring-opening reaction of 2[5]. In this reaction, we only detected a mixture
of pillar[5–15]arene homologs and no other soluble linear oligomers and polymers. No formation of soluble byproducts contrib-
uted to the easy isolation of higher pillar[n]arene homologs. However, the reaction proceeded under kinetic control; thus, we
needed to optimize the reaction condition to obtain higher pillar[n]arene homologs.
For the synthesis of pillar[5]arenes, we found good template solvent, 1,2-dichloroethane. However, the synthesis of pillar[6]are-
nes proceeded under kinetic control conditions in a nontemplate solvent, chloroform. The first pillar[6]arenes were reported by Cao
and Meier et al. in 2009.21 However, the yields were low (5–11%). They examined a wide range of reaction conditions to increase
the yields of pillar[6]arenes and successfully increased the yields up to 45% using iron(III) chloride.22 Recently, Zhang et al. synthe-
sized pillar[n]arenes with deep eutectic solvent choline chloride 2FeCl3.23 Under the optimized conditions, the yield of pillar[6]
arene increased to 53%. However, these reactions proceeded under kinetic control; therefore, we searched for good template
solvents for the synthesis of pillar[6]arenes. The cavity size of pillar[6]arenes ( 6.7 Å) is larger than pillar[5]arenes ( 4.7 Å);
thus, the large cavity allows pillar[6]arenes to capture various bulky guests. Thus, bulky hydrocarbons such as cyclohexane, chlor-
ocyclohexane, cyclooctane, and decaline were chosen as template solvents. Pleasingly, when chlorocyclohexane was used as the
solvent for the macrocyclization, pillar[6]arene was isolated as the major product in 87% yield (Fig. 5A).24
In contrast, pillar[6]arene was not obtained with the other bulky hydrocarbons as solvents. Pillar[5]- and pillar[6]arenes can
readily accommodate guest molecules carrying electron-withdrawing groups such as cyano and halogen moieties (details are

Scheme 2 Synthesis of pillar[n]arene homologs (n ¼ 5–10) by kinetic control.

 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 241

Scheme 3 Formation of pillar[n]arene homologs (n ¼ 5–15) by the ring-opening reaction of 2[5].

Figure 5 Selective synthesis of pillar[6]arene using chlorocyclohexane as the template solvent. (A) Synthetic scheme of pillar[6]arene. (B) Ratio of
monomer (green diamonds), pillar[5]arene (blue circles), pillar[6]arene (red squares), and oligomers (black triangles) determined by 1H NMR of the
reaction mixture over time. Reproduced with permission from Ogoshi, T.; Ueshima, N.; Akutsu, T.; Yamafuji, D.; Furuta, T.; Sakakibara, F.; Yamagishi,
T.A. Chem. Commun. 2014, 50(43), 5774–5777. Copyright 2014 Royal Society of Chemistry.

motioned in the next section); thus, using bulky solvents with a halogen moiety such as chlorocyclohexane as a solvent should lead to
a high-yield synthesis of pillar[6]arene. We monitored the reaction by time-dependent 1H NMR to clarify if the macrocyclization pro-
ceeded under thermodynamic or kinetic control. Fig. 5B shows the ratio of monomer, pillar[5]arene, pillar[6]arene, and oligomers
determined by time-dependent 1H NMR. At the beginning of the reaction (after 1 min), the monomer is converted to linear oligo-
mers. As the reaction progressed, the ratio of these oligomers decreased and that of pillar[6]arene increased. This reaction behavior
clearly suggests that the macrocyclization proceeded under thermodynamic control. However, the template solvent, chlorocyclohex-
ane, is not a good solvent for 1,4-dialkoxybenzene monomers with short alkyl chains. Thus, the development of a general method for
producing pillar[6]arenes in high yield should be an important next goal for the further development of pillar[n]arene chemistry.
Recently, Zyryanov et al. reported the selective synthesis of pillar[6]arenes by solid-state condensation of 1,4-dialkoxybenzenes
and paraformaldehyde by grinding in the presence of a catalytic amount of H2SO4.25 The highest yield of pillar[6]arene using this
method was 85%. The same group also reported high-yield synthesis of pillar[6]arenes in polar solvents such as acetonitrile, ethyl
alcohol, and acetone.26 The reaction mechanisms are not clear, but these procedures will be new useful routes for the synthesis of
pillar[6]arenes.

3.10.3 Supramolecular Assemblies Based on Molecular Recognition of Simple Pillar[n]arenes

One of the interesting aspects of pillar[n]arene chemistry is the superior hosting ability of pillar[n]arenes compared with other host
molecules.27,28 This is because pillar[n]arenes have more p-rich cavities than other host molecules. Fig. 6 shows electron density
mapping of pillar[5]arene, pillar[6]arene, and calix[5]arene.
242 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 6 Chemical structures, X-ray crystalline structures, and calculated electron potential profiles (DFT calculations, B3LYP/6-31G(d,p)) of pillar
[5]arene, pillar[6]arene, and calix[5]arene. Reproduced with permission from Ogoshi, T.; Yamagishi, T. Chem. Commun. 2014, 50(37), 4776–4787.
Copyright 2014 Royal Society of Chemistry.

The inner surfaces of pillar[5]- and pillar[6]arenes are p-electron-rich because the 1,4-dialkoxybenzene units are electron donors.
Furthermore, their pillar-shaped structures play an important role in enhancing the p-electron density of their cavities. The p-elec-
tron densities on the surface of pillar[5]- and pillar[6]arenes are higher than that of calix[5]arene. Pillar-shaped structures contribute
to a large p delocalization via the through-space within the cavity. In contrast, calix[5]arene forms an open-ended structure; thus, p
delocalization within the cavity hardly takes place. Therefore, owing to their p-electron-rich cavities, pillar[5]- and pillar[6]arenes
prefer to accommodate not only cationic molecules but also neutral molecules. The host ability of pillar[n]arenes can be enhanced
by introducing functional substituents. By installing appropriate substituents on both rims of the pillar[n]arenes, we can tune their
solubility and use various complexation media. However, in this article, we will discuss typical host ability of pillar[n]arenes
carrying simple alkyl chains.

3.10.3.1 Molecular Recognition of Simple Pillar[5]arenes

Pillar[5]arenes have a p-electron-rich cavity and thus can accommodate various cationic molecules. Viologen, pyridinium, imida-
zolium, and ammonium cations are good guests for pillar[5]arenes (Fig. 7A, K ¼ 103–104 M 1).29–36
The driving force for the complexation is cation–p interactions. Cation–p interactions are generally strong in nonpolar solvents
but weaken in polar solvents; thus, the nonpolar solvent chloroform was used for the complexation media. The type of counter
anion also affects the host–guest properties. Huang et al. investigated the effect of different counter anions on the complexation
between simple peralkylated pillar[5]arene and secondary ammonium salts.34 Pillar[5]arenes can form strong host–guest
complexes with n-octylethyl ammonium hexafluorophosphate (PF6  ) (Fig. 8, K ¼ (2.40  0.20)  103 M 1).
Counter anion exchange from PF6  to chloride anions induced dissociation of the complex. The strong ion pairing between
the n-octylethyl ammonium cation and the chloride anion prevented the complexation between pillar[5]arene and the n-octy-
lethyl ammonium cation. Li et al. reported effective binding of secondary ammonium cations with weakly coordinating tetra-
kis[3,5-bis(trifluoromethyl)phenyl]borate (BArF) counter anions by simple peralkylated pillar[5]arene.36 The host–guest
complexation ability between secondary ammonium cations with PF6  counter anions and peralkylated pillar[5]arene was
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 243

Figure 7 Good guest molecules for simple peralkylated pillar[5]arenes. (A) Cationic guests. (B) Neutral guests with electron-withdrawing groups at
both ends. (C) Alkane-shape-selective complexation by simple peralkylated pillar[5]arenes.

Figure 8 Complexation switch-off upon addition of Cl.

very weak (K ¼ 61  8 M 1). Conversely, exchange of the counter anion from PF6  to BArF resulted in effective binding of
secondary ammonium cations. The association constant of the complex with BArF anion was 3.4  0.4  104 M 1, which
was 560 times larger than that of the complex with PF6  anions. Ion pairing between the n-octylethyl ammonium cation and
the BArF anion was quite weak; thus, the free “naked” secondary ammonium cation was efficiently encapsulated in the
pillar[5]arene cavity.
Strong complexation with cationic guests is also observed in other host molecules such as crown ethers, calix[n]arenes, and
cucurbit[n]urils. However, pillar[5]arenes are unique in that they show strong binding affinities toward neutral guests in organic
media. CDs form complexes with neutral hydrophobic guests in aqueous media with the assistance of hydrophobic–hydrophilic
interactions. However, in organic media, hydrophobic–hydrophilic interactions do not work. Therefore, complexation between
neutral guests and pillar[5]arenes in organic media is a very unique feature. Li et al. reported high effective binding of neutral linear
alkanes with electron-withdrawing groups such as cyano, halogen, imidazole, and triazole groups at both ends with simple pillar[5]
arenes (Fig. 7B).37–40 The association constants of the complexes between the linear alkanes with electron-withdrawing groups and
simple pillar[5]arenes in chloroform were 102–104 M 1. The electron-withdrawing groups at both ends are very important for stabi-
lizing the complexation. From X-ray crystal analysis of the complexes, many physical interactions such as multiple CH/p, CH/N,
and CH/O hydrogen-bonding interactions contribute to the highly effective binding. Simple peralkylated pillar[5]arenes also encap-
sulated linear hydrocarbons by multiple CH/p interactions. Huang et al. reported the existence of multiple CH/p hydrogen-
bonding interactions between n-hexane and simple perbutylated pillar[5]arene by X-ray crystallography.29 Furthermore, pillar[5]
arenes show alkane-shape selectivity (Fig. 7C). Simple pillar[5]arenes only interacted with linear hydrocarbons and not with cyclic
and branched alkanes.41 This is because the cavity has a very narrow and well-defined cylindrical architecture. However, one of the
serious problems with alkane recognition is the weak binding ability of n-alkanes by pillar[5]arenes. CH/p interactions are the
weakest hydrogen bonds; thus, the association constants between n-alkanes and pillar[5]arenes are very low in CDCl3
(K z 10 M 1).41 Our group discovered unexpected alkane uptake behavior using perethylated pillar[5]arene 2[5] in the crystal
state.42 First, solvents in the crystals were removed by heating under reduced pressure, called the activation process. The activated
crystals could quantitatively take up linear n-alkanes containing more than five carbon atoms with gate-opening pressure, followed
by stepwise isotherms, during the adsorption process (Fig. 9).
During the desorption process, the adsorbed linear n-alkanes were not released even under reduced pressure because they were
stabilized by multiple CH/p interactions. In contrast, the cyclic and branched alkanes were not absorbed in the same way because
the pillar[5]arene cavity was a poor fit for these cyclic and branched alkanes.
244 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 9 Sorption isotherms of activated crystals of 2[5] toward the gases and vapors of several linear alkanes, including n-butane (C4, purple
squares), n-pentane (C5, black diamonds), n-hexane (C6, red circles), n-heptane (C7, blue triangles), and n-octane (C8, brown diamonds), and several
branched alkanes, including 2,2-dimethylbutane (2,2, green circles), 2,3-dimethylbutane (2,3, black circles), and cyclohexane (CyC6, yellow circles) at
25 C. Solid symbols ¼ adsorption; open symbols ¼ desorption. Reproduced with permission from Ogoshi, T.; Sueto, R.; Yoshikoshi, K.; Sakata, Y.;
Akine, S.; Yamagishi, T. Angew. Chem. Int. Ed. 2015, 54(34), 9849–9852. Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA.

MIMs have been synthesized based on the molecular recognition of simple peralkylated pillar[5]arenes. The first pillar[5]arene-
based rotaxane was reported by Stoddart et al. Endcapping of 1,8-diaminobutane with a bulky 3,2-di-tert-butylbenzaldehyde
stopper in the presence of a permethylated pillar[5]arene wheel afforded a [2]rotaxane (Scheme 4).43
However, its yield was low (7%) owing to the weak binding of 1,8-diaminobutane by permethylated pillar[5]arene 1[5] in
CDCl3 (K ¼ 70  10 M 1). Huang et al. also synthesized [2]rotaxanes by endcapping through ester and urethane bond forma-
tion.44,45 However, their yields were low because they used an unfavorable host–guest combination between pillar[5]arenes and
n-alkanes. We prepared a [2]rotaxane in high yield by employing a favorable host–guest combination (Scheme 5).35 The guest
molecule was a pyridinium derivative containing a bulky stopper and alkyne moieties at both ends, which was used as an axle.
Owing to cation/p interactions, the host–guest complex between the pyridinium axle and perethylated pillar[5]arene 2[5] was
very stable [K ¼ (7.6  1.1)  104 M 1]. An efficient copper-catalyzed alkyne–azide cyclization (CuAAC) was employed for the
rotaxanation.
The CuAAC reaction between the azide-terminated stopper and alkyne-terminated pseudo[2]rotaxane afforded a [2]rotaxane in
high yield (75%). A [3]rotaxane was also synthesized in moderate yield (45%) by connecting two pseudo[2]rotaxanes containing an
alkyne end with a diazide linker. A [2]catenane was also synthesized using ring-closing metathesis of a pyridinium derivative with
alkene moieties at both ends in the presence of perethylated pillar[5]arene.46
We also synthesized a pillar[5]arene-based [2]rotaxane using stepwise CuAAC reactions (Scheme 6).47 Linear alkanes with tri-
azole groups at both ends are good guest molecules [K ¼ (1.6  0.3)  104 M 1]. Triazoles are easily formed by the CuAAC reaction.
An axle containing a good station for pillar[5]arenes with reactive alkyne moieties at both ends was synthesized by the CuAAC reac-
tion of an excess of diyne with diazide. The CuAAC reaction was then used to synthesize a [2]rotaxane. The CuAAC reaction between
the alkyne moieties in a pseudo[2]rotaxane consisting of pillar[5]arene and the azide groups of the axle afforded the [2]rotaxane
(yield 54%). This approach can be used to design various pillar[5]arene-based [2]rotaxanes by selecting appropriate diyne and dia-
zide derivatives to form the axles.

Scheme 4 The first pillar[5]arene-based [2]rotaxane prepared by the endcapping reaction of pseudo[2]rotaxane consisting of 1[5] and diamine with
a stopper carrying an aldehyde moiety.
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 245

Scheme 5 Synthesis of [2]- and [3]rotaxanes in high yields using stable host–guest complexes and endcapping by an efficient CuAAC reaction.

3.10.3.2 Molecular Recognition of Simple Pillar[6]arenes

The pyridinium cations, which are good guests for simple peralkylated pillar[5]arenes, also work as guests for peralkylated pillar
[6]arenes. However, the K value of the complex is  20 M 1, which is about 400 times smaller than that observed with peralky-
lated pillar[5]arenes.48 The cavity size of pillar[6]arenes is larger than that of pillar[5]arenes; thus, the pyridinium cation is too
small to form a stable host–guest complex. Therefore, cations with bulky hydrocarbons, such as adamantine, tropylium, and 1,4-
diazabicyclo[2.2.2]octane (DABCO) cations formed relatively stable host–guest complexes with peralkylated pillar[6]arenes
(Fig. 10A, K z 103–104 M 1).36,49,50 As with pillar[5]arenes, the binding ability of bulky cationic guests by pillar[6]arenes
depends on the counter anion. The association constant of adamantine cation with weakly coordinating anion BArF
with pillar[6]arene was 3.4  0.2  103 M 1, whereas no interaction was observed between the adamantine cation and the
PF6  anion.36
The cavity size of pillar[6]arenes is also a good fit for polyaromatic derivatives with a cationic moiety (Fig. 10B).
Azobenzene derivatives with an ammonium moiety formed stable host–guest complexes with pillar[6]arenes.51 However, the
cavity size of pillar[6]arenes fits the trans form of the azobenzene guest but not to the cis form. Therefore, the trans form of the azo-
benzene cation formed a stable host–guest complex with pillar[6]arene (K ¼ (2.2  0.3)  103 M 1), whereas the cis form formed
a weak host–guest complex (K ¼ (2.6  0.3)  102 M 1). Pillar[6]arenes also formed stable host–guest complexes with the oxidized
form of the ferrocenium cation (K ¼ (2.2  0.3)  103 M 1) because the electron-rich cavity of pillar[6]arenes is suitable for cationic
ferrocenium but can hardly accommodate the reduced form (K ¼ 18  0.5 M 1).52 Trans and cis isomerization of azobenzene moie-
ties can be induced by photoirradiation. Interconversion between ferrocene and the ferrocenium cation can be switched by a redox
reaction. Therefore, these photo- and redox-responsive host–guest systems enabled us to construct various stimuli-responsive supra-
molecular assemblies.51,53–55
Huang et al. reported the photoresponsive aggregation of azobenzene cation–pillar[6]arene complexes (Fig. 11).51 The trans-
azobenzene guest formed a host–guest complex with pillar[6]arene, and the complexes formed irregular aggregates. Photoisome-
rization of the azobenzene from the trans to its cis form upon UV light irradiation resulted in vesicle-like aggregates. Switching
between the irregular and vesicle-like aggregates could be reversibly photocontrolled by irradiation with UV and visible light,
respectively.
246 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Scheme 6 A high-yield synthesis of [2]rotaxane by stepwise CuAAC reactions.

Figure 10 Good guest molecules for simple peralkylated pillar[6]arenes. (A) Bulky derivatives with a cationic part. (B) Stimuli-responsive poly-
aromatic compounds with a cationic moiety.

3.10.4 Supramolecular Assemblies Based on Functionalized Pillar[n]arenes

3.10.4.1 Monofunctionalized Pillar[n]arenes
Pillar[n]arenes can be easily functionalized by modifying the substituents at the desired positions. Stoddart et al. reported a new
method, namely, a cocyclization method, for the synthesis of monofunctionalized pillar[5]arenes (Scheme 7).43
A pillar[5]arene with one bromide group was prepared by cocyclization of 1,4-dimethoxybenzene (5 equiv.) with
nonsymmetrical 1-(2-bromoethoxy)-4-methoxybenzene (1 equiv.) in the presence of BF3,OEt2. In the cocyclization
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 247

Figure 11 Photoresponsive formation of irregular and vesicle-like aggregates. Reproduced with permission from Yu, G.; Han, C.; Zhang, Z.; Chen,
J.; Yan, X.; Zheng, B.; Liu, S.; Huang, F. J. Am. Chem. Soc. 2012, 134(20), 8711–8717. Copyright 2012 American Chemical Society.

Scheme 7 Synthesis of monobromide, monoazide, and monoamine pillar[5]arenes by the cocyclization method.

method, the monobromide can be produced by one-step reaction. The monobromide can be converted to a reactive
monoazide or monoamine. However, the cocyclization method still has two problems. One is the low yield (10%) of
the monobromide because other pillar[5]arenes with no bromide groups or more than one bromide groups are generated
at the same time. The other problem is that the cocyclization method cannot be used for the synthesis of higher pillar[n]
arene homologs, such as pillar[6]arenes, because in most cases, the major products of the cocyclization are pillar[5]arenes.
248 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Another pathway for the synthesis of monofunctionalized pillar[5]arenes is the deprotection method, which was first reported
by our group (Scheme 8).31
BBr3 (0.9 equiv.) and permethylated pillar[5]arene (1 equiv.) were reacted to form a monodeprotected pillar[5]arene. However,
as with the cocyclization method, the yield of the monodeprotected pillar[5]arene was low (22%). Cao and Meier et al. improved
the yield by optimizing the reaction conditions.56 They used excess BBr3 (4 equiv. to preformed pillar[5]arene) and investigated the
reaction temperature. They found that the monodeprotection proceeded smoothly at low temperatures ( 8 to  5 C) within 1.5 h,
which led to the synthesis of the target product in good yield (60%). Various monofunctionalized pillar[5]arenes have been
produced by etherification of the monohydroxylated pillar[5]arenes. Cao and Meier et al. reported a monophosphoryl pillar[5]
arene from monohydroxylated pillar[5]arene (Scheme 8A).56 Multiple noncovalent interactions, that is, CH/p, dipole–dipole,
and hydrogen bonding, contributed to effective complex formation between monophosphoryl pillar[5]arene and guests such as
1,4-butanediol and 1-butanol. Various supramolecular structures have been constructed by installing a guest moiety in pillar[5]

Scheme 8 Synthesis of monofunctionalized pillar[5]- and pillar[6]arenes by the deprotection method. (A) Monophosphoryl pillar[5]arene used for
recognition of alkanols. (B) A host–guest conjugate forming a self-inclusion complex. Reproduced with permission from Ogoshi, T.; Demachi, K.;
Kitajima, K.; Yamagishi, T. Chem. Commun. 2011, 47(25), 7164–7166. Copyright 2011 Royal Society of Chemistry. (C) Alternating supramolecular
polymer formation by mixing pillar[5]- and pillar[6]arenes carrying corresponding guest moiety. Reproduced with permission from Ogoshi, T.;
Kayama, H.; Yamafuji, D.; Aoki, T.; Yamagishi, T. Chem. Sci. 2012, 3(11), 3221–3226. Copyright 2012 Royal Society of Chemistry.
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 249

arenes. Pillar[5]arenes form stable complexes with cations; thus, our groups have synthesized a monofunctionalized pillar[5]arene
with a guest trimethylammonium moiety from monohydroxylated pillar[5]arene by etherification (Scheme 8B).31 The host–guest
conjugate predominantly formed a self-inclusion complex in CDCl3. We have also applied the monodeprotection method to
produce a monofunctionalized pillar[6]arene. A pillar[6]arene with one phenolic moiety was obtained in moderate yield (46%)
under optimized deprotection conditions.49 This result indicates that the deprotection method can be used for higher pillar[n]arene
homologs. Supramolecular polymers can be formed by the combination of monofunctionalized pillar[5]- and pillar[6]arenes.
Based on the highly selective multiple host–guest recognition system depending on the cavity size of pillar[5]- and pillar[6]arenes,
our group developed self-sorting supramolecular polymers (Scheme 8C).49 The DABCO cation moiety interacts with pillar[6]are-
nes, but not with pillar[5]arenes. The pyridinium cation moiety strongly interacts with pillar[5]arenes but hardly interacts with pillar
[6]arenes. Thus, we mixed pyridinium cation-modified pillar[6]arene and DABCO cation-modified pillar[5]arene, which were
produced by etherification of the corresponding guest parts with monohydroxylated pillar[5]- and pillar[6]arenes, respectively.
Consequently, the mixture formed a supramolecular polymer through a highly selective host–guest recognition system.
Various reactive monofunctionalized pillar[n]arenes with hydroxyl, bromide, azide, amine, and alkyne groups have been synthe-
sized using the cocyclization and deprotection methods. These reactive pillar[n]arenes are good key compounds to produce mono-
functionalized pillar[n]arenes with various functional groups. Installing a guest part into the structure of a pillar[5]arene allows the
formation of supramolecular polymers. The first pillar[n]arene-based supramolecular polymer was constructed by Huang et al.57
They synthesized pillar[5]arene with one decyl group by the cocyclization method. The monodecane formed a linear supramolec-
ular polymer in high yield because the decyl group is included in the pillar[5]arene cavity through multiple CH/p interactions
(Fig. 12A).
Formation of the supramolecular polymer was directly observed by X-ray crystallography. The same groups found that introduc-
tion of a bromide moiety at the end of the decyl group afforded another type of supramolecular structure. The pillar[5]arene with
a bromodecyl group, which was also synthesized by the cocyclization method, formed a cyclic dimer in the solid state (Fig. 12B).58
The dimer structure, namely, [c2]daisy chain, was stabilized through multiple CH/p and CH/O interactions. The same group also
reported the formation of an interlocked [c2]daisy chain by endcapping of the [c2]daisy chain consisting of monoamino-modified
pillar[5]arenes with bis(trifluoromethyl)phenyl isocyanate.59 It formed contracted and extended states in CDCl3 and DMSO-d6,
respectively; thus, it was termed a molecular spring (Fig. 12C). This phenomenon was induced by changing interaction sites
between the substituents and pillar[5]arene rings depending on the solvent. The rings were located on the urea groups in CDCl3

Figure 12 Synthesis of monofunctionalized pillar[5]arenes by the cocyclization method. (A) Supramolecular polymer from monodecane-
functionalized pillar[5]arenes, (B) supramolecular dimers from monobromodecyl-functionalized pillar[5]arenes, and (C) molecular springs by end
capping of the supramolecular dimers with bulky stoppers. Reproduced with permission from Zhang, Z. B.; Han, C. Y.; Yu, G. C.; Huang, F. Chem.
Sci. 2012, 3(10), 3026–3031. Copyright 2012 Royal Society of Chemistry.
250 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

because NH/p interactions were dominant in CDCl3, whereas the rings were located on the decyl groups in DMSO-d6 because
multiple CH/p interactions were dominant in DMSO-d6.
Pillar[5]arene dimers have been constructed by linking monofunctionalized pillar[5]arenes through physical interactions or
covalent bonds. Wang et al. constructed a pillar[5]arene dimer structure using complementary hydrogen-bonding interactions of
a ureidopyrimidinone moiety (Fig. 13).60
Pillar[5]arene with one ureidopyrimidinone moiety was synthesized from a pillar[5]arene with one amino group. The ureido-
pyrimidinone unit exhibited complementary hydrogen interactions with each other, which contributed to the formation of the
pillar[5]arene dimer structure. Therefore, the dimer formed linear supramolecular polymers at high concentrations with a bispara-
quat guest dimer. Our group synthesized a pillar[5]arene dimer by connecting two monohydroxylated pillar[5]arenes with 1,4-
bis(bromomethyl)-benzene (Fig. 14).41 As in the example described earlier, pillar[5]arenes capture n-alkane molecules inside
the p-electron-rich cavity through multiple CH/p interactions, but the binding ability is quite low to determine the association
constant. The pillar[5]arene dimer structure enhanced the host–guest interactions with n-alkanes sufficiently to allow determination
of the association constants in organic media. Yang et al. synthesized a pillar[5]arene with one anthracene moiety to prepare a pillar
[5]arene dimer structure by photodimerization of anthracene (Fig. 15).61
Anthracenes dimerize upon irradiation of UV light at wavelengths above  350 nm. Therefore, a pillar[5]arene with one anthra-
cene moiety formed supramolecular polymers by photodimerization of anthracene-terminated supramolecular monomers in the
presence of linear alkane with two bis-imidazoles at both ends. Anthracene dimers dissociated upon exposure to light with a wave-
length of less than 300 nm or heating; thus, dynamic polymerization/depolymerization of the supramolecular polymer could be
controlled by variation of the temperature and/or photoirradiation wavelength.
Hou et al. developed simple artificial channels using pillar[5]arene dimers for efficient transmembrane proton transport chan-
nels (Fig. 16).62
They prepared pillar[5]arene dimers by connecting pillar[5]arenes with one carboxylic acid moiety with various lengths of alkane
diols (Fig. 16A). A pillar[5]arene dimer with a hexamethylene linker was the best choice to apply as a water-wire-based artificial
transmembrane proton channel because the length of the hexamethylene linker induced good stacking matching for the connected
pillar[5]arene units (Fig. 16B). The dimer showed channel activities that were even higher than those of reported natural proton
channels.

Figure 13 Formation of supramolecular polymers by mixing physically linked pillar[5]arene dimers by multiple hydrogen bonds and a viologen
guest dimer. Reproduced with permission from Guan, Y. F.; Ni, M. F.; Hu, X. Y.; Xiao, T. X.; Xiong, S. H.; Lin, C.; Wang, L. Y. Chem. Commun. 2012,
48(68), 8529–8531. Copyright 2012 Royal Society of Chemistry.
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 251

Figure 14 Enhancement of n-alkane recognition by formation of a pillar[5]arene dimer structure. Reproduced with permission from Ogoshi, T.;
Demachi, K.; Kitajima, K.; Yamagishi, T. Chem. Commun. 2011, 47(37), 10290–10292. Copyright 2011 Royal Society of Chemistry.

Figure 15 Formation and response of double-dynamic supramolecular polymers. Reproduced with permission from Xu, J. F.; Chen, Y. Z.; Wu, L.
Z.; Tung, C. H.; Yang, Q. Z. Org. Lett. 2013, 15(24), 6148–6151. Copyright 2013 American Chemical Society.

One of the applications of monofunctionalized pillar[n]arenes is as chemical sensor to detect amine compounds and anions
using fluorescence changes. Stoddart et al. synthesized monopyrene-modified pillar[5]arene by the CuAAC reaction of a monoazide
with a pyrene carrying one alkyne group (Fig. 17A).43
Generally, primary amines are fluorescence quenchers through photoinduced electron transfer. Therefore, fluorescence of the
pyrene installed in the pillar[5]arene rim was quenched by encapsulation of primary amines in the pillar[5]arene cavity.
Stoddart et al. reported a monoazobenzene-functionalized pillar[5]arene that exhibits reversibly responsive morphologies
toward UV and visible light (Fig. 17B).63 The CuAAC reaction of 4-hydroxy-40 -ethynyl-azobenzene with a monoazide pillar[5]arene
afforded monoazobenzene-functionalized pillar[5]arene. Vesicles were formed when the azobenzene was in the trans form.
Conversely, the vesicle assemblies converted to stiffer solid nanoparticles by photoisomerization of the azobenzene to the cis
form. The structures could be reversibly converted between vesicles and nanoparticles by alternating irradiation with UV and visible
light.
Hu and Wang et al. reported the synthesis of a new p-conjugated polymer covering by pillar[5]arenes and anion sensing using
novel side-chain polypseudorotaxanes through the host–guest interactions between the pillar[5]arene units and an n-octylpyrazi-
nium salt (Fig. 18).64,65
These side-chain polypseudorotaxanes successfully detected anions (Cl, Br, and I) by using the difference in the fluorescence
enhancement. Such fluorescence enhancement differences could be attributed to the different ion-pairing binding affinity of Cl,
Br, and I to the n-octylpyrazinium cation, which lead to a different degree of electron transfer from the p-conjugated backbone to
the n-octylpyrazinium cation.
252 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 16 (A) Chemical structures of pillar[5]arene dimers. (B) Schematic representation of the switch mechanism for proton transport of pillar[5]
arene dimers. Reproduced with permission from Si, W.; Chen, L.; Hu, X. B.; Tang, G.; Chen, Z.; Hou, J. L.; Li, Z. T. Angew. Chem. Int. Ed. 2011,
50(52), 12564–12568. Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 17 Monofunctionalized pillar[5]arenes by CuAAC reaction. (A) A fluorescence sensor based on pyrene-appended pillar[5]arene. Reproduced
with permission from Strutt, N. L.; Forgan, R. S.; Spruell, J. M.; Botros, Y. Y.; Stoddart, J. F. J. Am. Chem. Soc. 2011, 133(15), 5668–5671. Copyright
2011 American Chemical Society. (B) Photoresponsive assemblies from azobenzene-appended pillar[5]arene. Reproduced with permission from
Zhang, H.; Strutt, N. L.; Stoll, R. S.; Li, H.; Zhu, Z.; Stoddart, J. F. Chem. Commun. 2011, 47(41), 11420–11422. Copyright 2011 Royal Society of
Chemistry.

3.10.4.2 Difunctionalized Pillar[n]arenes

Two approaches have been used to prepare difunctionalized pillar[n]arenes. The first method was cocyclization. Huang et al. synthe-
sized a copillar[5]arene containing four dimethoxybenzene (DMB) and one dibutoxybenzene (DBB) units by cocyclization of DMB
(4 equiv.) and DBB (1 equiv., Fig. 19).29
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 253

Figure 18 Formation of polypseudorotaxanes and their disassembly induced by halogen ions. Reproduced with permission from Sun, S.; Hu, X.-Y.;
Chen, D.; Shi, J.; Dong, Y.; Lin, C.; Pan, Y.; Wang, L. Polym. Chem. 2013, 4(7), 2224–2229. Copyright 2013 Royal Society of Chemistry.

By cocyclization of DMB (1 equiv.) and DBB (4 equiv.), copillar[5]arene containing four DBB and one DMB units was mainly
produced. Copillar[5]arene with one 1,4-dioctyloxybenzene and four DMB units was obtained by cocyclization of the correspond-
ing monomers. Subsequently, Cao and Meier et al. increased the yield of difunctionalized pillar[5]arenes using FeCl3 as a catalyst.66
Although the yield of the difunctionalized pillar[5]arene was 9% using BF3$ OEt2, the yield increased up to 71% using FeCl3. In
particular, copillar[5]arenes constructed from four 1,4-dimethoxybenzene units and 1,4-dialkoxybenzene with two bromide groups
were obtained in high yields. These dibromides were useful for producing diamines and diazides. Wang et al. synthesized [2]pseu-
dorotaxanes using difunctionalized pillar[5]arenes with two bis-urea groups, which were synthesized from pillar[5]arene containing
one 1,4-dialkoxybenzene with two bromide groups.67 To prepare the bis-urea-functionalized pillar[5]arene, the diamine was
synthesized from the dibromide by a Gabriel synthesis. The diamine was reacted with 1-isocyanato-4-methylbenzene to prepare
the bis-urea-functionalized pillar[5]arene. The [2]pseudorotaxanes were stably formed through the hydrogen bonding at both
rims between the bis-urea hydrogens and dicarboxylate oxygens (Fig. 20A).
Li et al. reported [c2]daisy chains constructed from difunctionalized pillar[5]arenes with two bromide groups (Fig. 20B).68
Because pillar[5]arenes can capture electron-poor linear compounds, difunctionalized pillar[5]arenes with two bromide groups
formed inclusion complexes with each other, namely, [c2]daisy-chain pseudorotaxane. A supramolecular polymer was formed
by mixing the [c2]daisy-chain pseudorotaxane and pillar[5]arene dimer.
Stoddart et al. synthesized a phenylene-substituted pillar[5]arene.69 First, they synthesized ditriflated pillar[5]arene from the
dihydroxylated pillar[5]arene. Subsequently, the ditriflate was reacted with 4-(methoxycarbonyl)phenylboronic acid with a Pd cata-
lyst to obtain phenylene-substituted pillar[5]arene with two carboxylic acid groups (Fig. 21A). A metal organic framework contain-
ing pillar[5]arenes (MOF-P5A) could be produced by using the diacid as building blocks for the MOF (Fig. 21B). Uptake of the
electron-poor guests by MOF-P5A induced color changes of the cubic crystals of the MOF-P5A from faint yellow to deep orange,
arising from charge transfer between the guests and the active domain of the pillar[5]arenes in MOF-P5A (Fig. 21C).

Figure 19 Preparation of copillar[5]arenes by cocyclization of different hydroquinone diethers. Reproduced with permission from Zhang, Z. B.; Xia,
B. Y.; Han, C. Y.; Yu, Y. H.; Huang, F. Org. Lett. 2010, 12(15), 3285–3287. Copyright 2010 American Chemical Society.
254 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 20 (A) Graphic representation of the formation of [2]pseudorotaxanes. Reproduced with permission from Duan, Q. P.; Xia, W.; Hu, X. Y.; Ni,
M. F.; Jiang, J. L.; Lin, C.; Pan, Y.; Wang, L. Y. Chem. Commun. 2012, 48(68), 8532–8534. Copyright 2012 Royal Society of Chemistry. (B) Synthesis
of copillar[5]arene, and schematic illustration of the supramolecular polymerization by mixing copillar[5]arene and pillar[5]arene dimer. Reproduced
with permission from Wang, X. Y.; Han, K.; Li, J.; Jia, X. S.; Li, C. J. Polym. Chem. 2013, 4(14), 3998–4003. Copyright 2013 Royal Society of
Chemistry.

The second method that has been used to produce difunctionalized pillar[n]arenes is oxidation followed by reduction of the
pillar[n]arene units. Generally, 1,4-dialkoxybenzene is changed to benzoquinone by oxidation. Our group and Huang et al. synthe-
sized pillar[5]arenes with one benzoquinone unit by oxidation of preformed pillar[5]arenes.70,71 By reduction of the benzoquinone
unit with NaBH4, dihydroxylated pillar[5]arenes were obtained (Fig. 22). The method is applicable for the synthesis of dihydroxy-
lated pillar[6]arenes.71,72
The dihydroxylated pillar[n]arenes were useful key compounds because the hydroxyl groups can be converted to other func-
tional groups. Our group synthesized a pillar[5]arene with two alkyne groups on the same unit by etherification of dihydroxylated
pillar[5]arene with propargyl bromide. The dialkyne was useful for introducing other functional groups using the CuAAC reaction.
To create a guest-induced fluorescence color change system, two pyrenyl groups were installed by using the CuAAC reaction between
the dialkyne and azide-substituted pyrene derivative (Fig. 22A).71 Pillar[5]arene with pyrene moieties exhibited fluorescence color
changes upon complexation with guests. The pillar[5]arene with two pyrene groups was also used to synthesize a Förster resonance
energy transfer (FRET) rotaxane system. Our group reported a [2]rotaxane composed of the dipyrene-appended pillar[5]arene
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 255

Figure 21 (A) Synthesis of phenylene-substituted pillar[5]arene with two carboxylic acid groups, (B) metal organic framework containing pillar[5]
arene domains (MOF-P5A), and (C) optical microscopy images of MOF-P5A crystals (a) without guest (scale bar, 200 mm), (b) after uptake of viol-
ogen guests (scale bar, 100 mm), and (g) after uptake of paradinitrobenzene (scale bar, 100 mm). Reproduced with permission from Strutt, N.L.;
Fairen-Jimenez, D.; Iehl, J.; Lalonde, M. B.; Snurr, R. Q.; Farha, O. K.; Hupp, J. T.; Stoddart, J. F. J. Am. Chem. Soc. 2012, 134(42), 17436–17439.
Copyright 2012 American Chemical Society.

wheel, a pyridinium axle, and a perylene stopper. The rotaxane showed efficient FRET from pyrene to perylene because the [2]rotax-
ane is an ideal platform to place donors and acceptors in close proximity for FRET.73
Other MIMs are catenanes consisting of two or more interlocked macrocycles. Our group first reported a dynamic planar chiral
inversion systems based on a new bicyclic pseudo[1]catenane (Fig. 22C).74 The compound was prepared by a CuAAC reaction with
the dialkyne and 1,12-diazidododecane. The bicyclic compound had four conformers: in-pS, in-pR, out-pS, and out-pR. The in-pS
and in-pR enantiomers were isolated by chiral-phase high-performance liquid chromatography. The in-pS or in-pR enantiomers
showed complete planar chiral inversion to out-pR or out-pS, respectively, upon addition of achiral guests.
Yu et al. synthesized a pillar[5]arene with two carboxylic acid groups in the same unit from dihydroxylated pillar[5]arene
through etherification (Fig. 23A).75 The diacid showed stronger association with alkyldiamines ranging from 1,5-
pentanediamine to 1,10-decanediamine than pristine pillar[5]arene. Proton transfer from the carboxylic acid groups of the pillar
[5]arene to the amines on the guest molecules could be achieved by undergoing an acid–base reaction. Driven by the cooperative
electrostatic interactions and multiple CH/p interactions, the diamine guests penetrate into the cavity to form stable [2]pseudoro-
taxanes, which was confirmed by the X-ray crystal structure of the complex (Fig. 23B). The diacid also formed stable host–guest
complexes with benzene moieties bearing parasubstituted amino groups such as p-xylylenediamine and p-phenylenediamine.76
Recently, Liu et al. reported a new mechanically self-locked molecule through a highly efficient one-step amidation (Fig. 23C).77
After complexation between a pillar[5]arene diacid and 1,8-diaminooctane, condensation reaction between the amines and the
acids gave gemini-catenanes with two enantiomers and one mesoform along with a pseudo[1]catenane.

3.10.4.3 Pentafunctionalized Pillar[n]arenes

Functionalized pillar[n]arenes can generally be synthesized by three methods including deprotection, cocyclization, and oxidation
followed by reduction. However, pentafunctionalized pillar[n]arenes cannot be produced by these methods. It is difficult to control
the number and positions of the deprotection points using the deprotection method, and thus, pillar[n]arenes with more than two
deprotection points have various conformers. Separation of pentadeprotected pillar[5]arenes from the mixture is quite hard. The
cocyclization and the oxidation followed by reduction methods can only be used to change the functional groups of one or two
pillar[n]arene units. Therefore, pentafunctionalized pillar[n]arenes are accessible only by cyclization of monomers with two
different kinds of alkoxy substituents.
256 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 22 Difunctionalized pillar[5]arenes by oxidation followed by reduction. (A) A chemical sensor from a pillar[5]arene with two pyrene moieties.
(B) Efficient FRET by formation of a mechanically interlocked [2]rotaxane. (C) Planar chiral inversion of pseudo[1]catenane. Reproduced with permis-
sion from Ogoshi, T.; Akutsu, T.; Yamafuji, D.; Aoki, T.; Yamagishi, T. Angew. Chem. Int. Ed. 2013, 52(31), 8111–8115. Copyright 2013 Wiley-VCH
Verlag GmbH & Co. KGaA.

Our group first reported synthesis of a pentafunctionalized pillar[5]arene, which had five ethoxy and five methoxy functional
groups.78 1-Ethoxy-4-methoxybenzene was reacted with paraformaldehyde to form the pentafunctionalized pillar[5]arene.
However, four constitutional isomers that were generated in the cyclization were not successfully separated. Separation of these
isomers was achieved by Cao and Meier et al. and Huang et al. They synthesized nonsymmetrical pillar[5]arenes with five methoxy
and five butoxy groups (Fig. 24).79,80
The four constitutional isomers can be isolated by silica gel column chromatography. Huang et al. also investigated the binding
ability of these pillar[5]arene constitutional isomers with n-octyltrimethyl ammonium hexafluorophosphate as a guest.79 The consti-
tutional isomers showed different binding abilities with the guest. Li et al. reported regioselective complexation between nonsymmet-
rical pillar[5]arene bearing different alkyl rims (methyl and pentyl rims) and nonsymmetrical guest, 5-bromovaleronitrile.81 The
nonsymmetrical pillar[5]arene can form two possible host–guest complex structures. However, it exhibited only one type of complex
structure with a specific directionality, in which the cyano and bromo groups are located on pentyl and methyl rims, respectively
(Fig. 25). The binding selectivity between the methyl/pentyl rims and CN/Br groups contributed to the self-sorted orientation.
The structure of nonsymmetrical pillar[n]arenes with different substituent rims is optimal for the construction of amphiphilic
compounds. Huang et al. synthesized a nonsymmetrical pillar[5]arene containing five amino groups and five pentyl chains on
each rim.82 The nonsymmetrical pillar[5]arene formed various supramolecular structures in water because it consists of five amino
groups as the hydrophilic head and five pentyl chains as the hydrophobic tail (Fig. 26).
It aggregated into vesicular entities in neutral conditions. Interestingly, these vesicles transformed into small globular micelles at
low pH. Moreover, these vesicles underwent further self-assembly to produce microtubes after 4 months, and the resultant micro-
tubes could adsorb 2,4,6-trinitrotoluene, which was driven by donor–acceptor interactions. Diao et al. reported that water-dispersed
reduced graphene oxide was formed by modifying the surface of reduced graphene oxide with an amphiphilic pillar[5]arene.83 The
water-dispersed reduced graphene oxide with pillar[5]arenes displayed high electrochemical response toward guest molecules.
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 257

Figure 23 Supramolecular assemblies using diacid and diamines. (A) Chemical strictures of diacid and diamines. (B) X-ray crystal structure of the
host–guest complex between a pillar[5]arene diacid and 1,7-heptadiamine. (C) Synthetic scheme of gemini-catenanes based on pillar[5]arene. Only
the pS-enantiomers are shown for clarity. Reproduced with permission from Li, S. H.; Zhang, H. Y.; Xu, X.; Liu, Y. Nat. Commun. 2015, 6, 7590.
Copyright 2015 Nature Publishing Group.

Ternary nanocomposites were prepared by self-assembly of gold nanoparticles onto the surface of the graphene sheets dispersed
with pillar[5]arenes. Modification with gold nanoparticles enhanced the electrochemical responses of the guests.

3.10.4.4 Perfunctionalized Pillar[n]arenes

3.10.4.1 Perhydroxylated Pillar[n]arenes
Perhydroxylated pillar[n]arenes were synthesized by deprotection of the alkoxy moieties of peralkylated pillar[n]arenes with BBr3
(Scheme 9).13
Zhang, Wang, and Yang et al. reported that crystals of perhydroxylated pillar[5]arene after an activation process exhibited highly
selective uptake of CO2 (Fig. 27).84 The crystals had permanent micropores even after the activation process because multiple
hydrogen bonds between the perhydroxylated pillar[5]arenes stabilized the micropores. The retained micropores acted as adsorp-
tion sites for CO2. In contrast, CH4 and N2 were barely adsorbed by the crystals up to 1 atm. The selectivity of CO2 over CH4 and
CO2 over N2 was 375/1 and 339/1, respectively. The highly selective CO2 uptake was mainly because of the porous nanostructure of
the crystals and the dipole interactions between CO2 and the hydroxyl groups of perhydroxylated pillar[5]arene. Our group reported
that activated crystals of perhydroxylated pillar[6]arene also showed uptake of gases and organic vapors.85 Highly ordered one-
dimensional channels (diameter of  6.7 Å) constructed by assembly of pillar[6]arenes acted as adsorption sites.
Because hydroxyl groups in perhydroxylated pillar[n]arenes can form multiple inter- and intramolecular hydrogen bonding,
hydrogen-bonding interactions have been used to synthesize new MIMs such as heterorotaxanes, which was reported by Stoddart
et al.86 Generally, it was difficult to form heterorotaxanes consisting of two different kinds of ring components, because hetero rings
do not coassemble when there are no interactions between them. Stoddart et al. synthesized two hetero[4]rotaxanes and one hetero
[5]rotaxane in high yields by designing axles and introducing intermolecular hydrogen bonds between pillar[n]arene and cucurbit
[n]uril rings (Fig. 28).
258 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 24 Synthesis and X-ray crystal structures of four constitutional isomers by cyclization of nonsymmetrical 1-butoxy-4-methoxybenzene with
paraformaldehyde.

Figure 25 Regioselective binding of the host–guest complex between nonsymmetrical pillar[5]arene with methoxy and pentyloxy rims and nonsym-
metrical guest 5-bromovaleronitrile. Reproduced with permission from Shu, X. Y.; Chen, W.; Hou, D. B.; Meng, Q. B.; Zheng, R. L.; Li, C. J. Chem.
Commun. 2014, 50(37), 4820–4823. Copyright 2014 Royal Society of Chemistry.

Perhydroxylated pillar[5]arene forms stable host–guest complexes with viologen; thus, viologen was introduced in the axles.
Copper-free alkyne–azide cyclization between the pseudo[2]- or pseudo[3]rotaxanes consisting of the viologen axles containing
azido groups at both ends and one or two pillar[5]arene wheels and a bulky cucurbit[6]uril stopper complex with one alkyne moiety
afforded two hetero[4]rotaxanes and one hetero[5]rotaxane in yields over 90%. The intermolecular hydrogen-bonding interaction
between the OH groups on pillar[5]arene and carbonyl groups on cucurbit[6]uril contributed to the high-yield formation of these
heterorotaxanes. They expanded the concept for the synthesis of hetero[4]rotaxane consisting of one pillar[6]arene and two cucurbit
[6]uril rings.87
Perhydroxylated pillar[n]arenes are composed of hydroquinone units. Hydroquinone is easily oxidized and converts to p-ben-
zoquinone and has therefore been used as a reducing agent. We investigated the reduction of polyaniline by a perhydroxylated pillar
[5]arene (Fig. 29).88
Pillar[5]arene reduced polyaniline more efficiently than hydroquinone. Formation of the poly(pseudorotaxane) structure
between polyaniline and pillar[5]arene wheels is the main reason why the pillar[5]arene ring acts as a stronger reducing agent
than the molecular hydroquinone. We also constructed a two-dimensional (2-D) planar sheet structure using the redox ability
of hydroquinone.89 Oxidation of the pillar[n]arene units from hydroquinone to benzoquinone by adding an oxidant contributed
to their 2-D supramolecular polymerization (Fig. 30) because intermolecular charge-transfer complexes formed between the hydro-
quinone and benzoquinone (quinhydrone) connected pillar[n]arene molecules. The 2-D supramolecular polymerization of
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 259

Figure 26 Self-assembly process of nonsymmetrical amphiphilic pillar[5]arene into microtubes. Reproduced with permission from Yao, Y.; Xue,
M.; Chen, J. Z.; Zhang, M. M.; Huang, F. J. Am. Chem. Soc. 2012, 134(38), 15712–15715. Copyright 2012 American Chemical Society.

Scheme 9 Synthesis of perhydroxylated pillar[n]arenes by deprotection of the alkoxy moieties of peralkylated pillar[n]arenes with BBr3.

Figure 27 Schematic representation of selective gas sorption and desorption by the activated crystals of perhydroxylated pillar[5]arene. Reproduced
with permission from Tan, L. L.; Li, H. W.; Tao, Y. C.; Zhang, S. X. A.; Wang, B.; Yang, Y. W. Adv. Mater. 2014, 26(41), 70277031. Copyright 2014
Wiley-VCH Verlag GmbH & Co. KGaA.

hexagonal pillar[6]arene molecules gave hexagonal 2-D porous sheets, whereas amorphous assemblies formed when pillar[5]arene
was used as a monomer. The highly symmetrical hexagonal structure of pillar[6]arene is very important to form 2-D hexagonal
sheets.

3.10.4.2 Perfunctionalized Pillar[n]arenes by Etherification

Etherification is a straightforward approach that can be used to functionalize pillar[n]arenes from perhydroxylated pillar[n]arenes.
Various functionalized pillar[5]arene derivatives are accessible by etherification of perhydroxylated pillar[n]arenes with alkyl
halides or alkyl tosylates in the presence of appropriate bases. Pillar[5]- and pillar[6]arenes with ester, cyclohexylmethyl, alkenyl
groups, and oligo(ethylene oxide) chains were synthesized by etherification of perhydroxylated pillar[5]- and pillar[6]arenes
with the corresponding alkyl halides or alkyl tosylates. Pillar[5]- and pillar[6]arenes with carboxylate anions and amine groups
were also accessible starting from pillar[5]- and pillar[6]arenes with ester moieties.
260 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Figure 28 Synthesis of hetero[4]- and hetero[5]rotaxanes consisting of pillar[5]arene and cucurbit[6]uril wheels by a copper-free alkyne–azide
cyclization reaction. Reproduced with permission from Ke, C. F.; Strutt, N. L.; Li, H.; Hou, X. S.; Hartlieb, K. J.; McGonigal, P. R.; Ma, Z. D.; Iehl, J.;
Stern, C. L.; Cheng, C. Y.; Zhu, Z. X.; Vermeulen, N. A.; Meade, T. J.; Botros, Y. Y.; Stoddart, J. F. J. Am. Chem. Soc. 2013, 135(45), 17019–17030.
Copyright 2014 American Chemical Society.

Figure 29 The reduction of polyaniline using perhydroxylated pillar[5]arene or hydroquinone. Reproduced with permission from Ogoshi, T.; Hase-
gawa, Y.; Aoki, T.; Ishimori, Y.; Inagi, S.; Yamagishi, T. Macromolecules 2011, 44(19), 7639–7644. Copyright 2011 American Chemical Society.

Pillar[n]arenes have planar chirality resulting from the position of the alkoxy substituents. The pS form converts to the pR form
by rotation of the pillar[n]arene units.90 Thus, if the rotation can be stopped, separation of the pS and pR forms should be possible.
Rotation of the units occurs in the case of pillar[5]arenes with linear alkyl chains.91 However, modification with bulky cyclohexyl-
methyl groups resulted in the inhibition of the rotation of the phenolic units and contributed to the separation of pS and pR forms
of pillar[5]arenes (Fig. 31A).33
Pillar[5]arenes carrying carboxylate anions (Fig. 31B),92 neutral amines,93 and tri(ethylene oxide)94 were soluble in aqueous
media. Therefore, aqueous media can be used as complexation media. Pillar[5]arene with 10 carboxylate moieties accommodated
paraquat as a guest with a relatively high association constant [K ¼ (8.2  1.7)  104 M 1],92 which is  70 times higher than the
corresponding association constant for the complex between perhydroxylated pillar[5]arene and paraquat in methanol.13 In
aqueous media, a hydrophobic–hydrophilic interaction synergistically stabilizes the host–guest complexation along with electro-
static and charge-transfer interactions. The first water-soluble pillar[6]arene, which was synthesized by Huang and coworkers by
introducing 12 carboxylate moieties, could capture paraquat in water with a high association constant (K ¼ (1.02  0.10) 
108 M 1),95 which is 1250 times higher than the anionic water-soluble pillar[5]arene.92 The reason is the size matching between
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 261

Figure 30 2-D supramolecular polymerization by oxidation of hydroquinone units of hexagonal perhydroxylated pillar[6]arene molecules. Repro-
duced with permission from Ogoshi, T.; Yoshikoshi, K.; Sueto, R.; Nishihara, H.; Yamagishi, T. Angew. Chem. Int. Ed. 2015, 54(22), 6466–6469.
Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 31 Perfunctionalized pillar[5]arenes by etherification. (A) Separation of planar chiral pillar[5]arene enantiomers by modification with bulky
cyclohexylmethyl groups. Water-soluble pillar[5]arenes by installing (B) carboxylate anions and (C) amphiphilic tri(ethylene oxide) chains.

pillar[6]arenes and paraquat. The size of the 4,40 -bipyridinium unit is suitable for the internal cavity of pillar[6]arenes ( 6.7 Å), but
not for that of the pillar[5]arenes ( 4.7 Å).
Pillar[5]- and pillar[6]arenes with tri(ethylene oxide) groups were also soluble in water at 25 C (Fig. 31C).53,94 Interestingly,
these solutions became turbid when heated to 50 C but became clear again when cooled to 25 C. The lower critical solution
temperature (LCST) behavior of these amphiphilic pillar[5]- and pillar[6]arenes was attributed to the combination between hydro-
philic tri(ethylene oxide) chains and the hydrophobic pillar[5]- and pillar[6]arene core. We successfully tuned the cloud point of
pillar[5]arene containing a tri(ethylene oxide) chain using a host–guest system using viologen as a guest and cucurbit[7]uril as
a competitive host.94 We have also demonstrated photoresponsive cloud point tuning using a photoresponsive host–guest system
between pillar[6]arenes and azobenzene derivatives.53

3.10.4.3 Perfunctionalized Pillar[n]arenes by the CuAAC Reaction

Pillar[n]arenes with alkyne and azide groups are useful key compounds because the CuAAC reaction is high yielding and very quick.
Pillar[5]arene carrying alkyne moieties has been accessible by two methods: cyclization of a dialkoxybenzene monomer with two
alkyne moieties and etherification of perhydroxylated pillar[5]arene with propargyl bromide (Scheme 10A).96,97
The synthetic pathway of pillar[5]- and pillar[6]arenes with azido moieties was established by Nierengarten et al. (Scheme
10B).98 First, the cyclization of the dialkoxybenzene monomer with two bromide moieties afforded pillar[5]- and pillar[6]arenes
with bromide moieties. Then, reaction of the pillar[5]- and pillar[6]arenes carrying bromide moieties with sodium azide afforded
pillar[5]- and pillar[6]arenes carrying azide moieties. Mannose-, ferrocene-, and mesogen-functionalized pillar[5]arenes have been
prepared by the CuAAC reaction of decaazide and dodecaazide with the corresponding monoalkynes.98–100 Pillar[5]arenes with
262 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry

Scheme 10 Perfunctionalized pillar[n]arenes by CuAAC reaction of (A) decaalkyne with monoazides or (B) decaazides and dodecaazides with
monoalkynes.

hexyl, benzyl, phenyl, pyrenyl, and azobenzene moieties have been synthesized by the CuAAC reaction between decaalkyne and the
corresponding azido derivatives.96,97,101–103 Pillar[5]arenes bearing 10 azobenzene moieties with different spacer lengths prepared
by the CuAAC reactions showed smectic liquid crystalline phases over a wide range of temperatures (Fig. 32),103 which were deter-
mined by Differential Scanning Calorimetry (DSC) measurements.
The observation of typical focal conic textures in both samples using polarized optical microscopy indicates the formation of
smectic liquid crystal mesophases. The lamellar periods were determined by small-/wide-angle X-ray scattering (SAXS/WAXS) anal-
ysis to be 72.4 and 59.7 Å, respectively. The lamellar distances of these systems were about 20% shorter than they were estimated
based on their molecular contour lengths, which suggested a partially interdigitated packing structure. The introduction of azoben-
zene moieties at all the substituents of pillar[5]arene resulted in pillar[5]arene derivatives showing liquid crystal properties.

3.10.5 Concluding Remarks

In this article, we have described the fundamental properties of pillar[n]arenes, including their synthesis, structure, functionaliza-
tion, and host–guest properties. Among them, one of the most important features of pillar[n]arenes compared with other host
molecules is their versatile functionalization. Numerous methods for the synthesis of mono-, di-, penta-, and perfunctionalized
pillar[n]arenes have been developed by different research groups. The superior solubility of pillar[n]arenes in organic media enables
the versatile functionalization of pillar[n]arenes because various organic reactions can be used in organic media. In particular, the
CuAAC reaction is the most powerful method to produce functionalized pillar[n]arenes because of the highly selective and reactive
nature of the CuAAC reaction. Based on the versatile functionality of pillar[n]arenes, they have been used as building blocks to
construct various supramolecular assemblies such as MIMs, vesicles, 2-D sheets, artificial transmembrane channels, nanocompo-
sites, and microporous materials. The versatile functionality of pillar[n]arenes will easily lead to the creation of numerous pillar
[n]arene-based supramolecular materials. However, we also need take advantage of the original features of pillar[n]arenes, such
as their highly symmetrical structures and alkane recognition by multiple CH/p interactions, to create new supramolecular
 Pillar[n]arenes: Versatile Macrocyclic Receptors for Supramolecular Chemistry 263

Figure 32 Liquid crystal pillar[5]arenes. (A) Chemical structures of azobenzene-modified pillar[5]arenes with different spacers (n ¼ 4, 10). (B)
Polarized optical micrographs of pillar[5]arenes with different spacers at 120 C. (C) DSC thermograms of pillar[5]arenes with different spacers in the
heating–cooling cycle. (D) Small-/wide-angle X-ray scattering (SAXS/WAXS) profiles in their liquid crystalline state (80 C). Reproduced with permis-
sion from Pan, S.; Ni, M. F.; Mu, B.; Li, Q.; Hu, X. Y.; Lin, C.; Chen, D. Z.; Wang, L. Y. Adv. Funct. Mater. 2015, 25(23), 3571–3580. Copyright 2015
Wiley-VCH Verlag GmbH & Co. KGaA.

materials that cannot be accomplished by other macrocyclic hosts. The unique properties and potential applications of pillar[n]are-
nes will make them a key player among various famous macrocyclic host molecules in future.

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 3.11 Trianglamines and Related Chiral Macrocycles
ski, M Kwit, and U Rychlewska, Adam Mickiewicz University, Pozna
J Gawron n, Poland
Ó 2017 Elsevier Ltd. All rights reserved.

3.11.1 Introduction 267

3.11.2 Synthesis 267
3.11.3 Supramolecular Structure and Properties 277
3.11.4 Applications 283
3.11.4.1 Chiral Discrimination 283
3.11.4.1.1 Chiral Anion Recognition 283
3.11.4.1.2 Neutral Guest Recognition 286
3.11.4.2 Asymmetrical Catalysis 287
Acknowledgment 291
References 291

3.11.1 Introduction

Chiral macrocycles of high symmetry are of interest not only due to their inherent beauty and their relevance to objects in real life
and in culture but also because of their applications in sciences, such as molecular building blocks and shape-persistent cages, chiral
catalysts, and chiral discriminating agents. One of the current, widely used methodologies for facile synthesis of macrocycles is
based on thermodynamically controlled imination reactions of dialdehydes with diamines. The readily formed polyimine macro-
cycles of regular structure can be easily reduced to cyclic polyamines.1–3 This methodology provides the means to control the struc-
ture of the products in the thermodynamically driven imination step, while product chemical stability and functional feasibility are
added in the reduction step.
In the obtained macrocycles, chirality originates from the use of enantiomerically pure diamine substrate of C2 symmetry,
either cyclic (trans-1,2-diaminocyclohexane, trans-1,2-diaminocyclopentane, and trans-3,4-diaminopyrrolidine) or acyclic
(threo-1,2-diphenyl-1,2-diphenylethane and threo-2,3-diaminobutanedioic acid). For comparison reasons, 1,2-diaminoethane
was occasionally used in place of its chiral congeners. The reaction initially requires combining equimolar amounts of a dialdehyde
and a diamine to form a cyclic product. This imination step determines the structure of the product, whereas the following step of
reduction of the imine functions makes the product chemically stable in the form of oligoamine. The most readily formed are
triangular products of [3 þ 3] cyclocondensation (Scheme 1).
The report4 of the successful, high-yield synthesis of triangular hexaimine 1 (later on called trianglimine5,6) and its reduction
product trianglamine 2 appeared at the turn of 20th century and soon received wide attention as a convenient and elegant method
of construction of chiral, symmetrical aza-macrocycles. Besides trianglamines 2, these aza-macrocycles include isotrianglimines 34 and
isotrianglamines 4, calixsalens 57 and calixsalans 6,8 and structurally related rhombimines 7 and rhombamines 8.9 Calixsalens and calix-
salans are distinguished by the presence of acidic phenol groups in the molecule, whereas isotrianglimines and isotrianglamines
contain additional nitrogen atoms in the heterocyclic rings.

3.11.2 Synthesis

Condensation of trans-1,2-diaminocyclohexane (DACH) with aromatic dialdehydes proceeds quickly at ambient temperature to
provide macrocyclic imines in high yield. The success of the synthesis is due to reversibility of the imination reaction, leading to a ther-
modynamically stable product of the reaction. In addition, there are structural factors, which contribute to favoring macrocyclization
over acyclic polycondensation. First, the molecules of the substrates should have limited flexibility, restricting the number of
conformers accessible at the temperature of the imination reaction. On the other hand, the formation of the most stable, cyclic struc-
ture under thermodynamic control requires that the adjustments are possible at the expense of the least energetically demanding
single-bond rotations in the molecules of intermediates. The structures of both DACH and aromatic aldehydes seem to ideally
suit these requirements. Both 1,4 (linear, 180 degree) and 1,3 (bent, 120 degree) aromatic dialdehydes can be used for macrocycli-
zation with 1,2-diamines; however, aromatic dialdehydes having a linear group arrangement, as in terephthalaldehyde, are ideally
geometrically predisposed to provide cyclic molecules with the generic name trianglimines (see Fig. 1 and Refs.4–17).
In the case of terephthalaldehyde, a thermodynamically stable product of [3 þ 3] cyclocondensation with DACH dominates
strongly over the [2 þ 2] product when the reaction is run in benzene, dichloromethane, tetrahydrofuran, or acetonitrile. Mass spec-
trometry analysis of the reaction products indicates that little (below 3%) of [2 þ 2] cyclocondensation product may be formed in
methanol solution.18 The condensation of terephthalaldehyde with cis-1,2-diaminocyclohexane, according to Gao and Martell,
gives a mixture of [2 þ 2] and [3 þ 3] cyclocondensation products. Trianglamine cis-2a could be isolated free from the cis-[2 þ 2]
product when the cycloimination and NaBH4 reductions were carried out as a one-pot reductive amination procedure.19 More

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12521-1 267

268 Trianglamines and Related Chiral Macrocycles

Scheme 1 Products of [3 þ 3] (A) and [2 þ 2] (B) cycloiminationdreduction of trans-1,2-diaminocyclohexane.

flexible (acyclic) diamines, such as threo-1,2-diphenyl-1,2-diphenylethane, react with dialdehydes to give, after reduction of the
imine bonds, the corresponding aza-macrocycles in lower yields.6,20
The syntheses of macrocyclic oligoimines are remarkable due to relatively low sensitivity of the yield of diamine–dialdehyde
condensation product to solvent polarity and to substrate concentration, which can be relatively high, usually at the 0.01–0.1 M level.
The ease of formation of trianglamine 2a by a two-step, one-pot procedure prompted the use of this reaction for the preparation
of [2]-catenane of 2a and b-cyclodextrin 9. Kuhnert and Tang carried out this reaction by condensation of the inclusion complex of
terephthaldehyde and b-cyclodextrin (1 equiv.) with terephthalaldehyde (2 equiv.), and DACH (3 equiv.) in methanol. After 2 days
at room temperature, a mixture of trianglimine and its catenane with b-cyclodextrin (3:1) was obtained, according to crude 1H NMR
spectrum. Since the trianglimine macrocycle is not chromatographically stable and the hexaimine catenane could not be isolated,
the reaction products were reduced with NaBH4, and the [2]-catenane 9 was isolated in 18% yield (Scheme 2).21 No X-ray deter-
mined structure of 9 could be obtained.
 Trianglamines and Related Chiral Macrocycles 269

Figure 1 Macrocyclic hexaamines 2, 4, and 6 (A) and tetraamines 8 (B) derived from DACH (aromatic dialdehyde groups in Ar are located as
shown in Scheme 1).

Scheme 2 Formation of trianglamine 2adb-cyclodextrin [2]-catenane (9).

270 Trianglamines and Related Chiral Macrocycles

Scheme 3 Imine macrocycles under thermodynamic equilibrium.

Condensation of DACH with aromatic 1,3-dialdehydes, such as isophthalaldehyde, is less selective compared with the reaction
of terephthalaldehyde discussed earlier. The [3 þ 3] cyclocondensation product was reported by us, and we proposed calling it iso-
trianglimine 3.4 However, reports of Kuhnert,10 Gotor,22 and Lisowski23 propose that there is a dynamic equilibrium in solution
between [3 þ 3], [2 þ 2], and [4 þ 4] cyclocondensation products. In fact, prolonged heating of the original [3 þ 3] DACHd1,3-
dialdehyde reaction product in dichloromethane solution or the use of a more polar alcohol as a solvent gave exclusively the ther-
modynamically controlled [2 þ 2] condensation product in the cases shown in Scheme 3.
According to a report of Gotor and coworkers,22 the condensation of DACH with pyridine-2,6-dicarboxaldehyde in methanol
solution yields products of [3 þ 3] and [2 þ 2] cyclocondensation in the ratio 64:36. Because of the presence of basic nitrogen atom
in the aldehyde molecule, the equilibrium mixture of the imine products could be shifted toward either of the two products by
metal ion coordination. Addition of an excess of Cd2 þ salt afforded [3 þ 3] product 4c exclusively, whereas [2 þ 2] product 10 could
be obtained by prior coordination with a Ba2 þ ion. This is in agreement with the earlier report of Fitzsimmons and Jackels who
obtained a [2 þ 2] cyclocondensation product with the yield 28% using the Ba2þ coordination procedure.24 From these complexes,
pure oligomeric hexa- or tetraamines could be obtained by NaBH4 reduction (Scheme 4). Moreover, Gotor and coworkers observed
a significant amplification of diastereoselectivity of the macrocycle forming reaction using racemic DACH as a substrate.25 1H NMR
study of methanol-d3 solution suggested the intermediacy of a-d3-methoxyamines in the reduction reaction. Because of its twisted
D2 symmetry structure, the reduced [2 þ 2] polyaziridine macrocycle 10 was used as a stereoselective receptor for dicarboxylates
under aqueous conditions.26 It is worth noting that enantiomerically pure hexaazamacrocyclic ligand 4c can assume either M or
P helical ring conformation in lanthanide(III) complexes. These diastereoisomers can be separated and characterized.27
According to Lisowski and coworkers,23 ESI mass spectrometry analysis of the reaction products of racemic DACH with pyridine-
2,6-dicarboxaldehyde in methanol, after reduction of the imine bonds, shows different results from those obtained by Gotor and
coworkers.22 The main product was the [2 þ 2] macrocycle meso-10, while the minor one was the [4 þ 4] cyclocondensation product
meso-11. Prior to the reduction of the imine groups, the macrocycles have shown limited dynamic stability.23
 Trianglamines and Related Chiral Macrocycles 271

Scheme 4 Effect of metal templates on the composition of dynamic library of oligoimines and derived oligoamines.

The group of Lisowski reported that similar reaction of (1R,2R)-1,2-diphenylethylenediamine with 2,6-diformylpyridine did not
give selectively the corresponding trianglimine product but rather a dynamic library of [2 þ 2], [3 þ 3], and [4 þ 4] macrocyclic Schiff
bases. However, the product of [2 þ 2] cyclocondensation 12 could be obtained selectively in a form of its Pb(II) complex, from
which the metal-free macrocycle could be obtained by NaBH4 reduction of the imine bonds (Scheme 5).20
Derivatives of isophthalaldehyde show significant steric effect of substituents in the vicinity of the aldehyde groups on their reac-
tivity, whereas 2,4,6-trimethoxy-substituted isophthalaldehyde reacts with DACH normally to give, after reduction with NaBH4, the
corresponding isotrianglamine 4e; 2,4,6-trimethylisophthalaldehyde fails to react.10
Since the imine-bond formation is reversible, the procedures of macrocycle isolation or purification, such as chromatography or
crystallization, may cause lowering the yield of the product. This is avoided by direct reduction of the imine to the amine bondsda
procedure that usually completes the synthetic reaction sequence.4 The reduction is carried out conveniently with NaBH4 in meth-
anol and tetrahydrofuran or their mixture as a solvent at ambient temperature. Under such conditions, the reaction is fast, and it can
be used to study the equilibrium of the imination reaction by freezing it out at the reduction step. The yields of the reduction reac-
tion are usually high, typically over 90%; however, the reduction is known to fail in cases when the imine substrate is of low
stability. Remarkably, the synthesis of trianglamine 2a is now simplified to a one-pot procedure of trianglimine formationdNaBH4
reduction, starting from inexpensive (R,R)-tartrate salt of (R,R)-DACH, with the 96% yield of the final isolated product.18 In a proce-
dure published by Gao and coworkers, trianglamine 2a was obtained as hexahydrobromide with an overall yield 90%.19 Deuterated
trianglamine 2a was prepared with the use of NaBD4 for the imine reduction step.28
In contrast, alternative synthetic route to symmetrical aza-macrocycles of DACH, based on direct alkylation of N,N0 -dialkyl-
DACH derivatives with di-(benzylic bromides), leads to other cyclic products. Padmaja and Periasamy have shown that the reaction
of (R,R)-N,N0 -diisopropyl-1,2-diaminocyclohexane with o-, m-, or p-xylylene dibromides gave predominantly products of [1 þ 1] or
[2 þ 2] condensations 13–15, in addition to other unspecified macrocyclic and oligomeric products. The [3 þ 3] condensation
product 16 was detected by MS only in the case of a reaction with the use of p-xylylene dibromide.29
272 Trianglamines and Related Chiral Macrocycles

Scheme 5 Selective formation of [2 þ 2] macrocycle 12.

Similarly, the reactions of aliphatic primary diamines with aromatic bis(bromomethyl) compounds gave macropolycyclic cage
compounds with very low yields.30
Structurally modified trianglamines can be obtained by the addition of C-nucleophile to the imine bonds in trianglimines or by
alkylation or acylation of the nucleophilic nitrogen in trianglamines. Savoia and coworkers synthesized C-hexamethyl, C-hexa-n-
butyl, and C-hexaphenyl trianglamines 17, 18, and 19 in high yield (over 94%) and a fully diastereoselective manner by the addi-
tion of the corresponding lithium reagents to trianglimine 1a. All the newly formed stereogenic centers had R configuration31,32
(Scheme 6).
 Trianglamines and Related Chiral Macrocycles 273

Scheme 6 Stereoselective addition of alkyl- and phenyllithium to trianglimine 1a.

N-methylation of trianglamine 2a is applicable to Eschweiler–Clarke reaction. The reaction of 2a with excess of formaldehyde–
formic acid afforded N-hexamethyltrianglamine 20 with the yield 71%.18 Furthermore, triaminal 21 was obtained in a good yield
just by condensing trianglamine 2a with paraformaldehyde.18 Formation of aminal bonds increases the rigidity of the aza-
macrocycle, which was lost in the process of reduction of the imines to secondary amine groups. As shown in the succeeding
text, macrocycle rigidity is important for the formation of shape-persistent porous organic solids.
Kuhnert and coworkers synthesized hexaacetyl derivative 22 in almost quantitative yield by acetylation of trianglamine 2a with
acetyl chloride, whereas the reaction with benzoyl chloride was reported as not complete.33 The N-alkylations can be performed
with alkyl or benzyl bromides to give the tertiary hexaamines or amides 23 in a high yield.18,33

1,3-Dibromopropane and 1,5-dibromopentane react with trianglamine 2a in acetonitrile in the presence of K2CO3 to give selec-
tively products of dialkylation of vicinal nitrogen atoms 24 and 25 with the yield 22–24%. No products of intermolecular dialky-
lation could be detected.33
274 Trianglamines and Related Chiral Macrocycles

Scheme 7 Synthesis of rhombimines 26 and 27 and rhombamines 28 and 29.

The first report of effective formation of a tetraimine macrocycle from acyclic 1,2-diamine and a dialdehyde derived from diphe-
nylmethane is due to Lehn and coworkers (Scheme 7).34
Their work demonstrated feasibility of imination reaction for the formation of [2 þ 2] cyclocondensation products of rhomb
shape (although the name of rhombimine was not introduced at that time). Reaction of 4,40 -diformyldiphenylmethane with equi-
molar amount of ethylenediamine in acetonitrile solution at a concentration 0.017 M at room temperature afforded rhombimine
26. After reduction with LiAlH4, rhombamine 28 was obtained in a good yield. Similar sequence of reactions has led to chiral tet-
raimine 27 and to tetraamine 29, derived from (R,R)-1,2-diaminobutanedioic acid.
In a general case, two molecules of DACH and two molecules of dialdehyde derived from diphenylmethane or diphenyl ether
condense to form a macrocycle having rhomb structural motif. It is now called rhombimine 7 and after reduction of the imine
bondsdrhombamine 8 (Scheme 1B). A number of rhombamines have been prepared in this way (Fig. 1). The difference in the
reaction products of DACH with 4,40 -diformyldiphenylmethane to form just [2 þ 2] cycloimination product and with isophthalal-
dehyde to form [2 þ 2] or [3 þ 3] cyclocondensation products seems to stem from the difference in size and flexibility of the dia-
ldehyde used as a substrate.
The formation of aza-macrocycles larger than [2 þ 2] or [3 þ 3] in thermodynamically driven cycloimination reactions is appar-
ently limited. The presence of [4 þ 4] and larger cyclocondensation products in the thermodynamically equilibrated imination reac-
tion has been reported;35 however, isolation of such molecules from the mixture has proved to be difficult. Nevertheless, the
synthesis of several structurally related oligoimines and oligoamines has been recently reported. These macrocyclization products
demonstrate the potential of thermodynamically driven cyclization reactions. Gregoli nski and coworkers developed a method of
conversion of thermodynamically formed [2 þ 2] macrocycle into an expanded [6 þ 6] macrocycle using a cadmium(II) template
effect and trans-1,2-diaminocyclopentane as a diamine in place of DACH. The structure of the expanded [6 þ 6] macrocycle could
be made stable by NaBH4 reduction of all 12 imine bonds, and the proposed structure of the cyclic polyamine product is shown in
Scheme 8.35
The X-ray structure of 30$12HCl is shown in Fig. 2.35 Based on this crystal structure, it has been postulated that in the neutral
macrocycle and in its imine precursor, the compartments consisting of two amine/imine nitrogen atoms attached to the cyclopen-
tane rings and the nearby situated pyridine nitrogen would accommodate the Cd(II) ions. Moreover, it has been anticipated that the
tendency of Cd(II) to coordinate to the three nitrogen atoms in each compartment is the origin of the unusual templation effect and
formation of large macrocycles and that the [6 þ 6] macrocycle may be the smallest symmetrical cycle that permits such a coordina-
tion pattern.
Lanthanide(III) complexation of chiral isotrianglamine 4c provides complex cation in which all nine nitrogen atoms of the mac-
rocycle coordinate to the metal ion and introduces two new sources of molecular chirality, that is, stereogenic centers at all nitrogen
atoms and helical twist of the macrocyclic ligand. Gregolinski and Lisowski reported a unique example of helicity inversion between
the kinetic and thermodynamic complexation products of a macrocyclic chiral isotrianglamine ligand and the isolation of both
products in diastereomerically pure form (Fig. 3). The process of the helicity inversion can also be observed by circular dichroism
(CD) spectroscopy, which reveals profound differences between the two forms.27
A further step forward in the development of the synthetic uses of cycloamination reactions was in the area of cage compounds.
These three-dimensional molecules can be readily constructed using cycloimination chemistry with tritopic substrate molecules.
 Trianglamines and Related Chiral Macrocycles 275

Scheme 8 Cd2 þ-templated formation of [6 þ 6] macrocycle 30$12HCl.

Figure 2 Top (A) and side (B) view of 30$12HCl: (A) the 6 outer chloride anions reside in characteristic 3 nitrogen compartments; (B) of the 12
chloride anions that balance the charge of the macrocycle, only 10 situated in NH/Cl hydrogen-bonding distances are displayed. The figure was
drawn based on data deposited in the CSD.36

The first synthesis of a cage, a three-dimensional analog of trianglimine, was reported by Skowronek and Gawronski in 2008.37
The reaction of DACH with 1,3,5-triformylbenzene afforded cleanly a tetrahedral dodecaimine 31 in almost quantitative yield
(Scheme 9). The unprecedented [6 þ 4] cyclocondensation was successful due to reversibility of the reaction, its error correction
capability, and production of a strain-free product of high symmetry (T). Similar features were observed previously in the case
of trianglimines.4 High symmetry of product 31 was confirmed by a very simple aromatic section of its 1H NMR spectrum,
276 Trianglamines and Related Chiral Macrocycles

Figure 3 Diastereoisomeric structures of opposite helicity induced by complexation of chiral isotrianglamine 4c with Yb(III): (A) (P)- and (B) (M)-
helicity. The figure was drawn based on data deposited in the CSD.36

Scheme 9 The formation of dodecaimine (31) and dodecaamine (34) cages.

 Trianglamines and Related Chiral Macrocycles 277

Figure 4 The solvated: (A) trianglamine cage 32, (B) the methylene-bridged trianglamine cage 33, and (C) collapsed monoaminal cage 34. The
figure was drawn based on data deposited in the CSD.36

consisting of just one singlet at d ¼ 7.9 ppm. Cooper and coworkers reported the synthesis of 31 on a large scale (over 100 g) and the
conversion of imine 31 in high yield to its fully reduced form 32 by NaBH4 reduction.38–40 They explored the rich and unexpected
properties of oligoamine 32. Remarkably, the molecule of amine cage 32 retains the tetrahedral shape of the parent imine cage 31
providing that methanol and water guests fill the pores in the structure. Desolvation of 32 by slow drying, supercritical fluid drying,
or solvent exchange resulted in an amorphous solid, showing no porosity to gases due to collapse of its cage cavity.41
Interestingly, the cycloimination reaction shown in Scheme 9 when carried out with vicinal diamines in the presence of trifluoro-
acetic acid did not lead to formation of a monomeric cage but to interlocked catenated dimeric cages via reversible imine-bond
formation.42
As in the case of triaminal 21, hexaaminal 33 could be readily obtained from dodecaamine cage 32 by the reaction with form-
aldehyde at 70 C. The “tied” hexaaminal cage 33 (Fig. 4A and B) retained the tetrahedral symmetry of the parent molecules, that is,
imine and amine and crystallized in the same F4132 space group with similar cell parameters. It shows shape persistence and
enhanced porosity, as well as unprecedented chemical stability toward acidic and basic conditions (pH 1.7–12.3).
The use of acetone as a carbonyl component resulted in the clean formation of monoaminal 34, most probably due to the steric
reasons limiting the number of reacting acetone molecules.41 X-ray data indicate that this new cage molecule crystallizes in the same
chiral cubic space group F4132, like the parent imine and amine cages, with comparable cell parameters. In view of the symmetry
braking taking place upon introduction of a single aminal ring into the cage molecule, the observed isostructuralism could only take
place if a single imidazolidine ring is disordered over the six diamine vertices. The crystalline solvate of the tied amine cage is stable
in the solid state up to around 300 C and also to immersion in water for 48 h. Reaction with a single acetone rigidifies the amine
cage 34 relative to the parent amine, but the molecule is still too flexible to retain permanent porosity. A slight loss in crystalline
order was observed after desolvation, and a further loss of crystallinity was apparent after gas sorption analysis. In addition, after
exposing the tied amine cage 34 to CO2 (5 bar), the formation of orthorhombic single-crystal phase has been noted (space group
P212121) (Fig. 4C). This phase comprised a conformation of a tied amine cage where the imidazolidine ring collapsed into the cage
cavity.
In summary, the broad knowledge accumulated over the past 15 years by several research groups in thermodynamically
controlled synthesis of cyclic oligoimines and oligoamines allows us to make simple generalizations. Using DACH as chiral diamine
and aromatic dialdehydes as electrophiles, trianglimines, products of [3 þ 3] cyclocondensation, are obtained in good to high yields,
using dialdehydes of linear structure, such as terephthaldehyde. Rhombimines, products of [2 þ 2] cyclocondensation, can be
cleanly synthesized from DACH and 4,40 -diformyldiphenylmethane and related dialdehydes. 1,3-Dialdehydes condense with
DACH and other vicinal diamines to form either isotrianglimines, products of [3 þ 3] cyclocondensation, or twisted rhombimi-
nesdproducts of [2 þ 2] cyclocondensation. In this case, the structure of the reaction product is highly dependent on the reaction
conditions and on the specific structural features of the reacting dialdehyde.

3.11.3 Supramolecular Structure and Properties

Whereas macrocyclic oligoimines have rigid, shape-persistent structures, products of their reduction, macrocyclic oligoamines, are
much more conformationally flexible. This is frequently demonstrated by low solubility of the former as opposed to free solubility
of the latter in organic solvents. Also, the 1H NMR signals of the latter frequently are not sharp at ambient temperatures due to
a slow rate of conformer interconversion, whereas macrocyclic imines usually produce one set of sharp signals.
Relative rigidity of the polyimine macrocyclic skeleton can be rationalized by the preference of each imine bond to one low-
energy conformation. Low-energy conformation of the imine group attached to the cyclohexane ring in DACH is shown in
Fig. 5. The two imine bonds are in equatorial positions; the diaxial conformation is much less favored. Furthermore, the imine
bonds have E configuration, and the imine hydrogen atoms are syn to the CH(N) atoms. This is consistently shown by molecular
structure calculations and by X-ray diffraction data.4,43
278 Trianglamines and Related Chiral Macrocycles

Figure 5 Preferred conformation of trans-1,2-diiminocyclohexane.

Figure 6 Top and side view of rigid trianglimine (A) and its reduced form 2a (B). The figure was drawn based on data deposited in the CSD.36

The reduction of the imine bonds renders the macrocycle more flexible while retaining formal D3 symmetry in the case of macro-
cycle 2a.22 We used a simple parameter to describe rigidity of the amine macrocycle, the sequence of ring torsion angles involving all
single bonds in the vicinity of DACH structural components, that is, a(a0 ) ¼ C(N)eC(N)eNeCH2 and b(b0 ) ¼ C(N)eNeCH2eC(Ar).
The two molecular frameworks present in the crystals of 2a and in its imine precursor are good illustrations of the situation and are
compared in Fig. 6, whereas trianglimine molecules in the crystal form nearly perfect equilateral triangles; trianglamine 2a molecules
display anti and gauche conformation around the a and b bonds, in some cases close to the limiting values of 150 and 30 degrees,
respectively. The molecular conformation is that of a twisted triangle, despite that it is stabilized by intramolecular hydrogen bonds
of the NeH/N type, which involve three out of six amine hydrogen atoms.
The conformers having all torsion angles aa0 bb0 equal trans (anti) are considered rigid, and such a case is observed for fully
protonated trianglamine 2a, its N-hexamethyl derivative 20, and triaminal 21.18 In these cases, the macrocycle has the most
expanded structure of all accessible conformers. Similar macrocycle structure frozen in all-trans conformation is seen in C-hexa-
phenyl trianglamine 19.31
Macrocyclic polyamines show unique structural and physicochemical properties with high potential for applications in supra-
molecular chemistry. They contain macrocyclic cavities with several basic nitrogen atoms, which are able to bind transition metal
cations, or when protonated, they may strongly bind anions. This property is observed even in aqueous solutions.44 Hodacová and
coworkers studied the binding of isomeric benzenetricarboxylic acids and 1,3,5-benzenetriacetic acid by trianglamine 2a. Potenti-
ometric titrations, NMR studies, and molecular modeling suggested a high degree of complementarity for the proposed structure of
2a with 1,3,5-benzenetricarboxylic acid (35).45
 Trianglamines and Related Chiral Macrocycles 279

Figure 7 (A) Top and side view of the protonated 2a; (B) packing of the protonated 2a molecules in crystal viewed along c direction (colors distin-
guish different z-levels); (C) a unique sixteen-membered water cluster situated in the intermolecular cavity formed around threefold symmetry axis.
The figure was drawn based on data deposited in the CSD.36

In crystals, the protonated trianglamine 2a in a form of the bromide salt is a highly symmetrical molecule, which utilizes a three-
fold axis.18 Crystals formed from such highly symmetrical and rigid molecules display both types of inclusion: intra- and intermo-
lecular. Water and methanol molecules, as well as bromide anions, separate the neighboring triangles in a sandwich-type mode,
Fig. 7.
Crystal structures of trianglamines with various included molecules differ.18 Trianglamine 2a on crystallization readily forms
inclusion complexes, both intra- and intermolecular, with solvents as guest molecules. The type of inclusion depends on the solvent,
whereas crystallization from ethyl acetate (which is apparently weakly bound and is easily removed from the host by drying in
vacuum at 70 C) gives crystals of 2a with mp 154–156 C, in which guest molecules occupy channels passing through the inner
cavities of the host molecules arranged in columnar stacks (Fig. 8A); crystallization from aromatic solvents provides channel inclu-
sion compounds of 2a, with different melting points and different types of channel inclusion (see Fig. 8B). For example, crystals
obtained from benzene, toluene, chlorobenzene, and hexafluorobenzene (1:1 molecular ratio) melt at 96–100 C and those ob-
tained from pyridine (2:1 host to guest ratio) have a much higher mp 193–196 C, indicating that intermolecular interactions
are much stronger in these complexes. Nonbonding host/guest interactions depend on the type of the included solvent molecule:
Aromatic solvent molecules tend to be involved in alkyl/aryl interactions, while alcohol molecules become acceptors of the NH/O
hydrogen bond. The flexible molecular frame of trianglamine is capable of opening or closing the entrance to the inner cavity, thus
either allowing or preventing intramolecular inclusion. In the various solvated crystals of trianglamines, the host molecules adopt
variable conformations depending on the type of the included solvent molecules and display disorder, which is another measure of
conformational flexibility.18
As shown by Tanaka and coworkers, trianglamine 2i having three azobenzene units and being consequently a larger macrocycle
forms inclusion compounds readily with aromatic guest molecules in the crystal. With benzene and toluene, the host to guest ratio
is 1:1; with xylenes, it is 2:1. In toluene-solvated crystals, triangular molecules pack densely in corrugated layers. The toluene solvent
molecules are included in molecular cavities and are situated roughly parallel to the main plane of the macrocycle (Fig. 9A).
However, the host molecules from the top and bottom layers are shifted with respect to the molecules from the reference layer,
which results in closing the entrance to the molecular cavity by means of three cyclohexane rings from both the top and the bottom
(Fig. 9B). In effect, no channel inclusion is observed.13
The methylene-bridged trianglamine 21, when crystallized from ethanol, shows solvent molecules accommodated in molecular
voids and the host molecules arranged in stacks.18 The stack axis, defined as perpendicular to the macrocycle mean plane, and the
channel axis do not coincide; this provides more space for inclusion of guest molecules (Fig. 10). The host/guest interactions
include NH/O and CH/p hydrogen bonds. The included molecules display a significant degree of disorder.

Figure 8 Trianglamine 2a molecules arranged in columnar stacks roughly perpendicular to the plane of the macrocycle and intramolecular inclusion
of ethyl acetate molecules depicted in ball-and-stick style (A). Inclusion complex of trianglamine with methyl benzoate molecules situated in intermo-
lecular channels (B). The figure was drawn based on data deposited in the CSD.28
280 Trianglamines and Related Chiral Macrocycles

Figure 9 (A) Supramolecular arrangement and intramolecular inclusion in crystals of 2i. The entrance to the molecular cavity of the host is closed
by the molecules from the neighboring layers (B). Two consecutive molecular layers differentiated by colors. The figure was drawn based on data
deposited in the CSD.36

Figure 10 Top and side view of the methylene-bridged 21 molecule in crystal (A) and the molecules arranged in columnar stacks with ethanol
solvent in intramolecular voids (B). The figure was drawn based on data deposited in the CSD.36

Similar macrocycle structure frozen in all-trans conformation is seen in C-hexaphenyl trianglamine 19.31 In crystals, the mole-
cules pack in columnar stacks (like the molecules of trianglamine in its complex with ethyl acetate, vide supra) with the acetonitrile
solvent molecules located in both intra- and intermolecular cavities, but each C-hexaphenyl trianglamine molecule in a stack is
separated from its neighbor by two sets of phenyl substituents. Consequently, the NH/N interactions operate solely between
host and guest molecules (Fig. 11).
The structure of isotrianglamine 4c was analyzed as was its hydrochloric salt. The X-ray diffraction analysis confirmed high
symmetry and rigidity of the protonated isotrianglamine. The salt contains seven chloride anions; six of them protonate

Figure 11 Top and side view of the C-hexaphenyl trianglamine macrocycle 19 (A) and the supramolecular arrangement of the molecules in crystal
(B). The figure was drawn based on data deposited in the CSD.36
 Trianglamines and Related Chiral Macrocycles 281

Figure 12 (A) C3-symmetrical protonated 4c with six chloride anions situated above and below the macrocycle mean plane. The seventh chloride
anion and the hydronium ion both occupy the threefold symmetry axis and (B) supramolecular architecture in crystalsdchloride ions and water mole-
cules are sandwiched between the layers of fully protonated isotrianglamine molecules. The figure was drawn based on data deposited in the CSD.36

cyclohexanediamine nitrogen atoms and are situated below and above the macrocycles arranged in (001) layers. The seventh chlo-
ride ion is located on a threefold axis passing through the middle of the molecule, filling the macrocyclic cavity and forming
hydrogen bonds with all of the ammonium groups of the macrocycle. The overall charge is balanced by the hydronium ion,
also situated on a threefold symmetry axis. All the pyridine heterocycles are twisted to the same side, transferring chirality
throughout the whole ring and forming a right-handed helical structure (Fig. 12).22
The structures of calixsalens (5) and calixsalans (6) are of special interest as they are strongly influenced by the formation of an
intramolecular hydrogen bond OH/N. For calixsalen, the main stereochemical features have been elucidated by 1H NMR, CD anal-
ysis, and ab initio calculations.7 There are two conformers, s-trans and s-cis1, whose structures are stabilized by the OH/N bond. The
s-trans structure is the most stable according to results of calculations at the DFT level. The structures existing in the equilibrium are
shown in Scheme 10.
As a result, the structure of the calixsalen molecule is vaselike, with the lower rim consisting of the methyl-substituted benzene
rings and the upper rim involving the phenol groups.
Whereas the calixsalen molecule has a rigid, shape-persistent structure,46 the product of its reduction, the calixsalan 6a, is much
more flexible and no longer displays a vaselike shape.8 The two skeletons have been compared in Fig. 13, which illustrates the cal-
ixsalen and calixsalan molecules present in crystals.
The crystal structure of the representative calixsalan molecule 6a was performed on single crystals grown by slow evaporation
from benzene. The macrocycle structure is stabilized by intramolecular (OeH/N and NeH/O) hydrogen bonds (Fig. 14A).
The molecules arranged in stacks along the c direction are joined together by NH/N hydrogen bonds (Fig. 14B). Crystallization
of 6a from methanol resulted in a solvated crystalline modification that is different from that obtained by Korupoju and Zacharias.8
In both crystal forms, the conformation of the macrocycle is very similar, so the main difference between the two forms is in the
crystal packing. Although in both forms the macrocycles are arranged in layers parallel to the (001) lattice planes, in crystals ob-
tained from benzene, these layers are stacked one on top of the other, while in the crystals grown from methanol, two different
types of layers are formed, and the molecules from one layer lie partially above the voids in the layer beneath. Additionally, the
crystal structure contains methanol molecules occupying both intra- and intermolecular voids (Fig. 14C).
Some rhombamines show size-dependent propensity toward formation of molecular complexes with neutral guest molecules.
Rhombamine 8a47 does not crystallize with solvent molecules. In crystals, the molecules of 8a are arranged in close-packed layers,
and the molecules in the neighboring layers are shifted with respect to each other. This results in a nearly complete close-up of the
entrance to the molecular cavity (Fig. 15A).17 Rhombamine 8d, obtained by Tanaka and coworkers, crystallizes from 1,4-dioxane in
a shape close to rhomb, with four guest molecules of 1,4-dioxane located in the cavity of the host molecules arranged in columnar
stacks (Fig. 15B).17
In summary, the overwhelming majority of so far investigated trianglamine and rhombamine molecules display inclusion prop-
erties in crystals. They tend to pack either in corrugated layers or in columnar stacks. In the former case, the molecules in the neigh-
boring layers are shifted with respect to the molecules in the reference layer. This kind of arrangement of host molecules leads either
to intermolecular inclusion of solvent molecules or to the inclusion in separated molecular cavities. In contrast to this, packing of

Scheme 10 Conformations of aromatic spacer in calixsalens involving OH/N bond.

282 Trianglamines and Related Chiral Macrocycles

Figure 13 Comparison of molecular shapes of (A) a vaselike-shaped calixsalen and (B) structurally more labile calixsalan 6a. The figure was drawn
based on data deposited in the CSD.36

Figure 14 (A) Conformation of 6a stabilized by intramolecular hydrogen bonds (dotted lined); supramolecular architecture viewed along c direction
in nonsolvated (B) and in methanol-solvated (C) crystals. Solvent molecules are not shown. The figure was drawn based on data deposited in the
CSD.36

Figure 15 (A) Supramolecular architecture of rhombamine 8a molecules that do not form inclusion compounds. The entrance to their inner cavities
is closed by cyclohexane rings belonging to the molecules (red and blue) situated above and below the reference molecule (green). The three
consecutive molecular layers are differentiated by colors. (B) Molecules of rhombamine 8d arranged in crystals in columnar stacks with dioxane
molecules (ball-and-stick representation) occupying channels running through the inner cavities of the macrocycle. The figure was drawn based on
data deposited in the CSD.36
 Trianglamines and Related Chiral Macrocycles 283

host molecules in columnar stacks leads to intramolecular inclusion in cavities arranged in columns that can in principle be con-
verted into intramolecular channels. Protonation of amine functionality or introduction of ring substituents in the macrocycle
results in positioning either the counter ions or the rings in between the neighboring host molecules, thus disturbing the formation
of regular stacks and replacing the NH/N hydrogen bonds operating between the host molecules by host/guest interactions.

3.11.4 Applications
3.11.4.1 Chiral Discrimination
Chiral tetra- and hexaazamacrocycles, such as rhombamines and trianglamines, are good chiral derivatizing agents for determina-
tion of relative configuration and enantiomer excess of the compound by NMR methods. This is due to the factors characterizing
these polyazamacrocycles: high symmetry, solubility in solvents of different polarities, the presence of nitrogen atoms and aromatic
residues, specific but modelable cavity size, and conformational mobility of the CSA molecules. These factors enhance enantiodis-
crimination of guest molecules by exerting chemical shifts due to aromatic ring current effects. Both chiral anionic and neutral guest
molecules are suitable for discrimination by macrocyclic derivatives of DACH. In general, rhomboidal macrocycles give better split-
ting of NMR signals compared with triangular ones, and the selectivity toward polar guests is enhanced if heteroaromatic fragments
constitute the selector’s skeleton. For the majority of selectors used so far, the useful spectral region in the 1H NMR spectra ranges
from 4.0 to 6.5 ppm.

3.11.4.1.1 Chiral Anion Recognition

The highly enantioselective discrimination of biologically important dicarboxylic anions 35–37 by the twisted macrocycle 10 was
demonstrated by Gotor and coworkers (Fig. 16).26,48
The combined potentiometric titrations, ESI-MS and NMR measurements, revealed that the receptor forms 1:1 supramolecular
complexes with both enantiomers of malate dianions (35a), in aqueous solution, in a wide pH range. The twisted macrocycle 10 of
all-R absolute configurations at the stereogenic centers forms a more stable complex with (S)-malate than with its enantiomer. The
enantioselectivity, measured here as the KS/KR ratio, is high in basic conditions and assumes the value 11.50. This corresponds to
a difference in the Gibbs free energies between the respective diastereomers equals to 6.12 kJ mol 1 (1.46 kcal mol 1). Under
neutral conditions, where the neutral diprotonated supramolecular complex [10$2Hþ$35a] predominates, the selectivity is still
high, and the KS/KR ratio equals to 6.76. Due to the protonation of the dicarboxylate that hampers the electrostatic interactions
with the azamacrocycle, the KS/KR ratio decreases to 3.89 at pH 2.26
The observed high enantioselectivity is explained by synergistic effect of electrostatic attractions, hydrogen bonding, solvophobic
interactions between the selector and the selectand, and, especially, the twisted conformation of the macrocycle. The lower stability
of the supramolecular complexes with the (R)-malate was confirmed by mass spectra measurements. The ESI-MS spectra showed
only peaks corresponding to the species [(R,R)-10$3Hþ$(S)-35a]þ and [(R,R)-10$4Hþ$(S)-35a]2 þ.
On the basis of NMR experiments and molecular modeling, the structures of diastereoisomeric complexes formed between
diprotonated (all-R)-10$2Hþ and respective malate dianion were proposed (Fig. 17). The diprotonated receptor itself is of D2
symmetry with all six nitrogen atoms at the vertices of octahedron, where the alternate secondary nitrogen atoms are protonated
(see Fig. 16B). The helical structure of (all-R)-10$2Hþ$is stabilized by a set of hydrogen bonds. The best fit of selector and selectand
is achieved for gauche conformer of the malate where the carboxylates bind to both ammonium groups. In the calculated structure of
the (all-R)-10$2Hþ$(R)-35a diastereoisomer, there is no hydrogen bond between the hydroxy group of the malate and b-carbox-
ylate group. This bond is characteristic for energetically more stable (all-R)-10$2Hþ$(S)-35a. The calculated energy difference
between diastereoisomeric complexes (3.75 kcal mol 1) is in a reasonably good agreement with the experimental data.

Figure 16 Structures of the dianionic chiral guests 35–37. In parentheses, the KS /KR selectivity ratios, measured at neutral pH conditions for
10$2Hþ$guest species, are given (A). Calculated structure of diprotonated 10$2Hþ (B). Dashed lines indicate the possible intramolecular hydrogen
bonds. Drawn on the basis of available Cartesian coordinates.26
284 Trianglamines and Related Chiral Macrocycles

Figure 17 The optimized geometries of the (all-R)-10$2Hþ$(S)-35a (A) and (all-R)-10$2Hþ$(R)-35a (B) complexes. Dashed lines indicate some
hydrogen bonds. Some hydrogen atoms in macrocycle skeleton were omitted for clarity. The figures were drawn on the basis on available Cartesian
coordinates.26

This study was extended to other biologically important dicarboxylates including free and N-acetylated amino acids (Fig. 16A).
Apart from the glutamic and phenylsuccinic acids, for the rest of analyzed selectands, the preference of (all-R)-10 for binding (S)- or
(S,S)-dianions is clearly visible.26
Macrocycle 10 and its congeners 38a–38e and 12 were used as CSA for a series of monocarboxylic acids.20,49,50

Peripheral modification of the macrocycle by implementation of ArCH2O group did not affect much its enantiodiscriminating
abilities.50
The enantiopure hexaazapyridinophanes 38a–38e have been used as CSA toward different a-hydroxycarboxylic acids. The
measured splitting of the CaH NMR signal varied from 0.05 ppm (for 38e and 40a) to 0.14 ppm (for 39a and 38d). This value
is slightly lower than that found for nonmodified macrocycle 10 (0.20 ppm; see Table 1). The upfield shift observed for the

Table 1 Selected splittings (DDd) of the CaH signals (in ppm) for diastereomeric complexes formed between macrocyclic selectors and carboxylic
acids

Selector (host)
Guest 10 a 38c b 8a c 8d d 2f e 6a f

39a 0.200 (1:4) 0.140 (1:4) 0.008 (1:4) 0.017 (1:4) – 0.042 (1:2)
39b – – 0.007 (1:4) 0.018 (1:4) – 0.018 (1:4)
40a 0.180 (1:4) 0.140 (1:4) 0.058 (1:4) 0.091 (1:4) 0.044 (1:10) 0.234 (1:4)
40c – – 0.034 (1:4) 0 (1:4) 0.066 (1:10) 0.061 (1:4)
40d – – 0.024 (1:4) 0.037 (1:4) 0.033 (1:4) 0.202 (1:4)
40f – – 0.014 (1:4) – 0.002 (4:1) – (1:4)
41a – – 0.104 (1:4) 0g (1:4) – 0.025 g,h (1:4)
41b – – 0.040 (1:4) 0g (1:4) – 0.030 g (1:2)

In parentheses, the optimal host to guest ratios (H:G) are given. Unless stated otherwise, the NMR spectra were recorded in CDCl3.
a
González-Álvarez, A.; Alfonso, I.; Gotor, V., Tetrahedron Lett. 2006, 47 (36), 6397–6400.
b
Busto, E.; González-Alvarez, A.; Gotor-Fernández, V.; Alfonso, I.; Gotor, V., Tetrahedron 2010, 66, 6070–6077.
c
Tanaka, K.; Nakai, Y.; Takahashi, H. Tetrahedron Asymmetry 2011, 22 (2), 178–184.
d
Tanaka, K.; Iwashita, T.; Sasaki, C.; Takahashi, H. Tetrahedron Asymmetry 2014, 25 (8), 602–609.
e
Gualandi, A.; Grilli, S.; Savoia, D.; Kwit, M.; Gawronski, J. Org. Biomol. Chem. 2011, 9 (11), 4234–4241.
f
Tanaka, K.; Fukuda, N. Tetrahedron Asymmetry 2009, 20 (1), 111–114.
g
Splitting of COCH3 signals was measured.
h
10% of acetone-d6 in CDCl3.
 Trianglamines and Related Chiral Macrocycles 285

Figure 18 Supramolecular complexes formed by (all-R)-38d and four molecules of (R)-40a (A) and (S)-40a (B). For the sake of clarity, the mandelic
carboxylate molecules are shown in blue color. The figure is based on literature data.50

diagnostic signals of the acids and the downfield move of the receptor signals suggested proton transfer from the selectand to the
selector. The optimal signal separation was obtained for a low ratio of the receptor (0.25 equiv.) to the acid. An increase of the selec-
tand’s amount caused complete disappearance of the splitting.
Molecular modeling calculations for the diastereoisomeric complexes formed by one molecule of tetraprotonated macrocycle
38d and four molecules of mandelic carboxylate in both enantiomeric forms showed that the receptor binds two carboxylates at
each face of macrocyclic ring (Fig. 18). Although the main binding interactions are of electrostatic origin, H-bonding and aryl–
aryl interactions are also involved. The complex with (R)-mandelate was calculated as more stable and more symmetrical than
that with (S)-mandelate.

Lisowski and coworkers proposed different approaches for the selector construction by changing the amine linker from trans-1,2-
diaminocyclohexane to threo-diphenylethylenediamine (12) or (S)-2,20 -diamino-1,10 -binaphthyl. The receptors were tested for a set
of carboxylic acid, including nonsteroidal antiinflammatory drugs.20 Enantiodiscrimination of acids was demonstrated by 1H NMR
spectra measurements, and DDd values reached 0.01 ppm. However, for baseline resolutions of the NMR signals, a large amount of
a macrocycle was required.
Expansion of internal cavity of the macrocycle makes diverse effect on its chiral discrimination properties. For rhombamines 8a
and 8d, addition of the phenyl ring to each rhombus side increased enantioselectivity determined by the difference in the chemical
shifts of diagnostic protons (see Table 1).17,47 Moreover, rhombamine 8d is selective not only for carboxylic acids but also for N-
protected amino acids. Among them, the largest chemical shift (DDd ¼ 0.214 ppm) was found for N-benzyloxycarbonyl-
phenylalanine. Based on NMR measurements, a possible recognition model for all-R 8a toward (R)-mandelic acid was proposed.
As expected, the model assumed hydrogen bonding between the carboxylate and the protonated amino group; however, the CH/p
286 Trianglamines and Related Chiral Macrocycles

Figure 19 Proposed by Tanaka, the enantiodiscrimination model for (all-R)-8a$4(R)-40a complex. The mandelic carboxylate molecules are shown in
blue color.

interactions between CaH hydrogen atoms of the guest and the aromatic rings of the host were considered as responsible for the
splitting (Fig. 19).
Both trianglamine and isotopically labeled trianglamine and calixsalan 6a were used as receptors for carboxylic and N-protected
amino acids.28,51–53 Kuhnert and coworkers used a combination of ESI-MS and ECD measurements for determination of diaster-
eoselectivity for binding acids 42–46 by isotopically labeled 2a. Although some preference for recognition of specific acids was
noted, the selectivity ratio was low (1.1:1.4), which precludes wider applications of these selectors.52
Modification of macrocycle structure by introducing an additional stereogenic center at the benzyl positions increases the ability
for enantiodiscrimination of a-substituted carboxylic acids.31 Among the macrocycles tested, the best results were obtained when
hexaphenyl-substituted macrocycle 19 was used as CSA. The optimal ratio between the selector and the selectand, allowing baseline
splitting of the signals in the 1H NMR spectrum, correlated well with the acidity of the guest. For example, for mandelic acid, the
optimal ratio is 10:1, which corresponds to a DDd ¼ 0.044 (see Table 1), however, in the case of weak O-acetylmandelic acid, the
H:G ratio allowing baseline separations of diastereomer’s signals in 1H NMR spectra changed to 1:0.25 (DDd ¼ 0.006 ppm). Gua-
landi et al. explained this phenomenon as the ability to complete proton transfer from the strong acid to the receptor in nonpolar
solvents. When further amounts of a strong acid are present, the multiprotonated species is formed, and there is no free acid in
solution. In effect, the increasing of DDd value was observed. The opposite effect was observed for weak acids.
In contrast, calixsalan 6a gave a good separations of diastereomer’s CaH signals in 1H NMR spectra for H:G ratios ranging
from 1:4 (guest ¼ 4-(trifluoromethyl)mandelic acid and DDd ¼ 0.340 ppm) to 1:2 (guest ¼ 3-chloromandelic acid and
DDd ¼ 0.043 ppm).53
In general, trianglamines and calixsalans may be treated as useful chiral shift reagents for the rapid determination of enantio-
meric excess and absolute configuration of carboxylic acids. However, still unknown mechanism of enantiodiscriminations results
in the lack of definitive determination of structural properties responsible for effective binding of chiral polar guests and thus sepa-
ration of the specific proton NMR signals.

3.11.4.1.2 Neutral Guest Recognition

Formally, D3-symmetrical structure of trianglamine 2a and its ring-expanded congener 2f provides suitable chiral environment for
neutral guests, such as secondary alcohols and diols 47–49.54
The binding is achieved through various interactions such as hydrogen bonding, p–p aromatic stacking, and CH–p interactions.
Although some promising results were obtained for a series of secondary alcohols and diols, the baseline resolution of respective
methine signals of selectand was obtained for carbinols with electronegative group in the carbon skeleton.
 Trianglamines and Related Chiral Macrocycles 287

Table 2 Selected splitting (DDd) of the CaH signals (in ppm) for diastereomeric complexes
formed between trianglamine selectors 2a and 2f and neutral guests

Trianglamine
Guest 2a 2f

47a 0.064 (1:1) 0.011 (2:1)

47b 0.040 (1:1) 0.064 (2:1)
47c 0.059 (1:1) 0.009 (1:1)
47d 0.032 (1:1) 0 (1:1)
48 0.099 (1:1) 0.035 (1:1)
49 0 (1:1) 0 (1:1)

In parentheses, the optimal host to guest ratios are given.

Data taken from Ref. 49.

In general, the smaller trianglamine 2a performs better as CSA than 2f. For better signal splitting, the presence of an electroneg-
ative group attached to the stereogenic center seems to be more important than the presence of an aromatic ring in the selectand
structure. The host to guest ratio, optimal for the best recognition, depends on the host structure, and for 2a and simple alcohols
such as mandelonitrile, it is 1:1, whereas for 2f, the optimal host to guest ratio is 2:1 (see Table 2). 1H NMR titration experiments
provided additional information about the stereostructure of the guests. For the majority of cases, the R absolute configuration of
the guest correlates with the upfield shift of the respective proton signals in 1H NMR spectra.54

3.11.4.2 Asymmetrical Catalysis

The presence in macrocyclic skeleton vicinal nitrogen atoms and other functional groups, all in the chiral environment, constitutes
a unique combination of functionalities of large potential in the asymmetrical synthesis. However, the initial attempts to use tri-
anglamines as organocatalyst in aldol or nitroaldol reactions (Scheme 11) did not provide satisfactory results (enantiomeric
excesses determined for the products remained below 40%; see Table 3, entry 1).19,55
A more significant role in the catalytic asymmetrical synthesis play of complexes of chiral, symmetrical polyamines and tran-
sition metals. Contrary to the vast majority of optically active ligands, where only one metallic center is incorporated, triangl-
amines and related compounds allow to utilize of up to three binding sites within the same macrocycle. Thus, chiral
multinuclear complexes may act in a similar way to that of metalloenzymes. Zinc complexes of trianglamine of various
metal–ligand stoichiometries were tested by Gao as catalysts in aforementioned aldol and nitroaldol reactions. The catalytically
active species were formed in situ by adding one, two, or three equivalents of diethylzinc to the reaction mixture containing
trianglamine ligand. The highest enantioselectivity was achieved with the use of trinuclear zinc complex, and the asymmetrical
induction level gradually increased with increasing of the number of zinc ions incorporated within the macrocycle cavity
(Table 3, entries 2–4). Under the same reaction conditions, the complex formed between (R,R)-N,N0 -dibenzyl-1,2-
diaminocyclohexane and diethylzinc gave the product with only 32% ee, further indicating the cooperative effects in the tri-
nuclear catalyst. The structure of the trinuclear metal–trianglamine complex 2a(ZnEt2)3 proposed by Martell and Gao is
unusual because of zinc oxidation state þ 4. Replacing the six-membered aromatic rings by heteroaromatic thiophene units
in the catalyst skeleton further increased the level of asymmetrical induction, although at the expense of the isolated yield
of the product (Table 3, entries 5–7).
The direct observation of the cooperative effect between metallic centers in a Zn–calixsalan complex was reported by Gao et al.56
The conformations of the macrocycle in the free ligand 50 and in trinuclear zinc complex [Zn36a](ClO4)3 are similar. Three chiral

Scheme 11 Model aldol (A) and nitroaldol (N) reactions.

288 Trianglamines and Related Chiral Macrocycles

Table 3 Effect of the catalyst structure and quantity (mol%) on yields, asymmetrical inductions (ee), and
absolute configurations (AC) of products of model aldol (A) and nitroaldol (N) reactions (according to Scheme 11)

Entry Reaction Catalyst Mol% Yield (%) ee (%) AC

1a A 2a 5 93 37 R
2a A 2a$ZnEt2 5 93 42 R
3a A 2a$2ZnEt2 5 92 48 R
4a A 2a$3ZnEt2 5 95 57 R
5b N 4g$ZnEt2 5 53 51 S
6b N 4g$2ZnEt2 5 63 57 S
7b N 4g$3ZnEt2 5 68 75 S
8c A ent-6a$ZnEt2 1 57 39 S
9c A ent-6a$2ZnEt2 1 86 86 S
10c A ent-6a$3ZnEt2 1 95 94 S
11c N 50$ZnEt2 1 44 45 S
12c N 50$2ZnEt2 1 67 84 S
13c N 50$3ZnEt2 1 84 92 S
14d Ne 2a$Cu(OAc)2 3 78 82 R
15d Ne 4a$Cu(OAc)2 3 62 86 R
16d Ne 2f$Cu(OAc)2 3 40 79 R
17d Ne 2e$Cu(OAc)2 3 15 58 R
18f Ng 2a$3Cu(OAc)2 5 93 84 R
19f Ng 17$3Cu(OAc)2 5 76 46 S
20f Ng 19$3Cu(OAc)2 5 72 19 R
a
Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1 (15), 2795–2800.
b
Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2801–2806.
c
Gao, J.; Zingaro, R. A.; Reibenspies, J. H.; Martell, A. E. Org. Lett. 2004, 6, 2453–2455.
d
Tanaka, K.; Hachiken, S. Tetrahedron Lett. 2008, 49 (16), 2533–2536.
e
Solvent-free conditions, 0 C.
f
Savoia, D.; Gualandi, A.; Stoeckli-Evans, H. Org. Biomol. Chem. 2010, 8 (17), 3992–3996.
g
EtOH, 0 C, 18 h.

diamine backbones form an equilateral triangle where N2O2 cavities are proximal to each other and allow the formation of multi-
nuclear chiral complexes containing three equal subunits in the same chemical and configurational environment (Figs. 13 and 20).

Intramolecular cooperative effect of the catalytic centers was demonstrated in a simple way (Table 3, entries 8–13). The enan-
tioselectivity of aldol and nitroaldol reactions catalyzed by 3 mol% of mononuclear Zn–calixsalan complex was much lower than
that catalyzed by 1 mol% of trinuclear complex.56

Figure 20 X-ray crystal structures of trinuclear [ent-6a$Zn(II)3](ClO4)3 (A) and 2a$3Cu(OAc)2 (B) complexes. Some hydrogen atoms and water
molecules are omitted for clarity. The figure was drawn based on data deposited in the CSD.36
 Trianglamines and Related Chiral Macrocycles 289

Scheme 12 Asymmetrical Zn-catalyzed hydrosilylation of prochiral ketones and imines.

The ability to bind up to three metals within the macrocycle cavity was successfully employed by Song et al. for highly enantio-
selective synthesis of esomeprazole, through 50$Ti-catalyzed oxidation of pyrmetazole. After optimization of the reaction condi-
tions, the multigram synthesis of sodium salt of esomeprazole was successfully carried out with 72% of total yield and very
high enantiomeric and chemical purity.57
The opposite conclusions regarding cooperativity were obtained by Gajewy et al. In the zinc-catalyzed asymmetrical hydrosily-
lation (AHS) reactions of various prochiral ketones (Scheme 12), the best results in terms of yield and enantioselectivity were ob-
tained for mononuclear 2a$ZnEt2 trianglamine–zinc complex.58,59 The level of asymmetrical induction decreased stepwise with
increasing the amount of diethyl zinc equivalents incorporated within the macrocycle cavity (Table 4, entries 1–3).
The calculated structure of mononuclear 2a$Zn(II) complex (shown in Fig. 21A) is close to the lowest energy conformation of
the free ligand18 and resembles the structure of ruthenium and rhodium species used for asymmetrical hydrogenations. The mono-
nuclear 2a$Zn(II) complex consists of two occupied and two unoccupied quadrants, the latter accessible to approaching substrates.
The role of sterical hindrance in the occupied quadrants can be ascribed to two of the three apexes of the triangle.58
The systematic variation of the reaction conditions led to conclusion that for effective asymmetrical induction, only 3.5 mol% of
the catalyst is required and the best reducing agents are diphenylsilane or poly(methoxyhydro)silane (PMHS). The highest enan-
tiomeric excess (92%) was achieved for ketones of significant difference in the size of carbonyl group substituents (cyclohexyl
vs. phenyl).
Modification of macrocycle skeleton as ligand has little effect on enantioselectivity and chemical yield of the reaction (Table 4,
entries 4–6).32 Activating the catalyst by addition of achiral or chiral diols as coligands significantly improved conversion of the
substrate and the isolated yield of the products, at the expense of the level of enantioselectivity of the product.59
Similar conditions were used for the Zn–trianglamine-catalyzed asymmetrical hydrosilylation of prochiral imines. The best
results (> 99% ee and 75% of yield) were achieved with the use of 5 mol% of the catalyst in toluene. This reaction could be carried
out also in protic media with negligible loss of enantioselectivity (Table 4, entries 7–9).60
The well-known ability of nitrogen-containing ligands to form complexes with copper was efficiently employed in Cu–
trianglamine-catalyzed asymmetrical Henry reaction (Scheme 11) under solvent-free conditions.11 The mononuclear Cu(OAc)2–
trianglamine complex was formed by simply stirring of equimolar amounts of copper acetate and 2a in dichloromethane solution.
Optimization of the model reaction conditions led to conclusion that the best enantioselectivity and chemical yield could be achieved
when the reaction was carried out at 0 C in open vial, for 48 h, using 3 mol% catalyst. Both trianglamine 2a and isotrianglamine
4a used as ligands provided a good chemical yield and enantioselectivity. Enlarging of the macrocycle cavity or decreasing of its
conformational flexibility led to a decrease of the asymmetrical induction level (Table 3, entries 14–20).
The Cu–trianglamine catalysis was expanded to solvent-free aldol reactions between cyclic aliphatic ketones and nitrobenzalde-
hyde. This reaction afforded anti-aldols as the major products with up to 93% ee, and ball milling was prerequisite to achieve high
enentioselectivities. Under conventional stirring, the reaction between cyclohexanone and 4-nitrobenzaldehyde, in neat liquid, gave
the product with only 4% yield and 63% ee, while ball milling led to the same product with 92% ee and 82% yield.61

Table 4 Effect of the catalyst structure on asymmetrical induction in AHS of acetophenone (entries 1–6)
and P,P-diphenyl-N-(1-phenylethylidene)phosphinic amide (entries 7–9)

Entry ZnL* Mol% ee (%)

1a 2a$ZnEt2 3.5 88
2a 2a$2ZnEt2 3.5 73
3a 2a$3ZnEt2 3.5 63
4a 4a$ZnEt2 3.5 82
5a 2f$ZnEt2 3.5 78
6a 8a$ZnEt2 3.5 61
7b 2a$ZnEt2 5.0 > 99
8b 2a$ZnEt2 5.0c > 99
9b 2a$ZnEt2 1.0c,d 98

All reactions were carried out in toluene with the use of Ph2SiH2 as hydride source.
a
Gajewy, J.; Kwit, M.; Gawronski, J. Adv. Synth. Catal. 2009, 351 (7–8), 1055–1063.
b
Gajewy, J.; Gawronski, J.; Kwit, M. Org. Biomol. Chem. 2011, 9 (10), 3863–3870.
c
Reaction was carried out in MeOH.
d
PMHS was used as reducing agent.
290 Trianglamines and Related Chiral Macrocycles

Figure 21 Calculated at the B3LYP/6-31G(d) level, the lowest energy structures of 2a$Zn(II) (A), 2a$2Zn(II) (B), and 2a$3Zn(II) (C) complexes.
Some hydrogen atoms were omitted for clarity.58

Trianglamine 2a was the best choice among the ligands tested. Another important parameter was the type of metal ion. In terms
of diastereo- and enantioselectivity, the best results were obtained when Co(II) was used, followed by Cu, Zn, and Ni ions. Addition
of more than one equivalent of the metal salt to the reaction mixture caused decrease of enantiomeric excess, diastereoselectivity,
and the yield of the aldol product. Although it was not possible to obtain the crystals of mono- or dinuclear Cu–trianglamine
complex, unexpectedly, the 1:3 complex between trianglamine 2a and Cu(OAc)2 was obtained (Fig. 20B). The most characteristic
feature of the complex is its triangular capsule-like structure where all the metal centers occupy the position outside the macrocycle
cavity. This may explain the low level of asymmetrical induction obtained when trinuclear Cu–trianglamine complexes were used as
catalysts.
Wang et al. reported synthesis of imidazolium salt (51) of trianglamine 2a in a reaction with trimethylorthoformate in xylene.
Subsequent reaction of 51 with silver oxide in DMSO within 2 days gave trinuclear Ag3(NHC)2 complex 52 of tubular structure
(Scheme 13). Although the synthesis and the structure of 52 itself are interesting, its catalytic abilities were not fully tested. The
data available so far indicate poor asymmetrical inductions in the Strecker reaction.62

Scheme 13 Synthesis and X-ray determined structure of 52. The hydrogen atoms were omitted for clarity. The figure was drawn based on data
deposited in the CSD.36
 Trianglamines and Related Chiral Macrocycles 291

Acknowledgment

This work was supported by National Science Center of Poland, grant no. UMO-2012/06/A/ST5/00230.

References

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3. Srimurugan, S.; Suresh, P.; Babu, B.; Pati, H. N. Mini Rev. Org. Chem. 2008, 5 (3), 228–242.
4. Gawronski, J.; Ko1bon, H.; Kwit, M.; Katrusiak, A. J. Org. Chem. 2000, 65 (18), 5768–5773.
5. Kuhnert, N.; Straßnig, C.; Lopez-Periago, A. M. Tetrahedron: Asymmetry 2002, 13 (2), 123–128.
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7. Kwit, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14 (10), 1303–1308.
8. Korupoju, S. R.; Zacharias, P. S. Chem. Commun. 1998, 12, 1267–1268.
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10. Kuhnert, N.; Rossignolo, G. M.; Lopez-Periago, A. Org. Biomol. Chem. 2003, 1 (7), 1157–1170.
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12. Hodacová, J.; Budesínský, M. Org. Lett. 2007, 9 (26), 5641–5643.
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14. Kuhnert, N.; Burzlaff, N.; Patel, C.; Lopez-Periago, A. Org. Biomol. Chem. 2005, 3 (10), 1911–1921.
15. Koby1ka, M. J.; Slepokura, K.; Acebrón Rodicio, M.; Paluch, M.; Lisowski, J. Inorg. Chem. 2013, 52 (22), 12893–12903.
16. Gawronski, J.; Kwit, M.; Grajewski, J.; Gajewy, J.; D1ugokinska, A. Tetrahedron: Asymmetry 2007, 18 (22), 2632–2637.
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23. Gregolinski, J.; Lisowski, J.; Lis, T. Org. Biomol. Chem. 2005, 3 (17), 3161–3166.
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25. González-Álvarez, A.; Alfonso, I.; Gotor, V. Chem. Commun. 2006, 21, 2224–2226.
26. González-Álvarez, A.; Alfonso, I.; Díaz, P.; García-España, E.; Gotor-Fernández, V. J. Org. Chem. 2008, 73 (2), 374–382.
27. Gregolinski, J.; Lisowski, J. Angew. Chem. Int. Ed. 2006, 45 (37), 6122–6126.
28. Kuhnert, N.; Le-Gresley, A.; Nicolau, D. C.; Lopez-Periago, A. J. Label. Compd. Radiopharm. 2007, 50 (13), 1215–1223.
29. Padmaja, M.; Periasamy, M. Tetrahedron: Asymmetry 2004, 15 (15), 2437–2441.
30. Kon, N.; Takemura, H.; Otsuka, K.; Tanoue, K.; Nakashima, S.; et al. J. Org. Chem. 2000, 65 (12), 3708–3715.
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 3.12 Amino Acid-Based Receptors
S Kubik, Kaiserslautern University of Technology, Kaiserslautern, Germany
D Mungalpara, Kaiserslautern University of Technology, Kaiserslautern, Germany
Ó 2017 Elsevier Ltd. All rights reserved.

3.12.1 Introduction 293

3.12.2 Recognition Mediated by Backbone Peptide Groups 294
3.12.3 Arginine-Derived Receptors 298
3.12.4 Histidine-Derived Receptors 302
3.12.5 Tryptophane-Derived Receptors 303
3.12.6 Serine/Threonine-Derived Receptors 304
3.12.7 Cysteine-Derived Receptors 304
3.12.8 Aspartate/Glutamate-Derived Receptors 306
3.12.9 Lysine-Derived Receptors 307
3.12.10 Conclusions 308
References 308

Nomenclature
ADP Adenosine diphosphate HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid
Ala Alanine His Histidine
AMP Adenosine monophosphate HPNP 2-Hydroxypropyl 4-nitrophenyl phosphate
Arg Arginine Ile Isoleucine
Asp Aspartate Leu Leucine
ATP Adenosine triphosphate Lys Lysine
Bn Benzyl Me Methyl
Boc tert-Butyloxycarbonyl Ph Phenyl
Cbz Benzyloxycarbonyl Pro Proline
GCP Guanidiniocarbonylpyrrole TRIS Tris(2-aminoethyl)amine
Glu Glutamate UMP Uridine monophosphate
Gly Glycine Val Valine
GTP Guanosine triphosphate

3.12.1 Introduction

Proteins play pivotal roles in the majority of biochemical processes. Their various functions generally depend decisively on the selec-
tive recognition of a respective substrate or cofactor. Substrate binding usually occurs within clefts along the protein surface or inside
of cavities buried within the folded protein chains. High selectivity of binding is achieved by a combination of various factors that
include size and shape complementarity of the protein binding site and the substrate molecule, in addition to specific interactions
between functional groups in the substrate with ones along the protein backbone. Of the 20 proteinogenic amino acids, mainly the
ones containing polar functional groups in their side chains contribute to these direct attractive interactions. In addition, the peptide
groups along the protein backbone are usually involved in substrate recognition. The number of functional groups available for
protein–substrate interactions is therefore relatively limited, yet the diversity of substrates that can be bound by proteins is enor-
mous ranging from a large variety of neutral organic compounds to organic or inorganic anions, cations, metal ions, etc. This versa-
tility is possible because the well-defined folding of protein chains allows a precise three-dimensional positioning of the available
functional groups along the binding sites. In addition, the functional groups in the proteinogenic amino acid side chains offer
binding elements for any type of substrate, for example, hydrogen bond donors (NH and OH groups), hydrogen bond acceptors
(oxygen and nitrogen atoms), groups for interaction with cations (carboxylate groups and aromatic residues) or anions (ammo-
nium, imidazolium, and guanidinium groups), or Lewis-basic groups for coordination to metal ions (imidazole and thiolate).
An attractive strategy in supramolecular chemistry to mimic nature’s versatility and efficiency in molecular recognition relies on
using the building blocks of proteins and incorporating natural amino acids or longer peptide fragments into a synthetic receptor.1
In this article, a selection of receptors is presented to illustrate the potential of this approach. These receptors are classified according

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12528-4 293

294 Amino Acid-Based Receptors

to the amino acid they contain or mimic, thus allowing a comparison of the binding properties of a receptor and its natural
counterpart.

3.12.2 Recognition Mediated by Backbone Peptide Groups

Backbone peptide groups are available in every protein and are, therefore, extensively used for substrate recognition in natural and
synthetic systems. Importantly, the polar nature of the peptide bond allows interactions with cations or hydrogen bond donors
through the carbonyl group, while anions can be bound via hydrogen bonding to the NH part (Fig. 1). Mimicking these types
of interactions can easily be achieved by simply incorporating an amide group into a receptor. The numerous examples of macro-
cyclic or macrobicyclic lactams are examples of this approach.2 In this section, we concentrate on receptors in which peptide groups
of amino acid residues are used for substrate binding.
Early approaches in the development of amino acid-based receptors aimed at mimicking the antibiotic properties of valinomy-
cin 1, a macrocyclic depsipeptide that efficiently and very selectively transports potassium ions across bacterial cell membranes.3
Potassium binding causes the valinomycin ring to adopt a conformation with six hydrogen bonds between each NH group and
the carbonyl group of the following valine moiety. In this conformation, the six remaining carbonyl groups point into the center
of the cavity where they can coordinate to the potassium ion. The Ovchinnikov and Gisin groups systematically studied the effects of
exchanging individual subunits along the valinomycin ring or of changing ring size on cation affinity.4,5 Also inverting the config-
uration of individual subunits was probed, as was replacement of hydroxycarboxylic acid and/or amino acid subunits with appro-
priate analogs. Incorporation of rigid proline units, in particular, provided information about how binding properties of these
valinomycin mimics are affected by their structure.
The use of nonnatural cyclopeptides as macrocyclic hosts for molecular recognition was pioneered by Blout and coworkers.6 In
this context, it was shown, for example, that cyclopeptide 2 (Chart 1) containing glycine and L-proline subunits binds to alkali and
earth alkaline metal ions, as well as ammonium ions, in aqueous solvent mixtures. Kojima and coworkers used N,N0 -ethylene
bridged dipeptide subunits to restrict the conformational mobility of cyclopeptides and to avoid intramolecular hydrogen bond
formation.7 The corresponding macrocyclic hosts 3 and 4 were shown to interact with divalent alkaline earth, transition metal
ions, and chiral ammonium ions. Compound 4 also enantioselectively transports chiral a-amino acids across liquid membranes.
In comparison to work involving cation binding to peptide C]O groups, significantly more studies addressed anion binding to
amide NH groups of amino acid-based receptors.1 Also in this context, the incorporation of rigid nonnatural amino acid subunits
into a macrocyclic receptor proved to be a valuable approach to improve binding properties. These subunits prevent the intramo-
lecular conformational collapse of the macrocycle resulting in solvent-exposed binding sites and a well-defined cavity for guest
complexation. An important step toward such hosts was made by Ishida and coworkers who introduced cyclohexapeptide 5 as
a receptor for phosphate esters in DMSO (Chart 2).8
Peptide 5 features an alternating sequence of alanine and 3-aminobenzoic acid subunits. This compound was shown to form
a 1:1 complex with 4-nitrophenyl phosphate in DMSO, which has a stability constant of 1.2  106 M 1. The underlying interactions
involve hydrogen bonds between the cyclopeptide NH groups and the oxygen atoms of the guest.
Extensive studies were also performed in the Kubik group to systematically investigate and optimize the receptor properties of
cyclopeptides containing 3-aminobenzoic acid moieties or derivatives thereof. Most cyclopeptides studied in this context contained
proline subunits as the natural amino acid, which were expected to improve the conformational rigidity. Work initially addressed
binding of quaternary ammonium ions or ion pairs to cyclopeptide 6a (Chart 2).9 Later, the 6-aminopicolinic acid-containing
analog 6b was developed, which was shown to efficiently bind to halide and sulfate anions even in highly competitive aqueous
solvent mixtures such as 80% water/methanol.10 On the basis of this finding, further investigations were performed to understand
the unusual binding properties of 6b and further improve them. This work has been reviewed and will therefore not be explained in
detail here.11
Other cyclopeptide-based receptors with aromatic building blocks are 7 containing 8-amino-4-isobutoxyquinoline-2-carboxylic
acid and 8a–c containing, respectively, imidazole, oxazole, or thiazole units (Chart 3). All of these receptors were shown to bind
anions, 7 most efficiently fluoride in acetonitrile,12 while cyclopeptides deriving from the Lissoclinum cyclopeptide alkaloids such as
8a–c recognize oxoanions, in particular, H2PO4 .13 High sulfate affinity was detected for the structurally related cyclopeptide 9
developed in the Jolliffee group.14 Although substrate recognition is predominately mediated by the thiourea groups in the side

Figure 1 Binding modes of the peptide group.

 Amino Acid-Based Receptors 295

Chart 1 Valinomycin 1 and conformationally constrained cyclopeptide-based receptors 2–4.

Chart 2 Cyclopeptide-derived receptors 5 and 6 containing 3-aminobenzoic acid (5, 6a) or 6-aminopicolinic acid (6b) subunits.

chains, the authors show that the cyclopeptide NH groups along the ring participate in sulfate binding. Other anions including
HSO4  that do not possess four hydrogen bond acceptors are bound significantly less strongly.
Recently, Kataev and Shumilova reported macrocycle 10 (Chart 3), which was expected to mimic the active site of 4-
diphosphocytidyl-2C-methyl-D-erythritol kinase.15 Receptor 10 forms a 1:1 complex with Cl, but oxoanions such as AcO,
HSO4 , and H2PO4  were shown to bind in a 1:2 fashion with two anions coordinating to the receptor. The authors assume
that coordination of H2PO4  involves the dimer of the anion, while the first equivalent of HSO 4 leads to receptor protonation,
thus promoting binding of a second anion to the resulting positively charged receptor.
296 Amino Acid-Based Receptors

Chart 3 Cyclopeptide-derived receptors 7–10 containing heterocyclic aromatic subunits.

Besides these macrocyclic receptors, also linear ones containing amino acid subunits were developed, mostly for anion, amino
acid, and/or peptide recognition. Examples are the cleft-type receptors 11,16 12,17 13,18, and 1419 shown in Chart 4. All of these
receptors feature a more or less rigid core structure with two appended amino acid substituents whose functional groups induce
affinity for amino acids and whose chirality mediates enantioselective recognition. In the case of 11, the central thiourea moiety
also contributes to binding, while receptors 13 and 14 contain fluorescence chromophores that report complex formation by
a change of their optical properties.
A related structural design formed the basis of the peptide receptors developed in the Wennemers group. Di(4-aminoproline)
diketopiperazines were used as the central core structure, which allowed appending short peptide chains (Chart 5).20–22 Because of
the configuration of the core units, the peptide substituents are oriented in a parallel fashion, thus enabling them to cooperatively
bind to the guests. Mostly, peptides were used as substrates in these studies, and it was investigated how the sequence of the amino
acids in the receptor substituents influenced binding selectivity. To this end, dye-labeled receptors were incubated with libraries of
resin-bound tripeptides. After this initial screening, affinity of the receptors for selected tripeptides was assessed in solution. In
general, receptors deriving from di(trans-4-aminoproline)diketopiperazine 15 proved to be more efficient than ones deriving
from di(cis-4-aminoproline)diketopiperazine 16 because the mutual arrangement of the two peptide chains in 15 is better suited
for complex formation.
Structurally relatively simple linear ditopic receptors of the general structure 17 (Chart 5) were developed in the Luis group
featuring two amino acid residues connected via alkyl linkers of variable length. These receptors were designed to bind N-
protected amino acids with two carboxylate groups such as Cbz-Asp-OH and Cbz-Glu-OH.23 Complex formation involves ion pair-
ing after proton transfer from the substrates to two amino groups of the receptors combined with hydrogen bonding between the
receptor amide groups and one carboxylate group of the guests. The additional substituents in the side chains of the receptors influ-
ence complex stability and enantioselectivity of binding to a certain extent. Similar receptors were also used for the NMR spectro-
scopic enantiomeric excess determination of a-hydroxy and arylpropionic acids24 and as chelate ligands for copper(II) ions.25
Together with the Alfonso group, the Luis group devised the macrocyclic receptor 18 for N-protected amino acids (Chart 6).26
Complex formation involves proton transfer from the substrate to the basic amino groups of the receptor. As a consequence, each

Chart 4 Acyclic receptors 11–14 with amino acid-derived substituents connected to a rigid core.
 Amino Acid-Based Receptors 297

Chart 5 Acyclic receptors 15–17 containing di(4-aminoproline)diketopiperazine subunits (15,16) or a central a,u-diaminoalkyl core (17).

Chart 6 Cyclic and acyclic pseudopeptidic receptors 18–20.

receptor can accept two substrate molecules. In addition to the electrostatic interactions in the ion pairs formed, structural effects of
the substrates also play a role in binding affinity. For example, aromatic amino acids bind to 18 with a slightly higher affinity than
aliphatic ones. This receptor is also moderately enantioselective.
The structurally related analog 19 (Chart 6) with a larger ring size was shown to prefer N-protected dipeptides as substrates.27
Receptor 20a contains three basic sites, two aliphatic amino groups and the acridine ring nitrogen atom. Addition of phosphoric
acid to a solution of 20a in chloroform causes a turn-on of fluorescence, which was ascribed to protonation of the acridine
subunit.28 The corresponding triprotonated form of 20a is stabilized by interactions with the H2PO4  anion. This assumption is
supported by the fact that the effect of other acids such as H2SO4, HCl, HBr, acetic acid, or trifluoroacetic acid is either significantly
less pronounced (H2SO4) or completely absent. The protonated form of the corresponding acyclic receptor 20b exhibits a smaller
affinity for the H2PO4  because of a lower level of preorganization.
The Luis and Alfonso groups also developed pseudopeptidic cages of the general structure depicted in Chart 7.29,30 Although the
binding pockets of these cages share similar geometric parameters, differences in chloride affinity were noted. This result was attrib-
uted to effects of the substituents in the amino acid side chains on complex structure. For instance, complete encapsulation of a chlo-
ride anion was detected for 21a containing three phenylalanine units, while the anion is only partial encapsulated into the cavity of
21b containing valine units. It should be noted that these cages feature three secondary and one tertiary amine group. Since
hydrogen halides were used in the binding studies, complex formation involved the fully protonated receptor species. A large share
298 Amino Acid-Based Receptors

Chart 7 Cage-type pseudopeptidic receptor 21.

Chart 8 Oligopeptide-derived chloride transporter 22.

of the overall binding strength, therefore, comes from electrostatic interactions with additional contributions of hydrogen-bonding
interactions between the amide NH groups and the anion. When varying the substrate, 21a exhibited a large affinity for chloride,
while bromide seems to be too large to enter the cavity. Fluoride is too small, so that the receptor cavity contains an additional water
molecule in the crystal structure of the corresponding complex.30
These cages were also used as carriers to mediate chloride transport across lipid bilayers. It was shown that the rate of transpor-
tation correlates with the lipophilicity of the receptor, with a higher lipophilicity leading to higher transport rates.31 Other receptors
used for membrane transport studies are derivatives of the amino acid-derived bisamides 17 and corresponding tripodal analogs
whose L-lactate, L-maleate, L-aspartate, and chloride transport properties were investigated.32 The development of chloride trans-
porters containing oligopeptide chains was pursued in the Gokel group.33–35 These transporters have the general structure (R2)
NCO–X–CO–(Aaa)n-OR0 ; an example is shown in Chart 8.
The hydrophobic alkyl chains at the N-terminal end of these compounds were chosen to mimic the hydrocarbon chains of fatty
acids in phospholipids. The connector unit X mimics the phospholipid glyceryl component, and the peptide chain (Gly)3Pro(Gly)3
serves as the chloride binding element. Finally, the benzyl (Bn) ester at the C-terminus was introduced to reduce polarity at this
position. The investigations showed that the structures of the anchor chains, those of the midpolar regime, and the length and
sequence of the peptide chain in 22 have a pronounced influence on chloride transport ability. To understand the effect of the chlo-
ride binding element, binding studies were performed in which chloride affinity of oligopeptides differing in the length and
sequence of subunits was systematically assessed.36–38 In this context, it was shown, for example, that replacing the central proline
unit in the (Gly)3Pro(Gly)3 motif with pipecolinic acid leads to a significant reduction of chloride affinity and that replacement of
a glycine unit with glutamate also causes chloride affinity to decrease because of repulsive interactions of the glutamate side chain
with the substrate.

3.12.3 Arginine-Derived Receptors

The guanidinium group in the side chain of arginine usually serves in proteins to interact with negatively charged groups or with
p-electron-rich aromatic moieties in the substrate.39,40 This type of interaction can be found in a variety of enzymes such as carboxy-
peptidase A, creatine kinase, fumarate kinase, malate reductase, and nucleases. In carboxypeptidase A, for example, a crucial inter-
action within the active center involves a salt bridge between the guanidinium group of an arginine residue and the carboxylate
group of the peptidic substrate. A guanidinium–phosphate interaction can be found within the active center of Staphylococcus nucle-
ases, which catalyze the hydrolysis of DNA and RNA.41 The interaction between guanidinium groups and oxoanions is schematically
shown in Fig. 2. The planarity and Y shape of the units that are involved in binding ensure an almost ideal structural complemen-
tarity and allow for the formation of two parallel hydrogen bonds. Stability is further enhanced by electrostatic interactions in this
salt bridge. In this context, the high pKa value of the guanidinium cation is advantageous, as it causes this group to remain proton-
ated over a wide pH range, in contrast to amino groups. It is also worth noting that guanidinium groups typically feature two iden-
tical binding sites allowing interactions with two oxoanions at the two edges.
In spite of the favorable binding geometry of guanidinium–oxoanion interactions, stability of a single guanidinium–carboxylate
salt pair is low (Ka < 5 M 1) in aqueous solution.42 The reason is that binding energy only barely compensates the energy required
to desolvate the strongly hydrated binding partners. The Schmuck group showed that acylation of a guanidinium group with 1H-
pyrrole-2-carboxylic acid containing additional substituents in the position 5 yields the guanidiniocarbonylpyrrole (GCP) moiety
 Amino Acid-Based Receptors 299

Figure 2 Binding modes of the guanidinium group: guanidinium–carboxylate interactions (left) and guanidinium–phosphate interactions (right).

whose interaction with carboxylates in water is significantly stronger than that of the guanidinium group itself.43 In early studies, the
prototype of a GCP-derived receptor, compound 23, was shown to bind to N-acetyl-L-alanine carboxylate in 40% H2O/DMSO-d6
with an affinity of 770 M 1, while the corresponding complex with the acetyl guanidinium ion has a stability of only 50 M 1 under
the same conditions.44 Stability of such GCP–carboxylate ion pairs was rationalized by cooperative hydrogen-bonding interactions
between the carboxylate group and the pyrrole and amide NHs moieties in an arrangement shown in Fig. 3.
In subsequent studies, the Schmuck group very systematically studied the influence of further substituents on the GCP group on
binding affinity and selectivity. In this respect, introduction of further substituents into the guanidinium group and/or attachment
of amino acids and short peptides to the pyrrole moiety was considered. The corresponding receptors were developed by rational
design or by combinatorial methods. Overall, this work shows that highly efficient and sequence selective peptide recognition can
be achieved with appropriately functionalized GCP-derived receptors even in water, demonstrating the strength of this modular
approach to receptor design involving a specific oxoanion binding motif combined with additional substituents, mostly derived
from amino acids, which mediate binding selectivity. As most of these results have been reviewed, they will not be described
here in more detail.1,43,45–47 Nucleotide binding was achieved by using tweezer-type receptor 24 containing two identical GCP-
containing arms connected to an aromatic scaffold (Chart 9).48 Affinity of 24 for various nucleotides in aqueous bis–tris buffer

Figure 3 GCP-derived receptor 23 and its mode of binding to acetate.

Chart 9 GCP-containing receptors 24–27.

300 Amino Acid-Based Receptors

(pH 7) revealed that 24 has the unusual property to prefer adenosine monophosphate (AMP) over adenosine diphosphate (ADP)
and adenosine triphosphate (ATP). The best substrate for 24 is uridine monophosphate (UMP) with a remarkable association
constant log Ka of the corresponding complex of 5.0.
To further increase the versatility of the GCP binding motif, Schmuck et al. also developed a series of amino acid derivatives 25a–
d with the GCP groups in their side chains (Chart 9).49 These amino acids can be incorporated into oligopeptides by standard solid
phase synthesis to study the contribution of the GCP oxoanion binding motif on the properties of the products. In this context, 25a
was shown to mediate hydrolysis of phosphoesters in water after incorporation into an octapeptide.50 Subsequently, also GCP-
mediated cleavage of RNA model compounds was investigated.51 Introduction of four residues of 25a into a polypeptide known
to accelerate the hydrolysis of the RNA model substrate 2-hydroxypropyl 4-nitrophenyl phosphate (HPNP), indeed, caused a signif-
icant improvement of activity.
More recently, the Schmuck group focused on using GCP-modified receptors or oligopeptides as vectors for gene delivery. An
earlier approach involved the use of receptor 24 and its analog 26 containing three identical side chains on the aromatic core.52
Binding affinities of both receptors toward linear and circular DNA were evaluated. Interestingly, receptors 24 and 26 both possess
high affinities for DNA amounting to, respectively, 106 M 1 and 107 M 1. In addition, both compounds compress DNA into tightly
packed cationic aggregates, which are then taken up by the cells. Only the trivalent receptor 26 is able to escape from the endosome
and efficiently cause transfection, however. In further studies, transfection efficiency of 24 was improved by optimizing the peptide
sequences between the aromatic core and the GCP units in combination with attaching a lipophilic tail as a third substituent to the
central aromatic unit.53 The approach was extended toward GCP-containing linear tetrapeptides such as compound 27, which
currently represents the smallest peptidic transfection vector and which has the further advantage of possessing negligible cytotox-
icity.54 Note that this compound is an oligomer of lysine with modified side-chain amino groups. For other examples of such recep-
tors, see Section Lysine-Derived Receptors.
Receptors featuring a combination of substituted guanidinium group and a linear peptide sequence were also developed in the
Kilburn and the Anslyn groups (Chart 10).55,56 Kilburn’s receptors possess a tweezer-type structure containing a central disubsti-
tuted guanidinium group and two appended chains. While receptor 28 was screened against a library of resin-bound peptides to
identify the best substrate,57 the immobilized receptors 29a and 29b were structurally optimized in a combinatorial fashion to iden-
tify receptors for the Ac-Lys-D-Ala-D-Ala-O tripeptide sequence, which represents the target motif of the antibiotic vancomycin.58,59
Interestingly, the resin-bound receptors exhibited a better defined binding model and a higher affinity than the corresponding free
analogs in solution, indicating that the resin plays a crucial role in substrate recognition. The same group also described 30 with

Chart 10 Guanidinium-containing receptors 28–31.

 Amino Acid-Based Receptors 301

a bicyclic guanidinium group as an anion binding motif, which in combination with additional linear peptides bound to the same
resin afforded polymeric binders for Val-Val-Ile-Ala, the C-terminal tetrapeptide sequence of the amyloid-b protein.60
Anslyn’s receptor 31 contains guanidinium groups for anion recognition connected to a trisubstituted 1,3,5-triethylbenzene core
(Chart 10).61 Two fluorophores F1 and F2 serve to allow optical detection and additional peptide chains, whose sequences were
optimized in a combinatorial fashion to induce substrate selectivity. These compounds were investigated with respect to nucleotide
recognition. A receptor was thus identified that interacts with ATP in 200 mM HEPES buffer (pH 7.4) with an association constant of
3400 M 1 and a high selectivity over GTP and AMP. These receptors were also used to construct a chip-based array for the optical
differentiation of AMP, GTP, and ATP.62
Regen and coworkers designed a molecular umbrella 32 from the three biogenic building blocks cholic acid, spermidine, and
arginine, which was shown to bind and transport ATP across the phospholipid bilayer selectively against glutathione (Chart 11).63
The molecular umbrella 33 containing four cholic acid residues, spermidine, lysine, and an octaarginine chain was shown to
transport small interfering RNA to HeLa cells. Transport efficiency was comparable to that of a commercially available transfection
agent, Lipofectamine 2000, but the conjugate was less cytotoxic.64
A series of fluorescence-labeled amphipathic peptides of the general structure CF-(VXLPP)n (n ¼ 1–3, X ¼ His (H), Arg (R), Lys
(K), P ¼ Pro, L ¼ Leu, V ¼ Val, and CF ¼ 5(6)-carboxyfluorescein) were developed by Giralt.65 These peptides were evaluated for their
ability to cross cell membranes. The results revealed that the arginine-containing peptides exhibited better transport properties,
which was ascribed to their stronger interactions with the phosphate diesters of the lipids comprising the outer part of the cell
membrane.
Demuth et al. designed several oligopeptides to mimic the recognition site for orthophosphate and sulfate that is present in the
enzyme purine nucleoside phosphorylase.66 Since substrate recognition in the enzyme mainly involves serine, arginine, and histi-
dine residues, these amino acids were used for receptor design. They were linked via flexible spacers in such a way that the relative
orientation found in the enzyme was preserved. Binding studies revealed a significant conformational change of one of the prepared
oligopeptides in the presence of sulfate anions. An analogous oligopeptide containing an alanine instead of the arginine residue did
not show this behavior indicating that the guanidinium group is required for the sulfate binding. Further binding experiments
showed that sulfate recognition is selective as phosphate anions or other oxoanions had no effect on receptor conformation.
The macrocyclic host 34, containing a bicyclic guanidinium moiety as an anion coordinating site and two alanine subunits, was
synthesized in the group of de Mendoza (Chart 12).67 This receptor was shown to efficiently bind to the diphenylphosphate anion.
In the complex, the anion seems to reside outside of the cavity and rapidly exchanges position between both receptor sides.

Chart 11 Molecular umbrellas 32 and 33.

Chart 12 Macrocyclic receptor 34 containing a bicyclic guanidinium moiety.

302 Amino Acid-Based Receptors

3.12.4 Histidine-Derived Receptors

The imidazole unit in the side chain of histidine is a versatile binding site.68,69 In the neutral form, imidazole can act as a hydrogen
bond donor and a Lewis base allowing the coordination of transition metal ions. Imidazole also acts as a Brønsted base and can
bind to anions in the form of the imidazolium group by a combination of hydrogen-bonding and electrostatic interactions. It is also
worth noting that 1,3-dialkylated imidazolium moieties contain a polarized CeH bond in the position 2, which can engage in
CeH/anion interactions.70 The different binding modes of imidazole are schematically depicted in Fig. 4.
Histidine residues in proteins are mainly responsible for general base catalysis, as well as for coordination of transition metals. A
proximal histidine residue coordinates, for example, to the metal center in the iron–porphyrin complex of hemoglobin. In carbonic
anhydrase, the imidazole units of histidine are responsible for binding the zinc cofactor.
In spite of the importance of histidine residues in natural systems and the use of imidazole units in synthetic receptors and tran-
sition metal ligands, there are only few examples of synthetic receptors containing histidine or a combination of amino acids and
imidazole units. Xie and coworkers developed a series of cyclic histidine-containing receptors 35a–d for amino acid methylesters
(Chart 13).71 Among the different receptors, 35d exhibits the highest affinity and enantioselectivity for the substrates investigated.
The D-enantiomer of the substrate is usually bound more strongly than the corresponding L-enantiomer. In addition, binding of
aromatic amino acids is stronger than of aliphatic ones, and the amino acid hydrochlorides are better bound than the free amines.

Figure 4 Binding modes of imidazole and imidazolium groups.

Chart 13 Receptors 35–37 containing imidazole groups and structure of the tripodal copper(II) complex 38.
 Amino Acid-Based Receptors 303

In combination, these results indicate that combined hydrogen-bonding, p–p stacking, and cation–p interactions are the factors
governing the recognition properties of these hosts.
The cyclic hexapeptide 36 with alternative glycine and histidine units was described by the group of Sarkar.72 Interestingly, 36
coordinates to copper(II) ions via the three imidazole subunits at pH 7, whereas at basic pH, copper(II) complexation involves three
deprotonated amide groups along the ring. Mallik and coworkers designed a series of tripodal receptors of the general structure 37,
which differ in the number and nature of the amino acid between the aromatic core and the histidine units.73,74 Affinity of these
receptors to tripodal copper(II) complexes was investigated. These investigations show that the combination of 37 with R ¼ H and
38 leads to a stable complex whose association constant log Ka in 25 mM HEPES buffer (pH 7, 25 C) amounts to 6.1.

3.12.5 Tryptophane-Derived Receptors

The indole unit in the amino acid tryptophane can engage into two complementary noncovalent interactions. The obvious one
relies on the ability of the indole NH group to act as a hydrogen bond donor (Fig. 5). An example for a protein in which this binding
mode contributes to substrate recognition is the sulfate-binding protein whose interaction with its substrate comprises seven
hydrogen bonds in the active site, one of which is a hydrogen bond between an indole NH group and an oxygen atom of the sulfate
anion.75 Less obvious and overlooked for quite some time is the fact that aromatic systems, in particular electron-rich ones like
indole, can engage in electrostatic interactions with cationic substrates by cation–p interactions.76–78 This binding mechanism is
crucial for many proteins that recognize cationic groups in neurotransmitters, posttranslationally methylated lysine side chains,
or phospholipids. An example is acetylcholinesterase whose binding pocket, the so-called aromatic cage, contains 14 aromatic resi-
dues, which engage in cation–p interactions with the cationic head group of the substrate.
Mimics of such aromatic cages were developed in the Hof group. The corresponding receptors 39a–c comprise short peptidic
chains with tryptophane and/or N-benzyl tryptophane residues (Chart 14).79,80 Comparison of the acetylcholine affinity of these
compounds revealed an increase in affinity with the number of Bn substituents. This trend reverses in chloroform, indicating that
the major contribution to substrate recognition in water likely does not come from cation–p interactions, but from hydrophobic
interactions that become more efficient as the number of hydrophobic residues on the receptor rises.
The same group also developed the tripodal receptors 40a,b with three deaminated tryptophan arms as potential hosts for tri-
methyllysine in water (Chart 14).81 Again, the hydrophobic effect turned out to be the major contribution to complex stability, as
clearly demonstrated by the higher affinity of 40a for tetrabutylammonium than for tetramethylammonium cations. Also short-
ening of the chains connecting the indole residues in 40b and the solubilizing carboxylate groups diminishes affinity, an effect
that was attributed to the reduction of the hydrophobic surface area of the host cavity combined with unfavorable structural effects
on complex structure.
He and coworkers developed the tryptophane-functionalized calix[4]arene derivatives 41, 42, and 43 as fluorescent probes for
chiral amino acids, alcohols, a-hydroxycarboxylates, and dicarboxylates (Chart 15).82 Binding studies were performed in DMSO,
and highly enantioselective binding was observed for the combinations 41/Boc-Ala and 42/mandelate. The same group also

Figure 5 Binding modes of indole groups.

Chart 14 Tryptophane-containing receptors 39 and 40.

304 Amino Acid-Based Receptors

Chart 15 Tryptophane-containing receptors 41–44.

described the open-chain optical probe 44a,b.83 These receptors were investigated with respect to their affinity and enantioselectiv-
ity for bis(tetrabutylammonium) dibenzoyl tartrate in DMSO.
The Gadhiri group used the ability of a cyclic octapeptide containing alternating D-leucine and L-tryptophane residues to
assemble into tubular structure for the development of an electrochemical sensor for complex anions.84 Sensing selectivity of
this peptide is controlled by its ring size with no contribution from the tryptophane residues to the recognition event.

3.12.6 Serine/Threonine-Derived Receptors

The hydroxyl groups in the side chains of serine or threonine are typical hydrogen bond donors. They contribute to substrate recog-
nition, for example, in the sulfate-binding protein75 or in the chloride channel proteins of Escherichia coli and Salmonella typhimurium
where chloride binding in the so-called ion filter involves two backbone NH groups and two OH groups, one from a serine and one
from a threonine residue.85
Synthetic receptors in which serine or threonine side chains are directly involved in substrate recognition are nevertheless rare. A
series of serine-containing synthetic analogs of patellamide A, a natural copper-binding cyclopeptide,86 were investigated in the
Comba group as ligands for Cu2 þ ions.87,88 Structural investigations indicated that the OH groups in the side chains of these
peptides do not contribute to copper coordination, however. A notable example demonstrating that OH groups can have
a pronounced effect on binding affinity is the cleft-type receptor 45a described by Hamilton (Chart 16).89 This compound binds
acetate anions as tetrabutyl-ammonium salts in acetonitrile with an association constant Ka of 2.7  105 M 1. The analog 45b, lack-
ing the OH group, has an acetate affinity of only 340 M 1 under the same conditions, demonstrating the stabilizing effect of the OH
group on the complex of 45a.

3.12.7 Cysteine-Derived Receptors

Thiol groups in the side chain of cysteine have two major functions in proteins: they serve as ligands for transition metal cofactors
after deprotonation and for the stabilization of protein tertiary structures after oxidation to disulfides. Examples of the former func-
tion are zinc finger and alcohol dehydrogenase enzymes, in which cysteine coordinates to Zn2 þ.90

Chart 16 Serine-containing receptor 45b and alanine-containing analog 45a.

 Amino Acid-Based Receptors 305

Chart 17 Cysteine-containing receptors 46–47.

Both functions have been transferred to synthetic receptors, although the number of examples is relatively limited. Cyclopeptide-
based receptor 46 containing cysteine units for transition metal complexation has been described by Ngu-Schwemlein et al.
(Chart 17).91 Peptide 46 preferentially interacts with Hg2 þ by forming a complex in which two cyclopeptide rings bind to one metal
ion. Complex formation is reported by the change of the fluorescence of the tryptophane residue. It should also be mentioned that
the SH groups in cyclopeptides 47a,b described by Göpel and coworkers served to attach these peptides on gold surfaces.92 The
surfaces were then used as sensing units in quartz microbalances.
Introduction of cysteine-derived disulfide groups (i.e., cystine moieties) into a cyclopeptide has several advantages. First, disul-
fide bonds preferentially adopt a well-defined conformation with an absolute dihedral angle of 90 degrees and a rotational barrier
that is intermediate between that of a typical carbon–carbon single bond and an amide bond. Second, introduction of cystine resi-
dues into a cyclopeptide facilitates synthesis, and third, cysteine groups allow the facile control over the relative direction of the
chains attached. Thus, disulfide groups structurally stabilize a receptor in a similar fashion as a protein.
After an initial attempt to mimic cation binding of valinomycin with a cystine-derived receptor,93 the Ranganathan group performed
systematic work on extending the concept of incorporating cystine units into receptors to other structural motifs and substrates.94 In this
context, the so-called cystinophane 48 (Chart 18) was developed, which was shown to interact with 1,u-dicarboxylic acids in CDCl3.95

Chart 18 Disulfide-containing receptors 48–50.

306 Amino Acid-Based Receptors

A similar concept was used by Cheng and coworkers when developing receptor 49 (Chart 18), which binds monovalent and
divalent metal ions such as Liþ, Naþ, Kþ, Mg2 þ, Ca2 þ, and Ba2 þ and halides.96 Consistent with the binding properties of peptide
bonds, cation complexation is believed to be mediated by the carbonyl groups, while anion binding takes place at the peptide NH
groups (see Section Recognition Mediated by Backbone Peptide Groups). Also the effects of pyrrole subunits in such receptors on
anion affinity have been explored.97 The cystine-based cyclic ureas 50a,b were reported by the Ranganathan group as receptors for
halide and nitrate anions in CDCl3.98

3.12.8 Aspartate/Glutamate-Derived Receptors

The coordination of cationic cofactors in proteins occurs in a number of cases through the carboxylate groups in the side chains of
aspartate or glutarate. For example, aspartic acid and glutamic acid carboxylate groups in addition to carbonyl groups in the protein
backbone mediate the binding of calmodulin to calcium ions.99 The corresponding binding modes of carboxylate groups can be
either monodentate or bidentate as depicted in Fig. 6.
The Imanishi group studied a series of cyclopeptide-based macrocyclic receptors containing carboxylate groups in side chains for
cation recognition.100,101 These investigations turned out to be inconclusive, however. For example, comparison of the Ba2 þ affinity
of cyclopeptides 51a and 51b revealed only small differences, indicating that the side-chain carboxylate groups in 51a do not partic-
ipate in binding (Chart 19). To investigate whether these tetrapeptides are too small for cation coordination, the analogous hex-
apeptides 52a–c were also considered. Of these peptides, only 52c exhibited affinity for Ca2 þ and Ba2 þ showing the importance
of the correct cyclopeptide stereochemistry for substrate recognition. The exact contribution of the side-chain carboxylate groups
to cation binding of 52c could not be clearly assessed, however.
Cyclopeptides 53, 54, and 55 contain alternating D- and L-amino acids were used for the recognition of transition metal ion-
s(Chart 20).91,102 Peptide 53 interacts with transition metal ions such as Cu2 þ, Zn2 þ, Cd2 þ, Hg2 þ, and Pb2 þ and Al3 þ, but not
to alkali or earth alkaline metal ions in water. Importantly, the fluorescence emission properties of the tryptophan chromophore
were only altered in the presence of Pb2 þ, Hg2 þ, and Cu2 þ even in the presence of an excess of other metal ions, rendering optical
detection rather selective. Comparison of the binding properties of 53 and 54 showed that complex formation is not significantly
affected by the position of the carboxylate groups in the cyclooctapeptide since the respective Hg2 þ, Pb2 þ, and Cd2 þ complexes of
both peptides have almost similar stabilities. However, replacement of glutarate subunits with lysine as in 55 caused a complete loss
of cation affinity in water.103 Note that Hg2 þ affinity could be improved by introduction of cysteine into these peptides (see Section
Cysteine-Derived Receptors).
The Kubik group described a series of receptors based on the general structure of 6a with aspartate or glutarate substituents on
the aromatic cyclopeptide subunits.104 These cyclopeptides were shown to bind various methyl glycosides in 4% CD3OD/CDCl3.
Binding is believed to be mediated by charge-assisted hydrogen bonds between the peripheral carboxylate groups of these receptors
and the neutral substrates.

Figure 6 Coordination modes of carboxylate groups to cations.

Chart 19 Carboxylate-containing receptors 51 and 52.

 Amino Acid-Based Receptors 307

Chart 20 Carboxylate-containing receptors 53 and 54 and lysine-containing receptor 55.

3.12.9 Lysine-Derived Receptors

Lysine residues can serve several purposes in a synthetic receptor, but they rarely contribute to binding in their native form. In
receptor 55 (Chart 20), the lysine residues serve as a negative control, for example, showing that a positively charged receptor con-
taining protonated amino groups in water is unable to bind cations. The basicity of the side-chain amino group in lysine renders
these substituents to be positively charged at physiological pH, which can be used to improve the water solubility of a receptor.
Compounds 24 and 26 (Chart 9) are examples of this strategy. The three functional groups in lysine also render this amino
acid a valuable building block for receptor design. In receptor 56 for N-acetyl amino acid carboxylates described by the Kilburn
group, for example, the a-amino and carboxy groups of two lysine subunits are used for macrocyclization, while the side-chain
amino groups are connected by a thiourea moiety making up a second ring (Chart 21).105,106
Lysine subunits also serve as important building blocks in the molecular umbrellas described by the Regen group to connect two
or more choline units (see Section Arginine-Derived Receptors). This work has been reviewed.107
In the peptidic transfection vector 27 (Chart 9), the side-chain amino groups of lysine were converted into GCP moieties to
introduce binding sites for nucleotides. Jolliffee and coworkers recently pursued a related strategy. They prepared dipeptides
57a,b and 58a,b containing lysine derivatives with side-chain thiourea or squaramide moieties, respectively.108 Binding studies
showed that these peptides interact with anions such as sulfate, acetate, benzoate, and chloride in water/DMSO-d6 mixtures. The
relative stereochemistry of the dipeptides only had a minor influence on the affinity, and the squaramides turned out to be superior
receptors over the thioureas. Sulfate affinity of 58a,b turned out to be too high to be quantified by NMR titrations even in 20% H2O/
DMSO-d6. Stabilization of the sulfate complex likely involves a network of hydrogen bonds between the oxygen atoms of the anion
and NH groups in the squaramide moieties and the backbone of the receptors.

Chart 21 Lysine-derived receptors 56–58.

308 Amino Acid-Based Receptors

Jung and Gauglitz incorporated lysine into cyclopeptides and used the side-chain amino group as the anchor group to immo-
bilize these receptors on silica surfaces.109,110 The corresponding materials were used to sense volatile analytes such as tetrachlor-
oethene, anisole, ethylacetate, or n-octane by reflectometric interference spectroscopy.

3.12.10 Conclusions

The selection of receptors presented in this article illustrates the versatility of amino acid-based receptors. Amino acids can give rise
to a large number of structurally diverse synthetic hosts ranging from noncyclic and cyclic ones to more elaborate structures such as
cages. Receptor design can be rational, but the introduction of a short peptide into a receptor also allows a combinatorial approach
to the optimization of binding properties. The individual amino acid subunits in these receptors serve similar purposes as in
proteins; the peptide bonds along the receptor backbones can interact with hydrogen bond acceptors and donors, whereas charged
functional groups in amino acid side chains can serve to attract oppositely charged substrates, for example. In addition, further types
of interactions are possible between side-chain functional groups and the substrate including cation–p interactions involving
aromatic amino acid side chains or coordinative interactions involving histidine or cysteine residues. A further advantage of an
amino acid-based receptor is the built-in chirality, which allows facile design of enantioselective receptors. As a consequence,
the structural space that can be covered and the binding properties that can be achieved with amino acid-based receptors are almost
unlimited.
Early approaches in the development of amino acid-based receptors were mainly aimed at mimicking the antibiotic properties of
valinomycin, and these receptors, therefore, targeted electropositive metal ions. Then, research concentrated more and more on
other substrates, such as amino acids, peptides, and also inorganic anions, while the interest in cation receptors somewhat dimin-
ished. In light of the biological relevance of inorganic and organic anions, this development is easily justified. However, it may be
worthwhile to also keep focus on cation receptors, because the growing resistance of bacteria to many known antibiotics continually
creates a demand for new ones. Mimics for valinomycin on the basis of amino acid-derived receptors can potentially be relevant in
this context. Moreover, using natural systems as a blueprint and designing receptors using the building blocks of nature is a prom-
ising approach to developing systems that work in the natural environment: in water, in membranes, or in the cytosol. Amino acid-
based receptors offer many opportunities in these contexts.

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310 Amino Acid-Based Receptors

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 3.13 Curved p-Receptors
T Matsuno, S Sato, and H Isobe, Tohoku University, Sendai, Japan
Ó 2017 Elsevier Ltd. All rights reserved.

3.13.1 Introduction 311

3.13.2 Chemical Structures 311
3.13.2.1 Bowl-Shaped Receptors 312
3.13.2.1.1 Bowl-Shaped Receptors Having a Single Interacting Unit 312
3.13.2.1.2 Bowl-Shaped Receptors Having Multiple Interacting Units 312
3.13.2.2 Belt-Shaped Receptors 312
3.13.2.2.1 Belt-Shaped Receptors Having a Single Interacting Unit 312
3.13.2.2.2 Belt-Shaped Receptors Having Multiple Interacting Units 318
3.13.3 Receptor–Guest Association 318
3.13.3.1 Overview of Analytical Methods 318
3.13.3.2 Association Constants (Thermodynamics) 321
3.13.3.3 Solid-State Structures 324
3.13.3.4 Features of the Concave–Convex Interfaces 326
3.13.4 Conclusion 326
References 326

3.13.1 Introduction

In an organic chemistry course, we learn the important concept of orbital hybridization: a linear combination of atomic orbitals
results in a formation of tetrahedral (sp3), trigonal (sp2), and digonal (sp) carbon centers.1 The shapes of organic molecules can
be readily understood by examining the hybridization level of carbon atoms, and the planarity of molecular structures composed
solely of sp2- or sp-hybridized carbon atoms is a primary feature of molecules with p-systems. In reality, however, p-systems can
tolerate non-planarity, and the molecular structures with sp2- or sp-hybridized carbon atoms can be bent out of the plane. The
molecular receptors possessing such non-planar p-systems, that is, “curved p-systems,” are reviewed in this article.
As has been described for molecular receptors in the very first article of the previous series by Weber and Vögtle,2 the chemistry of
supramolecular receptors begins with design of concave frameworks. The concave frameworks can most rationally be designed by
using folding-point structures, for instance, adopting non-planar sp3-hybridized atoms, as we observe in a rich variety of molecular
receptors in other articles. However, molecular receptors with p-systems do not necessarily recruit folding-point structures, and
concave frameworks can be designed by adopting exclusively curved p-systems. Examples of molecular receptors with such concave
shapes of curved p-systems have been increasingly accumulated to further enrich the library of synthetic receptors, and the unique-
ness of the curved p-systems is currently being exploited.3,4 Chemists elaborated unique strategies for the synthesis of curved p-
systems; however, as the strategies vary case by case, emphasis of this article is devoted on the molecular structures and properties.
Section “Chemical Structures” of this article discusses the molecular structures of curved p-receptors to provide an overview of the
structural variations in this category, and section “Receptor–Guest Association” summarizes the association thermodynamics of
the receptors to elucidate the current state of the unique curved p-receptors.

3.13.2 Chemical Structures

The structures of molecular receptors with curved p-systems are first divided into two categories based on the shapes of the mole-
cules: bowl- and belt-shaped receptors. Next, each category is further subdivided into two more categories based on the types of
receptor–guest recognitions: one type is singularly driven by one receptor unit and while the other is multiply driven by a combi-
nation of multiple receptor units. The former sub-category represents the unique and typical curved p-receptors.
Curved p-structures can be constructed not by replying on the folding-point structures but rather by using “geodesics.”5 The
geodesics is an architectural technique initiated by Buckminster Fuller, from which the term “fullerene” originated, to represent
curved, geodesic structures.6 Many of the examples of receptors in this article possess such geometry-induced, geodesic structures.
One of the most interesting and anomalous features of curved p-systems in supramolecular complexes can be found in this cate-
gory, where the concave molecular surface provides a convex surface of guests with an ideally intimate contact. The concave–convex
contacts are mainly driven by van der Waals interactions, which is the anomalous feature unique to this system. Most of the systems
target fullerenes as convex guests, which also have implications for other scientific fields, such as materials science.7 Except for modi-
fied fullerenes, structures of fullerene guests are omitted for clarity in the figures.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12518-1 311

312 Curved p-Receptors

3.13.2.1 Bowl-Shaped Receptors

3.13.2.1.1 Bowl-Shaped Receptors Having a Single Interacting Unit
The first bowl-shaped, curved p-receptor reported for the spherical guest of fullerenes has been corannulene (1) (Fig. 1).8,9 The
pentagon unit of corannulene at the center induces the curvature in the geodesic concave structure. As expected from its segmental
structure of fullerene, 1 serves as a receptor of a radical cation of fullerene ðC60 lþ Þ in the gas phase. Although the structures of supra-
molecular complexes of 1 and its penta-tert-butylated congener 4 with electroneutral C60 itself were also revealed by X-ray crystal-
lographic analysis in the crystalline state,10 the van der Waals interactions solely with the corannulene skeleton were not sufficient to
tightly accommodate the C60 guest in solution. Replacing the guest with more electron-deficient Liþ@C60 results in the formation of
association complex in solution.11 The reinforcement of interactions was also successful by introduction of electron-donating
groups on the receptor side to achieve the solution-phase complexation with C60. Thiolated congeners of corannulene, 2,3,5–7,
with sulfanyl substituents at the rim regions form 1:1 complexes with C60 in solution.12 As a corannulene congener with ten pro-
pylsulfanyl substituents fails to form the complex, steric contributions from substituents were concluded to be important for the
association.12 The introduction of an electron-donating nitrogen atom is also effective to facilitate the association with C60, and
azacorannulene 8 forms the 1:1 complex in solution.13 With this receptor, charge-transfer (CT) interactions have been suggested
to be involved for the association.
Larger bowl-shaped receptors have been reported. Hexa-peri-hexabenzocoronene 9 with a sterically induced curvature forms
a 1:1 complex with C60 in the crystalline solid state (Fig. 1).14 Co-crystallization at 1:1 ratio with C60 has also been demonstrated
with hexabenzocoronene 10 with a sterically induced curvature.15 The curvature in hexabenzocoronene has been more rationally
designed with geodesic structures through introduction of pentagon units in receptors 11 and 12, and complexation with fullerenes
has been observed in solution.16
Top-down synthesis of bowl-shaped receptors has been demonstrated by using C60 as the precursors for the receptors (Fig. 2). A
series of open-cage fullerene derivatives, 13–31, has thus been synthesized, and the encapsulation of small molecules, such as He,
H2, and H2O, has been demonstrated in solution.17,18 For the series of open-cage fullerenes, equilibrium constants have been
recorded for several complexes. However, as the measurements are different from conventional association constants,17f these
values are not included in this article.19 Curved p-systems can also be accessed with heteroaromatic structures (Fig. 3). The curvature
of conjugate systems in the heteroaromatic compounds, so-called subphthalocyanine and subporphyrins, is induced by an sp3-
hybridized boron atom that geometrically forces the formation of the concave structure. The association of C60 in solution was first
achieved by using a subphthalocyanine cage 32 as the receptor.20 The structure of a complex between subphthalocyanine and C60
has been revealed by X-ray crystallographic analysis of pyrene-fused subphthalocyanine 33,21 although this receptor fails to accom-
modate C60 in solution. The inherent association between subphthalocyanine and C60 has been revealed by 34 to show the ther-
modynamics and the formation of 1:1 complex.22 The structure–association relationships study with 34 and 35–38 shows that
electron-donating alkylsulfanyl substituents at the periphery are effective to reinforce the association through the formation of
2:1 complexes. Although the association of subporphyrins with C60 is not powerful enough to be quantified in solution, the aid
of alkylsulfanyl substituents at the periphery has also been effective to result in the formation of 1:1 complex with 39 in solution.23
The importance of curved structures in the association has been revealed with curved porphyrin 40, in which pyramidalized Zn at
the center induces the curvature (Fig. 3). The curved porphyrin 40 forms complexes in 1:1 and 2:1 manners with fullerenes in solu-
tion. The difference in the association constants for 1:1 and 2:1 complexes is not large enough to observe the stepwise association.
Because monomeric planar porphyrins cannot form a stable complex with fullerenes in solution, the curvature has been suggested
to be important to reinforce the association in combination with CH-p and CT interactions.24

3.13.2.1.2 Bowl-Shaped Receptors Having Multiple Interacting Units

Interactions between curved p-receptors and guests can be reinforced by using multiple receptor units (Fig. 4).25 Molecular recep-
tors 41–44 with multiple corannulene units have thus demonstrated the association of fullerenes, C60 and C70, in solution.26 An
increase in the corannulene units does not necessarily tighten the association (see later), and subtle structural feature, such as
rigidity, has been suggested to be important. The multi-corannulene receptor with a high association also results in a 2:1 complex
of [42]2 I C60.26c
Accumulation of receptor units has also been effective for p-extended analogs of tetrathiafulvalene, that is, exTTF. The curvature
in this unit is sterically induced by repulsion between the sulfur atoms and anthracene units. Although the inherent association of
exTTF has not been reported, recruitment of multiple exTTF units in 45–56 results in the formation of 1:1 complexes with fullerenes
in solution.27

3.13.2.2 Belt-Shaped Receptors

3.13.2.2.1 Belt-Shaped Receptors Having a Single Interacting Unit
Having a closed concave surface inside the molecular structure, belt-shaped molecules constitute a unique class of receptors with
curved p-systems. A resemblance of the molecular shapes of sp2/sp-hybridized receptors with carbon nanotube (CNT) has been
evolved into sp2-hybridized segmental structures. The complex with fullerenes is thus expected not only to provide an in-depth
understanding of carbonaceous complexes between CNT and fullerenes (so-called peapod28,29) but also to uncover the intrinsic
uniqueness of the curved p-systems.
The first series of belt-shaped receptors is the series of molecules with sp2/sp-hybridized carbon atoms (Fig. 5). Belt-shaped cyclic
aryleneacetylenes, typically cyclic [6]paraphenyleneacetylene ([6]CPPA, 58), form 1:1 complexes with C60 in solution.30 The
 Curved p-Receptors 313

Figure 1 Chemical structures of corannulene and related curved p-receptors.

314 Curved p-Receptors

Figure 2 Chemical structures of open-cage fullerene derivatives.

 Curved p-Receptors 315

Figure 3 Chemical structures of heteroaromatic curved p-receptors.

316 Curved p-Receptors

Figure 4 Chemical structures of receptors having multiple bowl-shaped, curved p-units.

 Curved p-Receptors 317

Figure 5 Chemical structures of belt-shaped, curved p-receptors with sp/sp2-hybridized conjugation (CPPA congeners).
318 Curved p-Receptors

Figure 6 Chemical structures of belt-shaped, curved p-receptors with sp2-hybridized conjugation (CPP congeners).

association depends on the sizes of the receptors and the fullerene guests (see later); the complex with C60 has been observed with
58, 59, 62, and 63, and the complex with C70 has been observed with 58, 59, and 62.31 The complimentarity of concave–convex
structures of cyclic aryleneacetylenes has also resulted in the formation of supramolecular complex comprising multiple compo-
nents.32 Two- and three-component complexes of 61 I 5833 and 61 I 58 I C6032 have been observed in solution. The introduction
of anthracene units in cyclic aryleneacetylenes has been performed to accommodate the fullerene guests in forms of 65 I C60 and
66 I C60. The structural modification of the fullerene guests 69–77 has also been used to accommodate the belt-shaped receptor 58,
and complexes with a series of fullerene guests have been reported.34 A combination of two units of cyclic aryleneacetylene in the
forms of 67 and 68 has been examined through in-situ aromatization reactions. The complexes encapsulating two fullerene mole-
cules have been detected by mass spectrometry.35
Belt-shaped receptors comprising solely of sp2-hybridized carbon atoms have been synthesized (Fig. 6). The variety of the molec-
ular structures is dramatically increasing,36 and the complexes possessing segmental structures of CNT peapods are expected to
deepen the understanding at the molecular level with the languages of chemistry. The first series of this type is [n]cyclo-para-phenyl-
enes ([n]CPP). A CPP receptor with 10 phenylene units, [10]CPP 78, has an ideal diameter to accommodate C6037 or Liþ@C6038 in
solution, and a larger [11]CPP receptor 79 can accommodated larger fullerenes, such as C7039 and endohedral metallofullerenes.40
Crystal structures have revealed the presence of p–p stacking motifs in the solid state (see later).38–41
Pre-organization and persistence in the belt-shaped structures are critically important to stabilize the convex–concave van der
Waals complexes.42 Belt-persistent receptors comprised solely of sp2-hybridized carbon atoms have thus demonstrated an associ-
ation of fullerenes at the utmost level (Fig. 7). The first series, [4]cyclochrysenylenes ([4]CC) 80–84, forms a 1:1 complex with C60 in
solution,43,44 and the diameter–association relationships have been revealed. A crystal structure has been solved with the tightest
complex of 80 I C60, which disclosed the presence of a smoothly curved interface (see later).45 A lengthened version of [4]cyclo-
anthanthrenylene ([4]CA) 85 also binds C60 tightly,46,47 and the comparison with the shorter congener revealed the effects of p-
lengthening on the association energetics. The belt-persistent receptors 80 and 85 tolerate modified fullerenes and encapsulate
C60 derivatives 86–94 and endohedral fullerenes, such as Liþ@C60 and H2O@C60.46,48

3.13.2.2.2 Belt-Shaped Receptors Having Multiple Interacting Units

Curved p-systems have also been utilized for the assembly of supramolecular complexes formed by multivalent interactions.25
Template-directed synthesis of butadiyne-linked porphyrin macrocycles has afforded a series of belt-shaped receptors containing
corresponding templates as the guests (Fig. 8).49–51 The receptor–guest complex 100 I [98]2 and 100 I [99]2 at a 1:2 ratio has
also been accessed through a so-called vernier templating method.52 The receptor–guest association is driven by the multivalent
interactions between metal centers on the receptors and pyridine ligands on the guests. Two units of the belt-shaped multivalent
receptor can be assembled to result in 104 having two guest molecules.53 Variation of the guests has been demonstrated with
the receptor 97 through exchanging the ligand with 105–108.50b Hydrocarbon receptor 58 accepts multivalent contacts with hex-
amethylbenzene in the crystalline solid state.54

3.13.3 Receptor–Guest Association

3.13.3.1 Overview of Analytical Methods
The most fundamental interest in the receptor–guest complexes is on the strength of the association. Therefore, determination of the
association constant (Ka) is one of the most important issues to be elucidated to describe any receptor–guest association. Although
 Curved p-Receptors 319

Figure 7 Chemical structures of belt-persistent, curved p-receptors.

the description of mathematical treatment for the determination is not within the scope of this article, some precautions are worth
describing. As is fully discussed in recent reviews,55 titration data for the association constants should not be analyzed by popular
yet outdated linear regression methods (Benesi–Hilderbrand, Lineweaver–Burk, Scott, Hans–Woolf, Scatchard, Foster–Fyfe or
incorrectly treated Stern–Volmer methods); instead, the data should be analyzed using modern nonlinear regression methods.56
320 Curved p-Receptors

Figure 8 Chemical structures of belt-shaped receptors having multiple interacting units.

 Curved p-Receptors 321

Specifically, for a 1:1 complex of a receptor (R) and a guest (G), a quadratic equation, such as the following equation, should be
used with an appropriate curve-fitting transformation specific for each analytical method:
8 ffi9

 sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi


1< 1 1 2 ½G0 =
½G ¼ ½G0  ½R0  þ ½G0  ½R0 þ þ4 (1)
2: Ka Ka Ka ;

where [G]0 and [R]0 are the total concentrations, and [G] is the unbound guest concentration.55,57 With the non-linear curve fitting
method, we can avoid an unnecessary assumption, such as [G] ¼ [G]0 or DA ¼ [RG]. The outdated linear treatment of the Stern–
Volmer analysis with an assumption of [G] ¼ [G]0 often appears in F0/F ¼ 1 þ KSV[G] to obtain so-called Stern–Volmer constants
(KSV; referred as K0 in this article). In this section, an overview of the association constants is presented. The constants in the tables
are shown in three categories: Ka is correctly obtained by nonlinear regression methods, Ka, comp is deduced by competition
analysis,58 and K0 is obtained by linear regression methods and/or with an assumption of [G] ¼ [G]0. For comparison, a special care
should also be taken of the analytical conditions, such as solvents and temperature, and some relevant conditions are also included.
Probably due to peculiar solvation effects on curved p-systems,59 deviations of the association constants in different solvents are
occasionally large, and the constants in the same medium should be adopted for the comparison. Determination of stoichiometry is
another important issue; the stoichiometry can be deduced by using a Job plot.55 Eq. (1) applies to the complexes with 1:1 stoi-
chiometry; for non-linear regression methods of complexes with other stoichiometries, the reader should refer to appropriate
reviews.55 In some cases, the stoichiometry has not been established, as noted in the tables.

3.13.3.2 Association Constants (Thermodynamics)

Representative association constants for corannulene and related curved p-receptors are summarized in Table 1. The unsubstituted
corannulene 1 does not form a stable complex with C60 that can be analyzed in solution, but the reinforcement of the association
has been achieved with Liþ@C60.11 Introduction of electron-donating groups on the receptor side is also effective for the reinforce-
ment, and thiolated congeners 3 and 5–7, as well as nitrogen-embedded congener 8, form stable complexes with fullerenes in solu-
tion with association constants on the order of 10–103 M 1.12,13 Only a minor effect of the solvents has been observed for this
series, as has been demonstrated by the comparison with 3 I C60.12a,b Deviations in the association constants have not been found
to be large between C60 and C70 for the corannulene congeners. The association constants of 11 and 12 with larger bowl-shaped
structures have been reported only for C70; although their stoichiometry has not been reported, the association constants on the
order of 105–106 M 1 have been recorded.16
The association constants for heteroaromatic curved p-receptors are summarized in Table 2. The heteroaromatic subphthalocya-
nine 34 forms 1:1 complexes with C60 and C70 in solution. As has been the case with corannulenes, the introduction of electron-
donating sulfanyl substituents (35–38) results in the reinforcement of the association, which not only increases the association
constants (on the order of 104–105 M 1) but also alters the complex stoichiometry to 2:1. The analysis of complex [38]2 I C70
has demonstrated the small difference in the first and second association constants (Ka1 and Ka2, respectively). The subporphyrins
forms a 1:1 complex 39 I C60 with a seemingly smaller association constant than those of subphthalocyanines. The formation of
2:1 complexes with a small difference in the first and second associations ( 103–104 M 1) has also been reported for the curved
porphyrin 40. The importance of curved structure has been verified with 40.
Representative association constants of receptors having multiple bowl-shaped, curved p-units are summarized in Table 3.
Multivalent interactions commonly reinforce the association.25 For the corannulene series, the constants are on the order of

Table 1 Representative association constants with corannulene and related curved p-receptors

Complex Constant (M  1) Note

1 I [Li@C60]þ11 K 0 ¼ (1.9  0.1)  10 PhCN, 25 C

K 0 ¼ (2.4  0.5)  10 oDCB, 25 C
2 I C6012a K 0 ¼ (4.74  0.28)  102 Toluene-d8, 25 C
3 I C6012a,b K 0 ¼ (3.58  0.27)  102 Toluene-d8, 25 C
K 0 ¼ (2.96  0.21)  102 CS2, 25 C
3 I C7012b K 0 ¼ (9.7  1.1)  10 CS2, 25 C
5 I C6012b K 0 ¼ (5.3  0.6)  10 CS2, 25 C
5 I C7012b K 0 ¼ (9.4  1.9)  10 CS2, 25 C
6 I C6012a K 0 ¼ (3.06  0.38)  102 Toluene-d8, 25 C
7 I C6012b K 0 ¼ (1.42  0.054)  103 CS2, 25 C
7 I C7012b K 0 ¼ (1.60  0.024)  103 CS2, 25 C
8 I C6013 K 0 ¼ 3.8  103 oDCB, temp.: n.r.
11 I C7016 K 0 ¼ 4.7  105 CH2Cl2, temp.: n.r., stoichiometry: n.d.
12 I C7016 K 0 ¼ 3.2  106 CH2Cl2, temp.: n.r., stoichiometry: n.d.

n.r., not reported; n.d., not determined.

322 Curved p-Receptors

Table 2 Representative association constants with heteroaromatic curved p-receptors

Complex Constant (M  1) Note

34 I C6022 Ka ¼ (2.10  0.11)  10 4

Toluene, temp.: n.r.
34 I C7022 Ka ¼ (6.60  0.46)  102 Toluene, temp.: n.r.
[35]2 I C6022 Ka ¼ (2.10  0.26)  104 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[35]2 I C7022 Ka ¼ (1.90  1.19)  104 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[36]2 I C6022 Ka ¼ (1.90  0.52)  105 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[36]2 I C7022 Ka ¼ (1.10  0.22)  104 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[37]2 I C6022 Ka ¼ (2.90  0.11)  104 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[37]2 I C7022 Ka ¼ (1.30  0.36)  104 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[38]2 I C6022 Ka ¼ (4.40  0.11)  104 Toluene, temp.: n.r., Ka1 ¼ Ka2a
[38]2 I C7022 Ka1 ¼ (3.60  0.27)  105 Toluene, temp.: n.r.
Ka2 ¼ (1.80  0.38)  105
39 I C6023 K0 ¼ (8.57  0.58)  102 Toluene-d8, 25 C
[40]2 I C6024 Ka1 ¼ (1.1  0.1)  104 oDCB, 25 C
Ka2 ¼ (1.2  0.2)  103
[40]2 I C7024 Ka1 ¼ (1.3  0.1)  104 oDCB, 25 C
Ka2 ¼ (2.2  0.3)  103

n.r., not reported.

a
The second association constant is assumed to be identical with the first association constant.

Table 3 Representative association constants with receptors having multiple bowl-shaped, curved p-units

Complex Constant (M  1) Note

41 I C6026a–c Ka ¼ (8.60  0.50)  103 Toluene-d8,a temp.: n.r.

Ka ¼ (5.20  0.20)  102 PhCl-d5, temp.: n.r.
41 I C7026b Ka ¼ (6.8  0.4)  103 Toluene-d8, temp.: n.r.
[42]2 I C6026c Ka1 ¼ (1.004  0.110)  104 PhCl-d5, 25 Cb
Ka2 ¼ (1.18  0.64)  103 PhCl-d5, 25 Cb
43 I C6026d Ka ¼ (4.6  0.1)  103 Toluene-d8, 25 C
43 I C7026d Ka ¼ (2.07  0.06)  104 Toluene-d8, 25 C
44 I C6026e Ka ¼ (1.50  0.05)  103 Toluene-d8, rt
44 I C7026e Ka ¼ (1.18  0.03)  103 Toluene-d8, rt
45 I C6027b Ka ¼ (2.82  0.16)  104 PhCl, rtb
46 I C6027a,b Ka ¼ (2.88  0.26)  104 PhCl, temp.: n.r.b
[46]2 I [C60]2,27a,c K0 ¼ (3.56  0.16)  103 CHCl3/CS2, temp.: n.r.
47 I C6027c Ka ¼ 2.0  105 PhCl, 25 C
47 I C7027c Ka ¼ 2.0  106 PhCl, 25 C
48 I C6027e Ka ¼ 1.0  104 PhCl, 25 C
49 I C6027e Ka ¼ 4.0  105 PhCl, 25 C
50 I C6027e Ka ¼ 2.5  103 PhCl, 25 C
51 I C6027e Ka ¼ 1.0  104 PhCl, 25 C
[51]2 I C7027e Ka1 ¼ 2.5  104 PhCl, 25 C
Ka2 ¼ 2.0  108
52 I C6027e Ka ¼ 6.3  104 PhCl, 25 C
53 I C6027e Ka ¼ 1.3  104 PhCl, 25 C
54 I C6027e Ka ¼ 2.0  104 PhCl, 25 C
[54]2 I C7027e Ka1 ¼ 1.0  106 PhCl, 25 C
Ka2 ¼ 2.0  1012
55 I C6027d,e Ka ¼ 3.2  106 PhCl, 25 C
55 I C7027e Ka < 2.5  108 PhCl, 25 Cd
56 I C6027e Ka ¼ 3.2  103 PhCl, 25 C
56 I C7027e Ka ¼ 7.9  105 PhCl, 25 C

n.r., not reported.

a
Two different constants were reported in two papers (Ref. [28a,c]).
b
Other association constants (different solvents, methods, and/or guests) are available in the literature.
c
Deduced with a modified Hill plot/equation using the [G] ¼ [G]0 assumption.
d
Overestimation of the constant has been mentioned in the literature.

102–104 M 1, and only a minor dependence of the values on the solvents or the guests (C60vs. C70) has been reported. A variety of
p-extended analogs of tetrathiafulvalene (45–56) show the association constants in a range of 103–1012 M 1. The solvent depen-
dence has not been found to be large, and an approximately 10-fold difference has been observed. For the congeners 54 and 56 with
large cyclic structures, the reinforcement of association has been recorded with C70.
 Curved p-Receptors 323

The first three classes of belt-shaped receptors are mainly hydrocarbon receptors without any electronically biasing moieties. In
this regard, these receptors are the most appropriate systems to learn and understand the intrinsic characteristics of van der Waals
interactions with curved p-systems. Representative association constants with belt-shaped, curved p-receptors with sp/sp2-hybrid-
ized conjugation (ie, CPPA congeners) are summarized in Table 4. The association constants in the range of 104–106 M 1 are re-
ported with fullerene guests, and those among the belt-shaped receptors are on the order of 10–102 M 1. The receptors with larger
p-systems show higher association constants, and a preference of the C70 guest over the C60 guest has been observed, especially with
p-extended congeners.
Representative association constants with belt-shaped, curved p-receptors with sp2-hybridized conjugation (ie, CPP congeners)
are summarized in Table 5. A relatively large solvent dependency has been observed, revealing a 103-fold difference in the associ-
ation constants. A smaller congener 78 prefers C60 over C70, and a larger congener 79 prefers C70 over C60. The preferences have been
ascribed to the structural origins (as described earlier). The dependence of the association constants on the endohedral substance in
the fullerene cage has also been reported.
Representative association constants with belt-persistent, curved p-receptors with sp2-hybridized conjugation are summarized in
Table 6. A 106-fold difference in the association constants for C60 has been observed between 78 and 80 in the same medium, and
pre-organization effects from the persistent belt-shape has been concluded to be one of the key factors.42 A large solvent effect has
also been observed with 80, which results in a 104-fold difference in the association constants. Having an identical chemical compo-
sition, the congeners 80–84 are isomers with the association constants of 104–109 M 1 in oDCB. The comparison of the association
constants shows a relatively large effect of the subtle structural differences, and the determinant role of the diameters has been
concluded. The association has been found to be insensitive to the fullerene guests or the endohedral substances in the fullerene
cage.48 Although lengthening of the belt shape (80vs.85) results in a minute change in the association, the detailed origins have

Table 4 Representative association constants with belt-shaped, curved p-receptors with sp/
sp2-hybridized conjugation (CPPA congeners)

Complex Constant (M 1) Note

58 I C6031 Ka ¼ (1.6  0.3)  10 4

Benzene, 30 C
58 I C7031 Ka ¼ (1.8  0.2)  104 CH2Cl2, temp.: n.r.
62 I C6031 Ka  1  105 CH2Cl2, temp.: n.r.a
62 I C7031 Ka  1  106 CH2Cl2, temp.: n.r.a
65 I C6035 Ka  5  106 CD2Cl2, temp.: n.r.a
60 I 5733
Ka ¼ (9.2  1.4)  103 CDCl3, 30 Ca
61 I 5832 Ka ¼ 4.0  10 CDCl3, 30 Ca
61 I (58 I C60)32 Ka ¼ (4.10  0.80)  102 CDCl3, 80 C
64 I 6332 Ka ¼ (4.70  0.80)  102 CDCl3, 30 Cb

n.r., not reported.

a
The accuracy of the constants has been reported to be low.
b
Temperature dependence of Ka has been reported in the literature.

Table 5 Representative association constants with belt-shaped, curved p-receptors with

sp2-hybridized conjugation (CPP congeners)

Complex Constant (M 1) Note

78 I C6020a,37,38 Ka ¼ (6.00  0.20)  103 oDCB, temp.: n.r.

K0 ¼ (2.79  0.03)  106 Toluene, temp.: n.r.
Ka ¼ (4.90  0.50)  105 PhNO2, temp.: n.r.
78 I C7039,40a Ka ¼ (8.40  0.30)  104 Toluene, 25 C
Ka ¼ (8.50  0.20)  103 oDCB, temp.: n.r.
78 I 7539 Ka ¼ (9.3  0.3)  104 Toluene, 25 C
78 I [Liþ@C60]38 K0 ¼ (4.80  0.66)  104 CH2Cl2, temp.: n.r.
79 I C7039,40a K0 ¼ (1.50  0.10)  105 Toluene, temp.: n.r.
Ka ¼ (5.30  0.80)  105 Toluene, 25 C
Ka ¼ (6.70  0.30)  103 oDCB, temp.: n.r.
79 I 7539 Ka ¼ (4.06  0.30)  104 Toluene, 25 C
79 I C3v-C7640a K0 ¼ (1.82  0.06)  106 Toluene, 25 C
79 I C2v-C7840a K0 ¼ (1.41  0.04)  106 Toluene, 25 C
79 I Sc3N@Ih-C8040a K0 ¼ (7.20  0.50)  105 Toluene, 25 C
79 I Gd@C2v-C8240a K0 ¼ (1.80  0.10)  106 Toluene, 25 C
79 I Tm@C2v-C8240a K0 ¼ (1.80  0.20)  106 Toluene, 25 C
79 I Lu2@C2v-C8240a K0 ¼ (1.80  0.20)  106 Toluene, 25 C
79 I La@C2v-C8240b K0 ¼ (3.00  0.20)  104 oDCB, temp.: n.r.

n.r., not reported.

324 Curved p-Receptors

Table 6 Representative association constants with belt-persistent, curved p-receptors

Complex Constant (M 1) Note

80 I C6043,44,46 Ka ¼ (8.0  0.5)  10 8

1-Methylnaphthalene, 25 C
Ka ¼ (4.4  0.2)  109 oDCB, 25 C
Ka ¼ (1.1  0.4)  1010 PhCN, 25 C
Ka ¼ (3.5  0.4)  1010 PhCl, 25 C
Ka ¼ (8.3  0.0)  1010 CH2Cl2, 25 C
Ka ¼ (8.8  0.1)  1010 CHCl3, 25 C
Ka ¼ (4.4  2.0)  1011 Toluene, 25 C
Ka ¼ (1.6  0.3)  1012 Benzene, 25 C
81 I C6043 Ka ¼ (2.8  0.3)  109 oDCB, 25 C
82 I C6043 Ka ¼ (1.6  0.0)  109 oDCB, 25 C
83 I C6043 Ka ¼ (2.7  0.1)  109 oDCB, 25 C
84 I C6043 Ka ¼ (3.8  0.2)  104 oDCB, 25 C
80 I C7044,48 Ka ¼ (3.8  1.1)  109 oDCB, 25 C
Ka ¼ (1.5  0.0)  1010 PhCN, 25 C
80 I H2O@C6048 Ka ¼ (1.1  0.1)  109 oDCB, 25 C
80 I [Liþ@C60]44,48 Ka ¼ (1.6  0.8)  109 oDCB, 25 C
Ka ¼ (8.5  2.5)  109 PhCN, 25 C
85 I C6044,46 Ka ¼ (4.9  1.3)  109 oDCB, 25 C
Ka ¼ (1.9  0.7)  1010 PhCN, 25 C
85 I C7046 Ka ¼ (5.4  4.7)  109 oDCB, 25 C
85 I [Liþ@C60]44 Ka ¼ (4.4  1.6)  108 PhCN, 25 C
80 I 8648 Ka ¼ (1.4  0.2)  105 oDCB, 25 C
80 I 8748 Ka ¼ (2.4  0.0)  105 oDCB, 25 C
80 I 8848 Ka ¼ 6.7  107 oDCB, 25 C
80 I 8948 Ka ¼ (1.3  0.2)  108 oDCB, 25 C
80 I 9048 Ka ¼ (3.4  1.3)  108 oDCB, 25 C
80 I 9148 Ka ¼ 3.2  105 oDCB, 25 C
80 I 9248 Ka ¼ 8.1  107 oDCB, 25 C
80 I 9348 Ka ¼ (1.6  0.2)  108 oDCB, 25 C
80 I 9448 Ka ¼ (3.6  0.7)  109 oDCB, 25 C

been investigated to show a difference in the energetics.43,46 As expected, the p-lengthening increased the association enthalpy (see
further).
The other class of the belt-shaped receptors possesses multivalent interactions with the guests, and the relevant association
constants are summarized in Table 7. Very large association constants have been reported in a range of 108–1036 M 1, confirming
the substantial effect of multivalency in the association.25

3.13.3.3 Solid-State Structures

Some examples of the crystal structures of receptor–guest complexes have been reported. Due to the stringent page limit, only a list
of crystal structures with corresponding CCDC numbers is presented in Table 8. Interested readers can readily retrieve the structure
by obtaining the structural data from the Cambridge Structural Database.60
A unique method for the analysis of intermolecular contacts in the crystal structures is worth introducing for the curved p-recep-
tors. The method adopts the Hirshfeld surface.61 By partitioning the space of the crystal into non-overlapping volumes of molecules,

Table 7 Representative association constants with belt-shaped receptors having

multiple interacting units

Complex Constant (M 1) Note

95 I 9649 Ka, comp ¼ 1.3  1037 CHCl3, 25 C

97 I 9850b Ka, comp ¼ 1.3  1036 CHCl3, 25 C
97 I 10550b Ka, comp ¼ 4.0  1029 CHCl3, 25 C
97 I 10650b Ka, comp ¼ 2.0  1022 CHCl3, 25 C
97 I 10750b Ka, comp ¼ 4.0  1015 CHCl3, 25 C
97 I 10850b Ka, comp ¼ 2.5  108 CHCl3, 25 C
97 I 9951 Ka, comp ¼ 7.9  1035 CHCl3, 25 C
102 I 10351 Ka, comp ¼ 1.0  1032 CHCl3, 25 C
 Curved p-Receptors 325

Table 8 Complexes with crystal data

Complex CCDC No. Complex CCDC No.

1 I C6010
864755 41 I C60 26a
645763
4 I C6010 864756 [42]2 I C6026c 1405183
8 I C6013 1406873 43 I C6026d 901792
9 I C6014 245392 58 I 6930 199147
H2O@2017j 658256 58 I hexamethylbenzene54 153427
H2O@2117j 658257 78 I C6041 874145
H2O@2317l 726568 78 I 7539 941082
H2O@2817o 962214 78 I [Liþ@C60]∙TFPB38 1038975
H2O@2917o 962215 79 I C7039 941083
H2O@3017o 962216 79 I La@C2v-C8240b 972622
33 I C6021 780573 80 I C6045 993074
39 I C6023 1052494 85 I C6046 1018830
40 I C6024 1038723 97 I 9850a 860774
[40]2 I C6024 1038724 100 I [98]253 Not available yet
[40]2 I C7024 1038722

the Hirshfeld surface of a molecule graphically provides various pieces of information, for example, regarding the shape of the space
dominated by an electron distribution of the molecule or the environment surrounding the molecule. A powerful software, Crys-
talExplorer, also enables the quantitative analysis of the intermolecular contacts by mapping structural parameters, such as the curv-
edness, the shape index, and distances from the external atoms (de).62,63 An interesting example is shown in Fig. 9.45,46 The

Figure 9 Hirshfeld surface analysis of curved-p receptors. Curvedness, shape index, and de are mapped in colors over the Hirshfeld surfaces.
326 Curved p-Receptors

Table 9 Thermodynamic data available for curved p-systems

Complex DH (kcal mol 1) DS (cal mol 1 K 1) Note

55 I C6027e 38  3 101  10 PhCl, van’t Hoff

60 I 5733
0.75 16 CDCl3, van’t Hoff
64 I 6332 4.5 2.4 CDCl3, van’t Hoff
78 I C6039 1.2  0.05 14.0  0.1 oDCB, van’t Hoff
79 I C7039 2.1  0.1 24.64  0.29 oDCB, van’t Hoff
80 I C6043 7.4  0.3 15.9  1.0 1-Methylnaphthalene, calorimetry
7.7  0.2 17.6  1.6 oDCB, calorimetry
8.0  0.2 18.9  1.6 PhCN, calorimetry
9.0  0.2 17.8  1.1 PhCl, calorimetry
11.6  0.4 10.9  1.3 CH2Cl2, calorimetry
10.3  0.2 15.3  1.6 CHCl3, calorimetry
11.3  0.1 15.2  1.3 Toluene, calorimetry
13.6  0.4 10.2  1.8 Benzene, calorimetry
80 I C7046 10.1  0.2 10.0  1.1 oDCB, calorimetry
85 I C6046 13.7  0.3 1.5  1.5 oDCB, calorimetry
85 I C7046 14.3  0.1 4.1  1.7 oDCB, calorimetry

curvedness mapping shows the presence of smoothly curved concave surfaces in 80 and 85 by using the convex surface of the guest
as a probe, which shows concave–convex intermolecular contacts in these cases. The presence of inflection points as well as face-to-
face p-stack contacts in 78 can also be visualized with the curvedness and the shape index mappings, respectively. The de mapping
confirms the predominance of the C–C contacts at the interface. The method may provide unique and convenient tools for the struc-
tural analyses and for the discussion of curved p-receptors to be developed in the future.

3.13.3.4 Features of the Concave–Convex Interfaces

Representatively, the unique concave–convex contacts with curved p-receptors that result in interesting features are as follows: (1)
a partial CT between the receptor and the guest at the ground state (1, 8, 10, 45–56, 78–80, 85),11,13,15,27b,c,e,38,40a,b,44,46,64 (2)
excited-state interactions, including electron transfer (1, 45, 46, 80, 85),11,27b,44 and (3) dynamic motions (such as rolling motions)
of the encapsulated guest (80, 85).43,46,48
Quantum chemical analyses of the supramolecular systems provide powerful methods to understand the nature of the nonco-
valent van der Waals interactions, and the curved p-systems have also been examined by theoretical calculations. Although the
subject itself is theoretically challenging to further develop in the future, representative examples are introduced. Corrections in
the van der Waals (or dispersion) interactions have been extensively examined for implementation in the density functional theory
(DFT) and dispersion-corrected methods, such as the pairwise description in DFT-D365 or, more recently, the many-body dispersion
description.66 As the treatment of entropy contributions from solvents and conformations requires careful considerations for the
comparison of experimental and theoretical results,65–67 providing experimental thermodynamic data of the enthalpy should
remedy such issues concerning the entropy. Representative data on the energetics available for curved p-systems are presented in
Table 9. A comparison of the experimental enthalpy shows that the long-range corrected DFT methods, such as LC-BLYP,64 excel-
lently reproduce the association energy of 80 I C60.68 The excellent reproducibility of the LC-BLYP method is most likely due to the
electronic communications as a result of van der Waals interactions, and the long-range corrected method may, at least presently, be
the method of choice for the theoretical analyses of supramolecular curved p-systems.

3.13.4 Conclusion

In this section, we provided an overview of the emerging field of curved p-receptors. Accelerated by the synthetic developments, the
supramolecular chemistry of curved p-receptors is being increasingly developed. The uniqueness of the curved p-receptors is to be
exploited to achieve state-of-the-art chemical tools, such as materials or molecular machines. The noncovalent chemistry at the
concave–convex interfaces should also deepen our understanding in the peculiar molecular recognitions.

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 3.14 Shape-Persistent Anion Receptors
JR Dobscha, Y Liu, and AH Flood, Indiana University, Bloomington, IN, United States
Ó 2017 Elsevier Ltd. All rights reserved.

3.14.1 Introduction to Shape-Persistent Anion Receptors 329

3.14.1.1 Shape-Persistent Receptors 329
3.14.1.2 Shape Persistence: Overview and Definition 329
3.14.1.3 Preorganization and Shape Persistence 331
3.14.1.4 Rigid Molecules, Narrow Conformational Spaces, and Shape Similarity 331
3.14.2 Historical Development of Shape-Persistent Receptors in Anion Recognition 332
3.14.2.1 Development of Shape-Persistent Receptors 332
3.14.2.2 Shape-Persistent Receptors in Anion Recognition 332
3.14.3 Neutral N–H Receptors 332
3.14.3.1 Fundamentals of N–H-Based Receptors 332
3.14.3.2 Amide Systems 332
3.14.3.3 Pyrrolic Systems 334
3.14.4 Neutral C–H-Based Receptors 337
3.14.4.1 Fundamentals of C–H-Based Receptors 337
3.14.4.2 C–H-Based Receptors 337
3.14.5 Anion–p-Based Receptors 341
3.14.5.1 Fundamentals of Anion–p Receptors 341
3.14.5.2 Examples of Anion–p-Based Receptors 341
3.14.6 Cationic N–H Receptors 342
3.14.6.1 Fundamentals of Cationic N–H Receptors 342
3.14.6.2 Cationic Nitrogen-Based Receptors 343
3.14.7 Transition Metal-Based Receptors 344
3.14.7.1 Fundamentals of Transition Metal-Based Receptors 344
3.14.7.2 Examples of Transition Metal-Based Receptors 344
3.14.8 Future Outlook of the Field 345
3.14.9 Conclusions 346
Acknowledgments 347
References 347

3.14.1 Introduction to Shape-Persistent Anion Receptors

3.14.1.1 Shape-Persistent Receptors
Shape-persistent macrocycles1 and receptors are two of the latest types of supramolecular hosts to be explored for anion recogni-
tion.2 Even though the first examples of anion recognition started in 1968 with the katapinands3 (1, Fig. 1), the use of shape-
persistent receptors emerged some time later along a continuum of concept development in host–guest chemistry (Fig. 1).
Shape-persistent receptors offer clear benefits like preorganization4 to enhance binding affinities. Such an outcome is rooted in
the well-defined conformational space of such molecules.5 Narrow conformational freedom also allows a high degree of correlation
between molecular design and experimental outcomes, which can enable deep understanding of host–guest chemistry. Recent
studies have also seen shape-persistent macrocycles highlight novel binding modes6 and their use as building blocks for multimo-
lecule assemblies.7
In this article, we review the concept of shape persistence in the context of host–guest chemistry and anion recognition. We
outline how shape persistence is related to concepts in supramolecular chemistry and on rigidity8 and shape similarity.9 A historical
review of the emergence of shape-persistent receptors is offered and placed in the context of anion recognition. We present various
host systems that span neutral receptors with NH and CH hydrogen bonds or p-surfaces, cationic NH receptors, and transition
metal-based receptors. Shape-persistent receptors have tended to be macrocycles built on aromatic architectures as opposed to
more flexible aliphatic backbones.1 Such macrocycles have also had a high degree of planarity. These tendencies are represented
in the examples presented here.

3.14.1.2 Shape Persistence: Overview and Definition

Shape persistence was originally described by Moore10 in the context of macrocycles as a structure composed of regular repeating
units with few degrees of conformational freedom. Moore’s definition has a few implications that we elaborate here. In particular,

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12517-X 329

330 Shape-Persistent Anion Receptors

Figure 1 Timeline of events leading to shape-persistent receptors.

we elaborate on the implication that a molecule’s shape is retained when it is subjected to a perturbation or an external stimulation.
Such events include guest binding, changes in temperature, solvation sphere, light irradiation, redox chemistry, or during changes in
state (e.g., gas, liquid, liquid crystal, and solid). Thus, we consider that a receptor would be shape-persistent if the perturbation
exerted by a guest produces only small changes in the original shape (Fig. 2). Alternatively, if guest binding results in significant

Figure 2 Comparison between shape-persistent and shape-dynamic receptors.

 Shape-Persistent Anion Receptors 331

deviations from the original shape, the molecules are considered shape-dynamic (Fig. 2). With these considerations in mind, we can
classify molecules as shape-persistent if they have minimal shape change between the initial states and the final stimuli-induced
states.
The connection of shape-persistent and shape-dynamic receptors to biological antecedents is clear; their modes of binding
resemble the extrema of lock-and-key and induced fit (Fig. 1). The lock-and-key binding mode, proposed in 1894 by Emil Fischer,11
describes a static picture of enzyme–substrate interactions where electronic and shape complementarity are enforced. At the other
extreme, the induced fit model, proposed by Daniel Koshland in 1958,12 allows the shapes of enzymes to adapt to the substrates.

3.14.1.3 Preorganization and Shape Persistence

The concept of shape persistence is related to Cram’s ideas of preorganization, as embodied in his spherands (2, Fig. 1).13 Cram
defined the concept of preorganization as follows: “the more highly hosts and guests are organized for binding and low solvation
prior to their complexation, the more stable will be their complexes.”4 That is, a high degree of preorganization requires a host to be
geometrically well defined such that binding energy is not used on conformational changes. This description is consistent with
Moore’s original definition of shape persistence and the broader definition outlined in this article. Thus, shape persistence becomes
unified with the concept of preorganization when considering guest binding. (We also note that shape persistence is a broader
concept that relates to other forms of stimulation.) In the context of host–guest chemistry, by limiting the number of thermally
accessible conformers, those specific conformers in which the binding cavity is well defined can predominate.5 For these reasons,
preorganization is a strategy to enhance the free energy of binding, DGbinding, that often emerges when the free receptors are shape-
persistent.13
Despite their clear similarities, there exists an additional difference between preorganization and shape persistence in the context
of molecular recognition. While shape persistence gives emphasis to the resistance of the host’s shape to any perturbations, it does
not necessarily lead to the complementary shape matching between host and guest. In contrast, one of the main purposes of pre-
organization is to define the cavity’s shape so that binding sites are ready to engage with guests (Fig. 3A).5 Shape persistence serves to
increase the preorganization of the host to enhance binding affinity. The converse is also true; when the shape-persistent cavity offers
a poor match to the guest, binding is reduced.4 Such receptors would have high selectivity biased toward guests with complementary
size and shape. In order to target guests with a broader class of shapes, a shape-dynamic host would be more appropriate (Fig. 3B).

3.14.1.4 Rigid Molecules, Narrow Conformational Spaces, and Shape Similarity

The term rigidity comes to mind when considering the limited conformational freedom expected of shape-persistent molecules.1
However, we note for completeness that rigidity has been used in many contexts.14 For example, a solid material that is rigid
has specific and measurable mechanical properties.15 A rigid material displays very little change in its shape (strain) under an exter-
nally applied force, for example, pulling or bending (stress). In molecular sciences, we found one definition provided for rigidity8:
a molecule with high rigidity has high energy barriers for conformational isomerization. Thus, rigid molecules are unable to access
other conformations and are thus configurationally fixed. The high energy barrier also resists shape changes when the molecules are

Figure 3 (A) A shape-persistent receptor is unable to adequately bind several uniquely shaped guests, exemplifying the lock-and-key model of
guest binding. (B) A shape-dynamic receptor deforming to accommodate uniquely shaped guests, exemplary of the induced-fit model of guest
recognition.
332 Shape-Persistent Anion Receptors

subject to external stimuli; that stimuli must overcome a higher energy barrier in a rigid molecule than in a flexible one. Overall,
rigid molecules have a limited number of accessible conformers and are resistant to deformation during recognition events.
The molecular definition of rigidity gives rise to an additional layer of subtlety: a shape-persistent receptor can remain persistent
if its many conformers are similar in their shapes. A nonobvious corollary of this idea is that shape-persistent molecules do not
necessarily require the number of accessible conformations to be small: those conformations just have to have similar shapes.16
Host molecules that meet such criteria are still rare.9a Investigation of a receptor’s rigidity and, by consequence, the number of acces-
sible conformers allows for a quantitative assessment of shape persistence.
These introductory remarks provide a clear connection between the concepts of shape persistence and preorganization. We finish
these remarks with restating our broader definition of shape-persistent molecules: molecules are considered shape-persistent if they
have minimal shape changes between the initial states and the final stimuli-induced states.

3.14.2 Historical Development of Shape-Persistent Receptors in Anion Recognition

3.14.2.1 Development of Shape-Persistent Receptors
The concept of shape-persistent receptors stems from Moore’s investigation of phenylacetylene macrocycle 3 (Fig. 1). While there
are earlier examples of receptors that would now be considered shape-persistent by our definition,17 the next step in the develop-
ment of the idea of shape-persistent receptors was taken by Hamilton with the creation of aryl-amide macrocycle 4. Hamilton
acknowledged at the time that “rarely have the binding groups been arranged in a convergent and rigid manner.”18 Gong’s work
with oligoamide foldamers, represented by foldamer fragment 5, provides us with a further step by quantification of rigidity
and structural stability.19 Gong experimentally measured the strength of the hydrogen bonds that are used to maintain the overall
conformation of the oligoamide foldamers.20 These measurements provided a convenient determination of relative conformational
stability. The next crucial step toward shape-persistent receptors was to combine, utilize, and acknowledge these advancements in
a single molecular format. This was done by Flood with the design, description, and evaluation of triazolophane 6 as a chloride-
selective and shape-persistent macrocycle.21

3.14.2.2 Shape-Persistent Receptors in Anion Recognition

Host–guest chemistry was first explored following Pederson’s discovery of the crown ethers22 and their affinity for alkali cations. The
development of anion recognition was slower to progress even though the first anion-binding system, katapinand (1, Fig. 1), was
published one year after Pedersen’s report.3 The slower maturation is often attributed to the greater challenge of binding anions:
anions are more weakly bound than cations. There are numerous reasons for this.2 Anions are of greater size23 thus more
charge-diffuse, making interactions with them generally weaker than cations. Though not routinely recognized, this larger size
demands larger receptors, which itself requires a greater degree of synthetic design to be evaluated and then realized. Anions
also have higher energies of hydration than cations of the same size and charge.24 Finally, anions come with greater geometric
variety, such as being tetrahedral, linear, and trigonal planar in shape, necessitating that a suitable receptor be complementary elec-
tronically and geometrically.
The field of anion recognition has grown significantly in recent years. In this field, shape-persistent receptors are an emerging
class of anion receptor that will be reviewed in detail. Discussed first will be receptors that utilize N–H containing functionalities
for anion recognition. N–H groups are well represented and, along with O–H, regarded as the classical example of a hydrogen-bond
donor.23b Focus will then be shifted to nontraditional hydrogen-bond donors based on polarized C–H bonds and anion–p inter-
actions. Finally, we will present cases involving cationic charge to achieve binding. In addition, the shapes of the represented recep-
tors display a wide range of geometries such as planar and twisted macrocycles, cylindrophane-like structures, 3-D receptors, and
shallow bowls.

3.14.3 Neutral N–H Receptors

3.14.3.1 Fundamentals of N–H-Based Receptors
N–H groups have been well-studied as hydrogen-bonding moieties for anion recognition. The disparity in electronegativity (0.84)25
between nitrogen and hydrogen leads to bond polarization and the capability of hydrogen-bond donation. NH groups are prevalent
in several organic functional moieties such as amines, amides, and ureas and in heterocycles like pyrrole. The synthetic modularity
surrounding N–H groups has led to their incorporation into an abundance of well-studied receptors.

3.14.3.2 Amide Systems

Amides are an attractive source of N–H groups for shape-persistent receptors on account of the trigonal planar geometry about the
nitrogen center. This geometry arises from the introduction of sp2 character to the nitrogen from resonance with the adjacent
carbonyl. Resonance stiffens the C–N bond between the carbonyl and the amide groups, increasing the barrier of bond rotation
and the overall rigidity.26 In addition, a group dipole of 4.0 Debye helps fortify anion binding.
 Shape-Persistent Anion Receptors 333

Figure 4 Hamilton’s parent macrocycle 4 and the fluorophore-grafted derivative 8.

One of the initial amide systems that exploits the benefits of shape persistence is aryl amide macrocycle 4 (Fig. 4) cultivated by
Hamilton.27 Hamilton noted that receptors containing convergent binding sites should have large affinities and selectivities for
matched guests but that preorganized macrocycles were a rarity in prior works. Aryl amide 4 displays a convergence of
hydrogen-bonding groups and the positive ends of amide group dipoles within the macrocyclic cavity permitting the formation
of stable host–guest complexes, even in polar media (e.g., DMSO). In addition, the rigidity and geometry of the
5 Å cavity allow
for the facile complexation of tetrahedral oxyanions such as HSO4  , H2 PO4  , and p-toluenesulfonate. Modification of the parent
structure, by grafting a coumarin fluorophore into the macrocyclic backbone, produced aryl amide macrocycle 8, which displayed
anion-dependent changes in fluorescence.28
Anslyn and coworkers developed a threefold symmetrical anion receptor 9 (Fig. 5) with an arrangement of three pincerlike, 2,6-
dicarboxamide-substituted pyridine rings.17a Tris-pincer 9 shows selectivity for the nitrate anion (NO3  , log K ¼ 2.5, and 1:3 v/v
DCM/MeCN). It was rationalized by Anslyn that the recognition of NO3  was achieved through the size complementarity and
the matched symmetry of the guest- and tris-pincer binding cavity. The minimal binding affinity to other environmentally relevant
anions by 9 (Table 1) led to the development of a disposable optical sensor by Santoyo-Ganzalez and coworkers for the determi-
nation of aqueous NO3  concentrations.29
Another system that utilizes the 2,6-dicarboxamide-substituted pyridine structure was synthesized by Gale (Fig. 6).30 The role of
preorganization within dicarboximide macrocycles 10a and 10b was probed by using a pyridyl functionality (10a) in place of
a phenyl ring (10b). The inclusion of pyridine results in a 10-fold average increase in anion affinity, a 100-fold increase in selectivity

Figure 5 Anslyn’s tris-pincer, receptor 9, and the MM2-minimized structure of the 9$NO3  complex viewed down the C3-axis.

Table 1 Binding affinities of tris-pincer 9 (NMR, 1:3 CD2Cl2/CD3CN)

Anion Ka (M  1) Log K

NO3 300 2.5
CN 120 2.1
Cl 40 1.6
H2PO4  25 1.4
Br 15 1.2
CH3CO2  770 2.9
HSO4  <5 <0.7
334 Shape-Persistent Anion Receptors

Figure 6 Gale’s dicarboxamide macrocycles and crescents that were used to systematically probe the effects of structural changes on guest selec-
tivity and affinity.

for acetate over H2 PO4  (Table 2), and an increased stability in aqueous and mixed aqueous/organic solvents. The favorable elec-
trostatic interactions between amide hydrogens and the pyridyl nitrogen were assumed by Gale to result in a stiffer, more preorgan-
ized structure. An analogous pair of acyclic dicarboximide receptors 10c and 10d was synthesized and generally exhibited lower
stability constants than their macrocyclic analogs. Gale’s work exemplifies the effect of preorganization by comparing cyclic recep-
tors and their acyclic analogs and that a change of an atom can significantly modify binding performance of a receptor.
The modularity of the dicarboximide pincer moiety was explored by Jeong and coworkers within the large macrocycles 11 and
12.6c A preference in binding geometry for complexation of naphthalene-2,6-dicarboxylate (Fig. 7) could be altered by changing the
substituent on the 4-position of the pyridine ring. The installation of electron-withdrawing chlorides (11) on two adjacent corners
resulted in the enhancement of the binding mode in which the dicarboxylate coordinates to the substituted corners. When an
electron-donating pyrrolidinyl substituent was installed (12), however, the preferred binding mode was to interact with the unsub-
stituted corners. Jeong proposed that this method of biasing a receptor’s preferred binding geometry could be of unique interest for
the field of molecular machines and switches, particularly if binding could be biased by a reversible stimulus such as a redox process.
Another receptor with unique binding behavior, spirofluorine macrocycle 13 (Fig. 8), was developed by Morán and cowor-
kers.17d The amide and urea functionalities are organized by the heterocyclic oxygen atoms. The incorporation of spirobifluorene
further rigidifies the macrocyclic backbone and introduces chirality to the structure allowing for enantiomeric recognition. It was
shown that macrocycle 13 binds (R)-lactate an order of magnitude more strongly than the S-enantiomer, log K ¼ 4.5 and 3.5
(DMSO), respectively.

3.14.3.3 Pyrrolic Systems

Pyrrole rings have found prominence in anion-binding receptors. Pyrroles confer resonance across the heterocyclic structure for
rigidity, a modest molecular dipole of 1.9 Debye for enhancing anion stabilization, and a nitrogen NH center that is neither strongly

Table 2 Binding affinities of dicarboximide 10a–10d (NMR, [d6]-DMSO/0.5% D2O)

Anion 10a (M  1) Log K 10b (M  1) Log K 10c (M  1) Log K 10d (M  1) Log K


Cl 190 2.3 12 1.1 <10 <1 38 1.6
Br 10 1 <10 <1 – – – –
HSO4  120 2.1 <10 <1 – – – –
H2PO4  140 2.2 610 2.8 680 2.8 300 2.5
NO3  <10 <1 <10 <1 – – – –
CH3CO2  16,500 4.2 940 3 420 2.6 140 2.1
C6H5CO2  6400 3.8 320 2.5 100 2.0 71 1.9
 Shape-Persistent Anion Receptors 335

Figure 7 The two unique binding modes of Jeong’s tetrapincer macrocycles 11 and 12 with their relative populations in 40/60 CD3CN/CDCI3 at
297  1  K.

Figure 8 ,
Chiral receptor 13 developed by Morán and the MMFF94-minimized structure of the 13 mandelate complex.

basic nor acidic.31 The aromaticity of pyrrole results in an ideal shape-persistent building block with only one single planar confor-
mation. With the pyrrolyl group unlikely to undergo a change in protonation state, the fortitude of a receptor can confidently be
assumed over a broad pH range when a wide receptor application space is demanded. On account of their similarities with pyrrole,
indolocarbazole-based receptors will also be included and discussed in this section.
Maeda and coworkers have published several studies on the acyclic oligopyrrole-based anion receptor 147d–f,32 and have
expanded it into a series of foldamers (Fig. 9).33 While receptor 14 and the corresponding foldamers, such as oligopyrrole 15a,
are not themselves shape-persistent, when crafted into macrocycle 15b, the covalent connections enforce a preorganized, persistent
binding cavity. The respectable Cl binding affinity of 14 (log K ¼ 3.4, determined by UV–Vis titrations in CH2Cl2) is magnified

Figure 9 Maeda’s pyrrolyldiketone-BF2 receptors.

336 Shape-Persistent Anion Receptors

significantly by four orders of magnitude in acyclic, dimer-like receptor 15a (log K ¼ 7.8, UV–Vis in CH2Cl2), which is inflated
further when formulated in macrocycle 15b (log K ¼ 10.3, determined by competition studies in CH2Cl2). The comparison between
macrocycle 15b and receptor 15a reveals that the 300-fold leap in affinity is achieved by covalently linking the two terminal pyrrole
functionalities together. The increase in Cl affinity achieved through both preorganizing and rigidifying the receptor exemplifies
the benefits of shape persistence.
A variant of the pyrrole functionality, indolocarbazole, was incorporated into rigid macrocycle 16 (Fig. 10) by Jeong and
coworkers.34 Shape persistence of the receptor is achieved by utilizing inflexible alkynyl groups to connect the two indolocarbazole
components together forming a cavity of 3.6 Å. The decrease in affinity with increasing halide size (Table 3) was attributed to the
inability of the macrocycle to contort to accommodate larger guests. In fact, the crystal structure of the complex formed between 16
and Bu4NþCl reveals that the Cl anion (ionic diameter of 3.6 Å) only partially inserts into the cavity34 and that the macrocycle
retains its planarity. This observation reflects our discussion (vide supra) on the difference between preorganization and shape
persistence; receptor 16 is shape-persistent but not preorganized for the binding of Cl.
In an effort to study further, the effects of cavity size on anion-binding, specifically on polyatomic anions, receptor 17 (Fig. 10)
was synthesized.6d The use of butadiynyl bridges extends the binding cavity’s length to
5.8 Å without compromising rigidity. A
comparison of the affinities of receptors 16 and 17 for polyatomic anions (Table 3) shows that the larger macrocycle (17) binds
larger anions more strongly than the smaller macrocycle (16). The complexes 16$N3  and 17$N3  were both crystallographically
characterized, and two different azide coordination modes were observed. With a cavity only large enough to fit a single nitrogen
atom, an end-on binding mode of the N3  anion is observed for the complex 16$N3  . In contrast, the complex 17$N3  sees the
azide anion bound in an end-to-end manner within the larger cavity of 17. Based on the similarities between the two macrocycles

Figure 10 Jeong’s indolocarbazole receptors, as well as the crystal structures of 16$N3  and 17$N3  in which the azide anion is bound in an end-
on and end-to-end fashion, respectively.

Table 3 Binding affinities of indolocarbazole receptors 16 and 17 (UV–Vis, 9:1 acetone[d6]/CD3OD)

Anion 16 (M  1) Log K 17 (M  1) Log K

Cl 1800 3.3 430 2.6

Br 72 1.9 320 2.5
I < 10 <1 2400 3.4
N3 2300 3.4 81,000 4.9
CH3CO2  21,000 4.3 170,000 5.2
NO3  94 2 15,000 4.2
HS04  81 1.9 13,000 4.1
H2PO4  4300 3.6 220,000 5.3
 Shape-Persistent Anion Receptors 337

Figure 11 Jeong’s helical indolocarbazole macrocyle and the crystal structure of the 18 $ CH3COO– complex.

and the difference in azide binding affinity, it was concluded that the full inclusion binding mode is more stable
(DDG ¼  8.8 kJ mol 1 in 9:1 acetone/MeOH).
Jeong has recently expanded his library of indolocarbazole receptors with the synthesis of the chiral receptor 18 (Fig. 11) that
was characterized by circular dichroism (CD) spectroscopy.35 The formation of 18 by imine condensation is sluggish in the absence
of a template but reaches completion within 30 min in the presence of a carboxylate guest. The use of an achiral carboxylate such as
acetate results in a CD-silent, racemic mixture of P- and M-helical macrocycles. Alternatively, the presence of an enantiopure chiral
carboxylate template, such as Boc-protected L- or D-alanine, results in an enantiomeric excess of one helix, with positive Cotton
effects observed for the D-enantiomer and negative Cotton effects observed for the L counterpart. A preference in helical stereochem-
istry was not observed when a racemic mixture of guest was employed, but CD intensity was shown to correlate linearly with enan-
tiomeric excess of guest. The linear correlation between CD intensity and enantiomeric excess holds a promise for the use of 18 as
a stereodynamic probe.

3.14.4 Neutral C–H-Based Receptors

3.14.4.1 Fundamentals of C–H-Based Receptors
C–H groups are present in approximately 97% of organic compounds,36 yet this abundant resource had been largely untapped in
the context of anion binding until recently. Classically, C–H bonds are considered to be weak hydrogen-bond donors37 because of
the minimal electronegative disparity (0.36) between the two atoms.25 The addition of a strategically placed polarizing group can
significantly enhance the C–H hydrogen bonding, rivaling the strength of more traditional N–H donors. The necessity of an extrinsic
polarizing group can often be combined with the synthetic needs; just as with amide or indole NH bonds, C–H-based receptors have
been quite fruitful.36 1,2,3-Triazoles, cyanostilbene, and glycoluril groups are some of the C–H-containing functionalities that have
been used for anion recognition, with the first two examples being isosteric with pyrrole and bis-aryl amides, respectively.

3.14.4.2 C–H-Based Receptors

1,2,3-Triazoles can be readily formed by copper-catalyzed azide-alkyne cycloaddition, and the reaction has arguably become the
favorite of the “few good reactions” that fall under the umbrella of Sharpless’ click chemistry.38 Being synthesized from easily incor-
porated substituents, with high isolated yields, triazoles have quickly been adopted by the fields of materials, pharmaceuticals, and
polymer chemistry.39 Triazole motifs have also begun to appear in shape-persistent receptors in a similar fashion to the pyrrole unit.
The similarities between triazoles and pyrroles can be seen quite easily: both are rigid, planar, five-membered heterocycles and
neither group contains a readily protonated/deprotonated atom. Where triazoles and pyrroles differ most, besides nitrogen content,
is in their molecular dipole. The molecular dipole of a typical pyrrole unit is 1.9 Debye. In comparison, the typical molecular dipole
of a triazole moiety is 4.6 Debye, which is more than twice as strong as the NH-based pyrrole.
Flood’s pioneering macrocycle, triazolophane (6, Fig. 12), alternates four aryl rings with four triazoles into a shape-persistent
core.21 The binding cavity of the planar triazolophane is oriented such that it is lined with only C–H bonds and the positive portions
of the triazole dipoles converge within the 3.8 Å cavity. The parent triazolophane 6 shows high affinity toward the halides in CH2Cl2
but binds Cl, log K ¼ 7,40 and Br, log K ¼ 6.9,40b,41 most strongly.41 The weaker binding of F and I is attributed to poor size
complementarity between the guest and inflexible host, with F being too small (diameter of 2.6 Å) to sufficiently contact all eight
binding sites and I being too large (diameter of 4.4 Å) to fit into the cavity.
Enhanced I binding was achieved by substituting two of the phenyl rings of the parent triazolophane with pyridyl rings to give
triazolophane 19.26 The formation of the 192 $I sandwich complex (log b2 ¼ 10.9) is attributed to the dipole-enhanced p–p
338 Shape-Persistent Anion Receptors

Figure 12 Structure of Flood’s original triazolophane 6, the pyridyl incorporated triazolophane derivative 19, and the oxoverdazyl decorated
analogue 20 synthesized by Chandrasekar.

interactions between macrocycles.6a Further studies of triazolophane 6 investigated the nature of complexing small, diatomic
anions, such as CN.41,42 It was revealed that the affinities for CN and Cl were approximately equivalent in both gas-phase calcu-
lations and experimentally in solution. The commensurate affinity of CN was rationalized to originate from the rapid rotation of
the anion within the shape-persistent binding cavity of triazolophane, amounting to a pseudospherical guest geometry.
In a more material-based application, the Chandrasekar Lab appended the triazolophane core with oxoverdazyl radicals to give
macrocycle 20.43 The system was shown to form paramagnetic organic tubes capable of guiding laser light and is the first example of
a wholly organic paramagnetic system to exhibit spin–photon interactions.
Electron-withdrawing groups, for example, nitro and nitrile, are of potential interest for enhancing C–H donor ability. One such
nitrile-containing functionality is cyanostilbene. It has a group dipole of 4.3 Debye and enhanced rigidity from p-conjugation and is
easily synthesized by Knoevenagel condensation. With these properties, the cyanostilbene moiety was incorporated into a fivefold
symmetrical, shape-persistent macrocycle called cyanostar (21, Fig. 13), by Lee and Flood.6b Macrocycle 21 is synthesized in a scal-
able, one-pot reaction from a metasubstituted difunctional benzene bearing a benzylic nitrile and benzaldehyde functionality. With
a diameter of 4.5 Å, the binding cavity of cyanostar is size-matched for large polyatomic anions.
The binding affinities of cyanostar macrocycle 21 with anions traditionally considered to be noncoordinating are unprecedented
for a neutral host, let alone one bearing a weak class of hydrogen-bond donors (Table 4). Binding constants were determined for
anions of various sizes, from a diameter of 3.4 Å for Cl to the 6.7 Å PtCl6 2 , with maximal affinity shown for the 4.6 Å PF6 
(log b2 ¼ 12.4, 40:60 MeOH/CH2Cl2). NMR titrations revealed that cyanostar macrocycles preferentially bind anions as persistent
2:1 sandwich complex, for example, 212 $ClO4  appears to persist in solution even in the presence of a hundred equivalents of
ClO4  .
The propensity of cyanostar macrocycles to form 2:1 sandwich complexes in the presence of anions was exploited in the unprec-
edented preparation of a [3]rotaxane (22, Fig. 13) by anion templation. Dipropargylphosphate was threaded inside of two cyanos-
tar macrocycles and then stoppered with bulky 3,5-methyl benzoate groups.
In recent works, the parent cyanostar macrocycle 21 was modified with phenylene–acetylene arms decorated with octyl chains
(Fig. 14) to help stabilize molecules as a crystalline monolayer on highly ordered pyrolytic graphite surfaces.44 Macrocycle 23 was
observed to pack in pairs of antiparallel rows. Ex-situ mixing of cyanostar macrocycle 23 and PF6  followed by deposition on the
graphite surface resulted in the same 2-D packing pattern observed for the monolayer but with additional bright circular features

Figure 13 (A) Structure of Flood’s cyanostar 21 and crystal structures of the empty receptor, (B) the 2:1 212 $ClO4  complex, and (C) the anion
template [3]rotaxane 22.
 Shape-Persistent Anion Receptors 339

Table 4 Binding affinities of cyanostar, receptor 24

(UV–Vis, 40% CH3OH/CH2Cl2)

Anion Log K1 Log K2

Cl 3.8 4.1

Br 4.7 4.9
NO3  4.6 5.1
BF4  5.1 6.0
SCN 5.0 5.5
I 5.2 5.5
ClO4  5.4 6.8
ReO4  5.7 6.0
IO4  5.5 6.8
PF6  5.6 6.8
SbF6  5.5 5.7
FeCL4  4.2 4.3
PtCl6  3.7 4.0

Figure 14 (A) Cyanostar 23 was used for surface assembly STM studies. (B) A scanning tunneling microscopy image of cyanostar 23 assembled
from a 5 mM 1,2,4-trichlorobenzene solution onto graphite, and (C) a packing model derived from collected images.

attributed to anion-templated 2:1 sandwiches. These results were reported to be the first observation of a surface-adsorbed anion
dimer complex.
Flood’s early success with triazoles and cyanostars eventually led to the one-pot synthesis of the threefold symmetrical tricarba-
zolo triazolophane (tricarb 24).7c Alternating 3,6-disubstituted carbazoles with triazoles produces a shape-persistent receptor with
a large binding cavity of diameter 4.8 Å lined with convergent C–H donors (Table 5). The large cavity size of tricarb macrocycle 24
results in maximal binding with the size-matched, polyatomic anions PF6  and SbF6  (log b2 ¼ 11.4 and 11.6, respectively).
Similar to cyanostars, tricarb macrocycles also display 2:1 complexation and positive binding cooperativity (a ¼ 4 K2/K1) with
values as high as 1200 for PF6  .
In addition to coordinating large anions, the tricarb macrocycle displays a high propensity to self-association in solution and on
graphite surfaces. By fitting variable concentration UV–Vis data to an isodesmic, equal K model, the aggregation (Ke) of tricarb was
determined to be Ke ¼ 300,000  10,000 M 1 in 20:80 MeOH/CHCl3.45 Ke was also observed to increase with decreasing solvent
dielectric constant, an observation consistent with a stacking model in which dipole-stabilized p-stacking exists between comple-
mentary triazole and carbazole dipoles of neighboring receptors. The rigidity and planarity of 24 must also assist by allowing neigh-
boring receptors to make intimate contact, maximizing the strength of the intermolecular interactions.
Scanning tunneling microscopy (STM) experiments revealed that tricarb macrocycles, in 1,2,4-trichlorobenzene, form two
unique polymorphs on a graphite surface depending on concentration (Fig. 15). At relatively high concentration (150 mM), a honey-
comb-like structure forms in which each macrocycle is in contact with three neighboring macrocycles. At lower concentrations
(75 mM), a cocrystallized structure is observed, in which the macrocycle is in contact with only two neighboring receptors and
one solvent molecule. The lateral contacts between receptors appear to be driven by hydrogen bonding between a carbazole C–
H donors and a triazole N-acceptors and, in the case of the cocrystallized structure, a Cl acceptor on the cocrystallized solvent.
STM image analysis combined with height profiles shows the formation of multilayers of up to five molecules thick on the surface,
with the macrocycle’s pore discernable up to the fourth layer. Previous works46 have shown that vertical surface growth appears to
terminate after the formation of either a bilayer or trilayer, making the tubular structures of macrocycle 24 the tallest reported self-
stacking surface structures under these dynamic self-assembly conditions.
340 Shape-Persistent Anion Receptors

Table 5 Binding affinities of tricarb, receptor 27 (UV–Vis, 20%

MeOH/CHCl3)

Anion Log K1 Log K2

I 4.3 5.1
Cl04  4.0 5.9
Re04  3.8 6.2
PF6  4.5 6.9
SbF6  5.2 6.4
FeCl4  4.0 3.7

Figure 15 (A) Structure of Flood’s tricarb 24, (B) STM image of the honeycomb polymorph (150 mM, 1,2,4-trichlorobenzene) and its packing
model (C) STM image of tricarb 24 (150 mM, 1,2,4-trichlorobenzene) after the in-situ addition of 0.001 equivalents of iodide. (D) Observations of
surface stacking in the honeycomb polymorph and associated packing model.

The glycoluril group is a rigid bicyclic heterocycle composed of two cyclic ureas that has been used extensively in cucurbituril
macrocycles.47 Recently, Sindelar and coworkers have developed toroidal macrocycle 25, bambus[6]uril, which is composed of
six repeating and methylene-bridged, N-substituted glycolurils.48 Bambus[6]uril 25 is threefold symmetrical, with the glycoluril
groups related by a sixfold improper axis (S6), and the six pairs of glycoluril C–H groups converge to form an octahedral-like
arrangement. The C–H groups of the glycolurils are polarized by nearby electronegative nitrogen atoms, resulting in a molecular
dipole of 3.9 Debye (Fig. 16). The binding cavity of bambus[6]uril 25 is size-matched for the ClO4  anion resulting in peak binding
affinity (log Ka ¼ 2.1  1010, ITC and CHCl3).49
Introduction of benzoate functionalities to the core bambus[6]uril structure afforded sufficient solubility such that the binding
of anions could be studied in aqueous solutions.50 A range of anion shapes and sizes were shown to form complexes presumably
due to the methylene bridges granting a slight amount of flexibility to the macrocycle.35 In fact, the trend in the anion affinity of
bambusuril in aqueous solution (Table 6) better correlates with the Hofmeister bias than anion size. The Hofmeister series catalogs
anions phenomenologically, and the series flows from strongly hydrated to weakly hydrated or from more hydrophilic to less
 Shape-Persistent Anion Receptors 341

Figure 16 (A) Chemical structure and MMFF94-minimized structure of a glycoluril moiety. (B) Sindelar’s Bambus[6]uril 25 and (C) the crystal
structure of the 25 $ I– complex (R ¼ H).

Table 6 Binding affinities of receptors bambus[6]uril 7 (1H NMR, D2O; ITC, CHCl3)

Anion H2O Ka (M  1) Log K CHCl3 Ka (M  1) Log K

1
F 1.1  102
2.0 1.8  106
6.3
Cl 9.1  102 3 1.5  107 7.2
CN 1.1  103 3.0 9.8  106 6.9
IO4  6.5  103 3.8 1.6  107 7.2
ReO4  3.0  104 4.5 1.1  108 8.0
Br 1.4  105 5.1 6.7  108 8.8
NO3  4.8  105 5.7 3.7  108 8.6
PF6  2.2  106 6.3 8.7  108 8.9
BF4  4.3  106 6.6 1.0  1010 10.0
I 1.0  107 7 1.5  1010 10.2
ClO4  5.5  107 7.7 2.1  1010 10.3

hydrophilic. While the trend of anion binding selectivity conforms qualitatively with the Hofmeister series instead of size matching,
the role of shape persistence of the empty macrocycle upon anion binding remains unclear at this stage.

3.14.5 Anion–p-Based Receptors

3.14.5.1 Fundamentals of Anion–p Receptors
Receptors that utilize anion–p interactions to achieve guest recognition have been recently explored.51 The anion–p interaction has
been shown to be predominantly electrostatic in nature, with the anion interacting as a p-base and the positive portion of the
molecular quadrupole of the receptor acting as a p-acid.52 The typical molecular quadrupole of an aromatic system displays a nega-
tive electrostatic potential above and below the molecular plane and an in-plane positive potential. Consequently, electron-
withdrawing groups like fluorine and nitro must be installed to reverse the molecular quadrupole. These substitutions can place
greater demands on the receptor’s design and synthesis by occupying space (sterics) or locations for connecting one moiety to
another.

3.14.5.2 Examples of Anion–p-Based Receptors

Originally synthesized by Klärner, molecular tweezers like 26 (Fig. 17) are shape-persistent. Their binding cavity is composed of the
faces of five aromatic rings capable of forming complexes with aromatic guests.17b Hermida-Ramón and coworkers have compu-
tationally explored molecular tweezers, 27 (Fig. 17), decorated with electron-withdrawing fluoro or cyano groups as possible recep-
tors for anions in both the gas phase and in solution.53 The presence of the electron-withdrawing groups makes the aromatic faces
electron-poor, facilitating interactions with electron-rich halides. In the gas phase, both 27-F and 27-CN showed favorable binding
energies (Ebinding) between receptor and anion, with the chloride complex 27  CN$Cl displaying the strongest binding
(Ebinding z  260 kJ mol 1). Solution-phase computations were also conducted (Table 7). The majority of the complexes formed
with the fluorine-substituted tweezer were shown to have positive binding interactions with only 27  F$Cl and 27  F$Br  being
342 Shape-Persistent Anion Receptors

Figure 17 (A) Structure of Klärner’s molecular tweezers, 26. (B) The molecular tweezer derivative 27 investigated by Estèvez. (C) Substituted cor-
annulene 28 and (D) sumanene-based 29 bucky bowls modeled by Rodríguez-Otero.

Table 7 Computational DGbinding values of molecular tweezers 29-F and 29-CN using the polarizable
continuum model at the MPW1B95/6-31þG* level

Solvent Cl  (kcal mol  1) Br  (kcal mol  1) I  (kcal mol  1)

17-F
Water 3.1 3.3 9.6
DMSO 3.1 3.3 9.6
Acetone 2.9 2.9 7.9
Chloroform 1.9 1.8 2.9
17-CN
Water 3.8 2.4 8.3
DMSO 4.3 2.9 7.3
Acetone 7.2 6.1 4.1
Chloroform 21 21 9.9

stable in chloroform. The majority of 27  CN$X  complexes, however, displayed favorable binding energies. Based on these find-
ings, it was concluded that synthetic efforts toward the cyano-substituted tweezers hold more promise for anion binding.
Rodríguez-Otero and coworkers performed similar computational studies on the anion-binding abilities of substituted bucky-
bowls by examining corannulene 28 and sumanene 29 (Fig. 17).54 The binding of halides and polyatomic anions was investigated
in the gas phase and in solution. Both of the buckybowls preferentially bound anions to their convex face with the strength of the
interaction decreasing for more charge-diffuse species. Additionally, it was found that, for polyatomic anions, the binding mode
that saw the largest number of electronegative atoms in contact with the convex face of the receptor was energetically preferred.54b

3.14.6 Cationic N–H Receptors

3.14.6.1 Fundamentals of Cationic N–H Receptors
Cationic N–H-based receptors possess many of the same qualities as their neutral cousins with the most prominent differences
being the addition of coulombic interactions, a potential pH dependence, and the presence of a counteranion. Coulombic interac-
tions are alluring for anion binding since the strength of the interaction is greater. Hydrogen bonding and dipole interactions, while
weaker, offer angle dependencies for greater geometric and orientational control. The introduction of multiple coulombic interac-
tions has its disadvantages, namely, increased receptor strain arising from repulsions between multiple binding sites that can only
 Shape-Persistent Anion Receptors 343

be eased by spatial separation. The ability of some binding sites, such as amines, to adopt different protonation states at different pH
levels must also be considered. Ideally, a balance must be struck between the pH ranges over which the receptor operates and over
which the guest exists as an anion. Ammonium species originating from secondary amines are a common source of cationic N–H
bonds, but other functionalities, such as expanded porphyrins, are also represented.

3.14.6.2 Cationic Nitrogen-Based Receptors

Expanded porphyrins have been investigated since the serendipitous synthesis and discovery of sapphyrin by the Woodward group
in 1966.55 Since then, interest in expanded porphyrins has steadily grown. In the search for larger porphyrin-like systems, it was
noted that the macrocycles often adopt a twisted shape instead of the idealized planar structure. The guest binding of porphyrin
and porphyrin-like systems is often associated with the complexation of metal cations, but the utilization of the porphyrin frame-
work to recognize anions has also been explored. One such porphyrin (30, Fig. 18), cyclo[8]pyrrole, was discovered by Sessler.56
Macrocycle 30 is aromatic with 30 p-electrons, formed by the oxidation of a,a0 -unsubstituted bipyrroles in acidic conditions. Crys-
tallographic analysis of 30$SO4 2 shows the expanded porphyrin is essentially planar with the anion bound in the center of the
cavity in contact with all eight pyrrolic N–H hydrogen bonds. The NMR spectrum of 30$SO4 2 is simplified significantly by
symmetry, with only one pyrrolic proton and three unique skeletal carbon signals present, suggesting that the planar structure
present in the solid phase persists in solution as well.
The existence of the diprotonated macrocycle at or near neutral pH, along with the observation that the sulfate complex readily
crystallizes, led to the consideration of 30 as a potential SO4 2 extractant.57 The nitrate salt, 30$ðNO3  Þ2, was prepared, and the
exchange with SO4 2 was measured at various nitrate concentrations. Under the conditions tested, 30 produced an exchange
0
affinity constant of log Kexch ¼ 4:9, indicating significant selectivity for the strongly hydrated sulfate (free energy of hydration,
  1 58
DG ¼  1090 kJ mol ). The complex 30$SO4 2 has also been explored as a component of a supramolecular liquid crystal.7g
Mascal has recently developed a threefold symmetrical, cylindrophane-type receptor 31 (Fig. 19), which utilizes cationic N–H
and anion–p contacts to bind fluoride.59 Cylindrophane 31 was designed first in silico, with modeling suggesting that F would be
selectively bound over Cl because chloride is too large.60 The shape-persistent nature of cylindrophane 31 was discovered upon
inspection of the crystal structures of the receptor in both the free and fluoride bound state. Gratifyingly, the geometry of the fluoride
complex was observed to be in close agreement with the one predicted computationally. The predicted selectivity for F over Cl

Figure 18 The structure of Sessler’s expanded porphyrin, cyclo[8] pyrrole 30, and the crystal structure of the 30$SO4 2 complex.

Figure 19 Mascal’s cylindrophane-like receptor 31 and the crystal structures of the empty receptor and the fluoride complex 31 $ F–, alkyl chains
truncated to methyl groups for clarity.
344 Shape-Persistent Anion Receptors

Figure 20 Chemical structure of Amendola’s cryptand-like receptor 7 and the crystal structure of the pertechnetate complex 7$TcO4  .

was confirmed by treating the empty, neutral, receptor 31 with concentrated HCl followed by an excess of aqueous HF in methanol.
Evaporation of the solvent followed by electrospray mass spectrometry showed a peak for the 31$F species and none for 31$Cl . In
fact, no peaks indicative of the 31$Cl complex were ever observed, even in the analysis of the trichloride salt, further supporting the
computational assessment.
Amendola and coworkers developed cryptand 7 (Fig. 20) and found that it selectively binds the pertechnetate anion (TcO4  ),
a nuclear waste product.61 In the style of azacryptand cages, 7 utilizes six cationic N–H bonds to bind anions. Receptor 7 shows
strong binding to TcO4  (log K ¼ 5.5) in aqueous media at pH 2, which at the time of publication was the highest reported value
for aqueous pertechnetate binding. In addition to solution-phase binding experiments, 7$TcO4  was also observed crystallograph-
ically with the TcO4  anion centered inside the receptor cavity.

3.14.7 Transition Metal-Based Receptors

3.14.7.1 Fundamentals of Transition Metal-Based Receptors
Transition metal-based receptors represent some of the earliest examples of host molecules that can be considered, with hindsight,
to be shape-persistent. The anion-binding ability of some metal complexes was discovered serendipitously after crystallographic
characterization. The discrete, generally predictable, nature of metal–ligand coordination geometries allows receptor shape to be
determined a priori with reasonable confidence, thus greatly assisting the process of receptor design and optimization. Transition
metal receptors most often achieve guest recognition through coulombic interactions and by forming Lewis pairs. Furthermore,
host–guest complexation often perturbs the environment around the metal center, causing a change in the d orbital splitting,
opening up the possibility for use in colorimetric sensing applications.

3.14.7.2 Examples of Transition Metal-Based Receptors

Mercuracarborands were developed by Hawthorn and coworkers and given the moniker “anticrowns.” They serve as one of the early
examples of a Lewis acid host capable of binding anions.62 For the sake of brevity, only the work with the triangular [9]-
mercuracarborand-3 32 (Fig. 21) will be discussed,63 but it is worth mentioning that a square [12]-mercuracarborand-4 was
also synthesized and characterized.62 Mercuracarborand 32 was synthesized by reacting lithiated carborane with mercury(II) acetate
to give the anticrown. NMR titrations of various halide salts into solutions of 32 showed increased affinity with increasing size up to
iodide. The triangular macrocycle 32 was shown crystallographically to form 2:1 sandwich complexes with Cl, Br, and I coor-
dinated in a distorted octahedral geometry.64 In fact, the 322 $I sandwich complex was the first example of an octahedrally coor-
dinated iodide.
Metallocryptands are an example of a shape-persistent receptor, inspired by cryptands and azacryptands that achieve anion
recognition by use of transition metal centers. One such matallocryptand that employs two Cu(II) centers is receptor 33
(Fig. 22), which was developed by the Fabbrizzi group.65 This metallated receptor was shown to bind the linear N3  and
NCO anions most strongly (log K ¼ 4.78 and log K ¼ 4.6 in aqueous pH 8 solution). The crystal structure of 33$HCO3  revealed
that the two Cu(II) centers were bridged by the bound bicarbonate. This evidence, in addition to the binding affinities for guests of
diverse geometries, led to the conclusion that the affinity for a given anion was predominantly determined by its ability to occupy
the vacant coordination sites of both Cu(II) centers.
An identical system to Fabbrizzi’s utilizing two Co(II) centers, 34 (Fig. 22), was developed by Lu.66 Receptor 34 was shown to
bind Cl (log K ¼ 5.7) and Br (log K ¼ 5.2) in acetonitrile, but not F or I. This selectivity is attributed to the rigidity of the
receptor and its inability to accommodate a guest of larger or smaller size. Antiferromagnetic coupling was observed for the chloride
and bromide complexes suggesting, and confirmed crystallographically, that the halide guests were bridging the two Co(II) centers.
Burkhalter and coworkers developed the calixarene-based system 35 (Fig. 23), which obtains its anion-binding abilities from the
incorporation of the four core aryl rings into metallocene moieties.17c The steric bulk of the metallocenes enforce the shape
 Shape-Persistent Anion Receptors 345

Figure 21 Hawthorne’s anti-crown, mercuracarborand 32, and the crystal structure of the 322 $ I– sandwich complex.

Figure 22 (A) The structure of Fabbrizzi’s (33) and Lu’s (34) metallocryptand receptors, and (B) the crystal structures of the solvent filled receptor
34 and the bromide complex 34 $ Br –.

persistence of the bowl-like structure of 35 by making the inversion of the internal aryl rings sterically disfavored. Additionally, the
metal centers polarize the interior of the bowl giving it an electropositive character much like the molecular tweezers and bucky-
bowls discussed previously. Calixarene 35 was shown to bind anions modestly in aqueous media with peak binding shown for
Cl (log K ¼ 2.7). The 35$I complex was crystallographically characterized, and the iodide guest (log K ¼ 1.7) was shown to
bind in the center of the calixarene cavity as predicted.

3.14.8 Future Outlook of the Field

The use of shape-persistent anion receptors in supramolecular chemistry has continued to grow in recent years. The characteristic
retention of shape allows for supramolecular interactions that are encoded into the molecule’s framework to be sustained under
various conditions and promotes a greater chance of successful molecular designs. As a consequence of this feature, shape-
persistent anion receptors have begun to be more extensively used in supramolecular contexts.
346 Shape-Persistent Anion Receptors

Figure 23 Burkhalter’s tetra-metallocene receptor 35 and the MMFF94-minimized structure of the 35 $ I– complex.

Shape-persistent receptors can be used as model systems to deepen our quantitative understanding of host–guest chemistry. The
confined conformational space of shape-persistent anion receptors results in minimal reorganization during the binding event.
Consequently, this feature opens up an invaluable opportunity to test many key concepts in host–guest chemistry such as binding
stoichiometry,6a,b,67 cooperativity,6b,68 and selectivity.18,37,59,61,68b
Shape-persistent anion receptors can serve as building blocks for self-assembled and stimuli-responsive materials that utilize
charge complementarity7f,67,69 or tunable aggregation.7c,44,70 The concept of shape-persistent anion receptors has even been applied
to help organize flexible molecules during self-assembly processes. Maeda, for example, has used anions to organize his conforma-
tionally flexible dipyridyl receptor (Fig. 9, 14) and to form liquid crystals by charge-by-charge assembly.7e,f Similarly, Sessler has
utilized his cyclo[8]pyrrole receptor (Fig. 18, 32) in combination with electron-deficient aromatic species to form discotic liquid
crystals.7g Flood has demonstrated that anions can tune the preferential surface morphology of an aryl-triazole crescent70 and influ-
ence the thickness of films formed from tricarb macrocycles (Fig. 15, 27).7c
Finally, shape-persistent receptors allow for the implementation of computer-aided design for virtual experimentation in supra-
molecular chemistry. These receptors are less time-consuming to describe and can be quickly modeled with high-level calculations.
Thus, by combining computer-aided design with shape-persistent receptors, areas of application that require increased structural
and functional complexity can more easily be designed. One such example is the computer-aided design of a bifluoride receptor,
demonstrating that the binding modes and binding affinity can be computationally predicted.40a

3.14.9 Conclusions

The inherent advantages of shape-persistent macrocycles and receptors mark them as a privileged class of hosts for anion recogni-
tion. They generally produce high binding strengths and selectivities, a feature they share with preorganization. Yet shape-persistent
molecules are more than just preorganized receptors. Rather, they resist shape changes when subjected to other stimuli. More gener-
ally, therefore, molecules can be considered shape-persistent if they have minimal shape change between their initial states and their
final stimuli-induced states. To date, shape-persistent receptors and macrocycles have been investigated using many different types
of binding sites and receptor frameworks. The receptors bear one or more of the hallmarks of shape persistencedbinding strength
 Shape-Persistent Anion Receptors 347

and selectivity. The benefits of shape persistence also include easy and predictable molecular design and more straightforward
understanding of recognition behaviors. Shape-persistent anion receptors are now being investigated for the creation of anion-
responsive, self-assembled materials. This transition from monomolecular species to multimolecule assembles is an exciting new
stage in the utilization of shape-persistent receptors.

Acknowledgments

We acknowledge the National Science Foundation (NSF CHE-1412401) for funding.

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 3.15 Amide-Based Tripodal Anion Receptors
P Ghosh, TK Ghosh, S Chakraborty, and R Dutta, Indian Association for the Cultivation of Science, Kolkata, India
Ó 2017 Elsevier Ltd. All rights reserved.

3.15.1 Introduction 349

3.15.2 Tris(2-amino ethyl) amine (TREN)-Based Tripodal Amide Receptors 350
3.15.3 Anion Recognition Studies with Protonated Tripodal Amide Receptors 354
3.15.4 Benzene Platform-Based Tripodal Amide Receptors for Anion Recognition 356
3.15.5 Recognition Through Bis-tripodal Receptors 360
3.15.6 Tripodal Amide Receptors-Based on Miscellaneous Platforms 361
3.15.7 Applications of Tripodal Amide Receptors 363
3.15.7.1 Chemical Sensing 363
3.15.7.2 Extraction 363
3.15.7.3 Transportation 365
3.15.8 Concluding Remarks 365
References 366

Abbreviations
ACN Acetonitrile ITC Isothermal titration calorimetry
APCI-MS Atmospheric pressure chemical ionization mass OAc Acetate
spectrometric oxy-TREN Tris-(2-(4-aminophenoxy)ethyl)amine
CHCl3 Chloroform TBA Tetrabutylammonium
DCM Dichloromethane THF Tetrahydrofuran
DMF N,N Dimethyl formamide TREN Tris-(2-aminoethyl)amine
DMSO Dimethyl sulfoxide

3.15.1 Introduction

Supramolecular chemistry of anion has grown over the last few decades depending upon receptor dimensionalities, function-
alities, platforms, and different noncovalent interactions. The first report on anion recognition with catapinands by Park
and Simmons1 evoked the potentiality of this field of research. Later on a wide variety of hosts containing different recogni-
tion elements such as ammonium, amide, urea, thiourea, guanidinium, pyrrole, indole, etc., with increasing dimensional
complexities from bipodal, tripodal, bis-tripodal to macropolycycles on various platforms like tris-(2-aminoethyl)amine
(TREN), arene, triazine–trione, and calix, etc., have been developed for anion recognition/encapsulation. Numerous weak
interactions like hydrogen bonding, coulombic anion ∙ p, halogen bonding, etc., are found to be responsible for the
recognition processes.
Our prior concern in this article is to enlighten on recognition of anions through tripodal amide receptors. The tripodal receptors
designed on different platforms provide some degree of preorganization into a conical conformation with all three binding
arms projected in one direction. We categorized tripodal amide receptors on the basis of various available platforms like, TREN,
tris-(2-(4-aminophenoxy)ethyl)amine (oxy-TREN), 1,3,5-trialkyl benzene, cyclotriveratrylene, triazine–trione on which the
tripodal amides are developed. Anion binding by tripodal amide receptors started with the pioneering works of Beer et al.2
and Reinhoudt et al.3 in the early 1990s. Such receptors are found to be selective for dihydrogen phosphate. However, in
this century, various research groups have shown that tripodal amide receptors can be potential scaffolds for recognition of
spherical, planar, as well as hydrated anions. In this context, it is important to mention that anions like phosphates, halides,
nitrates, and carboxylates play important roles in different biological and environmental processes. Environmental and water
pollution have raised alarm where different inorganic anions are also responsible. For example, excess use of phosphate-
containing fertilizers in agriculture is the key reason for eutrophication of water body. Acid rain, which is formed due to
NOx-containing anions like nitrates, causes erosion of our beloved sculptures. On the other hand, higher content of fluoride
in drinking water is linked with many health hazards. Thus designing of receptors for selective recognition of phosphates,
fluoride, nitrate, etc., is of prior interest to the researchers around the globe. In this direction, most utilized scaffolds for
tripodal amide-based receptors for such anion recognition are TREN and 1,3,5-trialkyl benzene. However, tripodal amides
on other platforms have also shown promise for recognition of aforementioned anions. For comprehensive highlight on
the strategic development of tripodal amide receptors for recognition and sensing of specific anion, we design the article in
chronological order based on its publication year.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12522-3 349

350 Amide-Based Tripodal Anion Receptors

3.15.2 Tris(2-amino ethyl) amine (TREN)-Based Tripodal Amide Receptors

TREN-based receptors with different binding motifs have been extensively studied from the beginning of anion recognition chem-
istry. However, Beer et al. reported a TREN-based tripodal cobalticinium appended neutral amide receptor, T1 (Fig. 1) in 1992,
which showed change in electrochemical property upon binding of anions, which can be regarded as the first report on anion
binding by a tripodal amide receptor.4 They reported that relatively simple acyclic cobalticinium derivatives containing amide
N–H groups could bind and electrochemically recognize anionic guest species via the cooperative binding forces of mutual electro-
static attraction between the positively charged host and anionic guest through favorable amide N–H$$$anion hydrogen bonding
interactions. Immediately after this, Beer et al. further established T1 for recognition of anions via 1H-NMR titration experiments
and electrochemically.2b Addition of tetrabutylammonium chloride (TBACl) into ACN-d3 of T1 produced substantial change in
chemical shift (Dd ¼ 1.28 ppm) of amide –NH protons that suggested binding of Cl with amide –NH protons. Here a combination
of positively charged cobaltocenium moiety along with pendant amide –NH protons created a favorable microenvironment for
successful complexation. Anion recognition properties of the ligand T1 was monitored via cyclic voltammetry where significant
cathodic shifts (DE ¼ 30 mV for Cl and DE ¼ 15 mV for Br) were observed when anions interacted with the amide –NH units.
During this period, Reinhoudt et al. reported anion binding with a series of neutral tris-amide receptors on TREN platform
T2–T7 (Fig. 1) by 1H-NMR and conductometric experiments.3 The amide –NH of T2–T7 shifted to downfield region
(Dd ¼ 1.5-2.0 ppm) during 1H-NMR titrations with (n-Bu)4NþX (X ¼ H2 PO4  , HSO4  , Cl) in CDCl3, where stoichiometry
of binding was found to be 1:1 (host/guest). On the contrary, H2 PO4  showed 1:2 (host/guest) binding stoichiometry, which
was confirmed by the characteristic5 P values for all host–guest complexes in ACN-d3 upon addition of 2 equiv. of (n-Bu)4Nþ
H2 PO4  . Table 1 incorporates the association constants (Ka) of T2–T7 with tetrabutylammonium salts (TBAX) (X ¼ H2 PO4  ,
HSO4  , Cl). As an instance, T7 showed shift of –NH with Dd ¼ 0.345 ppm upon addition of 1 equiv. of H2 PO4  and further
the peak shifted to Dd ¼ 0.374 ppm upto addition of 2 equiv. Such 1:2 (host/guest) ratio was also reported by others and is attrib-
uted to dimerization of the H2 PO4  through intermolecular hydrogen bonding interaction.6 The association constant values of
T2–T7 revealed selectivity toward dihydrogenphosphate (H2PO4> Cl> HSO4) and the highest binding affinity was observed for
T7 (Table 1), which was due to increased electrophilicity on sulfonamide –NH group and preorganization of the binding sites
by p-stacking interactions of the naphthyl group. After this seminal article, a range of TREN-based tripodal amide receptors have
been developed to accomplish selective anion recognition, although selectivity has been achieved only in few cases.
Further, Beer et al. reported ferrocenium appended neutral receptor for electrochemical detection of anions.2a This was the first
report on electrochemical detection of H2 PO4  in presence of excess amount of HSO4  and Cl. T8 (Fig. 1) showed downfield shift
upon addition of Bu4NþX (X ¼ H2 PO4  , HSO4  , Cl) salts in ACN-d3/DMSO-d6 binary solvent mixture with 1:1 binding

Figure 1 Chemical structures of TREN based metallic receptors (T1 and T8), amides (T2–T4), and sulfonamides (T5–T7).

Table 1 Association constant values (Ka) of T2–T7 with TBAX (X ¼ H2 PO4  , HSO4  , Cl)

TBAH2PO4 TBAHSO4 TBACl

T1 6100 170 1740

T2 280 31 290
T3 870 56 100
T4 510 73 190
T5 3500 79 540
T6 14,200 38 1600
 Amide-Based Tripodal Anion Receptors 351

Figure 2 TREN based tripodal receptors T9 and T10.

stoichiometry. Further, cathodic perturbations of the respective ferrocenyl oxidation current peak potentials in presence of guest
anions were also observed with T8. Interestingly, with increasing guest concentration, they observed a change in shape of the oxida-
tion wave from reversible redox process to EC mechanism. Tetrahedral cavity of T8 was found to be complementary toward
H2 PO4  for which 180 mV of cathodic shift was observed. Cathodic shift of ferrocene–ferricinium redox couple in presence of
H2 PO4  alone was comparable to that observed in presence of 10-folds excess HSO4  and Cl. These competitive electrochemical
experiments were of relevance to amperometric chemical sensor technology. In 1997, Stibor et al. investigated anion binding
property with receptors containing electron deficient pyridine substitutions, T9 and electron withdrawing fluorine substitutions,
T10 (Fig. 2).7
1
H-NMR titration studies carried out in various solvents to estimate anion binding affinity for T9 and T10. In every case, they
found 1:1 host/guest binding stoichiometry. Studies revealed that T9 was selective toward H2 PO4  (Ka ¼ 7550  310 M 1 in ACN-
d3) whereas T10 was selective toward HSO4  (5120  740 M 1) in CDCl3. Mass spectrometric tools for investigation of anion
binding properties of tripodal amide-based receptors by atmospheric pressure chemical ionization mass spectrometric (APCI-
MS) method was done by Kavallieratos et al.8 The technique utilized direct infusion followed by thermal desorption for detection
of anionic complexes in dichloromethane (DCM). Dansyl-amide derivative of TREN, T11 (Fig. 3) used as receptors for anion
binding. When solutions of receptors and anions in DCM were introduced into the mass spectrometer via direct infusion followed
by thermal desorption, the anionic supramolecular complexes [T11 þ X], (X ¼ Cl, NO3  , Br, and I) were observed in negative
mode APCI-MS with deprotonated receptors [T11 þ X-H]. Hay et al. showed the effect of change of substituents on aryl ring during
complexation with Cl and NO3  with ligands, T12–T14 (Fig. 4) through both N–H and C–H anion interactions.9 Extraction
studies suggested that T12 was the strongest NO3  receptor and this could be implemented as carrier in nitrate-selective electrode
and studies also revealed that it could form cavity, which was suitable for encapsulation of planer trigonal anion such as NO3  and
ClO3  . They calculated interaction energies and intermolecular distances, which confirmed that introduction of electron with-
drawing groups in the benzene ring strengthen the interaction and decreases the intermolecular distances between hosts and guests.
However, exactly opposite results were found in case of electron-donating substituents. In fact, interesting results were obtained in
case –NO2 substituted-receptor T14 that showed the formation of more stable complex as compared to the case where H2O was
used as H-bond donor. Molecular modeling showed that in addition to the amide protons the ortho C–H protons of the aryl
ring were also involved in H-bonding interaction with NO3  . Calculation showed that introduction of -NO2 group in the aryl
ring of T14 enhanced the binding affinity by 33% as compared to the unsubstituted one T13. It is also noteworthy to mention
that the increased binding affinity had been attributed mainly due to increase in binding affinity of C–H group with some assistance
from less increased affinity of N–H group toward anion binding. Parallel in time, Tucker et al. reported TREN and
tris(3-aminopropyl)amine-based two anion receptors T15 and T16 (Fig. 5) to mimic the enzymatic active sites of two
anion-binding enzymes vanadium haloperoxidase and acid phosphatase, respectively.10 The binding constants of HPO4 2 and

Figure 3 TREN based dansyl-amide receptor T11.

Figure 4 TREN based aryl-amide receptors T12–T14.

352 Amide-Based Tripodal Anion Receptors

Figure 5 Chemical structures of TREN based receptors T15 and T16.

Figure 6 Chemical structures of triamide receptors T17 and T18.

HVO4 2 with T15 calculated as 496 and 540 M 1, respectively with 1:1 binding stoichiometry in CD3CN. On the other hand,
comparatively larger receptor T16 exhibited recognition of H2 PO4  with comparable association constant values in 2:1 CD3CN/
CD2Cl2 mixture. Interestingly, addition of TBAH2VO4 into T16 showed net upfield shift of the amide –NH protons upon addition
of first 2 equiv. of anions and the –NCH2 peaks also shifted to upfield region, which indicated V–N bond formation from the apical
N atom, a required characteristic for good functional model of vanadium haloperoxidase.
Later on, Ghosh et al. reported solution-state 1H-NMR titration studies with tripodal positional isomers T14, T17, and T18
(Fig. 6) in DMSO-d6.11 These receptors were selective toward halides and did not bind oxyanions. The ortho isomer T17 showed
highest association constant value (log K ¼ 5.63) with Fin 1:1 host/guest binding stoichiometry. The para isomer T18 was selective
toward Fwhereas the meta isomer T14 failed to show any selectivity between the halides. These binding studies indicated partic-
ipation of both amide –NH and aryl –CH protons in anion recognition. The work dictated that positional isomers play an impor-
tant role toward guest selectivity. Later on they explored another set of TREN-based receptors functionalized with pentafluorophenyl
T10 and 2,3,4,5-tetrafluorophenyl T19 (Fig. 7) for anion recognition studies.12 Single crystals of [T10(F)(H2O)][N(Bu)4] (Fig. 8)
and [T10(Cl)][N(Bu)4] were obtained from a mixture of T10 with tetrabutylammonium fluoride (TBAF) and TBACl, respectively.
Single crystal X-ray studies of [T10(F)(H2O)][N(Bu)4] showed recognition of monohydrated Finside the C3v symmetric cleft of T10.
Encapsulated Fis bound strongly via three (N–H$$$F) bonds and one (O–H$$$F) hydrogen bond with three amide hydrogens of
T10 and trapped water molecule, respectively, in a distorted tetrahedral geometry. Crystal structure also revealed that Clwas encap-
sulated inside the tripodal cavity via formation of three N–H interactions with the amide unit. 1H-NMR titrations revealed that both
the receptors were selective toward Famong all the other halides with association constant values (log K) 3.95 and 3.35 with T19
and T10, respectively, in CDCl3 having 1:1 binding stoichiometry. Solid state structure of ligands revealed that T19 was preorgan-
ized in a C3v symmetric cavity whereas T10 formed a C2v symmetric geometry. Solid state structure showed that both Fand Clwere
engulfed in C3v symmetric cavity of T10 (formed after reorganization upon anion recognition) with three strong N–H/anion and
anion/p interactions.
In 2011, Das et al. developed a TREN-based di-nitrophenyl amide receptor T20 (Fig. 9) for selective recognition and sensing
of fluoride anion in presence of other competing anions.13 The recognition of fluoride could be monitored both by absorption

Figure 7 Chemical structures of TREN based amides; T10 and T19.

 Amide-Based Tripodal Anion Receptors 353

Figure 8 Crystal structures of (A) trapped [F.CHCl3] inside tripodal cavity (B) trapped [F.H2O] complex of T10.

Figure 9 (A) Chemical structure of tripodal amide receptor T20 and (B) crystal structure of Ftrapped complex of T20.

and 1H-NMR spectroscopy techniques. Intense orange/purple coloration upon addition of fluoride in polar aprotic solvents was
attributed to charge transfer interaction between the anion and electron deficient di-nitrophenyl receptor unit. Solid state structural
analysis revealed that F was fully encapsulated within the tripodal cleft via six strong hydrogen bonds from the amide –NH and
aryl –CH protons.
Nearly 20 cm 1 shift in stretching frequency of –C]O group in anion-complex as compared to free T20 suggested encapsula-
tion of fluoride anion inside the cavity of T20. Significant downfield chemical shift of amide N–H (Dd ¼ 3.55 ppm) and ortho-C-H–
(Dd ¼ 3.55 ppm) protons, respectively, upon addition of TBAF in DMSO-d6 confirmed the interaction between the F– and amide
–NH and aryl –CH protons and also produced a 1:1 binding stoichiometry. After that, they reported differential complexation
behavior of T20 toward fluoride anion depending upon the counter-cation.14 X-Ray crystallographic analysis revealed that T20
could encapsulate F– in the tripodal cavity when TBAF was employed as F– source (Fig. 9). On the other hand, when KF was
used as F– source, the receptor T20 was found to be involved in cleft binding of KF as contact ion pair. Crystal structure and Hirshfeld
surface analyses showed the structural similarities between hydrated KF complex of T20 and solvatomorphs of T20. IR spectrum of
KF complex of T20 showed two distinct peaks for N–H stretching, which was assigned to two different types of H-bonded N–H
protons (N–H$$$O and N–H$$$F). 1H-NMR and 2D-NOESY NMR experiments also confirmed the encapsulation and cleft binding
of F– and KF, respectively, with T20. In 2012, Ghosh et al. reported series of TREN-based tripodal hexa-amide receptors on amino
acid backbone, T21–T25 (Fig. 10) for anion recognition.15 ITC studies showed that T21, T22, T24, T25 formed complexes with
tetrabutylammonium (TBA) salts of Cl, OAc, C6 H5 CO2  , and HSO4  in 1:1 stoichiometry having highest binding affinity

Figure 10 Chemical structures of tripodal hexa-amides T21–T25.

354 Amide-Based Tripodal Anion Receptors

Figure 11 Ball and stick representation of crystal of Cl– encapsulated complex of T21.

toward tetrabutylammonium acetate (TBAOAc). On the other hand, T23 formed 1:1 complex only with TBAOAc. Other anions
like Br, I, and NO3  having TBA counter-anion did not show any heat change upon ITC titrations. Titration of strongly basic
anions like F and H2 PO4  with all the ligands did not fit into any suitable fitting model. Solid state structure revealed the recog-
nition of Cl by T21 in its cavity via formation of H-bond with the amide –NH protons and the cavity of the receptor was capped
by tetrabutylammonium counteraction via H-bonding and ion pair interactions (Fig. 11). Binding of Cl by all the receptors are
largely influenced by the counter cation involved and they followed the order of Bu4Nþ > Et4Nþ > Me4Nþ in terms of binding
constants.

3.15.3 Anion Recognition Studies with Protonated Tripodal Amide Receptors

After reviewing the anion recognition properties of TREN-based triamides for anion we turn our attention toward monoprotonated
state of such receptors for anion recognition studies. Bowman-James et al. designed N-octan-amide T26 (Fig. 12), which on proton-
ation with HNO3 showed first bilayer hydrogen bonded structure with ladder like cascade of the receptor.16 The lipophilic tails of
the amide bilayers were pointed toward inward direction and the quaternary ammonium head groups comprised the poles. As this
bilayer was formed due to protonation with HNO3, the channels were filled by nitrate guests (Fig. 12). They reported that T26
showed comparable association constant values for the studied anions and thus it was not a selective receptor for nitrate. The
elegance of this work was the lipophilic amide bilayer structure, which was confirmed by single crystal X-ray crystallography.
Later on, Ghosh et al. reported that T14 could not encapsulate guests inside the receptor cavity due to formation of intramolecular
H-bonding and aromatic p–p stacking among the tripodal arms.17 Infact, upon protonation guests preferred cleft (Cl, Br,
NO3  , ClO4  , SiF6  ) (Fig. 13) binding mode through N–H and C–H interactions in all the cases irrespective of their shapes
and sizes due to preorganization of the receptor in its protonate state. Sheet like structure of neutral T14 was modified to bilayer
structure upon protonation as shown previously by Bowman-James et al.16 The structural aspects of binding halides (eg, Cl,
Br) and oxyanions (eg, ClO4  , HSO4  ) with the protonated tris(amide) receptor T20 were carried out in detail by Das
et al.18 After protonation the bridgehead proton was oriented toward the ring and formed hydrogen bonding interaction with
one amide center. Thus the guest (Cl, Br, ClO4  , HSO4  ) bound with the ligand outside the cavity via N–H$$$anion and
C–H$$$anion interactions (Fig. 13).

Figure 12 Formation of lipid bilayers structure upon protonation of T26 with HNO3.
 Amide-Based Tripodal Anion Receptors 355

Figure 13 Crystal structures of (A) side cleft binding of SO4 2 with mono-protonated T20 and (B) binding of Cl with mono-protonated T14.

Figure 14 Chemical structures of TREN based receptor T27.

In 2015, Das et al. reported TREN based-amide receptor T27 (Fig. 14) for encapsulation of anions.19 Crystal structures of proton-
ated and nonprotonated T27 was found to form a C3v symmetric cavity via formation of intermolecular H-bonding between N–H
and –C]O units and thus found to be unsuitable for anion encapsulation and bind with the anions outside the cavity. 1H-NMR
suggested that T27 was reluctant to bind oxy-anions strongly but recognized only F and H2 PO4  as compared to other anions. All
these reports suggested that the TREN-based triamide receptors were not suitable for encapsulation of anions upon bridge-head
nitrogen protonation.
Thus Sun et al. introduced flexible oxy-TREN-based receptors for anion recognition upon protonation. A couple of C3v
symmetric N-bridged flexible higher homolog of TREN, that is, tris(2-(4-aminophenoxy)ethyl)amine-based receptors showed
encapsulation of NO3  in the cavity of tripodal receptor T28 and T29 (Fig. 15) upon protonation with HNO3.20 The 1H-NMR spec-
trum suggested formation of two distinctly different species in solution upon protonation with HNO3. One was the NO3  encap-
sulated complex of T28 and other was cleft bound NO3  complex. Mass spectrum analysis was performed on NO3  complex of
T28, which showed expected peak for [T28.NO3LH]. Single crystal X-ray structure of NO3  encapsulated complex of T29 was
obtained upon protonation in aqueous methanol. Interestingly, when BP (Fig. 15) was treated with the nitrate complex of proton-
ated T29, it formed the protonated nitrate adduct BP.2HNO3 in the filtrate and a self-assembled capsule of T29.T29 in the precip-
itate, as determined by 1H-NMR studies. When BP.2HNO3 was irradiated with 365 nm light, it yielded pure TP.2HNO3 (Fig. 15)
via [2 þ 2] cycloaddition process. Later, in 2013, Das et al. exhibited recognition of discrete [X2(H2O)2] (X ¼ Cl/Br) cluster inside
the dimeric capsular assembly of T30 (Fig. 16).21 Both isolated Cl– and Br– clusters were isostructural and were obtained upon

Figure 15 Chemical structures of oxy-TREN based tripodal receptors T28–T31.

356 Amide-Based Tripodal Anion Receptors

Figure 16 Crystal structures of (A) Br complex of T30 and (B) Cl complex of T30.

protonation with corresponding acid. The capsular dimension of the Br– complex was higher than that of Cl– due to larger ionic
radii of Br. Solid-state FT-IR analysis confirmed existence of halide-water cluster where distinct band at around  3250 cm 1 sug-
gested O–H stretching vibration of water. Further, the amide –NH was found to shift  58 cm 1 compared to that of T30, which
confirmed N–H/X hydrogen bonding interaction. Upon protonation with HI they observed a noncapsular 1D polymeric
assembly, which was structurally different from that of [X2(H2O)2] (X ¼ Cl/Br) clusters. Researchers proposed that larger size
and lower charge density of the iodide was responsible for this conformational change in the receptor. Downfield shift of amide
N–H was observed in the protonated [T30 D H]D in presence of Cl only. Same group in 2015 reported anion recognition by
T31 via solid and solution state studies.19 T31 could encapsulate anions in its large cavity via formation of C–H and N–H interac-
tions as observed in the crystal structure of encapsulated F and SiF6  in protonated T31. 1H-NMR suggested that T31 was reluctant
to bind oxy-anions strongly but recognized F and H2 PO4  quite strongly as compared to other anions.

3.15.4 Benzene Platform-Based Tripodal Amide Receptors for Anion Recognition

Alongside TREN platform, 1,3,5 substituted benzene platform is also one of the most popular backbone for designing anion recep-
tors. Beer et al. first reported a benzene platform-based neutral acyclic redox responsive tripodal amide receptor T32 (Fig. 17) for
recognition of anions where binding of guests was monitored by 1H-NMR titration and electrochemical experiments.2b,4 Addition
of TBACl to T32 in ACN-d3 resulted large downfield shift of amide –NH protons (Dd ¼ 1.28 ppm), which suggested binding of
anion. In this report, the combination of positively charged cobalticinium moiety along with pendant amide –NH protons created
a favorable microenvironment for successful complexation. Further, anion recognition properties of T32 was monitored via cyclic
voltammetry where significant cathodic shifts (DE ¼ 30 mV for Cl and DE ¼ 15 mV for Br) were observed when anion interacted
with the amide –NH units. In 2005, Schmuck et al. synthesized a tri-cationic guanidiniocarbonyl pyrrole receptor T33 (Fig. 18) for
selective recognition of citrate, G1, and other tricarboxylates in water.22 Absorption and emission studies revealed high association
constant ( 105 M 1) with citrate in water with 1:1 (host/guest) binding stoichiometry. Nuclear overhouser effect spectroscopy
(NOESY) and molecular modeling studies suggested that tricarboxylates were bound in the inner cavity of T33 due to ion pairing
between the carboxylate groups and the guanidiniocarbonyl pyrrole moieties with additional favor by the nonpolar environment of
the cavity. The binding of aromatic tricarboxylates were more favored due to aromatic interactions, which facilitated complex

Figure 17 Chemical structure of benzene platform based metallic receptor.

 Amide-Based Tripodal Anion Receptors 357

Figure 18 Chemical structures of guanidiniocarbonyl pyrrole based anion receptor T33 and T34.

Figure 19 Chemical structures anionic carbohydrates C1–C6.

formation and hence binding constant was further increased. They exhibited that T33 recognized citrate in tris buffer medium with
Ka ¼ 8.6  104 M 1 even in presence of large excess of competing anions such as tartrate and maleate. Subsequently, the same group
have developed another tris-cationic receptor T34 for naked-eye detection of citrate in water, which solely relies on reversible non-
covalent interactions.23 They have shown high selectivity of citrate in water via indicator displacement method over malate and
tartrate in water. The same group reported the recognition of anionic carbohydrate (in the form of carboxylates and phosphates)
by tri-cationic T33 in water.24 Among the carboxylate salts, galacturonate (C2, Fig. 19) (Ka ¼ 1500 M 1) bound more strongly
with T33 as compared to its monocarboxylate analog, glucuronate, C1 (Ka ¼ 450 M 1) in 7:3 water/DMSO binary solvent mixture.
On the other hand, phosphate salts, C3, C4, C5 showed similar binding constant values with T34, which were much larger as
compared to the noncarbohydrate based analog, C6. Combination of squaramide and ammonium functionality could provide
suitable receptors for the recognition of monocarboxylates. Utilizing this, Frontera and Anslyn et al. designed tris-sqauramid-
ammonium substituted receptor T35 (Fig. 20) for recognition of carboxylates in aqueous medium.25

Figure 20 Chemical structure of squaramide-ammonium based anion receptor T35 and guest molecules used for recognition.
358 Amide-Based Tripodal Anion Receptors

Figure 21 Chemical structures of benzene platform based anion sensors T36–T39.

The ammonium functionality was introduced in order to solubilize the receptor in aqueous medium. Extensive ITC studies in
1:3 H2O/EtOH binary solvent mixture revealed that T35 was selective toward tricarboxyltes (G1–G3) and dicarboxylates (G4–G5)
over monocarboxylates (Fig. 20). As the counter cations were different for bis and tris carboxylates, comparison could not be done.
The binding of tricarboxylates were entropy-driven with association constant in the order of 105 M 1. Further to assay binding of
carboxylates, they used indicator displacement technique. They choose mixture of fluorescein disodium salt and T35 as this
ensemble was nonfluorescent due to quenching of fluorescein emission band in the complex via photoinduced electron transfer
process. Progressive addition of citrate displaced the dye from T35-fluorescein complex and thus restoration of fluorescence of fluo-
rescein was observed. This method was used for quantitative detection of zinc citrate in commercial toothpaste. Extensive ITC
studies in 1:3 H2O/EtOH binary solvent mixture revealed that T35 was selective toward tricarboxyltes (G1–G3) and dicarboxylates
(G4–G5)
Anzenbacher et al. showed the binding of anions, including biologically important phosphates by using benzene-based tripodal
receptors T36–T39 (Fig. 21) in solution by 1H-NMR and fluorescence titrations.26 These receptors showed downfield shift of –NH
peak upon binding with guest anion with binding stoichiometry 1:1 where the arms of the C3 symmetric receptor was equally
involved in guest recognition. The anion-binding affinities evaluated from fluorescence titrations of T36–T39 with guests followed
the general order H2 PO4  > HPPi3  > AcO> > Cl > Br in DMSO. To recognize these biologically relevant anions in water,
T37–T39 were embedded in hydrophilic polyurethane matrices to resolve the solubility issues of the receptors and they were found
to be highly efficient sensors for anions in buffered solution at pH 7.4.
In 2009, Ghosh et al. demonstrated a unique example of hydrated fluoride encapsulation via formation of fluoride-water cluster;
[F2(H2O)6]2  in the cavity of a dimeric capsular assembly.27 On the other hand, other anions like Cl, NO3  , and OAc, showed
formation of noncapsular type molecular assemblies of T40 (Fig. 22). As in natural world anions like fluoride exists in hydrated
form, recognition of such species with synthetic receptors would be more relevance. Ghosh et al. have structurally demonstrated
[F2(H2O)6]2  templated formation of dimeric capsule of T40 (Fig. 23). Each of the tripodal ligand acted as a bowl-shaped half
capsule and encapsulated one F and three water molecules through the amide –NH groups. Two such half capsules intercalated
to form the dimer and encapsulated [F2(H2O)6]2  as a guest. It proved that [F2(H2O)6]2  cluster acted as a template to form the

Figure 22 Chemical structures of tripodal amide based anion receptors T40–T42.

 Amide-Based Tripodal Anion Receptors 359

Figure 23 Crystal structures of (A) [F2(H2O)6]2  complex of T40 (B) Cl trapped complex of T40.

Figure 24 Crystal structures of (A) [F2(H2O)6]2  complex of T41 (B) Cl encapsulated complex of T41.

capsule. Fluoride-water cluster was obtained upon charging TBAF into the solution of T40∙ ∙TBANO3 in dioxane. Further, in presence
of equal equivalents of TBA acetate and fluoride with T40 in dioxane, they obtained [F2(H2O)6]2  cluster. These results indeed
proved that fluoride was preferred over other anions and assisted in the formation of capsular assembly over other aggregation.
1
H-NMR titration studies were carried out in order to justify solution state binding. A Job’s plot analysis of the titration data showed
a 1:3 (host/guest) binding stoichiometry in solution for TBAOAc, whereas the solid state Single crystal X-ray study showed 1:1
binding. Same group has generalized their findings by a comparative anion binding study between T40 and its positional isomer
T41 with para-nitrophenyl substituents (Fig. 22). In case of T41, anion-water cluster encapsulation driven formation of dimeric
capsular assemblies were observed for F, Cl, AcO, and NO3  .28 In general, T41 was found to encapsulate [F2(H2O)6]2 ,
[Cl2(H2O)4]2 , [(AcO)2(H2O)4]2 , and two NO3  in its dimeric capsular assembly (Fig. 24).
Solution state 1H-NMR titration study revealed 1:3 (host/guest) binding stoichiometry for AcO with T41. Interestingly, compet-
itive crystallization experiment showed encapsulation of [F2(H2O)6]2  cluster by T41 from a mixture of F, Cl, AcO, and NO3  ,
like that in case of T40. DOSY NMR studies revealed higher diffusion coefficient of the F encapsulated complex compared to that
of free receptor T41, which suggested encapsulation of F inside molecular cavity. Later on, Ghosh et al. reported para-CN
substituted tripodal amide receptor T42 for recognition of nitrate in the form of capsule and recognition of acetate in the form
of half capsule (Fig. 25).29 In 2014, Ghosh et al. designed 4-pyridyl substituted tripodal amide receptor T43 that was able to isolate

Figure 25 Crystal structures of (A) trapped [CH3CO2.(H2O)] complex of T42 (B) NO3  encapsulated complex of T42.
360 Amide-Based Tripodal Anion Receptors

Figure 26 (A) Chemical structure of T43 (B) [F2(H2O)4]2  encapsulated complex of T43.

[F2(H2O)4]2  and [Cl2(H2O)4]2  cluster (Fig. 26) from acetone/water (1:1, v/v) binary solvent mixture.30 On the other hand,
complexation of T43 with fluoride in dioxane–acetone (1:1, v/v) solvent mixture, resulted the formation of SiF6 2 encapsulated
complex, [T43]2[SiF6(H2O)2][TBA]2. Here, SiF6 2 came from the reaction of TBAF with glass vials. Solution state 1H-NMR studies
with T43 in D2O/acetone-d6 (1:19, v/v) supported 1:4 (host–guest) binding stoichiometry with F, Cl, Br, NO3  , HSO4  , and
H2 PO4  .
1:1 binding model was utilized to calculate the binding constant values, which revealed the selectivity order NO3  z
HSO4  > F z Cl z Br > H2 PO4  . Further, solution state 19F NMR studies were carried out to establish the F binding of T43
in DMSO-d6. Peak at d ¼  108.3 ppm arose for free TBAF in 19F NMR, which was shifted to downfield region ( 94.68 ppm)
when 1 equiv. of TBAF was added to 1 equiv. T43 in DMSO-d6. 19F NMR of [T43]2[F2(H2O)4]2  and [T43]2[SiF6(H2O)2]2  showed
distinctly different peaks at  99.53 and  126.9 ppm, respectively. So, these chemical shift values indicated that F was able to bind
with T43 in solution and also suggested that no SiF6 2 encapsulated complex was formed.

3.15.5 Recognition Through Bis-tripodal Receptors

Benzene platform-based hexapodal amide receptors could be considered as bis-tripodal anion receptors based on their conforma-
tional diversities. Compared to conventional tripodal receptors based on benzene platform, hexapodal receptors are scarcely re-
ported in literature. First report on hexapodal receptor was by Vӧgtle et al. on 1974.31 Thirty four years later, in 2008, Allen
et al. designed hexa-amide receptor with alkyl substitution. 1H-NMR titration studies in CDCl3 showed that the receptor T44 bound
Cl (K ¼ 12 M 1) and CF3 SO3  (K ¼ 41 M 1) with very low association constant, which was also supported by DFT studies.5 The
association constants were found to be low due to the fact that the amide N–H centers were not acidic enough for anion binding.
In 2010, Ghosh et al. synthesized pentaflurophenyl substituted receptor T49 (Fig. 27), which showed compartmental recognition of
[(NO3)2H2O] in ababab conformation and acetate in aaabbb conformation (Fig. 28).32 In these two conformations, the orientation
of the side arms were such that it constructed two separate tripodal cavities for recognition of nitrate and acetate. 1H-NMR titration
studies were carried out to justify 1:2 (host/guest) stoichiometry of binding in DMSO-d6. Later on, authors reported
a m-nitrophenyl-substituted hexa-amide T51, which recognized acetate in chair like conformer aaabbb.33 Acetate was found to
bind the receptor in 1:2 stoichiometry, which was monitored by 1H-NMR titration.
Further, in 2014, Ghosh et al. reported ortho-trifluoromethylphenyl-substituted hexamide receptor, T51 which also recognized
acetate in aaabbb conformation. In this work they exhibited conformational diversities of hexamide receptors upon recognition of
[(F)4(H2O)6]4, NO3  , and CH3 CO2  (Fig. 28).34 ITC and 1H-NMR studies showed association constant of T51 with acetate

Figure 27 Chemical structures of bis-tripodal ligands T44–T51.

 Amide-Based Tripodal Anion Receptors 361

Figure 28 Crystal structures of (A) compartmental encapsulation of [(NO3)2H2O]2 by T49 in ababab conformation and (B) encapsulated AcO inside
compartmental cavity of T51 in aaabbb conformation studies.

(9.76  105 M 2) and (5.97  105 M 2), respectively. They continued their work on a series of hexamide receptors T45–T51
(Fig. 27) where they generalized aaabbb conformation for acetate anion.35 In this context, they introduced six different single crystal
X-ray structures of ligand–acetate adduct that showed aaabbb conformations. Recognition of Cl and [(Cl)2(H2O)2]2 showed two
different conformations, namely, aaabbb and ababab respectively. Extensive ITC and 1H-NMR titration studies were carried out to
enlighten the solution state binding of fluoride and acetate to the hexamide receptors. They generalized that hard anions like F
and CH3 CO2  preferred to direct the conformation of the hexamides toward a particular orientation, whereas comparatively
soft anions like NO3  and Cl failed to do so.

3.15.6 Tripodal Amide Receptors-Based on Miscellaneous Platforms

Moran et al. reported two cyclohexane platform based tripodal triamide (T52) and hexamide (T53) receptors (Fig. 29) for prefer-
ential binding of phosphates.36 The favorable C3v symmetric cavity formed by the receptors were suitable for binding the tetrahedral

phosphate anions. The association constant obtained from binding of PO4 3 with receptor T52 was 1.0  102 in DMSO-d6.
Receptor T53 having six amide binding sites also showed significant binding with phosphate salts having binding constant values
of 1.5  104 and >105 with phenyl phosphonate and phosphate, respectively in DMSO-d6. Zhang et al. prepared a tris-amide
receptor functionalized with cyclotriveratrylene, T54 (Fig. 30) and immobilized it on gold surface via formation of self-
assembled monolayer.37 Absorption and 1H-NMR titrations indicated that the receptor can selectively bind with acetate anion
among the investigated anions (eg, Cl, Br, NO3  , HSO4  , and H2 PO4  ) in CDCl3. Impedance spectroscopy with positively
and negatively charged redox couple showed the selective binding of acetate anion in aqueous medium. Ghosh et al. developed
a simple electron-deficient triazine–trione-based tripodal amide receptor T55 (Fig. 31), which was capable of encapsulating
fluoride/chloride anion via formation of C3v-symmetric cleft.38
Crystallographic results showed that T55 had an unsymmetrical cleft, where the third arm is perpendicularly disposed to the
other two arms. Interestingly, upon complexation of T55 with TBA fluoride/chloride, T55 showed encapsulation of monomeric
fluoride/chloride anion in the C3v symmetric cleft via formation of N–H$$$X (X ¼ F, Cl) hydrogen-bonding interactions in
both the complexes. The crystal structure of chloride complex of T55 showed anion-p interaction between the anion and the

Figure 29 Chemical structures of T52 and T53.

362 Amide-Based Tripodal Anion Receptors

Figure 30 Chemical structure of cyclotriveratrylene platform based anion receptor, T54.

Figure 31 (A) Chemical structure of triazine-trione platform based tripodal amide receptor (B) crystal structure of F encapsulated complex of T55.

pentafluorophenyl moiety (Fig. 31). Solution-state ITC studies of T55 with TBA salts of different halides and oxy-anions in aceto-
nitrile showed an exothermic binding profile with 1:1 (host/guest) stoichiometry for fluoride (log Ka ¼ 4.86 M 1), chloride (log
Ka ¼ 3.83 M 1), and bromide (log Ka ¼ 2.97 M 1). Although, in the case of iodide, no effective binding was observed. Oxyanions
like acetate and benzoate also showed exothermic binding profile with a 1:1 (host/guest) binding pattern, whereas other oxy-anions
like phosphate, sulfate, and nitrate failed to fit into a suitable binding model. Ozturk et al. reported amide-based neutral tripodal
anion receptors T56 and T57 (Fig. 32) for recognition of H2 PO4  and C6 H5 CO2  anions in presence of other anions such as PF6  ,
ClO4  , HSO4  , and Br.39 Pyridyl appended tripodal receptor T56 showed higher binding affinity toward anions as compared to
its benzene analog T57. Binding constants, Ka of H2 PO4  and C6 H5 CO2  with T57 were 241 and 110 M 1, respectively in DMSO-
d6, whereas T56 gave binding constants of 810 and 286 M 1 in DMSO-d6, respectively and the Job’s plot analysis showed that
H2 PO4  and C6 H5 CO2  bind with both T56 and T57 through 1:1 binding stoichiometry.
Hoffmann et al. reported triazine–trione-based neutral tripodal sulfonamide-based receptors T58–T60 (Fig. 33) for preferential
binding of Cl anion.40 Binding constant values for anions obtained during complexation studies via ITC measurements are given
in Table 2, which clearly showed that all three receptors T58–T60 bind with Cl anion more strongly as compared to other anions
such as Br and NO3  . Among conformationally preorganized receptors T59 and T60, T59 showed highest binding constant with
Cl ion. Among T59 and T58, conformationally preorganized receptor T59 showed higher binding constant with Cl as compared
to unorganized T58. These preorganization led to increase in binding constant (2.5 times) with Cl and decrease in binding
constant (0.4 times) with NO3  . ðKa ÞCl =ðKa ÞNO3  ¼ 105 for T59 as compared to the value of 13 in case of T58 suggested that
preorganization introduced selectivity in ligand in terms of binding with anions.

Figure 32 Chemical structures of tripodal amides T56–T57.

 Amide-Based Tripodal Anion Receptors 363

Figure 33 Chemical structures of triazine–trione platform based anion receptors T58–T60.

Table 2 Binding constant values of anions of TBA salt with T58–T60

T58 T59 T60

TBACl 4870  170 12,630  1100 4170  130

TBABr 1020  65 425  10 570  30
TBANO3 380  5 120  10 275  10

3.15.7 Applications of Tripodal Amide Receptors

3.15.7.1 Chemical Sensing
Anzenbecher et al. utilized phosphate selectivity of receptors T36–T39 toward the detection of biological phosphates by embedding
in hydrophilic polyurethane matrices.26 The detection was performed in water as well as in pH 7.4 using 4-(2-hydroxyethyl)-1-
piperazineethanesulphonic acid (HEPES) buffer. Their target was to sense phosphate present in blood serum. In this direction,
they performed principal component analysis, which revealed that films of T36–T39 were capable of distinguishing inorganic phos-
phates from adenosine mono-phosphate (AMP) and Adenosine di-phosphate (ADP) in water. The report also included studies on
thiourea-based sensors but those were not included as it falls beyond the scope of present focus. Later, In 2010, Bao et al. reported
amide-pyridinium based tripodal anion receptor T61 (Fig. 34) with nitrobenzene as a signaling unit.41 1H-NMR and absorption
spectroscopy studies showed that T61 was highly selective toward AcO and F binding over H2 PO4  and all other anions in
CH3CN. Also, T61 showed naked eye detection of F and AcO and showed 1:1 binding stoichiometry with AcO with binding
constant value of 105 M 1. 1H-NMR experiment showed that amide N–H and a C–H protons of pyridinium rings shifted downfield
upon addition of 1 equiv. of TBAOAc, which indicated interaction of anion with these binding units.
Further, Das et al. utilized T20 (Fig. 9) as F sensor with characteristic solvent dependent absorptions in the optical spectros-
copy.13 Due to addition of F, three new peaks were generated at lmax ¼ 388, 537, and 665 nm, which showed increase in absorption
intensity during gradual addition of F. Such deep coloration (colorless to red/blue) attributed to strong anion$$$p charge-transfer
interactions involving F and T20. They isolated the [TBA(T20$F)] complex from various solvents like acetone, CH3CN, DMF,
DMSO, and THF. Selectivity of T20 toward FL (log K > 7 M 1) was utilized for the transformation of charged anion complexes
[(T20) D AL] (A ¼ Cl, Br, ClO4  , HSO4  ) into [TBA(T20$F)].
In 2010, Hiratani et al. reported benzene-based tripodal receptors T62 and T63 for recognition of anions. Both T62 and T63
showed recognition of F, AcO, and H2PO 4 in CDCl3 whereas above receptors failed to recognize halide and HSO4

  
(Fig. 35). Fluorescence studies revealed that T62 could give prominent response upon addition of F , AcO , and H2PO4 as their
42

TBA salts in presence of other anions and the selectivity was in the order F > AcO > H2PO 4 in CHCl3. On the other hand, T63
showed highly selective response only in presence of Famong all the anions both in polar and nonpolar solvents.

3.15.7.2 Extraction
Beer et al. designed hetero-di-topic 15-crown-5 ether affixed tripodal anion receptor T64 and two controlled receptors T65 and T66
having three distinct amide groups as anion binding units (Fig. 36).43 T64 showed significant binding with Cl, I, and ReO4 

Figure 34 Chemical structure of pyridinium-amide based anion sensor, T61.

364 Amide-Based Tripodal Anion Receptors

Figure 35 Chemical structures of anion sensors T62–T63.

Figure 36 Chemical structures of ditopic receptors T64–T66.

Table 3 Binding constant values of T64–T66 with anions in presence and absence of Naþ ion

Ka (M 1)

In absence of Naþ In presence of Naþ

Cl I ReO4  Cl I ReO4 

T64 60 30 40 520 390 840

T65 75 40 40 – – –
T66 40 20 30 – – –

Figure 37 Amide receptors used for synergistic anion recognition and extraction studies, T67–T70.

having binding constants in the range of 40–60 M 1 in CDCl3 (Table 3). However, in presence of Naþ the binding constant values
found to increase around 10-folds due to cooperative effect of Naþ coordination with ethereal unit (Table 3). Also, efficient extrac-
tion and transportation of toxic anions obtained from nuclear waste were carried out using cooperative interaction via sodium ion
complexation.
In 2000, Bowman-James et al. employed a dual host strategy for extraction of CsNO3 into organic phase using several tripodal
amide receptors, T67–T70 (Fig. 37) along with Csþ selective tetrabenzo-24-crown-8.44 Binding constants of nitrate anion with
 Amide-Based Tripodal Anion Receptors 365

Figure 38 Crystal structure of KF encapsulated by dual host receptor, L10.

T67–T70 were estimated as 52, 56, 42, and 33 M 1 respectively with 1:1 binding stoichiometry in CD2Cl2. However, when liquid–
liquid extraction of aqueous solution of CsNO3 and HNO3 were carried out with organic solution of crown ether and T67, T68, and
T70, extraction efficiency increased by factors of 2.4, 1.7, and 4.4, respectively. But no such synergistic effect observed in case of the
monopodal analog. Even negative mode ESI-MS spectrometry confirmed the presence of NO3  bound receptors T67–T70 in gas
phase.
In 2011, dual host approach had been utilized by Ghosh et al. by employing 18-Crown-6 and a tripodal amide, T10 (Fig. 7) for
selective removal of KF and KCl via liquid–liqiud extraction technique.12a The extracted complexes were obtained by the liquid–
liquid extraction process where aqueous phase contained KF (100 mM) or KCl (100 mM) and organic phase contained equimolar
amounts of T10 and 18-crown-6 (10 mM) in CHCl3. Detailed analyses of single crystal X-ray structural studies, (Fig. 38) 1H-NMR
spectra indicated a 1:1 involvement of T10 and 18-Crown-6 in the course of extraction.

3.15.7.3 Transportation
Recently, Gale et al. reported TREN platform-based C3 symmetric anion receptors having phenylalanine amino acid residues and
amide-urea functionalities T71–T74 (Fig. 39) with potential ability to interact with the anions of biological interest (L-lactate, L-
maleate, and L-aspartate, etc.).45 Binding of anions are studied in solution by 1H-NMR titrations and transport phenomenon of
chloride and previously mentioned anions were studied through lipid bilayer membranes with all these ligands. The ligands
were found to bind selectively with Cl as compared to other organic anions. The transport of the anions were affected by the nature
of the aliphatic central spacer and the side chains. The receptor having shortest aliphatic side chain and longest spacer was found to
be the most active receptor T71.

3.15.8 Concluding Remarks

Early development of tripodal amide receptors were on the recognition of dihydrogen phosphate. Later on this category of receptors
had shown potentiality toward recognition of halide, hydrated halide, nitrate, and carboxylate. We have initiated our discussion
with TREN-based tripodal amide receptors, which showed selectivity toward dihydrogen phosphate. However, other design of
such receptors were found to be selective for halide. Monoprotonated state of TREN-based triamides were unsuccessful to encap-
sulate anion in the C3 symmetric cavity of the receptor but oxy-TREN-based triamides were successful for encapsulating anions like
nitrate and hydrated halides. Then our discussions moved toward 1,3,5-trialkyl benzene platform-based triamides, which mostly

Figure 39 Chemical structures of amino acid backbone based anion receptors T72–T74.
366 Amide-Based Tripodal Anion Receptors

showed recognition of phosphates, carboxylates, and hydrated halides. Gradually, we discussed how structural modifications on
arene platform could generate bis-tripodal amide receptors for anion binding in the tripodal clefts via conformational diversities.
Finally, we have highlighted the importance of these particular variety of receptor in the area of chemical sensing, liquid–liquid
extraction, and transportation. We hope this comprehensive review on the aspect of tripodal receptors for anion recognition will
definitely provide a consolidated overview on this specified area of interest.

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22. Schmuck, C.; Schwegmann, M. A Molecular Flytrap for the Selective Binding of Citrate and Other Tricarboxylates in Water. J. Am. Chem. Soc. 2005, 127 (10), 3373–3379.
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25. Frontera, A.; Morey, J.; Oliver, A.; Pina, M. N.; Quinonero, D.; Costa, A.; Ballester, P.; Deya, P. M.; Anslyn, E. V. Rational Design, Synthesis, and Application of a New Receptor
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 3.16 Interactions of Anions With Electron-Deficient p-Systems
M Giese, University of Duisburg-Essen, Essen, Germany
M Albrecht, RWTH Aachen University, Aachen, Germany
Ó 2017 Elsevier Ltd. All rights reserved.

3.16.1 Introduction 369

3.16.1.1 Early Findings 370
3.16.2 Nature of Anion–p Interactions 370
3.16.2.1 The Role of the Electron-Deficient Arene 371
3.16.2.2 Influence of the Anion 375
3.16.2.3 Hapticity of Anion–p Interactions 378
3.16.2.4 Additivity of Anion–p Interactions 382
3.16.2.5 Interplay of Anion–p Interactions With Other Noncovalent Forces 385
3.16.2.5.1 Interplay of Anion–p, Cation–p, and p–p Interactions 385
3.16.2.5.2 Interplay of Anion–p and Hydrogen Bonding 387
3.16.2.5.3 Interplay of Anion–p and Halogen Bonding 388
3.16.2.5.4 Interplay of Anion–p and Metal Coordination 388
3.16.2.6 Anion–p Interactions in Solution 389
3.16.2.6.1 Charged Receptor Systems 390
3.16.2.6.2 Charge-neutral Receptor Systems 391
3.16.3 Conclusion and Outlook 398
References 399

Nomenclature
CSD Cambridge Structural Database NOESY nuclear Overhauser effect spectroscopy
DABCO diazabicyclo[2.2.2]octane Qzz quadrupolmoment (B)
ESI-MS electrospray ionization mass spectrometry Re equilibrium distance (Å)
EBSSE interaction energy with basis set superposition error TBA tetrabutylammonium
correction (kcal mol
1) TBAX tetrabutylammonium halide
ITC isothermal calorimetric titration THF tetrahydrofuran
NCP N-confused porphyrins TMEDA tetramethylethylenediamine
NDI naphthalene diimide a|| molecular polarizability (a.u.)
NMR nuclear magnetic resonance

3.16.1 Introduction

Supramolecular chemistry relies on intermolecular forces, which play a crucial role in both chemical and biochemical processes.1 A
comprehensive understanding of the interplay of noncovalent interactions is vital to create novel functional materials by employing
a supramolecular approach.2 While intermolecular forces such as hydrogen bonds, ion pairing, hydrophobic effects, and p–p and
cation–p interactions can be considered and established to create functional assemblies, s/p–hole interactions3 like halogen
bonding4 and anion–p interactions5 are an emerging field in the supramolecular community. In this article, we focus on the inter-
actions of anions with electron-deficient arenes. Intuitively, an interaction between an anion and the p-system of an arene should be
expected to be repulsive, which led to the underappreciation of anion–p interactions. However, seminal computational studies by
Mascal, Alkorta, and Deyà provided first evidence of its existence and lead to some scientific interest in this intermolecular force.6 A
few years later, Hay et al. initiated a controversial discussion on the relevance of anion–p interactions in the solid state by the study
“Anion–p Interactions in Crystal Structures: Commonplace or Extraordinary?” In contrast, to earlier findings, their analysis of the
Cambridge Structural Database (CSD) did not yield a single hit of anion–p interactions.7 Frontera et al. set anion–p interactions
into perspective in 2011 and critically reviewed the recent findings in the field.8 However, experimental observations within the last
decade suggest the functional relevance of anion–p interactions in both chemical2a,9 and biological systems.5b,10
The following article comprehensively summarizes the theoretical and experimental findings of anion–p interactions within
the last two decades. First, we will briefly introduce the physical nature of anion–p interactions. Then, theoretical and
experimental findings of anion–p interactions and their interplay with various other noncovalent forces will be discussed. In

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12526-0 369

370 Interactions of Anions With Electron-Deficient p-Systems

section “Anion–p Interactions in Solution,” we will summarize studies of anion–p interactions in solution, a story with many
dead ends and misunderstandings, but also with some success. The conclusion and outlook will focus on the first promising
attempts to employ anion–p interactions and show their functional relevance.

3.16.1.1 Early Findings

The interaction of anions with the p-system of an arene appears counterintuitive and this explains why it remained hidden for
a long time, although it was previously observed. However, as early as 1987, Hiraoka et al. reported a series of highly symmetrical
complexes of anions (F
, Cl
, Br
, and I
) with hexafluorobenzene in the gas phase.11 The complexes were studied by pulsed
electron-beam high-pressure mass spectrometry. Initially, the complexes between hexafluorobenzene and fluoride were investiga-
ted.11a The determined association constants gave evidence for the covalent binding of the fluoride anion in a Meisenheimer-type
complex. However, the other halides show noncovalent interactions in the clusters with hexafluorobenzene.11b The authors suggest
the C6-symmetrical anion–p complex, with an anion located above the center of the C6F6 system. In the early 1990s, Schneider et al.
described a weak interaction between negatively charged groups and polarizable aryl groups in host–guest complexes.12 At this
time, anion–p interactions were unknown and the term “anion–p interaction” was not present in the literature. In their report,
Schneider and coworkers analyzed the interactions of aromatic host–guest complexes by nuclear magnetic resonance (NMR) spec-
troscopy.12b The calculated association constants for the dimerization of diphenylamine with dications, as well as with dianions, are
in the same range. However, it should be noted that none of the involved arenes is electron-poor, and therefore, the interaction of
the arenes with the anions is mainly attributed to the polarizability of the aromatic moieties.
One decade later, Mascal,13 Alkorta,14 and Deyà6,15 reported simultaneously their seminal computational studies on the attrac-
tive nature of the interaction of anions with electron-deficient arenes and introduced the term “anion–p interaction.” This was the
starting point for a number of detailed anion–p studies and a controversial discussion of this newly defined intermolecular force.

3.16.2 Nature of Anion–p Interactions

Extensive computational studies13,14,16 reveal that anion–p interactions rely mainly on electrostatic forces and ion-induced polar-
ization.15,17 The electrostatic term is correlated to the permanent quadrupolmoment Qzz of the aromatic system, which describes
the charge distribution of a molecule in respect to the perpendicular z-axis. For benzene, the quadrupolmoment is negative
(Qzz ¼
8.5 B). However, attaching strongly electron-withdrawing substituents to the arene turns the quadrupolmoment positive,
leading to a Qzz of, for example, þ 9.5 B for hexafluorobenzene. Accordingly, electron-rich arenes such as benzene form stable
complexes with cations, while electron-deficient systems such as hexafluorobenzene attract anions. The quadrupolmoment of are-
nes is well represented by charge-density calculations of the corresponding arene showing a lack of electron density (represented by
the blue color) in the center of the arene for hexafluorobenzene (Fig. 1).
While the polarization of p-systems by anions is relevant, the reverse distortion of the electronic distribution of the anion is
negligible. The ion-induced polarization can be correlated with the molecular polarizability a|| of the aromatic compound. Accord-
ingly, the polarization contributes significantly to the total interaction energy of anion–p complexes with high molecular polariz-
ability such as s-tetrazine (a|| ¼ 58.7 a.u.).19 In contrast, dispersion forces, which are in general an important factor in weak
interactions involving arenes, play a minor role in anion–p complexes.16
A detailed knowledge about the nature of noncovalent interactions helps to understand experimental findings and allows the
prediction of the behavior of the molecular species. The next sections correlate theoretical findings in anion–p studies with exper-
imental results of this weak interaction in the solid state, in solution, and in the gas phase.

Figure 1 Charge-density simulations of benzene (left) and hexafluorobenzene (right) visualizing the inverse charge distributions of the opposing
aromatic systems. The highly negatively charged p-system of benzene is represented in red and the lack of electron density in the p-system of hexa-
fluorobenzene is shown in blue. In addition, the concept of anion-induced polarization is illustrated.18
 Interactions of Anions With Electron-Deficient p-Systems 371

Figure 2 Overview of some of the electron-deficient p-systems and anions investigated in theoretical and experimental anion–p studies.13–15,16b,17,19,20

3.16.2.1 The Role of the Electron-Deficient Arene

Starting with the seminal reports by Mascal,13 Alkorta,14 and Deyà,6,15 a large number of anion–p studies were reported investi-
gating the intermolecular force between a broad variety of aromatic systems and anionic species (Fig. 2). For most of the systems
depicted in Fig. 2, theoretical results suggest attractive interactions between the p-systems and the anions.13–15,16b,17,19,20 However,
so far not all complexes have been observed by experiment.
As already mentioned earlier, the interaction of an anion with an arene is dominated by two effects, the electrostatic term, rep-
resented by the quadrupolmoment of the arene, and the anion-induced polarizability, which correlates to the molecular polariz-
ability of the aromatic system. Substitution of hydrogen at the aromatic system by strong electron-withdrawing groups, such as
fluoride moieties and nitro- or cyanido-moieties, turns the repulsive force between the p-system and an anion into a weakly to
moderately attractive interaction. Already Mascal,13 Alkorta,14 and Deyà6,15 reported significant binding energies for the interactions
of various anions (Table 1).
However, since the electrostatic term and the ion-induced polarizability are opposing effects and rule each other out, a broad
variety of arenes show attractive interactions with anions. For example, arenes with negligible quadrupolmoments but significant
polarizabilities interact with both anions and cations. Indeed, the modeled gas-phase complexes of s-triazine show attractive inter-
actions with chloride (
5.2 kcal mol
1) as well as lithium (
6.2 kcal mol
1).19a,21

Table 1 Calculated interaction energies DEBSSE (kJ mol
1) and centroid–anion distances (Re, in Å) for some
chloride–p complexes at MP2 level of theory

Aromatic system DEBSSE Re

1,3,5-Triazine13
20 3.2

2,4,6-Trifluoro1,3,5-triazine13
62 3.0
Hexafluorobenzene14
53 3.159
Pentafluoropyridine14
59 3.092
Tetrafluorofuran14
38 3.106
Tetrafluorothiophene14
34 3.252
Octafluoronaphthalene15
72 3.056a
1,3,5-Trinitrobenzene15
82 3.26
a
Anion located above the linking carbon atoms of the naphthalene.
372 Interactions of Anions With Electron-Deficient p-Systems

Figure 3 Calculated quadrupolmoments (Qzz) and molecular polarizabilities (a||) for the investigated cyanuric acid derivatives as well as the interac-
tion energies (E) and equilibrium distances (Re) of the anion–p complexes with chloride.20b

Frontera et al. reported a detailed study on these opposing factors and their compensation in a series of complexes of anions with
cyanuric acid derivatives.20b By successive replacement of oxygen by sulfur in cyanuric acid, the quadrupolmoment, as well as the
molecular polarizability, is systematically modulated. Interestingly, the binding energy of the four cyanuric acid derivatives with
chloride is essentially constant ( 15 kcal mol
1), which is attributed to the compensation of the decreasing quadrupolmoment
by the increasing molecular polarizability of the p-systems (Fig. 3).
Their calculations were accompanied by a detailed crystallographic study. Therefore, an ethylene ammonium group was attached
to one of the nitrogen atoms of the thiocyanuric acid (1) and the dithiocyanuric acid (2; Fig. 4). In contrast to their theoretical
results, the crystal structures of the chloride salts demonstrate a significant difference for the two systems. The thiocyanuric acid
revealed a distance of 3.18 Å between the center of the arene and the anion, while for the corresponding dithiocyanuric acid,
the distance increases to 3.28 Å.
Another important study by the same group investigated the effect of intercalating triple bonds between the aromatic core and
the substituents (Fig. 5, X ¼ H, F, or CN).22 Therefore, the interaction energies and equilibrium distances of the corresponding
anion–p and cation–p complexes were calculated. Interestingly, the electron-withdrawing effect of the substituent (X ¼ F or CN)
is significantly reduced for cation–p interactions by the introduction of the triple bonds leading to stronger complexes. However,
at the same time, the electron-withdrawing effect is boosted when an anion interacts with the arene. These results indicate that the
ethynyl units can be used to control the p-acidity of the arene and thereby the ion binding via anion–p or cation–p interactions. The
effect is reinforced by the intercalation of a second triple bond (n ¼ 2) between the arene core and the substituent.
In conclusion to the results presented earlier, an efficient anion–p binding site requires a large positive quadrupolmoment
combined with a large molecule polarizability. However, the magnitude of the opposing properties needs to be considered and
might be dominated by either the electrostatic or the polarization term. For example, the quadrupolmoment of 1,4,5,8,9,12-
hexaazatriphenylene is almost the same for benzene, but the molecular polarizability is nearly three times the value of benzene.20d
Thus, the interaction energy of the hexaazatriphenylene with bromide is
5.2 kcal mol
1, while the corresponding interaction for
benzene is þ 1.9 kcal mol
1.
An interesting study on the interplay of electrostatic and polarizability was reported by Deyà and coworkers. They calculated the
interaction energies for chloride–p complexes of pyridazino[4,5-d]pyridazine and expanded derivatives (Fig. 6). The anion–p
binding ability increases with the number of fused rings and is significantly higher than for pyrazine. This binding trend is attributed
to the dominance of the polarizability term in the interaction energies.

Figure 4 Molecular structures of the ethylene ammonium-substituted cyanuric acid derivatives 1 and 2 demonstrating the increase in the distance
between the anion and the center of the arene with increasing sulfur substitution.20b
 Interactions of Anions With Electron-Deficient p-Systems 373

Figure 5 Molecular structures, interaction energies (EBSSE), and equilibrium distances (Re) for the anion–p and cation–p complexes as reported by
Lucas et al.22

Figure 6 Interaction energies for the pyridazino[4,5-d]pyrazine complexes with chloride.

The results earlier clearly demonstrate the relevance of the nature of the arene in respect to the anion–p interaction ability. Exper-
imental findings support theory; however, these studies are less conclusive since solvent effects, interfering weak noncovalent inter-
actions, and packing effects make their interpretation difficult.
Matile, Schalley, and coworkers2a studied anion–p interactions in the gas phase by electrospray ionization and Fourier-
transform ion cyclotron resonance tandem mass spectrometry.23 By using equimolar solutions of NDIs with salts of different anions
in acetonitrile, the affinity sequence of the anion–p complexes was determined (Fig. 7). The naphthalene diimide (NDI) derivatives
3–7 were able to form stable complexes with chloride, bromide, and nitrate, and in addition for the macrocycle, seven complexes
with iodide, dihydrogen phosphate, triflate, and chlorate were observed. By thorough competition experiments, the authors were
able to show the selectivity sequence for the chloride complexes with decreasing stability in the order of 6 > 5 > 4 > 3. This result is in
agreement with theoretical studies and demonstrates increasing binding affinity with increasing p-acidity of the NDIs.
Kochi and coworkers performed a detailed study on the interactions between neutral, highly electron-deficient aromatic p-accep-
tors and a series of anions in the solid state and in solution.24 They observed a strong color change during the addition of tetrabu-
tylammonium halides to solutions of 8–10 (Fig. 8) in acetonitrile. Using UV–Vis titration experiments, the binding constants were
determined ranging from 0.8 (for 8) to 1.0 (for 9) to 7 (for 10) for the interactions with bromide. This shows that the increasing
acceptor strength leads to stronger binding constants accompanied with a bathochromic shift of the corresponding bands. Their
solution studies were supported by a series of solid-state structures showing close contacts between the anions and the electron-
deficient units. Taking the Cl
at 10 as a representative example (Fig. 8), the anion is surrounded by four electron-deficient arenes
showing close carbon–anion distances to all 10 units (3.07 Å as closest contact). The tetraethylammonium cation is located outside
this cavity.
An interesting solid-state study by Gotz et al. investigated concurrent anion–p interactions between the perchlorate anion and
four different aromatic systems ranging from the extremely electron-deficient 1,3,5-triazine to pentafluorophenyl to the electron-
rich phenyl moiety.25 The 2-(N,N-di(pyridine-2-yl))-4-(perfluorophenyoxy)-6-phenoxy[1,3,5]triazine (11; Fig. 9) was reacted
with Cu(ClO4)2 in methanol to form the [Cu(11)2(ClO4)2](H2O)5 complex. The crystal structure showed two orientations of
the perchlorate with several anion–p contacts to the triazine unit (centroid/O ¼ 3.20, 3.36, 3.19, 2.94 Å) as well as to the penta-
fluorophenyl group (C/O ¼ 3.65, 3.60 Å). The electron-rich phenyl unit is not involved in the anion–p interactions. To confirm
their experimental findings, the authors performed computational studies of the competing intermolecular forces at the BH and
H/6-31 þ G(d) level of theory proving that anion–p and lone-pair–p interactions contribute to the observed binding.
374 Interactions of Anions With Electron-Deficient p-Systems

Figure 7 Molecular structures of the NDI derivatives as investigated by Matile, Schalley, and coworkers in the gas phase.2a

Figure 8 p-Acceptors and anionic donors as investigated by Kochi et al. as well as a representative crystal structure showing the anion–p contacts
between 10 and chloride (tetrabutylammonium cation and cocrystallized solvent omitted for clarity).24

Figure 9 Molecular structure of the receptor 11 as well as a representative view of the solid-state structure of the [Cu(11)2(ClO4)2](H2O)5 complex.
The crystal structure shows close contacts between the ClO4
anion and the C5H5N, C3N3, and C6F5 units confirming anion–p interactions.25
 Interactions of Anions With Electron-Deficient p-Systems 375

Figure 10 Side and top view of fluorobenzyl-substituted DABCO bromide salts as observed in the solid-state structures demonstrating the rising
distance between the center of the fluoroarene and the anion in dependence of the degree of fluorine substitution at the aromatic unit (12–15).
Systems with ortho-hydrogen atoms (16) show a side-on binding of the anion in the crystal.26

Figure 11 Molecular structure and crystal structure of 17 demonstrating anion–p contacts with the electron-deficient C6F5 unit and CH/anion
contacts to the phenyl group (cocrystallized methanol omitted for clarity).27

A very systematic study on the effect of the electron density of the arene on the relative position of the anion in the crystal lattice
was reported by us.26 A series of 1-(fluorobenzyl-ammonium)-4-aza-1-azoniabicyclo[2.2.2]octane salts (fluorobenzyl-substituted
diazabicyclo[2.2.2]octane, DABCO, 12–16) were analyzed by means of the relative position of the anion in respect to the aromatic
moiety. It was possible to show that the attractive anion–p binding in the pentafluorophenyl derivative turns into a repulsive force
when less than four fluorine atoms are attached to the arene. Thus, the distances between the center of the aromatic unit and the
anion within this series change from 3.67 to 6.03 Å. In addition, the anion shifts to one of the edges of the p-system. For related
compounds bearing a hydrogen atom at the ortho-position of the arene, side-on binding of the anion was found (e.g., 16 in Fig. 10).
These findings are supported by computational studies on the MP2/6-311þþG** level of theory for a corresponding model
compound.
In addition, the crystal structure of the disubstituted DABCO derivative 17 (Fig. 11) was published, which bears an electron-
deficient C6F5 unit as well as an electron-rich phenyl group.27 The crystal structure clearly shows one bromide anion located on
top of the pentafluorophenyl group interacting by multiple anion–p contacts with the C6F5 unit (C/Br ¼ 3.79–3.86 Å and cen-
troid/Br ¼ 3.57 Å). In contrast, no anion was found above the p-system of the phenyl group. Thus, the second anion was exclu-
sively fixed by CH–anion interactions.

3.16.2.2 Influence of the Anion

The nature of the anion interacting with the arene plays a crucial role. Both the electrostatic and the polarization term of the inter-
action energies strongly depend on the anion–arene distance.6,16b,c,19a Small anions such as fluoride and chloride are strongly polar-
izing and have a short distance to the p-system. Accordingly, the resulting interaction energies are found to be more negative
(Table 2).
In addition to the polarizing effect, anions occur in various geometries ranging from spherical, to linear, to more complex struc-
tures, such as tetrahedral or octahedral (Fig. 12), which complicates the correct description of anion–p contacts. Anions such as
CO3 2
, NO3
, or N3
are found to interact by p–p stacking with the arene and therefore form very stable complexes.
We performed an extended crystallographic study to investigate the effect of the anion structure in anion–p complexes. There-
fore, a series of pentafluorobenzyl-substituted DABCO salts were crystallized with different anions.29 Initially, the size effect in
376 Interactions of Anions With Electron-Deficient p-Systems

Table 2 Interaction energies (EBSSE, kcal mol
1) with BSSE correction and equilibrium distances (Re, Å) of
various anion–p complexes at the MP2/6-311þþG** level of theory15,19a,20b,21,28

Anion EBSSE Re Anion EBSSE Re

Hexafluorobenzene Trifluoro-s-triazine
F

18.2 2.57 F

24.2 2.39
Cl

12.6 3.15 Cl

15.0 3.01
Br

11.6 3.20 Br

14.0 3.14
NO3

12.2 2.92 s-Tetrazine
CO3 2

34.7 2.72 F

19.3 2.24
1,3,5-Trifluorobenzene Cl

10.9 2.86
F

7.8 2.75 Br

7.8 3.24
Cl

4.8 3.32 Cyanuric acid
Br

4.5 3.36 F

28.1 2.19
NO3
5.6 3.47 Cl

16.8 2.80
CO3 2

17.3 2.81 Br

15.5 3.00
s-Triazine
F

9.7 2.59
Cl

5.2 3.22
Br

5.0 3.34
NO3

5.3 3.00
CO3 2

16.9 2.75

Figure 12 Versatility of anion geometries.

halide salts of pentafluorobenzyl-substituted DABCO compounds was investigated. The solid-state structures of the chloride,
bromide, and iodide salts were analyzed. The salts crystallized in the monoclinic space groups Cc (chloride and bromide) and
Pc (iodide). In all three crystal structures, the anion is located above the center of the arene. Comparison of the structural data
revealed the intuitively expected proportional dependence of the distance (Fig. 13) with rising distance between the anion and
the center of the arene in the order chloride < bromide < iodide (3.60–3.78 Å).
In 2013, we were able to show that the weak interaction between anions and electron-deficient arenes has a significant influence
on the molecular structure of pentafluorobenzyl phosphonium salts in the solid state.30 The solid-state structures of a series of 1,3-
bis(diphenylpenta-fluorobenzylphosphonium)propane dications with several anions 21–24 were analyzed (Fig. 14). The crystal
structure of the bromide salt 21 showed two independent anion–p contacts on opposite sides of the receptor backbone. In contrast,
bigger anions such as iodide (22), tetrafluoroborate (23), and hexafluorophosphate (24) show ditopic anion–p interactions to both
C6F5 units. The authors attributed the differences in the crystalline packing by the more efficient filling of the cleft between the two
electron-deficient arenes by bigger anions leading to closer anion–p contacts.

Figure 13 Representative view of the anion pairs in the solid-state structures of pentafluorobenzyl-DABCO salts (chloride, bromide, and iodide)
illustrating the increasing distance between the anion and the electron-deficient C6F5 unit with increasing size of the anion.29
 Interactions of Anions With Electron-Deficient p-Systems 377

Figure 14 Representative view of the solid-state structures of the 1,3-bis(diphenylpenta-fluorobenzylphosphonium)propane salts 21–24. The size of
the anion controls the molecular structure in the crystals. The smallest anion in this series (bromide, 21) shows two individual anion–p interactions,
while bigger anions such as iodide (22), tetrafluoroborate (23), or hexafluorophosphate (24) exhibit simultaneous anion–p interaction with the
paneling C6F5 units.30

Figure 15 Representative side and top view of the ion pairs as observed in the crystal structures of the Br
, NO3
, BF4
, and the PF6
salts (the
BF4
and the NO3
salt showed two different orientations of the anion with respect to the arene in the asymmetrical cell).32,33

As previously mentioned, anions show a variety of geometries, which is considered to be a major factor complicating the effec-
tive recognition of structurally diverse anions in comparison to the mainly spherical cations.31 The influence of the anion geometry
on anion–p bonding in the solid state was studied and significant differences in the relative position of the anion in respect to the
electron-deficient arene were found.32 The approved DABCO system was crystallized with spherical (Br
), linear (BrIBr
), planar
(NO3
), tetrahedral (BF4
), and octahedral (PF6
) counterions (Fig. 15). All crystal structures showed the anions located in close
proximity to the C6F5 unit. The spherical bromide anion is located on top of the center of the C6F5 group and shows close distances
to all six carbon atoms of the arene (3.51–4.16 Å). Also, the interhalide Br–I–Br
anion is located above the pentafluorophenyl
group and shows anion–p contacts between the central iodine atom and the perfluorinated arene. In addition, both ends of the
linear anion show short distances to the electron-deficient moieties of neighbored cations. A look on the crystalline packing reveals
that the anion is encapsulated in an electron-deficient channel showing numerous anion–p and CH/anion interactions. For the
NO3
and the BF4
salts, two different ion pairs were found in the asymmetrical unit showing different relative orientations of the
anions in respect to the p-system (Fig. 15). We explained the different orientation by a lack of directionality of the anion–p inter-
action. These results are in line with the fact that anion–p interactions are mainly based on electrostatic attraction. The crystal struc-
ture of the nitrate salt possesses two different orientations of nitrate with respect to the plane of the pentafluorophenyl group. One
parallel (face-to-face, as shown in Fig. 15), suggesting p–p interactions and a tilted orientation (edge-to-face) displaying only weak
anion–p interaction between one of the oxygen atoms and two carbon atoms of the C6F5 unit (tilted nitrate: h2-type:
C5/ONO2 ¼ 3.15 Å and C6/ONO2 ¼ 3.30 Å). The solid-state structure of tetrafluoroborate also revealed two different ion pairs
per unit cell (Fig. 15 is showing only one). In both subunits, the anion is located on top of the electron-deficient p-system. However,
in one of the subunits, one fluorine atom of tetrafluoroborate points directly to the center of the pentafluorophenyl unit showing
close anion–p contacts ranging from 2.879 to 3.399 Å and a centroid/FBF3 distance of 2.829 Å (Fig. 15). Since the separations
between the anion and the electron-deficient unit are shorter than the sum of the corresponding van der Waals radii, this interaction
is best described as h6 anion–p type. The second subunit shows the anion located above the p-system, but it is rotated. Thus, three
fluorine atoms are next to the arene. The distances between the fluorine atoms and the centroid are between 3.314 and 3.885 Å.
These structures illustrate that the description of anion–p complexes by the hapticity concept is insufficient for structurally complex
anions. Only the closest contacts between an atom of the anion and the arene are considered, but the orientation of the whole anion
with respect to the arene is not described by this concept.
Concluding from the observations in the solid state, the size of the anion mainly controls the interactions with electron-deficient
arenes. This is in agreement with theoretical investigations and can be explained by polarizability effects and efficient packing in the
378 Interactions of Anions With Electron-Deficient p-Systems

Figure 16 Schematic representation of noncovalent interactions involving arenes and anions. The anion might interact via nonclassical hydrogen
bonds (A, B) or hydrogen bonds to a protonated arene (C), as well as by halogen bonds (D). These interactions (A–D) fix the anion in a side-on
fashion. In addition, noncovalent interactions with the electron-deficient p-systems are possible (E–H) or the formation of a covalent bond in a Mei-
senheimer complex (I).

solid state. The geometry seems to play a minor role and highly symmetrical anions such as tetrafluoroborate and hexafluorophos-
phate behave like large spherical anions without a preferential orientation in respect to the p-acceptor system.30,32,34 However,
computational studies suggest strong interactions of arenes with planar and linear anions such as NO3
, CO3 2
, and N3
via
p–p stacking.

3.16.2.3 Hapticity of Anion–p Interactions

Anions show multiple interaction modes with arenes: “side-on,” “on-top,” or covalently in a Meisenheimer complex. The “side-on”
binding mode fixes the anionic species by nonclassical CH–hydrogen bonding (A/B), hydrogen bonding to, for example, a proton-
ated heterocyclic arene (C) or halogen bonding to the periphery of the aromatic system (D), while the anions located “on top” of the
arene (F–H) interact directly with the electron-deficient p-system by anion–p interactions. In addition, covalent binding of an
anion to the arene, the Meisenheimer35 complex (I), is possible (Fig. 16). While computational results usually postulate the highly
symmetrical (h6) C6–p complex, experiments (mainly in the solid state) show a variability of the relative position of the anion in
respect to the electron-deficient arene.
As already mentioned earlier, Hiraoka et al. investigated C6F6/F
complexes in the gas phase by pulsed electron-beam high-
pressure mass spectrometry and found experimental evidence for the covalent bonding between hexafluorobenzene and the fluo-
ride anion, which should be described as the Meisenheimer complex (Fig. 16I).11a Later, they found noncovalent interactions in gas-
phase clusters of hexafluorobenzene and various halides (C6F6/X
; X ¼ Cl, Br, I) and proposed a h6-type anion–p complex
(Fig. 16H) with the halide anions located on top of the centroid of C6F6.11b Schneider et al. continued the gas-phase analysis by
investigation of mass-selected complexes of anions with fluoroarenes (C6FnH6
n/X
; X
¼ Cl, I, SF6) by infrared photo dissocia-
tion spectroscopy.36 Assisted by computational methods, they found that the h6–anion–p complex is only possible for perfluori-
nated arenes (Fig. 16H); otherwise, the anion is bound by CH–anion hydrogen bonds (Fig. 16A and B).
In 2007, Hay et al. reported on “Structural Criteria for the Design of Anion Receptors” and defined three types of anion–p
contacts.37 They described the covalently bonded Meisenheimer complex (Fig. 16I), the C6-symmetrical anion–p complex
(Fig. 16H), and the weakly covalent donor p-acceptor complex between the anion and one carbon atom of the arene
(Fig. 16E). Albrecht and coworkers extended the anion–p binding modes by a crystallographic study revealing anion–p contacts
with two (Fig. 16F) or three carbon atoms (Fig. 16G), respectively. In order to describe the structural versatility, the hapticity
concept of organometallic complexes has been transferred to anion–p complexes.
In 2011, Deyà and coworkers studied the directionality of anion–p interactions by computational methods. Therefore, the inter-
action energies for selected positions of chloride in a plane parallel to the plane of hexafluorobenzene were calculated.38 The result-
ing interaction energies for the anion–p complexes were compared to the corresponding cation–p systems of benzene and sodium.
Significant differences between the energies calculated for anion–p and cation–p interactions were found. While for the anion–p
 Interactions of Anions With Electron-Deficient p-Systems 379

Figure 17 Interaction energy profiles (kcal mol
1) for the interactions of C6F6 and C6H6 with chloride and sodium during the movement of the
anion in the xy plane parallel to the plane of the arene as well as in the z-direction away from the arene. The calculations were performed at RI-
MP2(full)/aug-cc-p VDZ level of theory.8,38

interactions, only minor energy changes for the different positions of the anion in the xy plane were observed (Fig. 17), the cation–p
complexes showed a significant decrease in binding energy during the movement of the cation in the xy plane. These findings are in
agreement with crystallographic studies and explain the high structural versatility observed for anion–p complexes in the solid state.
In contrast, the elongation of the distance between the ions and the arenes along the z-axis leads to a significant reduction of binding
energies for both anion–p and cation–p interactions (Fig. 17). Concluding from their computational studies, the authors propose
more general criteria for the evaluation of anion–p interactions. Accordingly, anion–p contacts were approved in systems with
a distance between the anion and the bonded carbon atoms of the sum of the van der Waals radii of the involved atoms plus a toler-
ance of 0.8 Å.
In a similar way, Moha et al. investigated the interaction of bromide with a series of fluoroarenes computationally.39 Therefore,
the interaction energies of bromide and fluoroarenes possessing different substitution patterns and degrees of fluorination were
determined. For each fluoroarene, 2200 positions of the anion in the xy plane in equilibrium distance parallel to the arene were
calculated. The results were visualized in an energy map. For hexafluorobenzene, a highly symmetrical profile was observed showing
an energetic minimum for the anion located exactly above the center of the arene (h6; Fig. 18). Less-fluorinated aromatic moieties
reveal flatter and less symmetrical energy maps. Also, the asymmetries in the substitution patterns are reflected in the shape of the
energy profiles for the corresponding systems (Fig. 18).
A common method to support theoretical results on noncovalent interactions by experimental data is to analyze crystallographic
data bases. Quiñonero et al. provided experimental evidence for their outstanding computational study on anion–p interactions by
a comprehensive structural analysis of the CSD.6 Following this combinatorial approach, many of these structural studies have been
published. However, while initially the evidence for anion–p interactions in the solid state seemed to be unambiguously supported
by a large number of hits in the CSD,6,15,38 the weak interaction between anions and electron-deficient arenes turned to be an
extraordinary curiosity by changing the search criteria applied in the data mining.7 In the following, we still summarize important
structural database analyses focusing on anion–p interactions.
The structural study by Quiñonero et al. from 2002 revealed 1944 hits for anion–p and lone-pair–p interactions of perfluori-
nated arenes and F, Cl, Br, O, S, and N-atoms.6 Just 4 years later, Hay and coworkers reported their analysis of the CSD using slightly
different criteria and found only a couple of 100 examples for anion–p interactions in the solid state.37 The same authors refined
their analysis with tougher search criteria in 2009 revealing not a single structure to confirm the intermolecular interaction of an

Figure 18 Selected energy (kcal mol
1) maps of the anion–p complexes of C6F6 and C6H3F3 with bromide at MP2/6-311þþG** level of theory as
reported by Moha et al.39 Reproduced with permission from Verlag der Zeitschrift für Naturforschung.
380 Interactions of Anions With Electron-Deficient p-Systems

Figure 19 IsoStar plots showing anion contacts between C6H5 and BF4
(A and B), ClO4
(C and D), as well as anion–p interactions between
C6F5 and BF4
(E and F), ClO4
(G and H). In addition, the anion–p contacts between C6F5 units and heteroatoms (N-, O-, and S-atoms and F-, Cl-,
Br-, and I-anions) are shown as IsoStar plots.8 Reproduced and adapted with permissions from John Wiley and Sons.

anion with an electron-deficient arene.7 Concluding from these studies, the anion–p interaction turned from a “commonplace”
noncovalent force to an “extraordinary” and hypothetic interaction.
Responding to the studies of Hay and coworkers, Frontera et al. recently reported a novel CSD-based analysis focusing on the
interactions of anions with pentafluorophenyl units.8 The authors visualized their findings in an IsoStar plot and compared their
results with the perfluorophenyl and phenyl groups. For weakly coordinating anions such as BF4
or ClO4
next to a phenyl group,
the plots (Fig. 19A–D) show a preferred fixation of the anions in the periphery of the arene plane. However, for the pentafluoro-
phenyl group, the anions are mostly found above (or below) the electron-deficient arene (Fig. 19E–H). The authors also investi-
gated the intermolecular surrounding of pyridine moieties in the solid state and found results similar to the phenyl group.
However, a few hits were found for anions located on top of the arene. In conclusion, the study found an increase in the anion
clustering along the order benzene < pyridine < pyrazine < s-triazine. In addition, the same search criteria for anion–p and lone-
pair–p interactions between N-, O-, and S-atoms and F
, Cl
, Br
, and I
anions and the C6F5 unit were applied yielding similar
results (Fig. 19I and J).
A comparable survey on the directional and predictable character of the interactions between anions and the pentafluorophenyl
or phenyl moiety was performed by Mooibroek and Gamez.40 In their study, they focused on BF4
and PF6
, since only these
anions achieved a statistically significant number of hits in the CSD. As expected, the anions are mainly located in the periphery
of the phenyl group, while for pentafluorobenzene, the position above or below the p-system is preferred by the anions. In total,
150 contacts between the BF4
and any carbon atom of the C6F5 with an average carbon–anion distance of 3.05 Å were found. The
survey for PF6
resulted in 36 hits showing an interaction distance of 3.06 Å. The exact position of the anions relative to the arene
(taking the fraction of hits in a certain volume Pn * as a measure) was analyzed by the authors showing that the number of hits
decreased with longer distance from the center of the arene for pentafluorophenyl. In contrast, the number of hits for phenyl
increased in the same direction (Fig. 20).
In 2015, a detailed study analyzing the interactions of pentafluorophenyl derivatives and anions in the solid state was reported.41
Therefore, the anion–p contacts of 80 crystal structures of pentafluorophenyl-anion complexes were examined. Since many of these
structures revealed more than one distinct anion–p interaction, the total number of 101 anion positions (8 chloride, 58 bromide,

Figure 20 Fraction of hits (Pn *) versus parallel displacement (r) charts for molecule pairs involving the F-atoms of BF4
(A)/PF6
(B) and a phenyl
(gray) or pentafluorophenyl (black) unit within a 5 Å high and wide hemisphere. Reproduced from Mooibroek, T.J.; Gamez, P. CrystEngComm 2012,
14, 3902–3906 with permission from the Royal Society of Chemistry.
 Interactions of Anions With Electron-Deficient p-Systems 381

Figure 21 Graphical and statistical analysis of the anion positions in respect to a normalized fluoroarene [Cl
, green; Br
, red; I
, pink; other
anions (BF4
, PF6
, NO3
, I3
, BrIBr
, and I4 2
), blue].41

17 iodide, and 17 others, such as tetrafluoroborate, hexafluorophosphate, or nitrate) were evaluated. In order to visualize the results,
the relative position of the anions was plotted against a normalized C6F5 unit with the xy plane centered in the origin (Fig. 21). The
majority of the anions is located above or below the p-system (91 hits, 89%) showing anion–p interactions, while only 11 hits are
found in the periphery of the aromatic moiety.
However, the anions located on top of the arene show a broad distribution reflecting the structural versatility of anion–p
contacts in the solid state. Crystal structures are the result of a complex interplay of noncovalent interactions and packing effects
and might lead to the fixation of an anion in an unfavored position. On the other hand, anion–p interactions easily interfere
with other noncovalent interactions such as CH–anion or hydrogen bonding. Therefore, directing effects of substituents at the
electron-deficient arene has a significant influence on the position of an anion above the p-system; thus, the location of the anion
on top of the center of the arene becomes less favorable. Anion–p interactions are mainly based on nondirected electrostatic attrac-
tion. Consequently, the application of carefully selected evaluation criteria is crucial for the description of weak noncovalent forces,
and interactions of molecular species with a p-system should not be restricted to the position directly above the center of an arene.
In addition, the exact sum of van der Waals radii appears to be an insufficient criterion to evaluate anion–p contacts. Taking the
cation–p interactions as the pendant showing the whole range from h1 to h6, a combination of the “hapticity concept” with newly
adjusted criteria was recommended in order to provide a comprehensive description of anion–p interactions in the solid state.
Attractive interactions between anions and arenes were defined when the anion was located on top of the arene (criterion 1) in close
P
proximity to the arene plane ( vdW þ 0.4 Å, criterion 2). The tolerance of 0.4 Å was chosen due to the recent adjustment of the
tabulated vdW radii of halide anions as reported by Deyà and coworkers in 2011.38 Finally, a criterion determining the hapticity was
P
introduced based on the given arene atom/anion distances ( vdW þ 0.4 Å). This tool facilitates the description of the versatility
of anion–p interactions in the solid state.
In order to illustrate the importance of the defined criteria earlier and the need for a comprehensive description of the structural
versatility of anion–p interactions, the crystal structures of four representative examples will be discussed in the following. In 2008,
Albrecht and Rissanen reported a series of pentafluorobenzyl-substituted ammonium, iminium, and amidinium salts and thereby
initiated the discussion on the versatility of anion–p interactions in the solid state.42 The crystal structures of the pentafluorobenzyl
amidinium chloride and bromide (28; Fig. 22) showed the anion located above the center of the C6F5 unit (h6-type). Additionally,
two short anion–p contacts to the pentafluorophenyl moiety of the adjacent ion pair (C/Cl ¼ 3.34, 3.41 Å; C/Br ¼ 3.66, 3.73 Å)
were found. In the report, the highly flexible orientation of the anions relative to the electron-deficient arenes was assigned to the
electrostatic and dispersive nature of the anion–p interactions. Also, the crystal structure of the pentafluorobenzyl-substituted tet-
ramethylethylenediamine (TMEDA) derivative (29) as reported in 2009 by Albrecht et al. shows the bromide anion fixed above the
center of the arene (center/Br
¼ 3.48 Å). The anion is fixed by the symmetrical backbone of the ammonium salt via two CH–
anion interactions (CH/Br
¼ 2.98, 3.04 Å). Applying the evaluation criteria introduced in the preceding text, this anion–p contact
represents the h6-type. Closely related is the crystal structure of the imidazolium salt (30). The imidazoline-CH in 5-position
exhibits CH–anion interaction to the bromide (CH/Br ¼ 2.77 Å). The distances between the bromide and the ring carbon atoms
range from 4.04 (C1), 3.91 (C2), 3.65 (C3), 3.46 (C4), 3.59 (C5), and 3.87 Å (C6). Since the interaction to C1 slightly exceeds the
382 Interactions of Anions With Electron-Deficient p-Systems

Figure 22 Representative views of the pentafluorobenzyl-substituted amidinium, tetramethylethylenediamine, imidazolium, and dimethylphenyl
ammonium salts as reported by Albrecht and coworkers.33b,41,42

limit of criterion 2, the anion–p contact should be described best as h5. In contrast, the less symmetrical dimethylphenylpentafluor-
obenzyl ammonium bromide (31) shows the anion located above the rim of the electron-deficient arene. Also in this case, the anion
is fixed by CH–anion interactions above the C6F5 unit. However, the higher sterical demand of the phenyl group “pushes” the anion
toward the rim of the p-system; thus, the anion reveals an h2-type interaction with the arene.
Returning to the crystallographic analysis by us focusing on structures with a rigid and symmetrical backbone (e.g., the DABCO
or TMEDA systems) as well as excluding disturbance by cocrystallized solvent molecules supports the findings and conclusions
made for the representative crystal structures earlier. The anions are exclusively located above the p-system in close proximity to
the center of the arene (Fig. 23A). In contrast, structures without disturbing solvents, but a less symmetrical backbone, reveal
a broader positional distribution of the anions (Fig. 23B).
By applying the evaluation criteria to the investigated data set, the authors found that the majority of the anion–p contacts (for
40 anions) are observed with one to five of the carbon atoms of the fluorophenyl unit (Fig. 21). Concluding from this the symmet-
rical h6–p complex represents an exceptional, very rarely observed structure in the solid state.7 The main reason for this is the
competition with nonclassical CH/anion hydrogen bonds leading to an offset from the center.7,43

3.16.2.4 Additivity of Anion–p Interactions

The additivity of anion–p interactions was investigated by Garau et al. for s-triazine and trifluoro-1,3,5-triazine anion complexes in
theory.20c Therefore, the interaction energies for the 1:1, 1:2, and 1:3 (anion/arene) complexes (Fig. 24) with chloride and bromide
were calculated on the MP2/6-31þþG** level of theory. Interestingly, the distances between the anion and the center of the arene
remained almost constant, while the interaction energies were found to be approximately additive comparing the 1:1 and 1:2
complexes (Fig. 24). For the 1:3 complexes, secondary interactions lead to slight deviations from the additivity. The triazine
complexes show a somewhat higher interaction energy attributed to the stabilization by CH–N hydrogen bonds, while the

Figure 23 Comparative, graphical analysis of the crystal structure of the p-acceptors with a symmetrical, rigid scaffold without cocrystallized
solvent molecules (A) and for less rigid and symmetrical scaffold acceptors (B).
 Interactions of Anions With Electron-Deficient p-Systems 383

Figure 24 Schematic representation of the anion–p complexes of an anion with one, two, or three triazine units as well as the corresponding
binding energies (E, in kcal mol
1) with set superposition error (BSSE) correction and the corresponding equilibrium distances (Re, in Å) on “RI-MP”
level of theory.20c

trifluoro-triazine CF–FC interactions are slightly destabilizing in the formed complex. A closer study of the complexes by atoms in
molecules44 analysis revealed that neither the charge density of the p-systems nor the strength of the individual anion–p interac-
tions changed in the series going from the 1:1 to the 1:3 complex. By polarized continuum solvent model using RI-MP2(full)/6-
31þþG** basis set/level of theory, the trend was confirmed even in the presence of solvent (chloroform and water).
The same group investigated a series of p–anion–p0 sandwich complexes (Fig. 25) in which the anion (halides, nitrate, and
carbonate) interacts simultaneously with two different arenes (hexafluorobenzene, trifluorobenzene, s-triazine, and trifluoro-s-
triazine).45 Their computational study on the RI-MP2 and MPWB1K level of theory revealed the interaction energies are nearly addi-
tive in respect to the individual interaction energies of the arenes with the corresponding anion.
A series of ammonium salts with two, three, or four pentafluorobenzyl groups were synthesized and crystallized to investigate
cooperative anion–p binding in the solid state.27 The encapsulation of anions in the electron-deficient cavity created by the penta-
fluorophenyl units was expected. Unfortunately, none of the investigated solid-state structures revealed a cavity shielding the anions
efficiently from their surroundings, which was attributed to the flexibility and lack of preorganization of the receptor moieties.
Anyway, in one of the investigated structures, the anion is paneled by electron-deficient arenes from three sides (Fig. 26).
In 2007, Ghosh et al. reported the tris-(pentafluorobenzyl-aminoethyl)amine 33 (Fig. 27). By protonation of the receptor with
HCl and HBr, two isostructural solid-state structures were obtained, showing one of the anions encapsulated in between the three
C6F5 units. However, although this is an impressive example of cooperativity of anion–p interactions in the solid state, the
NHþ/anion interaction is dominant and the anions show only h2-type contacts (3.29–3.79 Å) to two paneling arenes.46 Five years
later, the same group reported a closely related system based on a pentafluorophenyl-substituted cyanuric acid derivative 34
(Fig. 27).48 The crystal structures of the anion complexes with fluoride and chloride were obtained by crystallization of the receptor
34 with the corresponding tetrabutylammonium salts. Both structures showed the encapsulation of the anions inside the tripodal

Figure 25 Schematic representation of p–anion–p0 complexes and the corresponding interaction energies (kcal mol
1) with BSSE correction as
well as the corresponding equilibrium distances (R, in Å) at RI-MP2(full)/6-31þþG** level of theory.45
384 Interactions of Anions With Electron-Deficient p-Systems

Figure 26 Representative part of the solid-state structure of X revealing the iodide paneled by three C6F5 units.27

Figure 27 Molecular structure and crystal structure of (H333)Br3 showing the encapsulated bromide anion surrounded by dominant NH/anion as
well as weak anion–p interactions (top). In addition, the molecular structure of 34 and two representative views of the crystal structure of 34∙Cl
are
shown to demonstrate the anion encapsulation in between four electron-deficient arenes (bottom, TBA cation omitted for clarity).46,47

receptor. Similar to the reported system 33, 34 also shows dominant interactions of the anions with the amide protons overruling
the anion–p contacts to the C6F5 units. Nevertheless, the anions are located directly on top of the cyanuric unit with short distances
of 3.03 Å for fluoride and 3.51 Å for chloride to the centroid, respectively.
Ballester and coworkers reported a more rigid and preorganized anion receptor system based on calix[4]pyrroles with two or four
attached arenes ranging from electron-rich, such as methoxyphenyl, to electron-deficient, like nitro- or pentafluorophenyl
(Fig. 28).49 A series of crystals were obtained by cocrystallization of the receptor with various tetraalkyl ammonium salts. Represen-
tative solid-state structures revealed that the anions are captured by NH groups in the center of the macrocycle receptor in close
proximity to the electron-deficient arenes. The crystal structures of the halides of the two-walled system bearing C6F5 units showed
the anions located between the two parallel orientated C6F5 units with distances of 3.90–4.12 Å to their centers (Fig. 28A and B). A
representative structure for a four-walled receptor with p-nitrophenyl moieties and chloride exhibited the anion located in the center
of the receptor paneled by the four arenes. However, the distances of 4.10–4.39 Å between the chloride and the centers of the arenes
do not support attractive anion–p interactions in this system.
In 2014, we reported the crystal structures of a series of polyhalides interacting with electron-deficient arenes. One of the re-
ported triiodide structures is remarkable since a linear anion is encapsulated (Fig. 29) in an electron-deficient channel created

Figure 28 Crystal structures of the two-walled calix[4]pyrrole receptor 35 with iodide (A, top view; B, side view) and the four-walled anion–receptor
complex 36 (C, top view; D, side view)49b,50 (tetraalkylammonium cations omitted for clarity).
 Interactions of Anions With Electron-Deficient p-Systems 385

Figure 29 Two perpendicular views of the crystal structure of the pentafluorobenzyl pyridinium triiodide 37 demonstrating the encapsulation of the
anion in a channel of C6F5 and C5H5Nþ units (the second triiodide anion was omitted for clarity and is exclusively surrounded by CH–anion
contacts).51

Figure 30 Schematic overview of interfering intermolecular forces influencing the strength of anion–p bonding.

by C6F5 and C5H5NRþ units (A). The iodine atoms of the polyhalide showed close contacts to the electron-deficient moieties and
especially the central iodine atom and revealed short distances to the centers of the C6F5 and the C5H5Nþ rings (C6F5:
C/I3
¼ 3.48–4.75 Å; center/I3
¼ 3.74 Å; C5H5NRþ: C/I3
¼ 3.66–4.10 Å; center/I3
¼ 3.63 Å).

3.16.2.5 Interplay of Anion–p Interactions With Other Noncovalent Forces

Anion–p interactions are relatively weak and easily interfere with other noncovalent forces either competitively or cooperatively. For
example, anions interact with electron-rich arenes if those are simultaneously involved in cation–p interactions (A) or p–p stacking
with electron-deficient arenes (B). In addition, anion–p interactions are significantly influenced by the participation of the arene in
other noncovalent interactions such as halogen bonding (C), hydrogen bonding (D), and metal coordination (E). Just recently, the
simultaneous anion–p interaction of an arene with an ion pair (salt bridge, f) was described (Fig. 30).52
Since supramolecular systems are the result of well-orchestrated noncovalent interactions providing their functionality, the
comprehensive understanding of the interplay of these intermolecular forces is of high importance. A nice overview of theoretical
results is given by Alkorta et al.53 In the following, the most important findings are summarized and some recent experimental
results are given, as well. However, since this review focuses on neutral organic electron-deficient receptors, only a few examples
are discussed involving simultaneous coordination of heteroaromatic compounds with metal ions. For a detailed description of
such systems, the reviews by Frontera54 and Dunbar are suggested.55

3.16.2.5.1 Interplay of Anion–p, Cation–p, and p–p Interactions

As mentioned earlier, anion–p interactions are the results of electrostatic attraction between the negatively charged anion and a large
positive quadrupolmoment. By installing a positive charge at the arene, the affinity can be further increased. However, computa-
tional studies suggest favorable anion–p interactions for electron-rich arenes by simultaneous interaction with cations from the
opposite side of the p-system (Fig. 31) resulting in large negative binding energies and short equilibrium distances for the ternary
complexes.28b,56 The comprehensive theoretical investigation by Quiñonero and Frontera et al. revealed that the nature of the
participating arene is of minor relevance and attractive interactions are found for p-systems with various quadrupolmoments
(C6H6, Qzz ¼
8.5 B; C6F3H3, Qzz ¼ 0.2 B; and C6F6, Qzz ¼ 9.5 B). Comparing the interaction energies and equilibrium distances
of the cation–p–anion complexes with the values determined for the individual anion–p or cation–p interactions clearly demon-
strates the synergistic effect of these interactions leading to lower energies and shorter distances in the cation–p–anion systems.
Atwood and coworkers provided experimental evidence for the cooperative interactions of anion–p and cation–p interactions
(Fig. 32).57 By complexation of transition metals such as ruthenium or iridium to calixarenes and cyclotriveratrylenes, an electron-
deficient cavity is created. NMR studies and crystal structures proved the attractive interaction between the p-acidic cavity and the
anion. The distances of the center of the arenes of the iridium complex 38 to the closest oxygen atom of the sulfate were found to be
386 Interactions of Anions With Electron-Deficient p-Systems

Figure 31 Structures, interaction energies (Eint, in kcal mol
1) and equilibrium distances (Re, in Å) of the investigated anion–p, cation –p, and
anion– p –cation complexes at the MP2/6-31þþG** level of theory.28b,56a

Figure 32 X-ray structure of the cycloveratrylene complexed by iridium 38 showing the encapsulation of an SO4 2
anion inside the cavity.57b
 Interactions of Anions With Electron-Deficient p-Systems 387

Figure 33 Molecular structures, binding (EBSSE), and synergistic energies (Esyn) (kcal mol
1) with BSSE correction as well as the corresponding
equilibrium distances (Re, in Å) at RI-MP2/6-31þþG** level of theory of the investigated anion- and cation–p–p-stacked assemblies.28b,56a

3.38 Å. Very similar results were reported by Fairchild58 and Holman59 for cryptophane-E capsules coordinated to a ruthenium
cyclopentadienyl complex.
In addition, the interplay of anion–p and p–p interactions and the interference of simultaneous p–p stacking and cation–p
interaction in an anion–p–p–cation stack was investigated (Fig. 33). Both anion–p and cation–p interaction energies were found
to be enhanced and equilibrium distances are shorter for the p–p-stacked aggregates. The more favorable binding constants and
shorter distances of the p-stacked complexes prove the synergistic effect of the cooperating intermolecular forces.

3.16.2.5.2 Interplay of Anion–p and Hydrogen Bonding

The interplay of anion–p interactions and hydrogen bonding was theoretically investigated by Deyà and coworkers.60 For a series of
heteroarenes such as pyrazine or pyridazino[4,5-d]pyridazine, a cooperative effect of anion–p and hydrogen bonding was found,
when the arene interacts with H-bond donors (Fig. 34). However, the opposite effect was observed when the aromatic unit acts as
the H-bond donor (e.g., pyromellitic imide). In this case, weakening of both intermolecular forces – anion-p as well as hydrogen
bonding – occurred. The interplay of anion–p interaction and hydrogen bonding was also investigated for extended arenes in which
the binding sites for the cooperative interactions are spatially separated.60d Interestingly, a very similar cooperative effect was
observed, and for a given series of complexes, the cooperativity energies are almost independent of the number of aromatic rings.
The simultaneous interaction of the arene by anion–p and hydrogen bonding mutually strengthens each other, as represented by
the shortening of the equilibrium distances (RHB and Re) in respect to the complexes, where only one interaction occurs. Concluding
388 Interactions of Anions With Electron-Deficient p-Systems

Figure 34 Interaction and cooperation energies with BSSE correction (in kcal mol
1) as well as the equilibrium distances (RHB and Re, in Å) at the
RI-MP2/6-31þþG** level of theory of the H-bonded anion–p complexes.60a,b,d

Figure 35 Representative part of the solid-state structure of 39 demonstrating the simultaneous interaction of nitrate anions with the 2-
aminopyrimidinium derivative via hydrogen bonding and anion–p interactions.61

from this, the authors stated that the aromatic rings are able to transmit the synergistic effect of the hydrogen bonding to the anion–
p interaction and vice versa.
A crystallographic indication for the cooperativity of anion–p interactions and hydrogen bonding was reported by García-Raso
et al.61 In combination with high-level ab initio calculations, they investigated the interaction of nitrate anions with 2-
aminopyrimidinium (39). The results showed the crucial relevance of the interplay of various weak intermolecular forces such
as CH–hydrogen bonds and anion–p interaction for the crystal packing. By their computational study, they were able to prove
that the participation of the aromatic heterocycle in hydrogen bonding reinforces the ability to interact with anions via anion–p
interactions (Fig. 35).

3.16.2.5.3 Interplay of Anion–p and Halogen Bonding

Anion–p interactions also interfere with halogen bonding,4d which was recently investigated by ab initio MP2 calculations
(Fig. 36).62 Lu et al. found a synergistic effect for simultaneous halogen bonding and anion–p interaction for pyrazine interacting
with halogen bond donors. In contrast, the involvement of tetrafluoro-1,4-diiodobenzene in halogen complexes significantly weak-
ened the anion–p complexes as demonstrated by the interaction energies and the increasing equilibrium distance between anion
and arene.
Saunders and coworkers published a remarkable crystal structure exhibiting infinite columns of alternating polyfluoroarenes and
anions.63 The crystal structure of 1-(4-bromo-2,3,5,6-tetrafluorophenyl)3-benzylimidazolium bromide 40 (Fig. 37) revealed
a columnar arrangement of anion–p complexes, in which bromide is sandwiched between two 4-bromo-2,3,5,6-
tetrafluorophenyl units. The two paneling fluorinated arenes show two short anion–carbon distances (C4/Br ¼ 3.52 and 3.57 Å
and C5/Br ¼ 3.43 and 3.72 Å) classifying the interaction as h2-type, and the centroid–anion distances are found to be 3.63 and
3.89 Å, respectively. The shortest intermolecular contact was found for bromide and the most acidic proton of the imidazolium
unit (C/Br ¼ 3.35 Å). In addition, halogen bonding between the bromine atom of the electron-deficient arene and the sandwiched
bromide anion with a distance of 3.27 and an angle of 177.4(1) degree was observed.

3.16.2.5.4 Interplay of Anion–p and Metal Coordination

Following, some important findings of the interplay of anion–p interactions and metal complexations are provided. However, for
a more comprehensive overview of this topic, we suggest the cited reviews.54,55
The effect of metal coordination to anion–p complexes of heteroarenes was theoretically studied by Deyà and coworkers
(Fig. 38).64 It was found that the coordination of silver(I) to the nitrogen of pyridine or pyrazine significantly enhances the inter-
action with anions. For example, the complex of pyridine with chloride is unfavored (2.0 kcal mol
1), while it becomes favorable
upon coordination of the pyridine–nitrogen to silver(I) ions (
14.8 kcal mol
1). Analogous effects were observed for pyrazine. In
2009, Gural’skiy et al. reported a study combining computational calculations with experimental findings in the solid state.65 They
investigated the anion–p complexes of s-tetrazine when coordinated to silver(I). s-tetrazine itself is electron-deficient enough to
form favorable anion–p interactions with anions. For the interaction with nitrate, an interaction energy of
9.6 kcal mol
1 was
found, which increases dramatically upon coordination to four silver(I) ions (
62.4 kcal mol
1). The enhancement of anion–p
binding is also demonstrated by the shortening of the equilibrium distance between arene and anion by 0.3 Å. The computational
results were supported by crystal structures. For both nitrate and perchlorate, very short anion–p distances were found, suggesting
 Interactions of Anions With Electron-Deficient p-Systems 389

Figure 36 Structures, binding energies (kcal mol
1), and distances of the halogen bond as well as anion–p contacts (Re, in Å) of the investigated
complexes at MP2/6-31þþG** level of theory.62

Figure 37 Molecular structure and crystal state structure of 40 demonstrating the alternating stacking of the electron-deficient arene with the
bromide anion as well as the involved hydrogen and halogen bonding.63

a strong interaction between the anions and the coordinated s-tetrazine moiety. It should be noticed that the anion–p distance
between the center of the tetrazine and the perchlorate of 2.61 Å is the shortest reported so far (Fig. 38).

3.16.2.6 Anion–p Interactions in Solution

The computational and solid-state studies summarized earlier provide clear evidence for the interaction of anions with aromatic
moieties. In theory, additivity of anion–p interactions or the interplay with other intermolecular forces is well understood.
However, computational studies are based on the investigation of pairs or small clusters of interacting molecules. In contrast, exper-
iments in the solid state or in solution are carried out in highly competitive surroundings and a large number of interfering weak
noncovalent interactions have to be taken into account. However, a number of crystallographic results prove experimentally the
existence of anion–p interactions. Crystal structures are the result of the interplay of a variety of intermolecular forcesdattractive
and repulsive. Thus, the interactions observed in the solid state are not necessarily the most favorable, but at least the less unfavor-
able. Most of the reported structures bear a positive charge closely located to the electron-deficient arene and therefore anion–p
390 Interactions of Anions With Electron-Deficient p-Systems

Figure 38 Molecular structures of the anion–p complexes as investigated by Deyà and Frontera and coworkers as well as a representative view of
the crystal structure revealing strong anion–p contacts between the nitrate anion and a fourfold coordinated tetrazine unit (41).64,65

interactions might be overestimated. Still, the systematic studies on, for example, the influence of the electronic nature of the arene26
as well as important key structures25,33b,42 give persuasive arguments for the attractive nature of anion–p interactions in crystals.
A number of anion–p studies give some insight into the interaction of anions with electron-deficient arenes in solution.
However, most of the results reported in literature are not unambiguous and an alternative explanation for increased binding
affinity might be suitable as well. For example, some of the effects described in literature assigning increased binding affinities
to anion–p interactions could also be explained by the enhanced acidity of the receptors due to the electron-withdrawing effect
of the electron-deficient arene. In addition, the proof of anion–p interactions separated from other competing intermolecular
forces, such as coulombic attraction/repulsion of the guest salt, interfering of receptor and guest cation interaction, dimeriza-
tion/oligomerization of the receptor molecules, or solvent effects is difficult, if not impossible.
The following section will summarize the efforts to prove anion–p interactions in solutionda story of several throwbacks but
also some significant findings.50b,66

3.16.2.6.1 Charged Receptor Systems

Gosh and coworkers described the tris-(pentafluorobenzyl-aminoethyl)amine 42 (Fig. 39).46 Protonation with p-toluene sulfonic
and hydrofluoroboric acid yielded the corresponding salts (H342)(TsO)3 and (H342)(BF4)3, which were analyzed in respect to the
anion-binding capacity in solution by NMR spectroscopy. Titration of the receptor with tetrabutylammonium chloride and bromide

Figure 39 Molecular structures of the protonated anion–receptor complexes (H342)X3 and (H343)X3 and the corresponding binding constants with
chloride and bromide (added as n-Bu4Nþ) determined in DMSO-d6.46 In addition, the solid-state structure of the (H342)Br3 is shown indicating the
encapsulation of one of the anions inside the receptor’s cavity.
 Interactions of Anions With Electron-Deficient p-Systems 391

Figure 40 Anion-exchange equilibrium as investigated by Albrecht and coworkers as well as a representative view of the crystal structure of penta-
fluorobenzyltriphenyl phosphonium iodide indicating the competing anion–p and CH–anion interactions as observed in the crystal structure.29 In
solution, the anion–p interaction is overruled by the competing nonclassical CH/anion hydrogen bonds.

revealed 1:1 complexes in DMSO-d6. Interestingly, the fluorinated receptors showed higher binding affinities for anions than the
corresponding nonfluorinated systems (H343)(TsO)3 (Fig. 39).67
In 2010, a receptor system based on pentafluorobenzyl phosphonium salts with weakly coordinating anions (BF4
and PF6
)
was reported and the differential affinity constants during titration with tetrabutylammonium halides (Cl
, Br
, and I
) in chlo-
roform were also reported.29 NMR titrations of the hexafluorophosphate 44a and tetrafluoroborate 44b salts were compared to
the analog benzyl-substituted receptors 45a and 45b (Fig. 40) in chloroform. However, no preference for the fluorinated systems
over the nonfluorinated model compounds was found. In contrast, a series of crystal structures of the pentafluorobenzyl phospho-
nium salts (Fig. 40) demonstrated the interaction of the electron-deficient arenes with various anions (Fig. 40).

3.16.2.6.2 Charge-neutral Receptor Systems

As already pointed out for solid-state investigations of anion–p complexes, a positive charge in close proximity to the electron-
deficient arene might lead to an additional electrostatic attraction of anions and might result in an overestimation of the anion–
p interaction. Therefore, anion–p studies of charge-neutral anion receptors are important to exclude this effect.
One of the first studies on anion–p interactions in solution was published by Kochi and coworkers in 2004.24b They investigated
the interactions of halides with tetracyanopyrazine (10) and other related heteroarenes in acetonitrile. The Mulliken correlation
between the energy of one of the energy bands in the UV–Vis spectra and the oxidation potential was employed to propose a charge
transfer complex for the 10, halide complexes. By Job plot analysis, the stoichiometry was found to be 1:1 for 10 with bromide. UV–
Vis titration experiments were used in order to determine the binding constants for the 10, Br complexes and were found to be in the
range of 7–9 M
1 depending on the tetraalkylammonium counterion (Fig. 8).
Structurally related is the 1,4,5,8,9,12-hexaazatriphenylenehexacarbonitrile 46 as reported by Dunbar and coworkers (Fig. 41).68
The anion-binding ability toward halides was investigated by UV–Vis spectroscopy in tetrahydrofuran (THF). The addition of the
colorless tetrabutylammonium halide (TBAX) solutions to the yellow solution of 46 resulted in the appearance of an additional
absorption band in the visible region, which was assigned to the formation of an charge transfer complex as concluded from
the Mulliken correlation.24b Job plot analysis revealed a 3:2 stoichiometry, which was supported by the X-ray structure obtained
for 46 with TBABr. However, the authors analyzed the titration data by applying a simple 1:1 model and found decreasing binding
affinities in the order Cl
> Br
> I
. This trend is in line with the differences in the Lewis basicity of the anions and was several
orders of magnitude higher than observed for comparable systems (Fig. 41).24b
Another systematic study of anion–p interactions in solution was reported by Furuta and coworkers in 2004. They investigated
the ability of metalated (M(II) ¼ Ni, Pd, and Cu) N-confused porphyrins (NCP) to bind anions in dichloromethane.69 It should be
noted that this receptor system is overall charge-neutral. UV–Vis signals were followed for the pentafluorophenyl derivative 47 as
well as for a phenyl substituted reference (Fig. 42) during successive addition of tetrabutylammonium (TBA) halides to the solu-
tions of the receptors in dichloromethane. By Job plot analysis, the formation of 1:1 complexes was approved. For all investigated
metal complexes, the binding affinity increased in the order Cl
> Br
> I
. Interestingly, the reference systems revealed significantly
weaker binding (< 0.0001 M
1). The authors explained this observation by the enhancement of acidity of the NH group due to the
electron-withdrawing effect of the pentafluorophenyl moiety and anion–p interactions (concluded from shifting signals in the 19F
NMR spectra).
An extended study on anion–p interactions in the NCP derivatives 48–50 bearing three pentafluorophenyl units in different
positions (Fig. 42) was reported by the same group.69b For these systems, slightly smaller binding constants for the nickel(II)
complexes with chloride were found, with respect to the tetra-substituted porphyrin 47. Remarkably, the authors found the highest
binding constant for 48, which bears no C6F5 unit next to the outer NH group. These results suggest that anion–p interactions are, if
at all present, of minor relevance for the anion-binding ability of the reported receptor systems. The observed shift of the 19F NMR
signals for the C6F5 unit next to the NH group was attributed to the shielding of the negative charge rather than to the presence of
anion–p interactions.
392 Interactions of Anions With Electron-Deficient p-Systems

Figure 41 Molecular structure of Dunbar’s hexacarbonitrile p-acceptor 46 as well as the corresponding charge transfer (CT) complex with bromide
as obtained by cocrystallization with tetrabutylammonium bromide (tetrabutylammonium cations omitted for clarity).68a

Figure 42 The N-confused porphyrin derivatives 47–50 as reported by Maeda et al. with the corresponding binding constants with halides (added
as n-Bu4Nþ salts) in CH2Cl2.69

Johnson and coworkers used a similar concept for their anion–p studies.70 They designed a receptor with an amide group next to
an electron-deficient aromatic moiety for cooperative binding of the anion by hydrogen bonding and anion–p interactions. The
same receptor bearing a phenyl group next to the amide unit was synthesized as a reference system. By following the sulfonamide
proton via 1H NMR titration, binding affinities for both systems 51a and 51b (Fig. 43) in chloroform were determined upon addi-
tion of TBA halides (Cl
, Br
, and I
). The obtained binding constants were found to be quite low for the fluorophenyl system 51a
and very similar for the investigated series of halides. However, the titration experiments with the reference system 51b revealed no
shift of the signals and therefore no binding. A cocrystal of the system bearing the electron-deficient unit was obtained, but did not
support attractive interaction between the C6F5 unit and the anion.
We followed the idea of cooperativity of hydrogen bonding and anion–p interactions and studied the anion-binding ability of
benzamide receptors 52a and 52b (Fig. 44).71 1:1 complexes were found for all investigated anion–receptor pairs in chloroform by
Job’s method. Following the 1H NMR signals of the amide proton resulted in slightly higher binding constant for 52a than for 52b
in the order of Cl
> Br
> I
(Fig. 44). However, the differences between the binding constants for both receptors were small and
a clear trend in binding affinities is not obvious. Therefore, a related ditopic receptor 53 (Fig. 44) was investigated by NMR titration
in CD3CN. Also, the ditopic benzamide receptor showed 1:1 complexes with the studied halides. The binding constants were
derived by following different signals in the 1H NMR and 19F NMR spectra upon successive addition of tetrabutyl ammonium
halides. The obtained binding affinities were significantly higher than for the monotopic receptor 52a and decrease in the order
Cl
> Br
> I
(Fig. 44). Two different structures were proposed for the anion–receptor complex 53$ X
(I and II; Fig. 44) and it
was demonstrated by DFT calculations that structure II is favored over I for the ditopic anion–p complex.
 Interactions of Anions With Electron-Deficient p-Systems 393

Figure 43 Molecular structures of the receptors used by Johnson and coworkers to quantify anion–p interactions in solution.70

Figure 44 Molecular structure of the anion–p complexes and binding constants Ka (M
1) for the 1:1 complexes of 52a, b and 53 with various
anions (TBAX, X ¼ Cl
, Br
, I
, BF4
, PF6
) in CDCl3 or CD3CN.71

The solution studies were complemented by the solid-state structures of pentafluorobenzamide complexing tetraethylammo-
nium bromide 54$ TEABr (Fig. 45). Close contacts between the pentafluorophenyl unit and the bromide anion (C/Br ¼ 3.65–
4.16 Å) were observed with a distance of only 3.67 Å to the centroid. This solid-state structure was the first example demonstrating
short anion–p contacts between an uncharged pentafluorophenyl derivative and an anion supporting the existence of anion–p
interactions for 53 in solution.
Just recently, Bretschneider et al. reported an anion–p study in solution employing 1,3-bis(pentafluorophenylimino)isoindoline
(55) (Fig. 46) and 3,6-di-tert-butyl-1,8-bis(pentafluorophenyl)-9H-carbazole (56).72 In both cases, the anion binding between the
two C6F5 units is supported by the simultaneous NH–anion interactions. The obtained crystal structures for 55$ Cl and 552$ Br
demonstrate the binding of the anions between the two pentafluorophenyl units with short contacts to at least two of the carbon atoms
of the paneling arenes (dCl-centroid ¼ 3.28–3.35 Å, dCl-plane ¼ 3.28–3.30 Å, and dBr-centroid ¼ 3.53–3.66 Å, dBr -plane ¼ 3.27–3.46 Å).

Figure 45 Molecular structures of the two possible binding modes of 53 for the interaction with an anion as well as a representative part of the
solid-state structure of the cocrystal of pentafluorobenzamide (54) with TBABr (TBA cation removed for clarity).71
394 Interactions of Anions With Electron-Deficient p-Systems

Figure 46 Molecular structures of the 1,3-bis(pentafluorophenylimino)isoindoline (55) and 3,6-di-tert-butyl-1,8-bis(pentafluorophenyl)-9H-carbazole

(56) as well as the solid-state structure of 55$ Cl showing the anion captured by NH/anion and anion–p interactions by the paneling C6F5 units
(cocrystallized solvent molecules and counter cations are omitted for clarity).72

Figure 47 Structures of the indole derivatives 57a and 57b as well as of the biphenylacetamides 58a,b and 59.73

The shift of the signals in the 1H NMR spectrum confirms the binding of halide anions by 55 and 56 in solution. Unfortunately, the
authors were only able to determine reliable binding data for the carbazole system 56 in different solvents (CDCl2, CD3CN, C6D6, and
THF-d8). By NMR titration, binding constants ranging from 2.8 to 500 M
1 were obtained, which were significantly lower than previ-
ously reported for related systems in acetonitrile.71 However, qualitatively, the trend for enhanced binding constants for chloride over
bromide, as well as the favored binding by the pentafluorophenyl derivatives over the nonfluorinated analogs, was reproduced. In
addition, the authors studied the binding ability of their receptor systems in detail by computational methods and were able to support
their experimental findings. The results indicated a significant contribution of anion–p interactions in the binding of anions.
Sun et al. employed in their anion–p study indole-based receptors bearing either a pentafluorophenyl or a phenyl group (57a
and 57b) (Fig. 47).73 Their NMR studies in acetonitrile were in agreement with the results previously reported by Giese71 and
Bretschneider et al.72 However, for a nonfluorinated system 57b, no specific binding was found. The same study also investigated
a series of biphenyl acetamides 58a, b and 59 (Fig. 47), which are designed to give some insight into cooperativity (see 58a) and
competition (see 59) of NH–anion and anion–p interactions. The three receptors interact with anions by the NH–amide proton,
and in the case of 58a and 59, an additional anion–p binding site is available. In contrast to the authors’ presumptions, 59 showed
the highest binding constants in the series (55 M
1 for 58a and 91 M
1 for 59 and no systematic shift of the proton signals for 58b)
as obtained from the NMR titration experiments. The higher binding constant of 59 was attributed to the formation of a “NH/CH–
chelate complex,”70 which is in line with the 2D nuclear Overhauser effect spectroscopy (NOESY) cross-peak intensities. However, it
should be noted that the differences in binding affinities appear negligible when the accuracy of the titration method is taken into
account.
The tripodal receptor system 60 (Fig. 48) was reported by Gosh and coworkers.47 1H NMR titration in DMSO-d6 revealed high
selectivity of 60a for oxoanions in the order H2 PO4
over NO3
, ClO4
, or CH3COO
. Furthermore, the authors found an
enhanced binding of 60a over 60b and 60c, which was assigned to the significantly higher acidity of the NH group due to the
electron-withdrawing effect of the pentafluorophenyl group in 60a. However, due to crystallographic evidence, an additional contri-
bution to the binding affinity of anions by anion–p interactions was postulated. The crystal structure of 60a with TBA(H2PO4)
demonstrated a dimer ðH2 PO4 Þ22
encapsulated in a pseudo-cage created by two 60a units.
A closely related fluorobenzamide system was also investigated (61).74 The determined binding affinities (log K) decreased in
the order of F
> Cl
> Br
> I
ranging from 3.35 to 1.36. The obtained crystal structure of the fluoride and chloride complex
(Fig. 49) confirms the binding motifs as also observed for receptor 60.
Ghosh’s group also investigated a series of pentafluorophenyl-substituted cyanuric acid derivatives 62 (Fig. 50) with respect to
their anion-binding ability.48 NMR titrations and isothermal calorimetric titration (ITC) in acetonitrile showed decreasing binding
constants in the order of CH3COO
> C6H5COO
> Cl
> Br
(Fig. 50). The NMR and ITC results were confirmed by electrospray
ionization mass spectrometry (ESI-MS) as well as by crystal structures (Fig. 27).
 Interactions of Anions With Electron-Deficient p-Systems 395

Figure 48 Molecular structures of the receptors 60a–c as well as the solid-state structure of 60a$(H2PO4) showing the encapsulation of a phos-
phate dimer inside the receptor’s cavity (TBA cation and cocrystallized solvent molecules omitted for clarity).47

Figure 49 Molecular structure of the tripodal pentafluorobenzamide receptor as well as the corresponding solid-state structure of the cocrystal of
61 with TBACl as investigated by Ghosh and coworkers.74

Figure 50 Molecular structure of 62 and thermodynamic parameters of ITC experiments in acetonitrile at 298 K. Anions added as n-Bu4Nþ-salts.48
396 Interactions of Anions With Electron-Deficient p-Systems

Figure 51 Molecular structure of the anion receptors 63a and b as investigated by Taylor and coworkers.75

Figure 52 Molecular structures of the tripodal urea receptors 64a and b as investigated by Watt et al.76

Taylor and coworkers reported a series of urea-based receptors capable of interacting by a combination of hydrogen and halogen
bonding with anions (Fig. 52).75 In their study, they also investigated a receptor bearing two pentafluorophenyl groups 63a and
calculated the differences in free binding energies by comparison with the corresponding benzoate ester 63b. The titration data
in acetonitrile revealed a slightly favored interaction between chloride and bromide with the C6F5-substituted receptor 63a over
the model compound 63b. Titration with benzoate and tosylate anions revealed significantly higher interaction values, which might
be attributed to either the stronger interactions of the oxoanions with the arene, the additional p-p interactions between receptor
and anion, or a combination of both (Fig. 51).
Johnson and coworkers reported another interesting urea-based anion receptor showing high selectivity for nitrate ions
(Fig. 52).76 The authors performed detailed 1H NMR studies to evaluate the binding affinity and found decreasing complex stabil-
ities for the fluorinated system 64a with anions in the order of NO3
> Cl
> Br
> I
. Remarkably, the nitrate selectivity is lost in
the absence of the fluorine atoms at the central arene 64b. The authors attribute this behavior to anion–p interactions between the
nitrate and the central trifluorophenyl group and found indirect proof for their hypothesis. A computational model suggests that the
nitrate is bound by the urea–hydrogen bonds above the central arene, whether it is fluorinated 64a or not 64b. However, the pres-
ence of the fluorine atoms at the central units enables additional anion–p interactions to the nitrate and therefore leads to a higher
binding constant. In contrast, 64b binds the anions exclusively by NH–anion bonds and is therefore more selective for chloride.
Another tripodal receptor system, utilizing dinitro-phenyl groups for anion–p binding studies in solution, was reported by the
same group (Fig. 53).77 In contrast to Ghosh’s systems, those tripodal anion receptors consist of arenes interacting with the anion
either via CH–anion or anion–p interactions. Supported by computational methods, the authors propose anion binding in receptor
65a exclusively by anion–p interactions, while for receptor 65b, CH–anion interactions are expected to occur. The binding abilities
of the receptors were determined by 1H NMR titration experiments in C6D6. According to the author prediction, higher binding
affinities were found for the anion–p complexes of 65a in respect to the CH–anion complexes 65b. Interestingly, the reference
compound 65c, lacking the nitro-groups at the paneling arenes, did not show relevant interactions with anions in solution. Quan-
tification of the energetic differences between the two binding modes by Ballester revealed that anion binding by anion–p interac-
tions is slightly stronger than by CH–anion binding.50b
In 2008, Wang and coworkers investigated a series of macrocyclic tetracalix[2]arene[2]triazine receptors 66 (Fig. 54).78 Neither
the signals of UV–Vis nor the NMR spectra were affected by the addition of chloride and bromide salts to the solution of 66.
However, a small change in the emission band intensities was used to estimate the binding constant for chloride. The highest
binding constants were found for the dichloro-substituted macrocycle 66. Remarkably, the binding constant of the corresponding
 Interactions of Anions With Electron-Deficient p-Systems 397

Figure 53 Tripodal anion receptors 65a–c as reported by Johnson and coworkers.77

Figure 54 Molecular structure of the macrocyclic receptor 66 as well as two representative crystal structures demonstrating the interactions of the
tetrahedral BF4
and the linear thiocyanate with the electron-deficient triazine panels.78

molecular cage offering the same binding sites is significantly lower than for the macrocycle (for chloride 4246  83 to 146 M
1).79
Crystallographic studies clearly demonstrated the interaction of the anions with the electron-deficient triazine moiety.78
Moreover, the same group reported tetraoxacalix[2]arene[2]triazine macrocycles decorated with pentafluorophenyl groups (67a
and 67b) (Fig. 55) and investigated their anion–p binding ability.80 By fluorescence titration in acetonitrile, binding constants
ranging from 3.52  103 to 1.33  103 M
1 were obtained upon addition of TBAF and TBAN3 salts. It should be noted that the addi-
tion of any TBA salt, even TBAF or TBAN3, did not show shifts in either the proton NMR nor the UV–Vis spectra. The reported
binding constants were determined by following the quenching of the emission bands at 322 and 365 nm, which is in agreement
with earlier findings.78,79,81

Figure 55 Molecular structures of the tetraoxacalix[2]arene[2]-triazine macrocycles decorated with pentafluorophenyl groups as reported by Li
et al.80
398 Interactions of Anions With Electron-Deficient p-Systems

Figure 56 Molecular structure of the investigated calix[4]pyrrole with two walls 68 and with four walls 69 as investigated by Ballester and
coworkers.49

In addition, Ballester and coworkers presented a series of macrocyclic receptor systems based on calix[4]pyrroles with two (68) or
four attached arenes (69) (Fig. 56) in order to quantify anion–p interactions in solution.49 These receptors fix the anion in the
center of the pyrrole in close proximity to the paneling arenes by NH–anion interactions as demonstrated by a representative crystal
structure (Fig. 28). The binding constants of the pyrrole receptors with halide anions were determined by 1H NMR and ITC. For the
“two-walled” systems, an increasing attraction of the anion following the increasing electron-withdrawing character of the substit-
uents on the aromatic unit was found. The contribution of the anion–p interactions to the binding energy of calix[4]pyrrole was
determined by comparing the “two-walled” systems with a reference system lacking the aromatic substituents (68a). The analysis of
the free Gibbs energies for the different receptors clearly shows that only electron-deficient arenes bearing nitro-groups or a C6F5
unit interact attractively with anions. Very similar binding strengths for chloride and bromide were obtained [
0.6
to
0.8 kcal mol
1] for the electron-deficient arenes. However, iodide showed slightly stronger binding (
1.0 kcal mol
1), which
was assigned to the increased size and polarizability of the iodide.
The thermodynamics of the receptor systems were also investigated demonstrating that the enthalpy term remains almost
constant for all investigated anion–receptor complexes in acetonitrile.49b Thus, mainly entropic reasons due to strong solvation
effects caused the differences calculated for the Gibbs free energies. In contrast, solvation effects are significantly reduced in chlo-
roform leading to changes in the Gibbs free energy mainly by enthalpy.
The “four-walled” system reported by Ballester et al. showed very similar results and attractive binding in terms of free Gibbs
energy, which was observed for the chloride complex with 69f.
The authors observed a strong binding of the nitrate in the cleft between the two electron-deficient arenes.49a The crystal structure
of 68f$NO3
demonstrated the fixation of the anion by four NH–anion interactions to one of the oxygen atoms of the nitrate (see
Fig. 56). The two other oxygen atoms interact with the arenes via anion–p interactions.
Concluding from those results, anion–p interaction in polar and nonpolar solvents (
0.7 to
1.0 kcal mol
1) appears weakly
attractive in nature.66 However, it should be noted that the binding energies are obtained by comparison with octamethyl calix[4]
pyrrole possessing itself CH/anion interactions. Thus, anion–p interaction might be slightly underestimated and therefore the re-
ported values of the free binding energy are not an absolute estimate of the anion–p interaction in solution. Nevertheless, these
studies prove that systems possessing anion–p interactions are slightly more favorable than the model system showing exclusively
CH/anion binding.5b,49b,82
The two-walled aryl-extended calix[4]pyrroles were also investigated with respect to their use in chloride-selective electrodes
based on multiwall carbon nanotubes.52 The selectivity of the electrodes was significantly affected by the receptors, which the
authors assign to the presence of anion–p interactions. For example, the employment of the calix[4]pyrroles with a p-nitro-
arene resulted in sensors showing anti-Hofmeister behavior against lipophilic anions such as salicylate and nitrate. In order to prove
their use in potential applications, sensors were successfully tested in the direct detection of chloride in body fluids.

3.16.3 Conclusion and Outlook

Within the past two decades, anion–p interactions have turned from a controversy-discussed phenomena to a well-established
intermolecular force. Theoretical and detailed experimental studies have proven its existence and given first insight in the strength
of this weak interaction in solution. However, there are still open questions that need to be addressed concerning the quantification
of anion–p interactions in solution. Many recent reports indicated the relevance of anion–p interaction in solution. A conclusive
 Interactions of Anions With Electron-Deficient p-Systems 399

report that is able to ascribe the binding events clearly to the presence of the interaction between an anion and an electron-deficient
arene is still missing. Nevertheless, significant progress has been made toward the employment of anion–p interactions in func-
tional systems. Reports by Mascal’s20a,83 or Johnson’s76 group indicate the relevance of anion–p interactions in the design of supe-
rior anion receptors for fluoride or nitrate and Saha and coworkers reported an anion sensor based on NDI.84 Matile and his group
were able to prove the relevance of anion–p interactions in artificial receptors for ion transport by employing NDI-based anion–p
slides.2a,10h,85 Preliminary studies proved their efficiency in transmembranal transport. Similar results were found for a series of
macrocyclic anion receptors based on the tetracalix[2]arene[2]triazine proving the superiority of anion–p interactions over halogen
bonding in respect to ion pair transport.10d In addition, Ballester’s group recently reported anion transport49a and chloride-selective
electrodes86 based on their two-walled calix[4]pyrroles. A first proof of the functional relevance of anion–p interactions was recently
given by Wang and coworkers. They reported that anion–p interaction induces self-assembly of anionic amphiphiles and the
control over the vesicle morphology occurs by the addition of anions.10f,g,87 Just recently, Matile’s group reported the first examples
of anion–p catalysis in the Kemp elimination9a and even more impressive in the synthetical highly relevant enolate chemistry.9b,c
The biological relevance of anion–p interaction was studied by Esterellas et al. and Bauza et al.10a-c,38,61,88 Their theoretical
studies have proved the crucial role of anion–p interactions in, for example, enzymatic processes and substrate/cofactor recognition
and were experimentally supported by a number of crystal structures.
These promising results are only the beginning of the rising interest in the functional use of weak noncovalent forces such as the
anion–p interaction and will lead to a number of novel concepts in chemistry, materials science, and biomedical applications.89

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 3.17 Halogen Bond-Based Receptors
MS Taylor, University of Toronto, Toronto, ON, Canada
Ó 2017 Elsevier Ltd. All rights reserved.

3.17.1 Introduction 401

3.17.2 Scope 402
3.17.3 Halogen Bonding to Anions 402
3.17.3.1 Anion Receptors Based on Halogen Bonding 402
3.17.3.2 Halogen Bonding to Anions in Functional Systems: Transport and Catalysis 405
3.17.4 High-Affinity Halogen Bonding to Uncharged Guests 407
3.17.5 Halogen Bonding in Chemical Separations 407
3.17.6 Halogen Bonding in the Synthesis of Mechanically Interlocked Architectures 409
3.17.7 Halogen Bonding in Encapsulated Structures 409
3.17.8 Conclusions and Outlook 415
References 415

Nomenclature
A 3 B Encapsulation complex of molecule A in molecule B LUV Large unilamellar vesicle
Ar Aryl Me Methyl
Bu Butyl NMR Nuclear magnetic resonance
t-Bu tert-Butyl QCM Quartz crystal microbalance
EC50 Half maximal effective concentration TBS tert-Butyldimethylsilyl
Grubbs II Grubbs’ second-generation metathesis catalyst TEGOH Tetraethylene glycol monomethyl ether
(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene) THF Tetrahydrofuran
dichloro(phenylmethylene)-(tricyclohexylphosphine) Tf Trifluoromethanesulfonyl
ruthenium) XB Halogen bonding
iPr Isopropyl
Ka Association constant

3.17.1 Introduction

Halogen bonding (XB) occurs when there is an attractive interaction between a Lewis basic site (the halogen bond acceptor) and an
electron-deficient, covalently bonded halogen (the halogen bond donor; Fig. 1). Although this interaction is a relative newcomer to
the supramolecular chemistry arena, it has a long history. In particular, studies of the interactions of molecular halogens X2 with
Lewis bases played important roles in advancing understanding of structure and bonding. For example, halogen-bonded complexes
of I2 and Br2 were central to the development of Mulliken’s theory of charge–transfer interactions.1 This work built on Benesi and
Hildebrand’s demonstration that I2 forms 1:1 complexes with arenes in solution, as determined by ultraviolet–visible absorbance
spectroscopy.2 (Of course, Benesi and Hilderbrand’s paper is familiar to supramolecular chemists because it introduced the graphic
analysis method for determining association constants from spectroscopic titration data.) In a similar way, trihalide anions X
3,
which arise from halogen bonding between X2 and X
, were used as models to develop the theory of three-center four-electron
(hypervalent) bonds.3,4
Several general characteristics of XB can be inferred from the interactions of the molecular halogens. Donor ability increases
moving down the halogen group (i.e., R–F < R–Cl < R–Br < R–I), which is a trend that is evident in association constants of Lewis
bases with X2.5 The interaction shows a pronounced directionality, with a 180 degree halogen bond angle being preferred. This is
reflected in solid-state structures of trihalides,6 as well as cocrystal structures of molecular halogens with Lewis bases first determined
by Hassel’s group in the 1950s.7 Although complexes of molecular halogens thus yielded important insight into the nature of
halogen bonding interactions, it was less clear how they could be used as a starting point for the design of more elaborate supra-
molecular systems. In fact, applications of halogen bonding are essentially absent from the early development of synthetic host–
guest systems.

Figure 1 The halogen bonding interaction.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12527-2 401

402 Halogen Bond-Based Receptors

Over the past two decades, significant progress has been achieved in using XB in molecular recognition and self-assembly.
Increased understanding of the ability of organohalogens to act as donors in XB interactions helped pave the way for these advances.
Organic halogen bond donors can be incorporated into preorganized, multifunctional molecules in ways that would be difficult to
achieve using molecular halogens. Work along this line has developed rapidly, beginning with proof-of-concept experiments and
evolving toward more challenging applications that take advantage of unique properties and features of halogen bonding. This
article provides an overview of applications of halogen bonding in receptor design, with an aim of highlighting the types of prob-
lems that can be addressed using this new addition to the supramolecular chemist’s toolbox.

3.17.2 Scope

Since the emphasis of this article is on applications of halogen bonding in supramolecular receptor design, fundamental investiga-
tions into the nature of the interaction will not be discussed in detail. Readers interested in trends in the thermodynamics of XB
between monodentate donors and acceptors, studies of solvent or substituent effects, or computational modeling of the interaction
may wish to consult review articles that discuss these topics.8–12 The focus will be on molecular recognition in the solution phase,
and so studies describing XB in the solid state (surveys of crystal structures and applications in crystal engineering13) or in
condensed phases14 will not be covered here. An effort has been made to include recent examples that have not been covered
by previous review articles.15–18

3.17.3 Halogen Bonding to Anions

3.17.3.1 Anion Receptors Based on Halogen Bonding
Anions are often strong Lewis bases and thus can act as good acceptors of halogen bonds. The development of anion receptors based
on preorganized halogen bond donor groups was among the first applications of the interaction in solution-phase molecular recog-
nition. Fig. 2 depicts early examples of anion receptors that incorporate halogen bond donor groups.
Triethanolamine-derived 1a was designed to interact with ion pairs through a combination of Lewis acid–base and halogen
bonding interactions.19 The ability of the iodoperfluoroarene group to participate in condensed-phase halogen bonding had
been established in previous studies by the group of Metrangolo and Resnati.13 A competitive complexation method, with data ob-
tained from 1H nuclear magnetic resonance (NMR) spectroscopic titrations, was used to determine the association constant of 1a
with NaI in CDCl3. Control receptor 1b, having fluorine in place of the iodine substituent, displayed a 20-fold lower association
constant for NaI. The corresponding DDGbinding of roughly 1.8 kcal mol
1 was consistent with a single I–I
halogen bond in the 1a–
NaI complex, as might be expected based on the geometry of the receptor. In contrast, the scaffold of receptor 2 was intended to
favor tridentate halogen bonding with guest anions.20 As determined by 19F NMR titration, 2 interacts with tetrabutylammonium

Figure 2 Early examples of anion receptors incorporating halogen bond donor groups.
 Halogen Bond-Based Receptors 403

chloride (Bu4NCl) in a 1:1 fashion with an association constant of 19,000 M
1 in acetone. This relatively high association constant
was driven by halogen bonding with the iodoperfluoraryl groups, as supported by data for control receptors having lower degrees of
fluorine substitution or lacking the key iodo substituent.21,22 Receptor 2 is likely flexible enough to interact with a range of guests,
and so the trend in association constants with anions (Cl
> Br
> I
> TsO
> NO3
; HSO4
) may be a reflection of their rela-
tive halogen bond acceptor ability toward this type of donor group.
Haloimidazolium and halotriazolium groups have emerged as potent donors for anion recognition applications. Cationic recep-
tors 3a and 4a were among the first examples to incorporate such functional groups. Bromoimidazolium-containing meta-cyclo-
phane 3a displayed an association constant of 889 M
1 for Bu4NBr in polar, protic solvent (9:1 CD3OD/D2O, 295 K).23 Both
its higher bromide affinity relative to unsubstituted 3b and the distinct anion selectivity patterns of these two receptors suggested
that halogen bonding was involved in anion complexation by 3a. Fluorescence-based halide detection using a related haloimida-
zoliophane architecture has also been reported.24 Receptor 4 is one of a series of bis(haloimidazolium) salts whose interactions
with anions were investigated by Huber and coworkers using isothermal titration calorimetry (ITC).25 It showed roughly similar
association constants for Cl
, Br
, and I
(Ka values of 5.2  105, 4.5  105, and 2.5  105, respectively, using Bu4Nþ salts in aceto-
nitrile at 303 K). These apparently resulted from an entropy–enthalpy compensation in which DHbinding favored I
> Br
> Cl

while the significant TDSbinding contribution favored Cl
> Br
> I
.
More recently, the first examples of redox-active halogen bonding anion receptors were generated by incorporating iodotriazo-
lium or iodotriazole substituents onto a ferrocene backbone.26 1H NMR spectroscopic titrations showed that compounds 5a and 6a
have appreciable affinities for Cl
and Br
in 9:1 acetonitrile/water (Fig. 3). In both cases, the corresponding unsubstituted hetero-
cyclic compounds (5b and 6b) had significantly lower Ka values for these anions. Cyclic voltammetry measurements on 5a and 6a
revealed cathodic shifts of the ferrocene/ferrocenium redox couples in the presence of Cl
and Br
, consistent with stabilization of
the ferrocenium oxidation state by the halide guest.
Although halide recognition was the focus of early studies of halogen bonding anion receptors, evidence for oxoanion binding
has also been obtained. For example, Metrangolo and coworkers found that a monodentate iodoimidazolium salt interacted more
favorably with tetrabutylammonium dihydrogen phosphate and acetate than with the corresponding chloride, bromide, and iodide
salts in dimethyl sulfoxide.27 Two groups have reported that halogen bond donors are able to bind to the d-block oxoanion
perrhenate, which is a potential model for 99TcO4
, a hazardous component of nuclear waste. Beer’s group found that bis(iodo-
triazolium) receptor 7 displayed an association constant of 44 M
1 for NaReO4 in water, as determined by 1H NMR titration
(Fig. 4).28 The host showed an increase in emission quantum yield upon addition of perrhenate, thus enabling fluorescence-
based sensing of this anion. meta-Phenylene ethynylene-based bis(iodopyridinium) 8, synthesized by Berryman and coworkers, dis-
played an association constant of 8900 M
1 for Bu4NReO4 in a CDCl3/d6-acetone mixed solvent system.29
Research on halogen bonding-based anion receptors is evolving toward more demanding applications, including systems that
show unusual types of selectivity or that function in aqueous environment. One useful approach has been the exploration of recep-
tors composed of both halogen bond donor and hydrogen bond donor groups (Fig. 5). An early step in this direction was taken by
Beer and coworkers, who studied the anion recognition properties of iodotriazolium-based rotaxane 9aD.30 The halogen bond-
templated synthesis of this and related mechanically interlocked structures will be discussed in the next section. The association
constants of 9aþ PF6
with tetrabutylammonium halides in CDCl3/CD3OD/D2O decreased in the order I
> Br
> Cl
, and compar-
isons with control receptor 9bþ PF6
indicated that both the amide NH groups and the iodotriazolium C–I group were involved in
anion coordination. My research group has also explored receptors that combine hydrogen bonding and halogen bonding func-
tions.31 Differences in the behavior of iodoperfluoroarene-functionalized 10a and the corresponding perfluorobenzoyl ester 10b
showed that the halogen bond donor groups had a selective stabilizing effect on complexes with halide anions (acetonitrile solvent
and Bu4Nþ counterion).
Beer’s group has developed a receptor that employs hydrogen and halogen bonding to achieve high affinity and selectivity for
iodide in pure water.32,33 The methylated cyclodextrin groups of 11a acted as stoppers for the rotaxane architecture and helped to
confer water solubility (Fig. 6). An impressive association constant of 2200 M
1 was achieved for I
binding (Naþ counterion) in
this challenging environment. Removal of the iodine substituents from the two triazole groups in the axle resulted in a decrease of

Figure 3 Redox-active halogen bond donors for anion recognition.

404 Halogen Bond-Based Receptors

Figure 4 Bidentate halogen bond donors capable of RuO

4 binding.

Figure 5 Anion recognition through the combined action of hydrogen and halogen bond donors.
 Halogen Bond-Based Receptors 405

Figure 6 A iodotriazole-functionalized rotaxane capable of I
recognition in water.

two orders of magnitude in the association constant, with a Ka of 20 M
1 being obtained for iodide binding by 11b. Receptors 11a
and 11b showed distinct thermodynamic signatures for iodide binding in water, with enthalpy providing the driving force for 11a–
I
complexation, in contrast to the entropically driven binding of 11b. It appears that the soft–soft XB interaction is enthalpically
favorable in aqueous solvent, whereas it is desolvation that drives anion complexation in the absence of the halogen bond donor
groups. These results suggest that halogen bonding may offer unique advantages for molecular recognition in aqueous solution.
A distinct way of combining halogen and hydrogen bond donor groups in anion receptor design was described recently by the
group of Schubert.34 The phenol groups of 12a were not intended to interact directly with the anion, but rather to increase anion
affinity through the preorganizing effect of intramolecular hydrogen bonds (shown as dotted lines in Fig. 7). Consistent with this
hypothesis, 12a showed higher affinities for Bu4NþCl
and Bu4NþBr
in tetrahydrofuran (THF) than control receptor 12b, which
lacks the phenol substituents. The higher affinities were manifested not only in the 1:1 association constants, which were roughly an
order of magnitude higher for 12a than 12b, but also by the formation of 2:1 receptor–anion complexes in the case of 12a. Ther-
modynamic data obtained by ITC provided support for the preorganization hypothesis, as the TDS term for halide complexation
was positive for 12a but negative for 12b.

3.17.3.2 Halogen Bonding to Anions in Functional Systems: Transport and Catalysis

Interactions of halogen bond donors with anions have been exploited in the design of catalysts for nucleophilic substitution reac-
tions. Huber’s group has evaluated several architectures, using both iodoperfluoroarenes35 and halogenated azolium or pyridinium
salts as donor groups (Scheme 1). Bis(iodobenzimidazolium) compound 13 displayed excellent activity for the reaction of a silyl
ketene acetal with 1-chloroisochroman, providing the coupled product in 70% yield at 0.5 mol% catalyst loading.36 Kinetic studies
revealed that the catalytic activity of 13 in this reaction is higher than that of the uncharged, tridentate donor 14. Compound 13 also

Figure 7 Preorganization of an iodotriazole-based anion receptor by intramolecular hydrogen bonding.

406 Halogen Bond-Based Receptors

Scheme 1 Nucleophilic substitution reactions catalyzed by halogen bond donors.

showed a relatively high association constant of 3.5  106 for Bu4NBr in acetonitrile solvent. The trifluoromethyl substituent had
a preorganizing effect, resulting in restricted rotation about the N–Caryl bonds. This catalysis concept has also been applied to other
classes of electrophiles, including heteroaromatics,37 carbonyl compounds,38 imines,39 and halosilanes.40
Synthetic anion transporters equipped with halogen bond donor groups have been developed.41 Proof-of-concept studies by
Matile and coworkers targeted haloarene-functionalized calix[4]arenes as ditopic agents for Me4Nþ/X
symport across lipid
membranes (Fig. 8).42 The idea was to introduce variable substituents capable of interactions with anions at the lower rim while
maintaining affinity for tetramethylammonium cations at the upper rim. Calix[4]arenes 15a–d were among the derivatives studied
for their ability to mediate the decrease of a pH gradient across membranes of large unilamellar vesicles composed of egg yolk phos-
phatidylcholine (EYPC LUVs). The authors proposed that a net Cl
/OH
antiport process took place as a result of Me4NCl symport
out of the vesicles and Me4NOH symport into the vesicles. This hypothesis was consistent with the inability of the calix[4]arenes to
dissipate a pH gradient when the Me4Nþ counterion was replaced by other cationic species. p-Acidic, pentafluorophenyl-substituted
15a showed appreciable ion transport activity, as measured by its EC50 value of 25 mM, which corresponds to the concentration
needed for half-maximal transport activity. Replacing the C6F5 groups with meta-oriented halogen bond donors (compound
15b) had a significant, deleterious effect on ion transport. A “Goldilocks effect,” in which the halogen bond donor 15b interacted
too tightly with the anion for efficient transport, was supported by its appreciable affinity for Bu4NCl in acetone (Kd ¼ 18 mM). In
keeping with this hypothesis, structural variants having lower anion affinity than 15bdpara-substituted isomer 15c, having an

Figure 8 Calix[4]arene-based ditopic ion transporters.

 Halogen Bond-Based Receptors 407

Figure 9 A halogen bonding oligomer for anion transport through lipid membranes.

unfavorable geometry for chelation, and electronically deactivated, nonfluorinated 15ddshowed improved activity in the anion
transport assay. Hill plot analysis suggested that a transient 2:1 calix[4]arene/Me4NX complex was responsible for anion transport
by compound 15c. In a subsequent study, the Matile group investigated the ability of relatively simple, monodentate halogen bond
donors to act as anion transporters.43 Iodoperfluorohexane gave an EC50 of 3.1 mM for pH-driven Cl
/OH
antiport across EPC
LUVs. The Hill coefficient n ¼ 3.3 indicated that ion flux was largely mediated by donor–anion complexes of higher than 1:1 stoi-
chiometry, generated endergonically from the resting-state monomers.
Considerations of geometries that might be superior for transport, as opposed to binding, led the Matile group to synthesize
a series of halogen bond donor-functionalized linear oligomers such as 16 (Fig. 9).44 The design hypothesis involved a cascade
of XB interactions along the span of an oligomer or bundle of oligomers traversing the lipid membrane. An impressive 2360-
fold increase in Cl
/OH
antiport activity was observed for 16 relative to the monomeric model compound iodoperfluorobenzene,
as judged by the type of transport experiment described in the preceding paragraph. Halogen bonding seems to be particularly well
suited to this type of design, in that XB donors are able to participate in strong, directional interactions with anions while being
sufficiently hydrophobic to permit their entry into a lipid membrane.

3.17.4 High-Affinity Halogen Bonding to Uncharged Guests

Whereas significant progress has been achieved in developing halogen bonding anion receptors and in creating functional mole-
cules (sensors, transporters, or catalysts) based on such systems, few examples of high-affinity halogen bonding to uncharged guests
exist. Interactions of inorganic halogen bond donors with neutral acceptors can be quite favorable; for example, the association
constant between I2 and tetramethylthiourea is 58,000 M
1 in dichloromethane at 298 K and remains impressively high in the
polar, protic solvent methanol (Ka ¼ 2700 M
1).45 Achieving comparable association constants with organic halogen bond donors
has been challenging.
Triazole-based foldamer 17 was shown to act as a preorganized host for a tris(iododifluoroacetate)-functionalized halogen bond
donor (Fig. 10).46 A helical conformation was assigned for 17 based on two-dimensional 1H nuclear Overhauser effect spectroscopy
in CDCl3 and was further supported by the observation of a pyrene-based excimer by fluorescence emission spectroscopy in
dichloromethane and acetonitrile. An association constant of 3.2  104 M
1 was determined for complexation of 18 by 17 in
CH2Cl2, taking advantage of the increase in excimer emission induced by the addition of the tridentate guest. Replacing the iododi-
fluoroacetyl group with the bromo- and chlorodifluoroacetyl groups had only a minor effect on the association constants with tri-
azole foldamers (less than a 10-fold decrease in Ka). This is somewhat unusual, as more significant drops in halogen bond donor
ability are generally observed when such replacements are made.
Three-point halogen bonding between donor 19 and orthoamide 20 gave rise to an association constant of 5.8  103 M
1 in
cyclohexane, as determined by 19F NMR spectroscopy (Fig. 11).47 This impressive affinity reflects a high level of geometric comple-
mentarity between donor and acceptor that was further evident through X-ray crystallography. Consistent with this idea, other
nitrogen-centered acceptors (amines, diamines, triamine, and guanidine) showed association constants for 19 that were at least
two orders of magnitude lower than that of 20.

3.17.5 Halogen Bonding in Chemical Separations

Halogen bonding has been explored as a way to selectively sequester specific components from mixtures of compounds. One of
the first demonstrations of this idea was the preparation of a molecularly imprinted material by free radical copolymerization of 4-
iodotetrafluorostyrene with styrene and divinylbenzene in the presence of 4-(dimethylamino)pyridine (DMAP) as a templating
agent. The resulting cross-linked material was able to take up DMAP from acetonitrile solution and showed selectivity for this guest
over other amines or nitrogen heterocycles.48 In another pioneering study, a,g-diiodoperfluoroalkanes of a given length
(I(CF2)mI) were selectively extracted from mixtures by cocrystallization with a hexamethylalkane-a,g-diaminium iodide
408 Halogen Bond-Based Receptors

Figure 10 Tridentate halogen bonding to a triazole-based foldamer.

Figure 11 Halogen bonding between a tridentate donor and an orthoamide acceptor.

(Me3Nþ(CH2)mþ 6NMe3þ$2I
).49 These selective cocrystallizations provided an operationally simple and robust way to obtain
pure components from the mixtures of a,g-diiodoperfluoroalkanes generated by radical telomerization reactions. A combination
of NMe3þeI
and CF2IeI
interactions was responsible for the size-matching effect (Fig. 12).
Tris(iodoimidazolium) receptor 213 þ$3PF6
(Fig. 13) was found to sequester bromide from dichloromethane/DMF solutions
containing other anions such as Cl
, I
, ReO


4 , HSO4 , and NO3 .

50
Under these conditions, the crystalline 213 þ$2Br
$PF6

complex was formed selectively in roughly 60% yield. The selectivity for bromide was consistent with the relative anion affinities
of 213 þ$3PF6
determined by ITC in acetonitrile.
The groups of Huber and Waldvogel explored iodine-substituted meta- and para-perfluorophenylenes as affinity components for
high fundamental frequency quartz crystal microbalances (QCMs).51 As discussed earlier, these compounds were initially devel-
oped as catalysts for nucleophilic substitution reactions and had been shown to have appreciable halide anion affinities.
 Halogen Bond-Based Receptors 409

Figure 12 Cocrystallization of diiodoperfluorohexane with hexamethyldodecane-1,12-diaminium iodide.

Figure 13 A tris(iodoimidazolium) receptor capable of selective binding and sequestration of Br
.

Electrospraying was used to deposit the halogen bond donors onto the electrode of the QCM. The QCM bearing compound 14 (see
Scheme 1) displayed a distinct response to volatile analytes: the relatively high affinity of 14 for acetone vapor, which was not
accompanied by an enhancement in binding of water or ethanol, was ascribed to its XB donor ability and hydrophobic nature.
Compound 14 was incorporated into QCM-based sensor arrays that were capable of vapor-phase detection of acetone at concen-
trations as low as 0.2–0.5 vol% in aqueous solution.

3.17.6 Halogen Bonding in the Synthesis of Mechanically Interlocked Architectures

A general strategy for the synthesis of mechanically interlocked architectures is to bring two molecules into proximity through an
intermolecular interaction and then to trap this assembly through a covalent bond formation (e.g., through cyclization or “capping”
with sterically hindered stopper groups). Beer’s group has shown that XB is a useful and versatile interaction for this purpose. Their
first step in this direction was the construction of a pseudorotaxane (an assembly in which a linear component is reversibly threaded
through a cyclic one), driven by halogen and hydrogen bonding interactions to a halide anion template.52 Component 22aþCl

and macrocycle 23 interacted with an association constant of 254 M
1 in CDCl3 at 293 K (Scheme 2). A pseudorotaxane structure
was assigned based on one- and two-dimensional 1H NMR spectroscopy and was further supported by computational modeling.
The low association constants of 23 with the corresponding 22aþPF6
salt and the non-brominated imidazolium 22bþCl
pointed
toward the importance of the XB interaction in the formation of the assembly. Building upon this result, the formation of a rotaxane
was achieved by incorporating bulky tetraarylmethyl substituents onto the iodotriazolium thread component 24 and using ring-
closing olefin metathesis to close the isophthalamide-based macrocycle around 24 in the presence of bromide anion as a template.30
After ion exchange of Br
for the weakly coordinating PF6
, the authors studied the behavior of 9aþPF6
as an anion receptor (see
Section “Anion Receptors Based on Halogen Bonding” for details). Beer and coworkers also achieved the first halogen bond-
templated synthesis of a catenane, using twofold ring-closing metathesis to trap the 2:1 assembly of a bromoimidazolium-
containing precursor and a bromide ion template (Scheme 3).53 Product 262 þ2PF6
was found to act as a selective anion receptor
after the removal of the template anion.
A second approach toward catenane formation involves incorporation of a Lewis basic moiety into the macrocyclic precursor.
Association with a halogen bond donor can thus be achieved directly rather than through a templating anion as described in the
preceding text. By taking this approach, Beer’s group demonstrated that a single, charge-assisted halogen bond was sufficient to
enable catenane assembly by ring-closing metathesis of 27 in the presence of 28 (Scheme 4).54 Bromopyridinium 27b and parent
pyridinium 27c had significantly lower association constants for pseudorotaxane formation with 28 (80 M
1 and 30 M
1 in
CD2Cl2, respectively, as opposed to 180 M
1 for 27a).

3.17.7 Halogen Bonding in Encapsulated Structures

Encapsulation is a useful way to stabilize molecular arrangements (complexes and conformations) that would have a fleeting exis-
tence under normal solution conditions.55 Rebek’s group has observed that certain halogen-bonded complexes can be amplified by
410 Halogen Bond-Based Receptors

Scheme 2 Pseudorotaxane and rotaxane synthesis via halogen bonding.

incorporation into a self-assembled capsule.56 For example, iodoheptafluoropropane and 4-methylpyridine were coencapsulated in
the dimeric capsule generated from resorcinarene derivative 29 (Fig. 14). NMR spectroscopic evidence indicated that the CF3 and
CH3 groups of the two partners were at opposite ends of the capsule, while the C–I–N halogen bond was located at the “seam.” This
halogen bond was significantly more favorable in the presence of the capsule than in its absence, as judged by the higher upfield
change in 19F NMR chemical shift of the CF2I group in the former case (
12.2 ppm vs.
1.9 ppm). A similar halogen-bonded
complex was obtained by coencapsulation of iodoperfluoropropane and d-valerolactone. Esters are rather weak halogen bond
acceptors, and observation of their halogen-bonded complexes in solution has generally been difficult. In the absence of a halogen
bond acceptor, two CF3CF2CF2I molecules were encapsulated but with an orientation different from that described earlier for the
complex: the CF2I groups resided at the ends of the capsule, where a favorable interaction with the electron-rich aromatic moieties
could take place.
The enclosed space of a self-assembled coordination cage has also been used to amplify halogen bonding interactions.57 When
1,8-diiodoperfluorooctane and cage 30 (Fig. 15) were heated to 80 C in water, a 1:2 host–guest complex was obtained. Its
 Halogen Bond-Based Receptors 411

Scheme 3 Halogen bond-templated catenane synthesis.

Scheme 4 Formation of a catenane via a single halogen bond.

formation was accompanied by upfield shifts of the CF2I signals in the 19F NMR spectrum, consistent with halogen bond donation.
Indeed, X-ray crystallography revealed short I–O contacts to NO3
counterions and water molecules at the “portals” of the octahe-
dral cage. The monodentate halogen bond donors heptafluoro-1-iodopropane, heptafluoro-2-iodopropane, and iodoperfluoroben-
zene also underwent inclusion, generating 1:4 host–guest complexes stabilized by halogen bonding to nitrate counterions. Selective
412 Halogen Bond-Based Receptors

Figure 14 Halogen bonding in self-assembled molecular capsules.

Figure 15 Self-assembled coordination cage capable of encapsulating halogen-bonded complexes.

 Halogen Bond-Based Receptors 413

coencapsulation was achieved when tridentate donor 31 and N,N-dimethylaniline (32) were mixed in the presence of 30. Changes
in the 19F and 1H NMR chemical shifts of the two components were consistent with the formation of a halogen-bonded, mixed
complex 30$(31)$(32)3.
Each of the “container” molecule described in the preceding two paragraphs was assembled using conventional interactions
(hydrogen bonding or metal–ligand complexation). The prospect of generating new types of capsular assemblies using XB as the
driving force has led to several interesting studies in recent years. Aakeröy and coworkers investigated the formation of capsules
via interactions of pyridine-functionalized cavitands 32a and 32b with halogen bond donors (Fig. 16).58 Cocrystallization of 4-
pyridyl-substituted derivative 32a and para-diiodoperfluorobenzene did not generate a capsule, but rather a one-dimensional,
zigzag array having 2:1 donor–acceptor stoichiometry. However, assembly of 3-pyridyl isomer 32b with calix[4]arene 33 led to
the formation of discrete, heterodimeric structures in the solid state. Solving the structure proved to be challenging due to a relatively
high level of disorder, but the authors were able to determine that the cocrystal was composed of a “closed” dimer, having four I–N
halogen bonds, along with an open, pseudocapsular species in which three halogen bonds were present.
A distinct approach toward the formation of a capsular structure in the solid state involved the dimerization of ammonium-
substituted resorcin[4]arenes through I2–Cl
halogen bonding interactions (Fig. 17).59 Cocrystallization of ammonium chloride
salt 34 with molecular iodine gave rise to discrete dimers, each held together by halogen bonds to two I2 molecules. Three molecules
of dioxane were found in the interior of the capsular structures. Although evidence of halogen bonding between 34 and I2 was ob-
tained using 1H NMR spectroscopy, it is unlikely that analogous dimers would be generated in dilute solution by Cl
–I–I–Cl

halogen bonding. Nonetheless, this study provides an interesting illustration of how an inorganic halogen bond donor such as
I2 can be used to construct more complex supramolecular assemblies.
Solution-phase assembly of a halogen-bonded capsule was accomplished recently by Diederich and coworkers.60 An important
design feature was the use of a benzimidazole-functionalized resorcin[4]arene scaffold having a relatively high degree of preorga-
nization. Complementary halogen bond donor–acceptor pairs were generated by incorporating either haloperfluoroaryl or lutidinyl
substituents at the 2-position of the upper-rim benzimidazole groups (Fig. 18). In an optimized solvent mixture of d6-benzene/d6-
acetone/d4-methanol (70:30:1), iodo-substituted 35a and the complementary Lewis base 36 interacted with an association constant
of 5370 M
1. The association constant between a monodentate benzimidazole-substituted iodoperfluoroarene and 3,5-lutidine

Figure 16 Capsular structures via interactions of functionalized cavitands.

414 Halogen Bond-Based Receptors

Figure 17 Iodine-mediated assembly of a capsular structure in the solid state.

Figure 18 Solution-phase capsule assembly through interactions of complementary halogen bonding resorcin[4]arene derivatives.
 Halogen Bond-Based Receptors 415

was found to be < 1 M
1 under these conditions, thus pointing toward a substantial level of chelate cooperativity in the assembly of
the capsule. The fact that the corresponding bromo-substituted 35b also showed an appreciable interaction with 36 (Ka ¼ 602 M
1),
despite its lower halogen bond donor ability, is a further reflection of the chelate effect in this system. As expected, the chloro- and
fluoro-substituted derivatives 35c and 35d did not interact with 36 to any measurable extent. The 35a/36 complexation stoichi-
ometry was determined to be 1:1 through Job plot analysis and mass spectrometry, and the assignment of a capsule structure for the
heterodimer was based on heteronuclear Overhauser effect NMR spectroscopy (1H, 19F heteronuclear Overhauser effect spectros-
copy). Inclusion complexes of 1:2 host–guest stoichiometry were generated from the 35a/36 capsule using 1,4-dioxane and
1,4-dithiane as guests. In d12-mesitylene containing 3,5-dimethylbenzyl alcohol (for stabilization of the capsule by hydrogen
bonding to the benzimidazole groups), formation constants of 5.8  105 M
2 and 9.0  108 M
2 were determined for the (1,4-
dioxane)2 3 35a/36 and (1,4-dithiane)2 3 35a/36 complexes, respectively.

3.17.8 Conclusions and Outlook

Halogen bonding has now been firmly established as a component of the toolbox of interactions available for the design of molec-
ular receptors and host–guest systems. The studies described earlier illustrate the ways that halogen bond donors and acceptors can
be incorporated into complex molecular architectures and the types of functions that can arise from these strong and directional
noncovalent interactions. Halogen bond donors are not simply surrogates for hydrogen bond donors: as relatively hydrophobic
moieties that are capable of attractive interactions with Lewis basic groups, they provide a unique combination of properties. Appli-
cations aimed at taking advantage of these features (e.g., molecular recognition in water using halogen bonding and anion transport
through membranes) have already begun to appear. Further exciting developments are to be expected as more supramolecular
chemists come to appreciate the power and potential of this fascinating noncovalent interaction.

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49. Takeuchi, T.; Minato, Y.; Takase, M.; Shinmori, H. Tetrahedron Lett. 2005, 46, 9025–9027.
50. Chakraborty, S.; Dutta, R.; Ghosh, P. Chem. Commun. 2015, 51, 14793–14796.
51. Linke, A.; Jungbauer, S. H.; Huber, S. M.; Waldvogel, S. R. Chem. Commun. 2015, 51, 2040–2043.
52. Serpell, C. J.; Kilah, N. L.; Costa, P. J.; Félix, V.; Beer, P. D. Angew. Chem. Int. Ed. 2010, 49, 5322–5326.
53. Caballero, A.; Zapata, F.; White, N. G.; Costa, P. J.; Félix, V.; Beer, P. D. Angew. Chem. Int. Ed. 2012, 51, 1876–1880.
54. Gilday, L. C.; Lang, T.; Caballero, A.; Costa, P. J.; Félix, V.; Beer, P. D. Angew. Chem. Int. Ed. 2013, 52, 4356–4360.
55. Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem. Int. Ed. 2002, 41, 1488–1508.
56. Sarwar, M. G.; Ajami, D.; Theodorakopoulos, G.; Petsalakis, I. D.; Rebek, J., Jr. J. Am. Chem. Soc. 2013, 135, 13672–13675.
57. Takezawa, H.; Murase, T.; Resnati, G.; Metrangolo, P.; Fujita, M. Angew. Chem. Int. Ed. 2015, 54, 8411–8414.
58. Aakeröy, C. B.; Rajbanshi, A.; Metrangolo, P.; Resnati, G.; Parisi, M.; Desper, J.; Pilati, T. Cryst. Eng. Comm. 2012, 14, 6366–6368.
59. Beyeh, N. K.; Pan, F.; Rissanen, K. Angew. Chem. Int. Ed. 2015, 54, 7303–7307.
60. Dumele, O.; Trapp, N.; Diederich, F. Angew. Chem. Int. Ed. 2015, 54, 12339–12344.
 3.18 Multitopic Receptors
A Dalla Cort, Department of Chemistry and IMC-CNR, Università La Sapienza, Rome, Italy
Ó 2017 Elsevier Ltd. All rights reserved.

3.18.1 Introduction 417

3.18.2 Ditopic Receptors 417
3.18.2.1 Ion-Pair Receptors 417
3.18.2.1.1 Heteroditopic Receptors 418
3.18.3 Multitopic Receptors 426
3.18.3.1 Some Examples of Multitopic Receptors 426
3.18.4 Applications of Ion-Pair Receptors 429
3.18.4.1 Salt Solubilization 429
3.18.4.2 Salt Extraction and Transport 430
3.18.4.3 Sensing 432
3.18.5 Conclusions and Outlook 434
References 434

3.18.1 Introduction

Multitopic receptors are molecules with different binding sites for targeted substrates. Historically, the evolution of this topic has
been, and still is, deeply related to the search of hosts able to mimic recognition events occurring in Nature. Such kind of receptors
are indeed omnipresent in Nature because multivalent binding1 and cooperative binding2 are two major tools used to guarantee the
necessary efficiency and selectivity in biological recognition events.3 Due to the presence of different binding sites potentially able to
interact with substrates, receptors usually display different conformational changes upon binding with the guests.4 It is well known
that in biological systems, conformational changes are controlling the activity of proteins and enzymes5 producing an activating
(positive cooperation) or deactivating (negative cooperation) effect influencing the binding of another substrate at a different
binding site. An inspiring example found in Nature of multitopic receptor displaying a positive cooperation is hemoglobin whose
affinity toward oxygen increases with every oxygen molecule that is bound to one of the four binding sites. The curve describing the
binding of oxygen to hemoglobin isolated from red blood cells displays a marked sigmoidal behavior which is indicative of coop-
eration between subunits. This can be ascribed to conformational changes induced by every binding event. A similar, although
different in nature, example is the allosteric binding of cyclic AMP of Escherichia coli to the gene transcription-regulating cAMP
receptor protein (CRP) to DNA. The cyclic AMP receptor protein is a dimer made up of two identical subunits. Each CRP subunit
contains a cyclic nucleotide binding pocket and the CRP dimer exhibits in this case negative cooperativity in binding cAMP.6 In
general in positive cooperativity, the binding of the first guest induces a change in the host resulting in stronger binding of the
second guest, while in noncooperative one the binding of the first guest lowers the binding affinity of the second one for the multi-
topic receptor. Finally, in the case of noncooperative effect, the binding of the first entity has no effect on the second binding event.
The concept of cooperativity is strictly related to that of multivalency that can be described as “the simultaneous binding of
multiple ligands on one entity to multiple receptors on another.”7 Thus the valency of a particle is the number of ligating function-
alities of the same or similar type connected to this entity. The term multivalency can be properly used for the self-assembly of well-
defined complexes in “which the separation of any entity or part from the complex requires the dissociation of at least two
interactions.”7,8
The binding of two or more guests to a host can be examined depending on whether the guests are identical (homotropic) or not
(heterotropic). The case of multihomotropic binding is more related to the principle of multivalency, which we will not examine
here, as we will focus our attention on multitopic receptors provided with different binding sites that can be involved in heterotropic
recognition.

3.18.2 Ditopic Receptors

3.18.2.1 Ion-Pair Receptors
Our first step in this area will deal with receptors able to give simultaneous complexation of both a cation and an anion thanks to
the presence of heterotopic binding sites. The development of such kind of receptors has recently attracted a lot of attention.9 Ion-
pair recognition is indeed an important field due to the numerous applications in the development of salt extraction, solubilization,
and membrane transport agents. There are peculiar binding paradigms that can be found in the host–guest complexes when the
guest is an ion pair. These can be summarized in the following way considering the structure of the receptor and the nature of
the ion pair. It is possible to have heteroditopic receptors able to bind the two partners of the ion pair as a contact ion pair

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12529-6 417

418 Multitopic Receptors

Figure 1 Complexes formed by a ditopic receptor and (A) a contact ion pair; (B) an ion pair separated by the solvent; (C) a triplet, that is, two
cations and an anion entrapped between them. Reproduced by permission from McConnell, A.; Beer, P. D. Angew. Chem. Int. Ed. 2012, 51, 5052–
5061.

(Fig. 1A), or as an ion pair separated by the solvent (Fig. 1B). Moreover a so-called cascade complex can be obtained when two
homotropic binding sites coordinate two cations, for example, and at the same time an anion is entrapped between them
(Fig. 1C).10
In many cases, ion-pair receptors show enhanced affinities and selectivity for the ion pair as compared with analogous single ion
receptors.11 This is attributed to allosteric effects and enhanced electrostatic interactions between the partners of the ion pair, as well
as decrease in competing solvation effects. Positive conformational allostery is obtained when cation binding helps organize the
receptor to receive the anion; thus the geometrical reorganization penalty is lower for binding the ion pair than for either cation
or anion separately. Electrostatic cooperativity should come from the attraction between anion and cation inside the receptor
and is governed by Coulomb’s law.
We should report that such an intuitive principle, that is, cooperativity principle, is neither general nor predictable, as reported by
Roelens and coworkers.12 Quantitative studies that outline the geometric and electrostatic contributions to cooperativity are rare.
The competition between ion binding and ion pairing may even lead to inhibition rather than enhancement of the binding of an
ion to a ditopic receptor. As a matter of fact, obtaining a detailed comprehensive picture of ion-pair binding is a challenging task due
to the occurrence of multiple equilibria that need sophisticated binding models13–15 and several affinity measurements. The vast
majority of examples reported in the literature up to date aimed to prove the higher efficiency of ditopic receptors versus monotopic
ones in ion-pair recognition, rely on phenomenological “turn-on methods of evaluation” that do not give access to the thermody-
namic data needed for truthful assessment of the origin and strength of cooperativity in binding.
An accurate binding model should take into account all the important equilibria present in solution. These include anion
binding, Kanion, cation binding, Kcation, and the ternary ion-pair binding, boverall from which we obtain the cooperativity factor, a:
a ¼ boverall =Kanion $Kcation (1)
Only cooperativity factors > 1 indicate a stabilization effect within the ternary ion-pair complex, that is, positive cooperativity.
We do believe that quantification of cooperativity is important for the understanding and rational design of ion-pair receptors with
desired affinity and selectivity and this is the challenge that has to be faced in the future work.

3.18.2.1.1 Heteroditopic Receptors

In the following part our attention will be focused on a selected number of heterotopic ion-pair receptors reported in the literature
that feature simultaneous complexation of both cationic and anionic species. The combination of structural motifs used to coor-
dinate the ionic species is one of the leading issues of this part. In such receptors, we can easily recognize the presence of well-
characterized functionalities for cations and anions to promote the recognition and binding of the targeted ion. For example,
structural motifs as crown ether units, calixarene scaffolds, or Lewis basic groups are often included for cation recognition, while
hydrogen-bonding groups, positively charged nitrogen units, or Lewis-acidic groups are inserted for anion binding. These func-
tionalities can be closely located or placed far away from one another in the receptor scaffold, depending on how the ion pair
has to be complexed, that is, as a contact ion pair, as a solvent separated one and host separated. The relative organization of
the bound ions depends on the spatial location of the binding sites, the choice of the ion-pair components, and the fashion
in which the binding takes place (sequential/concurrent). For those receptors provided with well separated binding sites for
the two partners of the ion pair, the inherent binding ability toward one of the ion is not expected to be significantly altered
by the presence of the other ion. However, some exceptions can be found thus confirming the well-known limits of any
classification.9d

3.18.2.2.2.1 Binding of Contact Ion Pairs

Historically the advantage of heteroditopic receptors over monotopic receptors was demonstrated by Smith and coworkers.16 The
data obtained for the affinity of monotopic receptor 1a toward tetrabutylammonium dihydrogen phosphate in CD3CN, through 1H
NMR titrations, results in the expected 1:1 binding isotherm, leading to an association constant of 400 M 1. When the titration is
repeated with a solution of the host containing 1 M equiv. of potassium tetraphenylborate, then a different isotherm is observed.
Indeed the first 1 M equiv. of dihydrogen phosphate does not show any affinity for the urea NH residues, but subsequent additions
produce a “normal looking” titration curve. The reason is that potassium stoichiometrically sequesters the first equivalent of dihy-
drogen phosphate generating the ion-pair equilibria described in Eq. (2). This happens because in most organic solvents, as
 Multitopic Receptors 419

previously mentioned, the salts of alkali cations do not exist as free ions, but are present as solvent-separated ion pairs, contact ion
pairs, and/or aggregated contact ion pairs.
 
Mþ þ A  #Mþ A  # Mþ A  n (2)

To relieve cation-induced inhibition, the heteroditopic host, 1b, which simultaneously can bind both the metal cation and the
anion, was successfully used. This allowed to establish positive cooperativity, since the presence of the metal cation, coordinated by
the crown ether moiety, close to the anion, increases anion association constants. Similar effects can be observed for competing
anions in the presence of monotopic cation receptors where the binding selectivity can be dramatically influenced.17

Structure 1A and 1B

The majority of ion-pair receptors reported to date have been constructed on the basis of heteroditopic systems, like 1b, which
consists of one cation and one anion-binding site.
One of the first report of a ditopic salt receptor that binds a contact ion pair in solution more strongly than either of the free ions
was that reported by Smith and coworkers in 2001.18 The evaluation of salt-binding ability of compound 2 was obtained by 1H
NMR titration experiments in highly polar DMSO-d6. Chloride affinities were measured by adding aliquots of tetrabutylammonium
chloride (TBACl) to a solution of the receptor in the absence and presence of 1 M equiv. of potassium or sodium tetraphenylborate.
Under these conditions, receptor 2 shows negligible affinity for the tetrabutylammonium cation and tetraphenylborate anion, so
that they can be considered simply “spectator ions.” The changes in chemical shift were consistent with the recognition of chloride
by isophthalamide NH unit. Kþ and Naþ affinities were determined by adding increasing amounts of the appropriate metal tetra-
phenylborate to a solution of 2 in the absence and presence of 1 M equiv. of TBACl. Obviously cations were complexed by the crown
ether moiety.
Receptor 2 showed a weak affinity for Cl in this medium, whereas its association constant was slightly affected by the presence
of Naþ, and increased more than 10-fold by the presence of Kþ (Table 1). If we consider this in terms of cation binding, the weak
affinities that receptor 2 has for Naþ and Kþ are increased 5- and 40-fold, respectively, by the presence of Cl. These results highlight
that the heteroditopic receptor 2 binds ion-paired potassium chloride more tightly than either free Kþ or Cl. Greater increase can be
obtained in the less polar solvent mixture of CDCl3:DMSO-d6 (85:15) in which the percentage of contact ion pair is higher. Further
confirmation of the binding mode came from X-ray crystallography (Fig. 2, right).
More recently, a heteroditopic macrocycle, 3, which combines a rigid aryl–triazole unit for binding anions together with a gly-
colic linker for stabilizing cations, was designed for binding contact ion pairs. This compound, quite simple in its synthetic design,
was used in the analysis of cooperativity, trying to examine the two different contributions, the electrostatic and the allosteric
ones.19 The small cavity size and the flexibility of the glycol chain guarantee that, once the ions are bound inside the receptor,
they will make direct contact with each other forming a tight ion pair. Indeed the X-ray structure of the sodium perchlorate, NaClO4,
complex with macrocycle 3 (Fig. 3, center) confirms the formation of such kind of ion pair inside the cavity.

Table 1 Association constants, K (M 1), in DMSO-d6 at T ¼ 295 K

KCl KNa þ KK þ
D D L
2 2 D Na 2DK 2 2 D Cl 2 2 D ClL
35 50 460 5 25 8 340

Figure 2 Left, compound 2; right, X-ray crystal structures showing 50% probability ellipsoids and no CH residues of the 2@KCl structure found in
the unit cell. Reproduced by permission from Mahoney, J. M.; Beatty, A. M.; Smith, B. D. J. Am. Chem. Soc. 2001, 123, 5847–5848.
420 Multitopic Receptors

Figure 3 Left: chemical structure of 3; center: solid-state structure of 3@NaClO4; right: chemical structure of compound 3a. Reproduced by permis-
sion from Qiao, B.; Sengupta, A.; Liu, Y.; McDonald, K. P.; Pink, M.; Anderson, J. R.; Raghavachari, K.; Flood, A. H. J. Am. Chem. Soc. 2015, 137,
9746–9757.

Table 2 Equilibrium constants, K, for ion-pair binding of NaClO4 to receptors 3 and 3a

Receptor 3 Receptor 3a

ClO4, Kanion (M 1) 50  10 60 

Naþ, Kcation (M 1) 50  30
NaClO4, boverall (M 2) 1,000,000  600,000 <10,000
Cooperativity a 400  250

In this case, it was possible to highlight the pure electrostatic contribution to the overall cooperativity. All ion-pair receptors that
bring their cation and anion reasonably close to each other are expected to benefit from this type of stabilization. Qualitatively here
the cooperativity was established by 1H NMR titrations. The peak shifts accompanying the addition of NaClO4 were compared to
shifts for addition of the constituent ions (Naþ or ClO4) when added “alone.” The Naþ was added as the tetraphenylborate
(BPh4) salt and ClO4 as the tetrabutylammonium (TBAþ) salt. These counterions are too large to associate with receptor 3.
Measurements provided an indication of weak individual binding (Table 2), while the addition of NaClO4 caused shifts of the
protons to new positions indicative of complex formation.
Titration data were analyzed quantitatively to obtain DGanion, DGcation, and DGoverall, respectively. Titrations were also under-
taken with the anion-binding control macrocycle 3a for comparison. This macrocycle is isosteric with 3, but it only possesses an
anion-binding site and cannot behave as an ion-pair receptor. Analogous experiments were carried out with the two receptors in
the presence of sodium iodide, NaI, and found that in this case the cooperativity is higher (a ¼ 1300  600). Iodide has a smaller
ionic size relative to ClO4 and this is consistent with the higher level of cooperativity that was found. The distance between the two
ions in the ion pair, that is, in NaþClO4 and in NaþI, influences the electrostatic attraction determining the electrostatic contri-
bution to cooperativity. The study showed that the size of the ions masters this contribution, but only if the ions are in direct contact
with each other. Allostery contributes to the cooperativity only in a minor extent and an increase of solvent polarity may reduce the
electrostatic contribution significantly while having a smaller effect on allostery. Density functional theory calculations supported
this separate examination of conformational allostery and electrostatic contribution to cooperativity.
At this point we would like to discuss the fact that having a rigid receptor, which cannot reorganize itself, means that only a few
ion pairs could be bound inside it as a contact ion pairs. However for these few particular ion pairs we expect a very high selectivity.
This design approach has found application in the hemicryptophane 4.20 Binding affinities toward a series of anions of various
geometries (e.g., F, Cl, Br, I, CH3COO, HSO4, H2PO4) were investigated in CDCl3 through 1H NMR spectroscopic titra-
tions with tetra-n-butylammonium salts (nBu4NþX).

Structure 4
 Multitopic Receptors 421

From chemical shift variations, it was possible to establish that anions interact with the triamide part of the receptor, while no
variation was detected for the resonances of the TBA cation, indicating that this is too big to enter the cavity so remaining far from
the anion. When TBA cation was replaced by Me4Nþ and Et4Nþ highfield shifts of their protons were observed, which correspond to
the encapsulation of the cation in the cyclotriveratrilene, CTV, cavity through CH–p and cation–p interactions. The highest binding
constant was obtained with tetramethylammonium (TMA) chloride that better matches the size of the cavity and allows efficient
hydrogen-bonding and CH–p/cation–p interactions together with a maximized enthalpic gain on the contact ion pairing. Coop-
erativity decreases in the order Cl > F > AcO, Br and the weaker values can be attributed to a looser size-fit relationship, there-
fore the selectivity between F and Cl appears inverted in the presence of TMA cations.
The ferrocene unit is one of the most popular redox signaling motif often being used for the incorporation into suitable receptors
to bind cations, anions, and neutral molecules and allowing their electrochemical sensing. This is a quite useful feature as recog-
nition sites located close to the redox function induces a positive shift in the redox potential of the ferrocene/ferrocenium redox
couple, when the cation is recognized, and a significant cathodic shifts when the recognition event involves an anion. Recently
Molina et al. reported the synthesis of highly preorganized tricyclic bis(heteroaryl)substituted ferrocenyl-imidazo-quinoxalines,
5a–b, that behave as ion-pair receptors for cations and anions. In these receptors, the redox activity of the ferrocene group is
combined with the fluorogenic behavior of the quinoxaline ring and the binding ability of the imidazole ring.21 Remarkably the
addition of metal cations, Ni2 þ or Mg2 þ, that do not interact with the free receptors, to a solution of these receptors containing
HSO 22
4 , originates a dramatic increase in the binding affinity toward the ion pair. This is a clear example of AND logic, in which
the receptor displays no affinity for either of the “free” cation yet binds the cation and anion ion pairs strongly.

Structure 5A and B

Another interesting class of contact ion-pair receptors that has shown in some cases binding behaviors consistent with AND logic
is that reliant on the proximal inclusion of calix[4]diquinone cation binding and isophthalamide-based anion-binding fragments,
within the same macrobicycle.23 In this context, receptors 6 and 7 were designed to provide optimal size and shape complemen-
tarity to contact ion-pair species, that is, alkali metal halides. The addition of one equivalent of TBACl in acetonitrile-D3, followed by
1
H NMR, was found to induce only very small (Dd ¼ 0.01 ppm) downfield shifts in the signals arising from the amide unit and iso-
phthalyl C–H protons of the respective receptors. However, upon addition of one equivalent of TBACl to 1:1 mixtures of 6 or 7 and
a Group 1 metal or ammonium salt, strong interaction was detected (log K > 4) highlighting the “switching on” of chloride recog-
nition in both receptors. The AND nature of the recognition is postulated to arise in these cases from the self-inhibition of the
receptor by intramolecular hydrogen bonds, which may only be disrupted by the presence of both a suitable cation and anion.

Structures 6 and 7
422 Multitopic Receptors

Calix[6]arene-tris(urea) based receptors were studied by Jabin and coworkers.24 This is an example of fluorescent receptor
that can bind organic contact ion pairs in CDCl3. The presence of fluorophores, that is, pyrenyl groups, in close proximity to
the tris(urea) binding site leads to the variation of the excimer to monomer emission intensity ratio upon formation of the
host–guest complex. This helps to monitoring the binding and provides information on the conformational changes of the
receptor. It was found that the complexation of the sulfate anion can only proceed when an ammonium ion is present in
the calixarene cavity, and conversely, without SO42  receptor 8 is inefficient at binding the ammonium ion. In other words,
the complexation of the anion preorganizes the binding site for the ammonium cation, leading to a positive cooperativity.
Interestingly, this cooperative binding of ammonium sulfate salts was also evidenced in a protic environment.

Structure 8

Such induced fit process was found in calix[6]cryptamide as well and investigated by the same group to establish the poten-
tiality as contact ion-pair receptors.25 Addition of an excess (up to 15 equiv.) of ammonium salts RNH3þCl (R ¼ Et or Pr) to
a solution of 9 in CDCl3 produced the corresponding endo-complexes (Fig. 4). The in and out guest exchange appears to be
slow on the NMR timescale, and involves an induced fit process with the expulsion of methoxy groups from the calixarene cavity.
In addition to the endo-complexation of the ammonium ion RNH3þ, the simultaneous binding of the chloride counterion by the
amide groups of the host is evidenced by the strong downfield shift of the resonances of the NHCO protons indicating a strong

Figure 4 Four possible conformations of calix[4]pyrrole 11 and the equilibrium in the presence of an anion: its presence fixes the calix[4]pyrrole in
the cone conformation. Reproduced by permission from Kim, S. K.; Sessler, J. L. Calix[4]pyrrole-Based Ion Pair Receptors. Acc. Chem. Res. 2014,
47, 2525–2536.
 Multitopic Receptors 423

hydrogen-bonding interaction of these protons with the counter anion occurring through a convergent arrangement of hydrogen-
bonding NH groups.

Structure 9 Reproduced by permission from Le Gac, S.; Jabin, I. Chem. Eur. J. 2008, 14, 548–557.

Another example of ion-pair receptors is that reported by Kubik26 of cyclopeptides composed of natural amino acids and 3-
aminobenzoic acid in an alternating sequence. The cation affinity of receptor 10 depends on the anion present in solution. With
anions, such as phosphonates and sulfonates, which bind to the NH groups of the cyclopeptides, allosteric effects have been
observed. Binding of the positively charged guests with the cyclopeptide anion complexes is due to cation–p interactions with
the aromatic subunits of the peptide as well as electrostatic interactions with the anion. Thus the positive cooperativity of the
counteranions is not only an effect produced by the conformational reorganization of the receptor, but it is also due in this
case to the proximity between cation and anion in the final complex. The combination of both binding mechanisms leads to
an increase of the complex stability by a factor of 103–104 in comparison to that of cation complexes without the influence
of counter anions.

Structure 10

Quite similar is the case of calix[4]pyrrole, 11, described by Sessler et al.27 as a stoichiometric ion-pair receptor. The origin of the
cation dependence on the anion-binding affinities has clearly a structural basis.
Calix[4]pyrrole 11 in its uncomplexed form is extremely flexible and interconverts rapidly between all possible conformations,
while on average favoring the 1,3-alternate arrangement. Upon interaction with a tightly bound anion, such as benzoate or chloride
anion, A in Fig. 4, it becomes frozen into the cone conformation. This structural arrangement creates a cavity distal to the pyrrole
NH donor atoms that can complex a tetraalkylammonium cation of suitable size and shape. The increase in the resulting anion-
binding association constant values up to a 103-fold variation in the case of benzoate or chloride in dichloromethane is severely
depending on the choice of countercation. But contact ion pairs can be bound by a more sophisticated derivative of calix[4]pyrrole,
that is, 12, where a calix[4]pyrrole core is covalently linked to an m-dibenzo-[26]crown-8 subunit through phenyl spacers.28 The
424 Multitopic Receptors

Figure 5 Schematic view of the varying complexation behavior seen for the chloride complex ([12$Cl]; TBA salt) upon exposure to various metal
cation perchlorate salts in acetonitrile. M1þ ¼ Kþ and Liþ; M2þ ¼ Naþ, Mg2þ, and Ca2 þ; M2þCl ¼ NaCl, MgCl2, and CaCl2. Reproduced by permission
from Kim, S. K.; Sessler, J. L. Acc. Chem. Res. 2014, 47, 2525–2536.

receptor was found to act as an anion-modulated, cation selective ion-pair receptor in CDCl3 and CD3CN, with selectivity for
specific cation and anion combinations within a series of strictly related salts of alkali and alkaline earth metals. The receptor
supports the formation of two different ion-pair complexes that are formed depending on the nature of the cation. It was observed
that when the receptor–chloride complex [12$Cl](as TBAþ salt) was treated with various alkaline-metal ions (as their perchlorate
salts), for example, with the cesium salt, a receptor-shared ion-pair complex in which a Csþ ion can bound to the cup of the calix[4]
pyrrole is formed. Addition of CsClO4 results in the formation of a cup bound ion-pair complex, as well as a crown ether-bound
contact ion-pair complex. Complete decomplexation is observed upon subsequent addition of NaClO4, while only partial decom-
plexation of the bound chloride was achieved upon treatment with Kþ, Ca2 þ, and Mg2 þ. Different behavior is observed in the case
of the complex [12$F] for which complete decomplexation of the bound fluoride ion is observed when Naþ, Liþ, Caþ, and Mgþ, as
perchlorates, were added (Fig. 5). This supports the idea that the nature of the cobound cation and anion plays a major role in
defining the structure of the resulting ion-pair complex.
A key component of derivative 13 is the 1,3-alternate calix[4]crown-6 subunit that has high selectivity and affinity for the Csþ
cation.29 X-ray analysis showed that receptor 13 forms a stable 1:1 complex with CsF in the form of a solvent-separated ion pair. The
cesium cation is complexed within the calix[4]arene crown-6 ring, while the fluoride anion is hydrogen-bonded to the pyrrole NH
protons of the calix[4]-pyrrole subunit.
In a competitive media, such as chloroform:methanol, 9:1, little evidence of fluoride anion binding was observed in the absence
of a cobound cesium cation. 1H NMR analysis performed in deuterated chloroform:methanol, 9:1 confirmed that the complexation
of the Csþ cation within the calix[4]arene crown-6 ring helps to enhance fluoride binding by the calix[4]pyrrole subunit. On the
other hand, no fluoride binding is seen when Csþ is replaced by TBAþ, supporting the hypothesis that, due to the less-
coordinating nature of the TBAþ cation, solvation of F by the methanol present in the solvent mixture strongly competes with
the calix[4]pyrrole unit for anion binding, as represented in Fig. 6.
Nice examples of contact ion-pair receptors are those including a metal center that binds anions through Lewis acid–base inter-
actions.30 As an example, we mention uranyl salophen (salophen ¼ N,N0 -bis(salicylidene)1,2-phenylenediamine) complexes in
which suitable synthetic variations of the ligand skeleton introduce binding motifs for the cation. It is known that complexes
formed by salophen ligand with uranyl dication bind strongly to hard anions in organic solvents.31 The introduction on the
ligand skeleton of appended aromatic units, 14, provide stabilizing cation–p interactions with tetralkyl cations. Indeed it has
been found that uranyl salophen complexes of this kind behave as effective ion-pair receptors for tetralkylammonium halides
and iminium salts in solution and in the solid state.32 Consistent with the hard Lewis acid character of the uranyl, binding affin-
ities for complexation of quaternary salts to uranyl-salophen receptors in solution are higher the harder the anion, confirming the
idea that the major driving force for complexation arises from anion coordination to the metal center. Less important, yet
 Multitopic Receptors 425

Figure 6 Binding interactions involving 13 and various Csþ and F salts in 10% (v/v) CD3OD in CDCl3. Reproduced by permission from Sessler, J. L.;
Kim, S. K.; Gross, D. E.; Lee, C.-H.; Kim, J. S.; Lynch, V. M. J. Am. Chem. Soc. 2014, 130, 13162–13166.

significant contributions to complex stability in solution arise from cation–p/CH–p interactions of the quaternary ions with the
aromatic pendants.

Structure 14

Compared with the parent receptor, the one without the aromatic arms, receptors 14 was found to bind TMACl and TBACl with
higher efficiency in CHCl3. The existence of stabilizing cation–p interactions and CH/O/Cl hydrogen bonds to oxygens of the
ligand and to the chloride anion coordinated to uranium (closest donor–acceptor distances are 3.16–3.38 Å for C/O and
3.68–3.97 Å for C/Cl interactions) is confirmed by solid-state structure of complex of receptor 14 with TMACl (Fig. 7).33 Receptor
14 forms also similar complexes with alkaline halide salts.34 In particular, the solid-state structures of 14 with CsCl, KCl, and RbCl
reveal the existence of dimeric supramolecular assemblies in which two receptor units assemble into capsules fully enclosing (MX)2
ion quartets (Fig. 7).
426 Multitopic Receptors

Figure 7 Left: crystal structure of the 1:1 complex of receptor 14 with tetramethylammonium chloride (chloride: green); center: asymmetric unit of
the RbCl complex of 14 drawn as VDW presentation; right: dimeric assembly of the CsCl complex of 14. Reproduced by permission from Cametti, M.;
Nissinen, M.; Dalla Cort, A.; Rissanen, K.; Mandolini, L. J. Am. Chem. Soc. 2007, 129, 3641–3648 and Cametti, M.; Nissinen, M.; Dalla Cort, A.;
Mandolini, L.; Rissanen K. J. Am. Chem. Soc. 2005, 127, 3831–3837.

3.18.3 Multitopic Receptors

The receptors presented in the previous part are ditopic by nature, but, although few, some reports of more complex multitopic
receptors are present in the literature and these will be discussed in the following session. Such receptors utilize many structural
motifs already described, but generally they are larger molecules, and their behavior is more complex. In this way, the interactions
between receptors and ions can be manipulated on a higher level and make these systems attractive for use in ion transport, recog-
nition, and extraction.

3.18.3.1 Some Examples of Multitopic Receptors

A first example in which chemists have moved from ditopic hosts to tritopic hosts is the one reported by Lünig for the complexation
of an alkaline earth metal halide as ion triplet.35 Macrocycle 15 displays two anion-binding sites (amidic hydrogens) and a cation
binding site (ether oxygens) and complexes calcium dichloride in its ion-triplet form.

Structure 15

Cooperative binding properties of a tetratopic ion-pair host were reported by Thordarson et al. in 2014.15 The receptor reminds
closely the one used by Lünig, but it is characterized by a larger macrocyclic size since it has a crown-6 unit instead of a crown-4 one
and combines two isophthalamide anion recognition sites with two “half-crown/two carbonyl” units for cation recognition, 16.
This structural design allowed the study of the cooperativity of cation binding, anion binding, and the combination of both in
a single, well-established host system. A detailed analysis of the validity of the different binding models that can be used to describe
the possible 1:1 and 1:2 equilibria present and whether they point to cooperativity is carried out in this work. Without cations
present, the receptor binds anions (chloride, acetate) very weakly in the polar 9:1 CDCl3/CH3OH solvent mixture while, in the pres-
ence of Ca2 þ cations, the receptor goes through conformational changes, allowing chloride binding thanks to allosteric positive
cooperativity (Fig. 8). Such observation was also supported by the crystal structures of the receptor and its [Ca(ClO4)2]2 complex.
In the solid state, the receptor shows a closed conformation due to intramolecular hydrogen bonding. However, in the presence of
Ca2 þ cations, the macrocycle undergoes a conformational change forming two crown ether-like cavities for Ca2 þ complexation,
“freeing” the amide protons for anion binding.
 Multitopic Receptors 427

Figure 8 Receptor 16 binds chlorides only when the addition of Ca2 þ ions has induced conformational changes. Reproduced by permission from
Howe, E. N. W.; Bhadbhade, M.; Thordarson, P. J. Am. Chem. Soc. 2014, 136, 7505–7516.

In 2005, the group of Nabeshima in Japan reported the synthesis and the binding behavior of a receptor in which three different
types of ion-binding sites are arranged on a calix[4]arene skeleton, 17.36

Structure 17

The result is an interesting biomimetic model capable of the effective and efficient multistep regulation of anion recognition by
utilizing two different cationic guests. On the lower rim of the conical calix[4]arene framework, compound 17 possesses two ester
substituents and two polyether units containing an urea group connected to a bipyridine moiety. The receptor recognizes Naþ and
Agþ simultaneously and quantitatively and captures also an anionic guest. Its ability to recognize anions, including CF3SO3 and
BF4, remarkably increases in a stepwise manner using Naþ and Agþ as effectors. In the presence of both Naþ and Agþ, the binding
constant is enhanced by factors of 1500 and 2000 for NO3 and CF3SO3, respectively (Fig. 9).
The anion affinity of 17, achieved through hydrogen bonding to the urea moieties, is enhanced in a stepwise fashion thanks to
the electrostatic interactions of the soft and hard cationic guests, which are bound by the bipyridine and ester units, respectively.
Upon complexation of the bipyridine moieties with a cationic guest, a conformational change occurs in the receptor that brings
the two urea moieties in close proximity, favoring anion binding.
An example of a cascade receptor binding an ion triplet in a close-contact mode is that reported by Ballester et al. of a calix[4]
pyrrole-based cylindrical homoditopic receptor.37 The two 1,3-diynyl linkers provide conformational rigidity and prevent the
collapse of the macrotricyclic structure. The two distal heteroditopic binding sites (calix[4]pyrrole units) are located at an ideal
distance and in a perfect relative orientation to achieve the cooperative binding of two identical or distinct ion pairs. The receptor
was used to recognize alkylammonium chloride and cyanate ion pairs. They demonstrated that receptor 18 binds two chloride or
428 Multitopic Receptors

Figure 9 Stepwise regulation of anion recognition for receptor 17. Reproduced by permission from Nabeshima, T.; Saiki, J.; Iwabuchi, J.; Akine, S.
J. Am. Chem. Soc. 2005, 127, 5507–5511.

cyanate TBA ion pairs yielding complexes through a highly cooperative process (a > 105). One ion pair is bound in a close-contact
geometry, while the other in a receptor-separated arrangement.

Structures 18 and 19

Jabin and coworkers have reported metal-free tritopic receptors, tail-to-tail built bis-calix[6]arenes, that incorporate two diver-
gent hydrophobic cavities linked by amide or urea groups, 20–21. Compound 20 is especially efficient for the cooperative binding
of organic ion triplets, where an anion is “sandwiched” between two ammonium ions.38 This receptor displays a high selectivity for

Figure 10 X-ray structure of 20@(EtNH3þ)2SO42  showing the array of 12 hydrogen-bonding interactions (stick representation). Reproduced by
permission from Moerkerke, S.; Le Gac, S.; Topic, F.; Rissanen, K.; Jabin, I. Eur. J. Org. Chem. 2013, 5315–5322.
 Multitopic Receptors 429

linear ammonium ions associated with doubly charged anions such as sulfate. The resulting neutral quaternary complexes represent
rare examples of metal-free cascade complexes. Remarkably, in this case the first X-ray structure of a host–guest complex with contact
ammoniums salts has been obtained, 20@(EtNH3D)2SO42 L (Fig. 10).39
Moreover, NMR-based complexation studies demonstrated that when the two divergent cavities are linked by thiourea groups,
21, the receptor is much more efficient than the previous one, 20, in the cooperative binding of organic ion triplets even in protic
environments. Indeed ammonium nitrate salts are selectively extracted from water to chloroform as the nitrate anion combines
weak hydration with good geometrical complementarity with the tris-thiourea binding site. A remarkable feature of these cascade
complexes is their chirality due to the helical arrangement of the thiourea linkers wrapping around the anion.

Structures 20 and 21 Reproduced by permission from Moerkerke, S.; Le Gac, S.; Topic, F.; Rissanen, K.; Jabin, I. Eur. J. Org. Chem. 2013,
5315–5322.

3.18.4 Applications of Ion-Pair Receptors

This part will provide some examples of the application of ion-pair receptors as salt solubilization, salt extraction, membrane trans-
port, and sensing agents. Such processes can be achieved by utilizing many of the receptors already described.

3.18.4.1 Salt Solubilization

One of the most important applications of multitopic receptors is the solubilization of otherwise insoluble salts in organic solvents.
Here we report just a couple of examples since some of the receptors already described can achieve such goal.34,38
One of the earliest examples of an ion-pair receptor was reported in 1991 and comprises a crown ether moiety for cation recog-
nition coupled to a Lewis-acidic boron center for anion recognition, 22. The receptor forms a 1:1 complex with KF in which the Kþ
cation is bound within the crown ether and the fluoride anion is bound to the boronic center. The consequence is that this receptor
allows the otherwise insoluble salt, KF, to dissolve in dichloromethane within 4 h.30

Structure 22

The ditopic receptor based on quinoline and crown ether moieties prepared by Albrecht et al.,40 23, can bind anions as well as
ion pairs showing positive cooperativity effects when binding ion pairs in solution. It can solubilize inorganic salts into organic
phases, such as chloroform and DMSO, behaving as a phase-transfer carrier, and it can be subsequently regenerated.
430 Multitopic Receptors

Structure 23

The simple dual-host receptor, dibenzo-18-crown-6 based pentafluorophenyl substituted urea, 24, recently described by Gosh
et al. shows selective solid–liquid extraction of KBr from mixtures containing solid KCl, KBr, and KNO3.41

Structure 24

It was shown that 24 interacts with bromide most strongly both without potassium (K ¼ 851 M 1) and in the presence of potas-
sium (K ¼ 2455 M 1) in acetonitrile, supporting the selectivity of the solubilization experiments. Such selectivity was associated
with the suitable size and the charge density of the ion compared to the cavity within the receptor, and the electronic characteristics
of the receptor produced by the pentafluorophenyl substituent.

3.18.4.2 Salt Extraction and Transport

A considerable number of ion-pair receptors have been investigated for use in solvent extraction.42 This is a very important appli-
cation, for example, in industrial and environmental processes, where valuable or hazardous ions need to be extracted selectively
from waste streams. An example of extraction of harmful species is the one reported by Beer and coworkers concerning the pertech-
netate anion TcO4, which is a noxious radioactive by-product in nuclear waste. 99TcO4 is separated from used nuclear fuel in
a reprocessing method known as the plutonium–uranium extraction process (PUREX process). It is a kinetically stable molecule,
but it has a hazard potential ascribable to its high solubility in water. Compound 25, a tren-based ion-pair receptor, selectively
and efficiently extracts sodium pertechnetate under aqueous conditions simulating nuclear waste streams and proving the extraction
efficiency of the multitopic system, compared to control receptors, with only anion-binding sites or simple 15-crown-5 for ion
extraction. The derivative complexes sodium cations, and in the presence of 1 equiv. of Naþ the resulting positively charged complex
shows increased affinity toward all the studied anions, comprising perrhenate anion, ReO4, that is structurally similar to pertech-
netate, with large increase in binding affinity.43

Structure 25

Extraction can be also achieved by utilizing polymeric structures. One example is the polymer based on L-ornithine scaffold. This
one has been used for the construction of molecular receptors bearing three recognition sites, including one cation binding and two
 Multitopic Receptors 431

Figure 11 Ditopic L-ornithine-aza-crown ether-based receptors, 26, prepared by Romanski and coworkers. Reproduced by permission from
Romanski, J.; Pia˛ tek, P. Chem. Commun. 2012, 48, 11346–11348.

strong anion-binding sites, 26.44 They have shown positive cooperativity toward various anions especially in the presence of
sodium.45 The receptor consists of an aza-crown ether connected to the L-ornithine molecular scaffold having urea and thiourea
groups as first anion recognition unit, and amide or urea/thiourea functionality as a secondary anion recognition unit. The meta-
crylamide group present in the derivatives allowed, when reacted with butyl methacrylate, to obtain polymeric materials containing
receptors 26 as pendant groups (Fig. 11). Such polymers were able to transfer nitrate anions into chloroform with an extraction
efficiency of 32%.46
A poly(methyl methacrylate) polymers decorated with calix[4]pyrroles and benzo-15-crown-5 subunits, 27, were prepared in
Sessler’s group.47 As previously mentioned, calix[4]pyrrole subunits are known to bind halide anions in a 1:1 ratio in organic media,
while benzo-[15]crown-5 subunits are capable of forming 2:1 sandwich complexes with potassium cations. The presence in the
polymers of pendant calixpyrrole and crown ether subunits permits the concurrent complexation of both halide and potassium
ions. The efficiency of extraction from aqueous media exceeds those expected on the basis of the effective concentration of the indi-
vidual recognition units.48

Structure 27

Another copolymer prepared from a 10:1 molar ratio of methyl methacrylate and a methacrylate functionalized benzocrown-6-
calix[4]arene was also reported by the same group.49 Under aqueous-dichloromethane liquid–liquid extraction conditions, the
copolymer shows an enhanced selectivity for cesium over sodium and potassium (in the form of their picrate salts). Indeed the
copolymer was capable of removing cesium nitrate from aqueous solution in the presence of various other anionic (e.g., F,
Cl, and SO4) and cationic species (e.g., Kþ and Naþ).
Liquid extraction and liquid membrane transport are fascinating aspects of multitopic receptor chemistry with several potential
applications not only in purification processes, but also in diagnostics.50 There are two kinds of primary transport processes, that
is, the ion exchange or antiport, that couples the transport of two components of like charge across a membrane in opposite direc-
tions, and synport that occurs when two ions of different charges are transported at the same time in the same direction.51 Most
frequently, synthetic ion-pair receptors are able to perform synport processes across membranes.52 The control of ion concentrations
is crucial to cell survival and the dysfunction in ion transport through membranes might lead to severe diseases like cystic fibrosis
which is caused by dysregulation of chloride transport across epithelial cell membranes.53
As mentioned previously, many of the receptors already seen in this article have been used also as transmembrane carriers, with
the advantage of avoiding temporary separation of charge. One of the first comprehensive transport study was reported in 1995 by
Reinhoudt and coworkers. They compared the membrane transport properties of ditopic calixarene receptors such as 28, with
different mixtures of cation and anion receptors providing a detailed description of the process.54 This “classical” combination
of calix[4]arenes and crown ether bridges was also applied to solve the problem of selective removal of 137Csþ from medium-
level radioactive waste, facing an important environmental and technological problem.55
432 Multitopic Receptors

Structure 28

As previously mentioned, receptor 2 is able to form organic soluble complexes with many alkali halide salts that are bound as
contact ion pairs. Smith and coworkers demonstrated that the ditopic receptor 2 is a more effective membrane transporter, under
salt-saturating conditions, than a binary mixture of separate cation and anion receptors. Indeed in the case of the ditopic receptor,
the polarity of the receptor/salt complex is lowered as the salt is bound as an associated ion pair (a contact ion pair is the best case).
This is likely to produce faster diffusion of the complex through the membrane, due to reduced intermolecular interactions, and
a higher maximal flux.56
Most recently, Matile57 and coworkers have also investigated a series of ditopic calix[4]arene receptors that utilize anion–p or
halogen-bonding interactions for anion transport. Although the systems are not so efficient, the work evidences the functional rele-
vance of weak interactions that are otherwise difficult to observe. Receptor 29, decorated with strongly electron-deficient perfluoro
aromatic rings on the lower rim, recognizes the anion through anion–p interactions, while the TMA counter cation interacts,
through cation–p interactions, with the aromatic rings of the upper rim of the calixarene. The presence in receptor 30 of iodine
substituents allows instead anion recognition through halogen-bonding interactions. Receptor 29 was found to be the most efficient
carrier for chloride/TMA and hydroxide/TMA ion pairs within a series of six receptors, able to establish different interactions, that is,
anion–p interactions, halogen or hydrogen bonds with the anion, thus demonstrating the functional relevance of anion–p
interactions.

Structures 29 and 30
Ditopic ion transport systems based on calix[4]arene scaffolds, 29 and 30. Reproduced by permission from Vargas Jentzsch, A.; Emery, D.;
Mareda, J.; Metrangolo, P.; Resnati, G.; Matile, S. Ditopic Ion Transport Systems: Anion–p Interactions and Halogen Bonds at Work. Angew. Chem.
Int. Ed. 2011, 123, 11879–11882.

3.18.4.3 Sensing
In general the development of receptors able to behave as sensors is crucial for the fast and efficient detection of environmentally
and biologically relevant analytes. Many of the receptors we already reported have been modified by the introduction of “signaling
units” to highlight binding.
For example, the calix[6]arene-tris(urea) based receptor 8 is a good illustration.24 The three pyrenyl subunits on the calixarene
skeleton signal the cooperative binding of ammonium sulfate salts in CHCl3 and in protic media by fluorescence intensity changes.
 Multitopic Receptors 433

Structure 31

Ferrocene reporter groups58 have also been exploited to detect ion-pair binding as previously illustrated in the case of recep-
tors 5a–b.21 Such signaling unit is also present in receptor 3159 together with a benzocrown ether unit. After addition of 10 M
equiv. of fluoride (as its tetrabutylammonium salt), the acetonitrile solution of 31 from colorless turns to yellow. The subsequent
addition of Kþ reverses the chromogenic process leading to a clear solution. The hypothesis is that the presence of Kþ weakens the
interactions established between F and the urea moiety. So the receptor behaves as a simple chromogenic molecular ON–OFF
switch. A lot of work has been done in this area by the group of Molina that through the development of systems displaying the
key intermediate ferrocene–triazole–pyrene triad give access to multichannel ferrocenyl recognition receptors for anions, cations,
and ion pairs.60
An example of nanosensor technology in terms of a general approach for the detection of multiple analytes from biological and
environmental samples containing various interferents is reported here, even if this type of systems are a little bit out of the focus of
this article. Nanoparticles themselves, when properly functionalized, provide a practical approach to the challenge of multiscale
sensing. The immobilization of receptor scaffolds on their surface makes them “peculiar” multitopic receptors, although the philos-
ophy results to be quite different from that of having multiple binding sites within the same molecule. Nevertheless the advantages
of surface-bound receptors are numerous and include preorganization of the receptor on the surface, amplification of sensing
response, and possibility of receptor recycling.61
A nanosensors with the potential capability to detect multiple ions, including Hg2 þ and H2PO4 , by enhancement, and S2  by
quenching of fluorescence intensity, has been reported by Yu Tang and coworkers.62 Silica nanoparticles have been functionalized
with single-type receptors, that is, rhodamine, acting as both metal binding site and hydrogen bond donor (Fig. 12).
Upon addition of Hg2 þ ions color changed to red that could be seen by the naked eye, a remarkable fluorescence enhancement
and an obvious red to purple emission color change were observed when H2PO4 was added to the neutral solution of Hg2 þ bound
to the cation binding site on rhodamine functionalized silica nanoparticles (RFSNP). The interaction playing a role in the recogni-
tion of H2PO4 is hydrogen-bonding interaction with the imino group near the pyridine ring, while the rhodamine unit undergoes
a ring-opening reaction as a result of the high selective Hg2 þ affinity over other competing metal ions. Upon exposure to S2  ions,
a substantial fluorescence decrease was detected which indicates the reversibility of binding between RFSNP and Hg2 þ ions. The
system can be applied for the imaging and biosensing of multiple ions in living cells thanks to its low cytotoxicity and good cell
permeability.

Figure 12 A schematic representation of the detection systems of silica nanoparticles functionalized with rhodamine for multiion sensing. Repro-
duced by permission from Wu, W.; Sun, Z.; Zhang, Y.; Xu, J.; Yu, H.; Liu, X.; Wang, Q.; Liu, W.; Tang, Y. Chem. Commun. 2012, 48, 11017–11019.
434 Multitopic Receptors

3.18.5 Conclusions and Outlook

In recent years, multifunctional receptors which provide multiple binding sites and some geometrical preference have seen progress.
The largest part of articles present in the literature deals with ditopic receptors, mainly ion-pair receptors for which many compre-
hensive reviews and book chapters have been written and some were here cited.9b,c,d,10,11a,12 Such systems, designed to bind specif-
ically ion pairs, feature numerous advantages in terms of affinity and selectivity, aptitudes that are enhanced relative to those of
simple ion receptors, as illustrated here through selected examples. Less numerous are the examples of multitopic receptors in which
“multi” means more than two, despite the fact that such receptors are ubiquitous in nature witnessing the importance of multivalent
and cooperative binding. In this context, we think that the big tool box of switchable binding motifs and building blocks, patrimony
already available within the supramolecular community, should be used to promote the development of systems in which multi-
binding is necessary to achieve a specific function.

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51. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; John Wiley & Sons: Chichester, 2009.
52. Ko, S.; Kim, S. K.; Share, A.; Lynch, V. M.; Park, J.; Namkung, W.; Van Rossom, W.; Busschaert, N.; Gale, P. A.; Sessler, J. L.; Shin, I. Nat. Chem. 2014, 6, 885–892.
53. Haynes, C. J. E.; Gale, P. A. Chem. Commun. 2011, 47, 8203–8209.
54. Chrisstoffels, L. A. J.; De Jong, F.; Reinhoudt, D. N.; Sivelli, S.; Gazzola, L.; Casnati, A.; Ungaro, R. J. Am. Chem. Soc. 1999, 121, 10142–10151.
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56. Mahoney, J. M.; Nawaratna, G. U.; Beatty, A. M.; Duggan, P. J.; Smith, B. D. Inorg. Chem. 2004, 43, 5902–5907.
57. Vargas Jentzsch, A.; Emery, D.; Mareda, J.; Metrangolo, P.; Resnati, G.; Matile, S. Angew. Chem. Int. Ed. 2011, 123, 11879–11882.
58. Beer, P. D.; Chen, Z.; Ogden, M. I. J. Chem. Soc. Faraday Trans. 1995, 91, 295–302.
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 3.19 Metal Complexes as Receptors
E Delgado-Pinar, E Garcı́a-España, B Verdejo, and J Pitarch-Jarque, University of Valencia, Valencia, Spain
Ó 2017 Elsevier Ltd. All rights reserved.

3.19.1 Introduction 437

3.19.2 Mononuclear Complexes 442
3.19.2.1 Macrocyclic Ligands 442
3.19.2.1.1 Tetrazacycloalkane derivatives without auxiliary groups 442
3.19.2.1.2 Monocyclic ligands with auxiliary groups within the macrocyclic framework 443
3.19.2.1.3 Macrocyclic cages with auxiliary groups 445
3.19.2.1.4 Mononuclear complexes of macrocycles with pendant arms 447
3.19.2.2 Open-Chain Ligands 449
3.19.2.2.1 Mononuclear complexes of open-chain ligands with auxiliary groups in side chains 449
3.19.2.2.2 Tris(2-Aminoethyl)amine open-chain derivatives 450
3.19.2.3 Ligands of Other Topologies 451
3.19.2.3.1 Ligands based on extended aromatic structures/terpyridine derivatives 451
3.19.2.4 Second Sphere Recognition Induced by First-Sphere Metal Coordination 453
3.19.3 Binuclear Complexes 454
3.19.3.1 Macrocyclic Complexes 454
3.19.3.1.1 Metal complexes of polyazamacrocycles and cryptands as anion receptors 454
3.19.3.1.2 Monocyclic binuclear complexes 455
3.19.3.1.3 Monocyclic binuclear complexes with pendant arms 460
3.19.3.1.4 Tren-derived cryptands 461
3.19.3.2 Open-Chain Ligands 465
3.19.4 Trinuclear Complexes 467
3.19.4.1 Trinuclear Complexes of Macrocyclic Ligands 467
3.19.4.2 Trinuclear Complexes of Open-Chain Ligands 468
3.19.5 Metallocages as Receptors 469
3.19.6 Conclusions and Outlook 474
References 474

3.19.1 Introduction

Complexed metal ions can express their Lewis acid properties when they are coordinatively unsaturated or if they are bound to labile
ligands that can be readily replaced by stronger Lewis bases. In this way, metal complexes can act as anchoring points for the recog-
nition of guest species. These guest species are often anionic in nature although they can be also neutral or even cationic species.
This recognition mechanism is the strategy of choice of many metalloproteins dealing with the fixation and/or activation of
substrates, particularly if the substrate is a small molecule with a large activation barrier.1–3 Classical examples are the proteins
myoglobin and hemoglobin in which penta-coordinated high-spin Fe2 þ centers are, with the aid of other amino acid residues
in their neighborhood, able to momentarily accumulate (myoglobin) or transport oxygen (hemoglobin) (Fig. 1).4 In the latter
case, the transport process needs the cooperative action of the four peptidic chains present in the protein.
Carbonic anhydrases (CAs) constitute another relevant example of the role played by metal coordination sites in biology. CAs
are ubiquitous enzymes which catalyze the reversible hydration of carbon dioxide and play crucial roles in processes as important as
photosynthesis, respiration, calcification, and pH buffering of fluids. Human carbonic anhydrase II (HCA II) is located in the eryth-
rocytes and is the fastest isoenzyme of the family, accelerating CO2 hydrolysis by a factor of 107. The active site of HCA II is formed
by a Zn2 þ metal ion coordinated to three imidazole fragments of different histidine (His) residues and a water molecule.5 The water
molecule is hydrogen bonded to a threonine residue and to a “relays” of water molecules that end up in a histidine (Fig. 2).6 This
histidine assists as a base for the proton removal of the coordinated water molecule. The dissociated proton is transferred through
the “relays” of water molecules. Precisely, this deprotonation and proton transfer process, which leads to the formation of a Zn-OH
nucleophile, is thought to be the rate-limiting step in the mechanism of action of HCA II. The generated Zn-OH species attacks
CO2 to give HCO3  .
Another well-studied Zn2 þ family of mononuclear Zn2 þ proteins is carboxypeptidase A (CPA). CPA is a metaloexopeptidase
found in the pancreas of fish and mammals that operates extracellularly helping to digest proteins in the duodenum. The biological
role of CPAs is the hydrolysis of the peptide bond closest to the C-terminus of the protein, particularly if this amino acid has a bulky
hydrophobic group. A series of asparagine, arginine, and tyrosine residues along with a hydrophobic zone in the active site pocket
contribute to fix the peptide and to select the hydrophobic groups at the C-end of the peptide (Fig. 3).7

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12530-2 437

438 Metal Complexes as Receptors

Figure 1 View of the active center of human hemoglobin. Adapted from Soman, J.; Olson, J. S. in press. PDB 5sw7.

Figure 2 View of the active center of CA II. Adapted from Kim, C. U.; Song, H. J.; Avvaru, B.; Gruner, S.; Park, S. Y.; McKenna, R. Proc. Natl. Acad.
Sci. U.S.A. 2016. PDB 5dsi.

Crystallographic studies revealed the presence in the active site of a Zn2 þ coordinated to two histidine residues, one bidentate
glutamate and a water molecule. Besides, another glutamate residue is hydrogen bonded to the coordinated water helping the
removal of the proton and binding it to give a protonated carboxylic group. The peptide bond needs to be cleaved efficiently
through a concerted nucleophilic and electrophilic attack, which is thought to be carried out by the Zn-OH and protonated
COOH groups, respectively.
Superoxide dismutases (SODs) are the enzymes in charge of the dismutation into dioxygen and hydrogen peroxide of
unbalanced superoxide radical concentrations.8 Mammal SOD II has manganese in its mononuclear center and is located in the
mitochondrion where oxidative phosphorylation occurs; a lack of SOD2 may produce septic shock and lead to the death of the
organism. The coordination geometry is trigonal bipyramidal with three histidine residues, an aspartate, and a water molecule
surrounding the Mn2 þ ion (Fig. 4).9
 Metal Complexes as Receptors 439

Figure 3 View of the active center of CPA. Adapted from Rees, D. C.; Lewis, M.; Lipscomb, W. N. J. Mol. Biol. 1983, 168, 367–387. PDB 5cpa.

Figure 4 View of the active center of Mn-SOD. Adapted from Dennis, R.; Micossi, E.; Mccarthyy, J.; Moe, E.; Gordon, E.; Leonrad, G.; Mcsweeeney,
S. Acta Crystallogr. Sect. F 2006, 62, 325. PDB 2cdy.

The water molecule is hydrogen bonded to a glutamine amino acid that in its turn is further hydrogen bonded to a tyrosine,
which takes part of the door of the access funnel of superoxide to the active center. When the manganese is oxidized to the 3þ state,
the water molecule does not leave the coordination sphere of the metal but it loses a proton, which is then transferred to the super-
oxide anion.
Ribulose 1,5-biphosphate carboxypeptidase (rubisco), the most abundant enzyme in nature, is a magnesium or manganese
protein which is present in all the photosynthetic organisms participating in the first stage of the Calvin cycle. A lysine residue
interacts with CO2 to form an elusive carbamate bond that is further stabilized by interaction with the Mg2 þ ion by a hydrogen-
bond network with other groups of the polypeptidic chain (Fig. 5).10,11
On the other hand, an important number of metalloproteins require the joint action of more than one metal to select and/or
activate their biological target molecules. One typical example of this behavior is enzyme phosphatases in charge of the hydrolysis
of phosphate monoesters. Escherichia coli alkaline phosphatase has two Zn2 þ ions and one Mg2 þ metal ion in the active center
(Fig. 6).12,13
In the first step of the catalytic mechanism, the phosphate group interacts as a bridging m,m0 -bis(monodentate) ligand through
two of its oxygen atoms with the two Zn2 þ ions, the remaining two oxygen atoms of the phosphate form hydrogen bonds with an
arginine residue rightly disposed in the polypeptide chain.
Polynuclear metal complexes are very frequent in the biochemistry of copper. Tyrosinases are binuclear Cu2 þ enzymes that cata-
lyze the conversion of mono-phenols into ortho-quinones via ortho-diphenols, using molecular oxygen, while catechol oxidases
440 Metal Complexes as Receptors

Figure 5 View of the rubisco active site. Adapted from Varaljay, V. A.; Satagopan, S.; Noth, J. A.; Witte, B.; Dourado, M. N.; Anantharam, K.; Arb-
ing, M. A.; McCann, S. H.; Oremland, R. S.; Banfield, J. F.; Wrighton, K. C.; Tabita, F. R. Environ. Microbiol. 2016, 18, 1187–1199. PDB 5c2c.

Figure 6 Details of the active site of alkaline phosphatase. Adapted from Bobyr, E.; Lassila, J. K.; Wiersma-Koch, H. I.; Fenn, T. D.; Lee, J. J.;
Nikolic-Hughes, I.; Hodgson, K. O.; Rees, D. C.; Hedman, B.; Herschlag, D. J. Mol. Biol. 2012, 413, 102–117. PDB 3tg0.

catalyze only the second step. Tyrosinases are essential copper enzymes that occur in all organisms.14,15 They are involved in processes
such as the browning of skin, hair, and fruit as well as in wound healing of the immune response. Tyrosinases and catechol oxidases
belong to the so-called type 3 copper proteins that when the metal ions are in the 2þ oxidation state bound oxygen in a m2,m2-biden-
tate manner, the trigonal bipyramidal coordination sphere of each metal center is completed by histidine residues (Fig. 7).16
Hemocyanine,3 another type 3 copper protein with an identical metal coordination site, performs a different role transporting
dioxygen in arthropods and mollusks. This puts into evidence the role of the indirect ligands and the protein structure in defining
the final function of a metalloprotein.
Copper proteins with higher nuclearities also play fundamental role in copper biochemistry.3 Copper blue oxidases present
a triangular copper site (Type 2/3) and a Type 1 copper center (Fig. 8),17 which take care of the four-electron reduction of dioxygen
into water to oxidize substrates such as ascorbic acid (ascorbate oxidase), phenols and polyphenols (Laccase), Fe2 þ (ceruloplasmine), etc.
Biological systems have served as inspiration for coordination and supramolecular chemists to design simpler, although
sometimes rather intricate, metal sites to recognize and/or activate target guest species.
There are several characteristics that metal recognition sites should meet. The first one is stability; the metal complex should be
stable enough to be present quantitatively in solution. Regarding this point, Fabbrizzi and Poggi, in a review article,18 have analyzed
the ability of the simple [Cu(NH3)4]2 þ complex to form mixed species with halide or pseudohalide anions. Based on distribution
curves, these authors concluded that the ammonia complex is not adequate as an anion receptor because for an 4:1 ammonia:Cu2 þ
 Metal Complexes as Receptors 441

Figure 7 View of the active center of tyrosinase. Adapted from Bijelic, A.; Pretrzler, M.; Molitor, C.; Zekiri, F.; Rompel, A. Angew. Chem. Int. Ed. Engl.
2015, 54, 14677–14680. PDB 5CE9.

Figure 8 View of the triangular copper site type 2/3 of ceruloplasmine. Adapted from Samygina, V. R.; Sokolov, A. V.; Bourenkov, G.; Petoukhov,
M. V.; Pulina, M. O.; Zakharova, E. T.; Vasilyev, V. B.; Bartunik, H.; Svergun, D. I. Plos One 2013, 8, e67145. PDB 4ENZ.

molar ratio the desired [Cu(NH3)4]2 þ complex is only a minor species in water, being present at 7%, whereas [Cu(NH3)3]3 þ is 47%
and [Cu(NH3)2]2 þ would be 41%. Therefore, complexes of ligands of higher denticity would be required for this purpose.
The second one is kinetic inertness, which should apply to the metal complex receptor core but not to the substitution reaction of
the exogenous ligands, substrate capture, and release, which should be as fast as possible. In this respect, complexes of macrocyclic
ligands can be useful since the binding of the metal ion in this type of ligands is kinetically inert. An example is 1,4,8,11-
tetraazacyclotetradecane (cyclam, 1), a ligand imparting high stability and kinetic inertness in their complexes.
The third one is selectivity. In earlier described biological examples, it was apparent that auxiliary ligands in the polypeptidic
chain along with the protein conformation build binding pockets to facilitate the selective uptake and/or activation of the guest
species. In synthetic systems, however, this needs to be achieved through an adequate design of the receptor features such as number
and position of metal sites, presence of functional groups in the ligands, hydrophobic/hydrophilic balance, etc.
In this review, we analyze some relevant examples of synthetic metal-based recognition sites starting with mononuclear
complexes, progressing with binuclear ones to end up with topologically more sophisticated metal sites. The criterion that should
meet all these sites is that the incoming substrate has to coordinate to the metal at some extent. The guest species will span from
simple anions to biological anions as nucleotides. Examples of neutral and cationic guests will be also covered. However, since the
field has experienced an exponential growth in the last years, we would like to apologize for any oversight we may have committed.
Many interesting review articles and books regarding aspects of this chemistry are included in Refs. [19–38].
442 Metal Complexes as Receptors

3.19.2 Mononuclear Complexes

Mononuclear complexes able to work as receptors usually need the aid of auxiliary functionalities built up in the ligand skeleton. In
this respect, Fabbrizzi and Poggi18 described as even though the [Cu(bis-diamine)2]2 þ complexes would have enough stability to be
present in solution as discrete species, studies on the addition of halide anions conducted in MeOH showed little selectivity.
Interestingly, the log K values measured for the addition of the halide anions to the complexes were of the same order of those
measured for the solvated metal ions. The authors concluded that precoordination by a polyamine framework to leave a vacant
position does not importantly affect the affinity of the metal ion for anions, opening the way to the design of more sophisticated
receptors, hopefully able to exerting selective discrimination.

3.19.2.1 Macrocyclic Ligands

3.19.2.1.1 Tetrazacycloalkane derivatives without auxiliary groups
As described earlier, the use of cyclam (1) complexes might be particularly interesting because of their very high stability and
kinetically inertness. Studies on the interaction of the [Cu(1)]2 þ complex with halide anions in water showed, however, no signif-
icant ternary complex formation of Cl and F (log K < 1).18,39 However, appreciable interactions were observed for polyatomic
anions as N3  and NCS, log K ¼ 2.1 and 1.8, respectively. The authors attributed the higher interaction of the polyatomic anions
to their less significant dehydration energy, being its single negative charge spread over three atoms. To increase the affinity for
anions, complexes of tetra-N-methylated cyclam (Me4cyclam, 2) were used.40 N-methylation of 1 leads to a predominant trans-I
configuration of its metal complexes with the methyl groups pointing toward the same side of the macrocyclic plane. At difference
with 1, in which the metal ion fit well within the average plane defined by the nitrogen atoms, in these complexes the metal ions lie
clearly above this plane weakening somewhat the M–N bonds and reinforcing the interaction with exogenous ligands. In particular,
in the Co2 þ and Ni2 þ complexes, the metal–exogenous anion distance is shorter than the average M–N(amine) distances. The
opposite occurs for the Cu2 þ complexes since in this case the apical metal–exogenous anion distance is larger than the M–N(amine)
distances.
The study of the interaction of the linear N3  , NCS, and NCO anions with Co2 þ, Ni2 þ, and Cu2 þ complexes of 2 by visible
spectroscopy denoted, in line with the structural data, the formation of more stable ternary complexes of Co2 þ and Ni2 þ than with
Cu2 þ (Fig. 9).41 Calorimetric studies showed that ternary complex formation was in the case of Co2 þ and Ni2 þ accompanied favor-
able enthalpy and entropy terms. Moreover, the interaction of the [Co(2)]2 þ and [Ni(2)]2 þ complexes with the anion was favored
with respect to the corresponding aqua ions, whereas the opposite behavior was observed for Cu2 þ. It seems that coordination by 2
reduces the endothermic dehydration of the uncomplexed aqueous ion facilitating the interaction with the anion.
Complexes of permethylated tetraza macrocycles are, on the other hand, very useful as peroxidase enzyme mimics since they can
stabilize high oxidation states of the metal in a reversible manner in nonaqueous solvents.42–45 A very nice example of this chem-
istry was the isolation of a mononuclear side-on (h2) Ni3 þ-peroxo complex of 2 (Fig. 9C).46

Figure 9 Chemical structure of 1 and 2. (A) X-ray crystal structure of [Cu(1)(NCS)]þ; (B) [Ni(2)(N3)]þ; (C) [Ni(2)(O2)]þ. Adapted from Micheloni,
M.; Paoletti, P.; Bürki, S.; Kaden, T. A. Helv. Chim. Acta 1982, 65, 587–594; Cho, J.; Sarangi, R.; Annraj, J. S.; Kim, Y.; Kubo, M.; Ogura, T.; Solomon,
E. I.; Nam, W. Nat. Chem. 2009, 1, 568–572; a) Wagner, F.; Mocella, M. T.; D’Aniello Jr., M. J.; Wang, A. H. J.; Barefield, E. K. J. Am. Chem. Soc.
1974, 96, 2625–2627; b) Lu, T.-H.; Tahirov, T. H.; Liu, Y.-L.; Chung, C.-S.; Huang, C.-C.; Hong, Y.-S. Acta Crystallogr., Sect. C: Cryst. Struct. Commun.
1996, 52, 1093–1095.
 Metal Complexes as Receptors 443

Figure 10 Chemical structure of 3 and X-ray crystal structure of the cationic complex [Ni2(3)2(C2O4)]2 þ. Adapted from Bencini, A.; Bianchi, A.; Gar-
cía-España, E.; Jeanin, Y.; Julve, M.; Marcelino, V.; Philoche-Levisalles, M. Inorg. Chem. 1990, 29, 963–970.

On the other hand, [M(1)]2 þ and [Me2cyclen)]2 þ (Me2cyclen ¼ 1,7-dimethyl-1,4,7,10-tetraazacyclododecane, 3) complexes are
able to form sandwich complexes with oxalate anions that behave as a bis-didentate ligand being both cyclam moieties in the
R,R,R,R-conformation (Fig. 10).47,48
In spite of all these findings, the main conclusion drawn from these studies was that monometallic polyamine complexes do not
provide any defined selectivity with anionic guests. The polyamine structure has to be modulated synthetically implementing auxil-
iary groups to achieve high binding constants and selectivity.

3.19.2.1.2 Monocyclic ligands with auxiliary groups within the macrocyclic framework
One way to introduce auxiliary groups is by adding additional donor groups in the macrocyclic structure but keeping them
separated enough to prevent simultaneous coordination to a unique metal ion. Introduction of alkyl or aryl spacers is the most
frequently used strategy.
Cyclophane macrocycles like 4 and 5 (Scheme 1) match this feature. The crystal structure of the Hg2 þ complex of the macrocycle
6 (Fig. 11),49 containing a durene spacer, shows that the coordination of one of the Hg2 þ ions involves one of the benzylic nitrogen
atoms and the amino groups at the center of the chain. Geometric reasons prevent the other benzylic nitrogen atom from partici-
pating in the binding of the same metal ion. Calorimetric and other solution studies confirmed similar features for the mononuclear
Cu2 þ and Zn2 þ complexes of the macrocycles 4 and 5. Therefore, also in these compounds one of the benzylic nitrogen atoms
would not participate in the coordination of the metal ion, presenting the metal ions unsaturated coordination sites.50–53

Scheme 1 Chemical structure of 4, 5, and 6.

Figure 11 X-ray crystal structure of the neutral complex [Hg2(6)Cl4]. Adapted from García-España, E.; Latorre, J.; Luis, S. V.; Miravet, J. F.;
Pozuelo, P. E.; Ramírez, J. A.; Soriano, C. Inorg. Chem. 1996, 35, 4591–4596.
444 Metal Complexes as Receptors

Figure 12 Percentage of carbonate bound to free 5 and to the Cu2 þ and Zn2 þ solutions at pH values 7, 8, and 9. Adapted from Andrés, S.;
Escuder, B.; Doménech, A.; García-España, E.; Luis, S. V.; Marcelino, V.; Llinares, J. M.; Ramírez, J. A.; Soriano, C. J. Phys. Org. Chem. 2001, 14,
495–500.

Figure 13 (A) Chemical structure of 7. (B) Crystal structure of the [(Zn(7))3(m3-CO3)]4 þ cation. Adapted from Bazzicalupi, C.; Bencini, A.; Bencini,
A.; Bianchi, A.; Corana, F.; Fusi, V.; Giorgi, C.; Paoli, P.; Paoletti, P.; Valtancoli, B.; Zanchini, C. Inorg. Chem., 1996, 35, 5540–5548.

The ability of these complexes to bind additional guests, particularly carbon dioxide, was investigated. Potentiometric titrations
of aqueous solutions containing the Cu2 þ and Zn2 þ metal complexes of 4 and 5 and carbonate at basic pH were titrated with
perchloric acid.51 It was possible to follow the measurements until pH 7. Below this pH, CO2 evolution was prevented from obtain-
ing stable readings. The measurements were also performed for the binary system receptor-carbonate. Comparison between the two
systems evidenced, particularly in the case of the Zn2 þ, a clear increase the percentage of complexed carbonate in the presence of the
metal ions (Fig. 12).
An interesting example of CO2 uptake by a synthetic metal complex mimicking the mechanism of CA is provided by the ligand 7
(Fig. 13).54 Both Zn2 þ and Cu2 þ complexes with 7 readily adsorb atmospheric CO2 in water at alkaline pH, giving rise to
{[M(7)]3(m3-CO3)}$(ClO4)4 (M ¼ Zn2 þ, Cu2 þ) complexes. The complexes are isomorph and their molecular structures show
the m3 CO3 2 anion bridging the three metal ions through the three oxygen atoms of the carbonate group (Fig. 13). Related
work in this field is included in Refs. [55,56].
The CO2 uptake by these M-7 complexes is very fast in comparison with other metal complexes that can fix CO2 from the air. The
fixation is due to the presence of solution of [M(7)OH]þ species, which act as nucleophiles toward CO2, giving rise to
[M(7)(HCO3)]þ complexes. Further reaction with [M(7)(OH)]þ species forms the trinuclear complexes, which can be isolated
in very high yields.
In the case of the Zn2 þ complex, the first step, namely the reversible formation of a hydrogen carbonate adduct, which equilibrates
with an aquo-Zn2 þ complex and HCO3  (Scheme  2), resembles the mechanism currently accepted for hydration of CO2 by CA.
Furthermore, the constant for the equilibrium Znð7Þ2þ þHCO3  % Znð7ÞðHCO3 Þþ (log K ¼ 2.2) is similar to that found for CA.
Compounds somewhat mimicking the active site of rubisco were prepared to achieve atmospheric CO2 fixation at neutral pH. The
assistance of the metal ion as Lewis acid, the presence of the basic lysine residue for forming the carbamate bond, and the presence
of other groups able to participate in a hydrogen-bond network with the fixed carbon dioxide are, as advanced in the introduction
 Metal Complexes as Receptors 445

Scheme 2 Proposed mechanism for the CO2 hydration promoted by [Zn(7)]2 þ.

Scheme 3 Chemical structure of 8 and 9.

Figure 14 Schematic representation of the cations [Cu(H8)(H2O)(carb)]3 þ (carb ¼ carbamate) and [Cu2(H28)(CO3)(H2O)(ClO4)2]2 þ. Adapted from
García-España, E.; Gaviña, P.; Latorre, J.; Soriano, C.; Verdejo, B. J. Am. Chem. Soc. 2004, 126, 5082–5083.

section, key features for the recognition and activation of carbon dioxide by this enzyme. Following these ideas, a macrocycle
containing the coordinating spacer 2, 20 :60 , 200 -terpyridine connected at its 5, 500 positions through methylene groups to the highly
basic polyamine bridge 1,5,8,11,15-pentaazapentadecane (8, Scheme 3) was prepared.57
Interestingly enough, dilute aqueous solutions of this ligand and Cu(ClO4)2$6H2O in 1:1 molar ratio at pH 9 exposed to an
open-air atmosphere yielded after a few minutes acidification down to pH 6.8 and formation of a crystalline material suitable
for the X-ray analysis. The crystals contained carbamate groups bound to the Cu2 þ metal ion and further stabilized by an intramo-
lecular hydrogen-bond network that involved amino and ammonium groups of the bridge and the water molecule coordinated to
the metal ion (Fig. 14).
When the Cu2 þ:8 molar ratio was 2:1 instead of 1:1, carbon dioxide reacted with the binuclear center giving a carbonate h1,h1-
bridging ligand. Potentiometric studies proved that the species precipitating at neutral pH were among those existing in aqueous
solution at this pH. Interestingly enough, this behavior was not reproduced when terpyridine was either removed from the ligand or
replaced by a pyridine unit.58 When phenanthroline (9, Scheme 3) was used instead of terpyridine, there were indications of
carbamate formations although the behavior was not as remarkable as in the case of 8. The Lewis acid assistance can be afforded
by other metal ions. Potentiometric, Nuclear Magnetic Resonance (NMR), and UV–Vis spectroscopic studies have proved that Zn2 þ
plays a similar role to Cu2 þ.59,60

3.19.2.1.3 Macrocyclic cages with auxiliary groups

A second way to introduce auxiliary groups is to change the ligand topology. The introduction of additional bridges in the ligand
permits to include new functionalities in them. Vieri et al. reported an example of this strategy a few years ago.61 These authors
described the synthesis and characterization of a macrocyclic ligand with a cage topology, derived from the Me2[12]aneN4 (3)
macrocycle, in which two opposite nitrogen atoms were bridged by a chain containing two squaramide moieties (10) (Fig. 15).
446 Metal Complexes as Receptors

Figure 15 Chemical structure of 10 and schematic representation of the complex cations (A) [Cu(10)(F)]þ and (B) [Cu(10)(Cl)]þ, highlighting
contacts involving the halide ions. Adapted from Ambrosi, G.; Formica, M.; Fusi, V.; Giorgi, L.; Guerri, A.; Micheloni, M.; Paoli, P.; Pontellini, R.;
Rossi, P. Chem. Eur. J. 2007, 13, 702–712.

This ligand forms mononuclear Cu2 þ complexes involving the four nitrogen atoms of the macrocyclic core. The bridge containing
the squaramide moieties, not implicated in the coordination to the metal ion, forms an overstructure rich in hydrogen-bonding
donor groups that allows the interaction with different hydrogen-bond acceptors. Taking advantage of these features, the
[Cu(10)]2 þ species was studied as a host for halide ions by means of UV–visible spectroscopy. It was observed that the
[Cu(10)]2 þ species binds F, Cl, and Br to form ternary [Cu(10)X]þ species, but does not bind I.
The X-ray crystal structures obtained for the [Cu(10)F]þ and [Cu(10)Cl]þ species show the metal ion inside the cavity coordi-
nated by the nitrogen atoms of the macrocyclic base and by the halide ion that interacts through a hydrogen-bond network with the
amide functions of each squaramide moiety (Fig. 15). The same authors performed related studies for the recognition of halides
with mononuclear zinc complexes.62 The Zn2 þ-10 system is able to interact with chloride and fluoride at the physiologically
relevant pH 7.4.
García-España et al. recently reported an example of a metal-assisted anionic receptor induced by coordination of metal ions. In
this article, the authors describe the synthesis of a [1 þ 1] azamacrocycle in which a 1H-pyrazole spacer is connected to the tetramine
1,5,9,13-tetrazatridecane (3.3.3-tet) through methylene spacers (11) (Fig. 16).63 Upon addition of 1 equiv. of Cu2 þ, two

Figure 16 Chemical structure of 11. (A) Schematic representation of the cation [Cu3(H 1(11))2(CO3)(H2O)]2 þ. (B) View highlighting with different
colors the two macrocycles present in the X-ray structure. Adapted from Belda, R.; Pitarch-Jarque, J.; Soriano, C.; Llinares, J. M.; Blasco, S.;
Ferrando-Soria, J.; García-España, E. Inorg. Chem. 2013, 52, 10795–10803.
 Metal Complexes as Receptors 447

Figure 17 Chemical structure of 12 and X-ray crystal structure of (A) [H2(12)3(H2O)1.5]2 þ and (B) [Cu(12)(H2O)]2 þ. Adapted from Chand, D. K.;
Bharadwaj, P. K. Inorg. Chem. 1996, 35, 3380–3386; Chand, D. K.; Bharadwaj, P. K. Inorg. Chem. 1998, 37, 5050–5055.

macrocyclic units stick together through the pyrazole nitrogen atoms and the adjacent secondary amine groups leaving free the other
four amino groups; two in each one of the chains. It was observed that the free amines of one of the chains incorporate another
Cu2 þ and this mononuclear center interacts very strongly with carbon dioxide which is fixed as a bidentate carbonate anion.
The crystal structure of [Cu3(H 1(11))2(CO3)(H2O)](ClO4)2$8H2O shows all these features (Fig. 16).
An earlier example of water recognition by a metal complex is the cryptand developed by Chand and Bharadwaj (12)
(Fig. 17).64,65 This ligand coordinates a Cu2 þ at the tris(2-aminoethylamine) (tren) moiety of the cavity to form mononuclear
complexes. The crystal structure of the complex [Cu(12)(OH2)](picrate)2$H2O revealed that the oxygen atom of a water molecule
is strongly bonded to the metal ion inside the cavity, while its hydrogen atoms presented H-bonding interactions with two of the
benzene rings of the cryptand. Moreover, treatment with HCl or HClO4 promoted the diprotonation of the ligand and the binding
of two water molecules inside the cavity. This cryptate was the first X-ray crystallographically characterized complex,
[H2123(H2O)1.5]$(ClO4)2$(H2O)0.75, with two water molecules inside the cavity of the cryptand.

3.19.2.1.4 Mononuclear complexes of macrocycles with pendant arms

Very often the auxiliary functions are introduced in lateral chains appended to the ligands.66–76 For example, Licchelli et al. have
used this design to exploit the hydrogen-bond-forming abilities of urea moieties as auxiliary groups in the recognition of anionic
species. These authors reported the synthesis of two novel macrocyclic compounds, 13 and 14, in which one or two genuine urea
fragments were appended onto an azacyclam or a diazacyclam structure, respectively (Fig. 18).66
In principle, these compounds could make full use of the hydrogen-bond-forming abilities of the urea subunits, along with the
metal–ligand interaction, in the recognition process.
The interaction of different anionic species such as carboxylates and phosphates with both ligands was investigated by spectro-
photometric titrations carried out in acetonitrile. The stability constants of the adducts are considerably higher than the ones
determined for the interaction of the same anions with plain urea, confirming the synergistic action of the metallomacrocyclic

Figure 18 (A) Chemical structure of 13 and 14. (B) Schematic representation of the cation [Cu(14)]2 þ interacting with succinate. Adapted from
Boiocchi, M.; Licchelli, M.; Milani, M.; Poggi, A.; Sacchi, D. Inorg. Chem. 2015, 54, 47–58.
448 Metal Complexes as Receptors

Figure 19 (A) Chemical structure of 15. (B) Schematic representation of the cation [Eu(15)(F)]2 þ. Adapted from Tripier, R.; Platas-Iglesias, C.;
Boos, A.; Morfin, J.-F.; Charbonnière, L. Eur. J. Inorg. Chem. 2010, 27352745.

Figure 20 (A) Chemical structure of 16. (B) Schematic representation of the cation [La(16)(Cl)]2 þ. Adapted from Lima, L. M. P.; Lecointre, A.; Mor-
fin, J.-F.; de Blas, A.; Visvikis, D.; Charbonnierè, L. J.; Platas-Iglesias, C.; Tripier, R. Inorg. Chem. 2011, 50, 1250812521.

and the urea subunits. The crystal structure of the bis-urea derivative copper complex with succinate shows two anions bound by the
metal ion and one urea moiety, providing a scorpionate-like structure (Fig. 18). Recently, the same group has reported related anion
coordination studies using copper complexes of nitrophenyl substituted cyclams.72
Tripier et al. have reported another related approach.73 These authors analyzed the binding properties of different lanthanide
complexes (Ln3 þ ¼ Eu, Tb, and La) of a cyclen-based receptor having trans-disposed 2-methylpyridyl and N-[2-(2-
hydroxyethoxy)-ethyl]acetamide pendant groups (15). The [Ln(15)(H2O)]3 þ complex interacts selectively with F over Cl or
Br in buffered aqueous solutions. The stronger F binding observed in solution was most likely attributed to supplementary inter-
actions such as the C–H/F hydrogen bonding observed in the solid state (Fig. 19). The F replaces the apical water molecule
yielding drastic changes in the luminescence spectrum of the Eu3 þ complex.
The pyridine rings in 15 play an important role in anion recognition since the interaction with fluoride of the europium complex
of a cyclen derivative containing only N-[2-(2-hydroxyethoxy)ethyl]acetamide pendants arms (16)74 (Fig. 20) has a much lower
constant (log K ¼ 1.4  0.1 compared with log K ¼ 2.83  0.01 for [Eu(15)]3 þ).
In a separate publication, Fabbrizzi has reported the synthesis of a multicomponent coordination assembly 17 that can be
electrochemically switched between two different forms.75 Complex 17 consists of two four-coordinate Ni2 þ cyclam-like mac-
rocycles each one attached to a separate bipyridine fragment that is coordinated to a single Cu2 þ metal ion. Inorganic anions
(N3  , NCO, NCS) can displace the water molecule bound to the Cu2 þ center to form complex 17a (Fig. 21). The nickel
centers are then oxidized electrochemically to Ni3 þ, an oxidation state that requires a further ligand in the axial position.
Different pulse voltammetry experiments showed that the anion coordinated to the Cu2 þ center jumps across and coordinates
to the Ni3 þ forming 17b (Fig. 21). Therefore, a precise electrochemical control could be exerted over the position of the anion
in this complex.
Recently, Bencini et al. have described an interesting receptor obtained by assembling an iminodiacetic fragment, as a Zn2 þ
binding site, with a polyamine macrocyclic portion containing two trans-1,2-diaminocyclohexane units and a pyrrole ring, as
a cationic binding site (18).76 Potentiometric measurements together with 1H and 31P NMR investigation showed that, in
a wide pH range including values of physiological interest, the Zn2 þ is bound to the carboxylate and to the tertiary amino
group while the macrocycle is in its diprotonated form. Making use of the vacant coordination sites in the Zn2 þ coordination
sphere and of the protonated macrocycle, this system binds di- and triphosphates, such as adenosine diphosphate (ADP),
adenosine triphosphate (ATP), inorganic pyrophosphate (PPi), and triphosphate (TP), far better than monophosphate
(MP). The authors claimed that this receptor showed the highest binding affinity reported to date for Zn2 þ complexes in water
(Fig. 22).
 Metal Complexes as Receptors 449

Figure 21 Schematic representation of the redox process associated to complex 17. Adapted from DeSantis, G.; Fabbrizzi, L.; Iacopino, D.; Pallavi-
cini, P.; Perotti, A.; Poggi A. Inorg. Chem. 1997, 36, 827–832.

Figure 22 Schematic representation of the ternary complex [Zn(H218)(HP2O7)]. Adapted from Francesconi, O.; Gentili, M.; Bartoli, F.; Bencini, A.;
Conti, L.; Giorgi, C.; Roelens, S. Org. Biomol. Chem. 2015, 13, 1860–1868.

3.19.2.2 Open-Chain Ligands

3.19.2.2.1 Mononuclear complexes of open-chain ligands with auxiliary groups in side chains
The use of open-chain ligands as receptors has become very popular in recent years due to their easy preparation with respect to
macrocyclic receptors as well as to the facility with which they can be functionalized.
In this respect, Esteban-Gómez et al. have reported the synthesis of a ditopic receptor containing a bis(2-picolyl)amine unit for
cation binding and a urea moiety for anion recognition (19).77 The analysis of the interaction of the Cu2 þ and Zn2 þ complexes with
different oxo- and halide anions in DMSO revealed the formation of 1:2 metal complex/anion ternary complexes. In the case of
SO4 2 and Cl, a cooperative binding mode is observed, that is, the simultaneous coordination of the anion to the metal ion
and to the urea moiety through hydrogen-bonding interactions (Fig. 23). However, for anions like NO3  and PhCO2  ,

Figure 23 (A) Chemical structure of 19. (B) X-ray crystal structure of the [Cu(19)(H2O)(SO4)] complex. Adapted from Carreira-Barral, I.; Rodríguez-
Blas, T.; Platas-Iglesias, C.; de Blas, A.; Esteban-Gómez, D. Inorg. Chem. 2014, 53, 2554–2568.
450 Metal Complexes as Receptors

Figure 24 (A) Chemical structure of 20. (B) X-ray crystal structure of the [(Zn(20))2(SO4)2] complex. Adapted from Ghosh, T. K.; Dutta, R.; Ghosh,
P. Inorg. Chem. 2016, 55, 36403652.

Figure 25 Schematic representation for the binding mode between 21, Zn2 þ, and ATP. Adapted from Rao, A. S.; Kim, D.; Nam, H.; Jo, H.; Kim, K.
H.; Ban, C.; Ahn, K. H. Chem. Commun. 2012, 48, 3206–3208.

noncooperative binding modes are observed. Thus, first anion coordinates only to the metal ion, while the second anion interacts
with the urea moiety through hydrogen-bonding interactions.
Ghosh et al. developed a related ditopic receptor exhibiting metal ion and anion binding features.78 The ligand was prepared
with a bis(2-picolyl)amine as metal-binding unit and a pendant tertiary-butyl urea group as anion recognizing unit. This receptor
showed selective trapping and separation of metal sulfates as sulfate-bridged bimetallic ion pairs from aqueous and semi-aqueous
solutions. The dimeric assembly of metal sulfates with the receptor observed in the crystal structures is supported in solution by
Isothermal Titration Calorimetry (ITC) and 1H DOSY NMR spectroscopy (Fig. 24).
Ahn et al. reported a mononuclear zinc complex based on 6-acetyl-2-(dimethylamino)naphthalene (acedan) as a two-photon
fluorophore, which shows significant fluorescence enhancement upon binding nucleoside polyphosphates such as ATP and ADP
under physiological conditions (Fig. 25).79 The probe (21) shows significant fluorescence enhancement upon interaction with
ATP or ADP among various anions examined including PPi and adenosine monophosphate (AMP). The fluorescence and 1H
NMR studies suggest that p–p interaction between the fluorophore and the nucleobase is also responsible for the analyte selectivity.

3.19.2.2.2 Tris(2-Aminoethyl)amine open-chain derivatives

Tris(2-aminoethyl)amine (tren) is a frequently used building block in receptor chemistry. This ligand tends to impart trigonal
bipyramidal coordination environment in metal binding, particularly for Cu2 þ, so that a coordination position is occupied by
a solvent molecule or a labile ancillary ligand.
In the complex [Cu(22)]2 þ shown in Fig. 26, the axial position is occupied by the nitrogen atom of the azide anion, N3  .80 The
structure illustrates a unique feature of recognition based on metal–ligand interactions: directionality. More examples of azide
binding by mononuclear complexes can be found in Refs. [81–83]. Moreover, auxiliary groups can be added to the arms of the
tripodal polyamine to assist the bound metal in the recognition of different guest species.
An interesting example of this approach was reported by Tobey and Anslyn a few years ago.84 These authors linked benzylamine
groups to the arms of a tren unit (23). The Cu2 þ complex of this receptor seemed to exhibit recognition of hydrogenphosphate
anions over other anions of different shapes and sizes (Fig. 27). The same authors reported a related ligand in which guanidinium
moieties were added to a tris[(2-pyridyl)methyl]amine fragment (24) (Fig. 28). Although this receptor also showed high affinity for
phosphate in water at neutral pH, the reaction was enthalpy driven contrarily to the ligand with benzylamine, for which it was
entropy driven. The high affinity and selectivity for phosphate allowed the authors to develop a dye displacement assay for the
quantification of phosphate levels in horse serum and saliva.85
Fabbrizzi et al. reported a receptor containing two separate compartments suitable for the interaction with a pair of anions of
either the same or different nature.86 In particular, they designed a tripodal system, in which a nitrophenyl-urea subunit was linked
 Metal Complexes as Receptors 451

Figure 26 Directionality of metal–ligand interactions in the azide-mixed complex of [Cu(22)]2 þ. Adapted from Sardone, N.; Pallavicini, P. unpub-
lished results.

Figure 27 Chemical structure of 23 and schematic representation of the interaction its Cu2 þ complex with hydrogenphosphate. Adapted from
Tobey, S. L.; Anslyn, E. V. Org. Lett. 2003, 5, 2029–2031.

Figure 28 Chemical structure of 24 and schematic representation of the interaction its Cu2 þ complex with hydrogenphosphate. Adapted from
Tobey, S. L.; Jones B. D.; Anslyn, E. V. J. Am. Chem. Soc. 2003, 125, 4026–4027.

to each terminal amine group of a tren platform (25). It was observed that coordination of the metal ion by the tren subunit pre-
organizes the ligand for the interaction with one pair of anions. The first interaction site is available on the axial position of the
[Cu(tren)]2 þ moiety (X ¼ halide, N3  , NCS, NO2  , H2 PO4  ) (Fig. 29). Then, the second anion X interacts with the trisurea
cavity, but this occurs only with the stronger H-bond acceptors, such as N3  and H2 PO4  . Binding of the second anion is favored
by the preorganizing effect exerted by the metal and disfavored by the steric and electrostatic repulsions between the anions.

3.19.2.3 Ligands of Other Topologies

3.19.2.3.1 Ligands based on extended aromatic structures/terpyridine derivatives
Terpyridines are extensively used to complex transition metal ions and might serve as building blocks for supramolecular gel
systems.87 Rissanen et al. have studied the interaction of a mononuclear Zn2 þ complex of a terpyridine derivative (26) with anions
in water (Fig. 30).88 Both UV–Vis and emission spectroscopy carried out in a HEPES-buffered solution (HEPES, 4-(2-hydroxyethyl)-
1-piperazinethanesulfonic acid) at pH 7.4 showed no significant changes upon the addition of F, Br, I, SO4 2 , AcO, NO3  ,
CO3 2 , and MP anions.
However, a sharp bathochromic shift of the maximum absorption band centered at 410 nm was observed upon the addition of
PPi and TP mononucleotides. Interestingly, an unprecedented  500-fold enhancement in fluorescence intensity of [Zn(26)Cl2] was
observed at 591 nm upon addition of 50 mM of PPi but no changes were observed in the presence of the nucleotides. Job plots
revealed that the ZnL complex forms with PPi a 3:1 ternary complex; a possible structure of this complex is depicted in Fig. 30.
The sharp change in luminescence allows to reach a detection limit for PPi of z20 nM. The excellent sensitivity of [Zn(26)Cl2]
for PPi permitted to map entire cells for the presence of this anion, even regions with minimal PPi concentrations, what converts
this chemosensor in a good alternative for using it in diagnosis and other clinical applications.
452 Metal Complexes as Receptors

Figure 29 Cascade mechanism for the formation of the heterodianionic complex [Cu(25) (X/Y)]. Adapted from Allevi, M.; Bonizzoni, M.; Fabbrizzi,
L. Chem. Eur. J. 2007, 13, 3787–3795.

Figure 30 Schematic illustration for the binding mode between 26, Zn2 þ, and PPi. Adapted from Ghosh, B. N.; Bhowmik, S.; Mal, P.; Rissanen, K.
Chem. Commun. 2014, 50, 734–736.

Very recently, Zhang et al., by following this approach, synthesized a new coumarine-based terpyridine ligand (27) for sensing
PPi through the formation of a [(Zn(27))2PPi] ternary complex (Fig. 31).89 This complex was successfully applied to fluorescence
imaging of PPi in Hi-5 cells and Caenorhabditis elegans, demonstrating its utility as a fluorescent sensor for detecting PPi in in vivo
imaging.
Functional molecular gels represent one kind of smart soft matter, which recently have exhibited potential as a valuable platform
for molecular recognition. In this sense, in 2005 Hamachi and coworkers first applied molecular organo-hydrogels as efficient
supports to immobilize an artificial sensor for phosphate derivatives.90 Liu and coworkers took into account these results and
reported the visual discrimination of ATP in preference to ADP and AMP via cationic organogel collapse in alcoholic aqueous
media, although the limit of detection was relatively high (6.25  10 3 M).91 The research work developed by Tu and coworkers
is based on the use of a simple zinc-terpyridine mononuclear complex [Zn(28)]2 þ able to recognize ATP via a selective coordination
assembly, which derives in the formation of a two-component metallohydrogel (Fig. 32).92
The authors concluded that the selective metallohydrogel formation is achieved by a molecular self-assembly process. By
performing fluorescence spectroscopy and Density Functional Theory (DFT) calculations, they proposed that the driving forces
of the process are: (1) the coordination ability of the phosphate group to interact with the zinc center; (2) the intramolecular
p–p stacking between the planar nucleobases of ATP; (3) the metallohybrid aromatic ring of the complex. This selective recognition
is achieved with a remarkable 44-fold enhancement of the fluorescence emission, providing a new approach for selective ATP
discrimination. Since the cytotoxicity of this zinc pincer complex is relatively low, it was applied to monitor ATP in HeLa cells.
The authors concluded that metallogel formation could be considered as a visible, practical, and reliable in vitro rehearsal toward
cellular imaging.
 Metal Complexes as Receptors 453

Figure 31 Schematic illustration for the proposed binding between 27, Zn2 þ, and PPi. Adapted from Zhaoa, R. R.; Xub, Q. L.; Yanga, Y.; Caoa, J.;
Zhoua, Y.; Xub, R.; Zhang, J. F. Tetrahedron Lett. 2016, 57, 5022–5025.

Figure 32 Visual discrimination of ATP out of its homologs via selective gel formation. Adapted from Fang, W.; Liu, C.; Yu, F.; Liu, Y.; Li, Z.; Chen,
L.; Bao, X.; Tu, T. ACS Appl. Mater. Interfaces 2016, 8, 20583–20590.

Scheme 4 Chemical structure of 29.

The group of Abarca and coworkers have prepared tridentate ligands based on the triazolopyridine–pyridine nucleus during the
last decade. These systems possess fluorescent properties, and have been tested as chemosensors for metal ions and anions.93 The
ring-chain isomerization of [1,2,3]triazolo[1,5-a]pyridines or [1,2,3]triazolo[1,5-a]quinolines has been efficiently employed as
a tool to provide tridentate fluorescent structures (Scheme 4). Based on these scaffolds, the authors synthesized a new family of
highly fluorescent compounds and evaluated them for the recognition of zinc or copper cations. The 1:1 [Zn(29)]2þ complex of
a naphthalene triazolopyridine–pyridine derivative revealed high efficiency as sensor for anions, providing large binding constants
for nitrite and cyanide.

3.19.2.4 Second Sphere Recognition Induced by First-Sphere Metal Coordination

In spite of the fact that in these systems there is not a direct metal–substrate interaction, in this section we have highlighted a couple
of examples in which the coordination of the metal ion in the first sphere preorganizes the second sphere groups for substrate
binding (Fig. 33).22
Regarding this approach, Loeb, Gale et al. developed a simple monodentate ligand 30 based on an iso-quinoline ring system.
The coordination of an inert Pt2 þ center to four ligands arranges four urea groups, one in each ligand, into a single binding site.
Strong 1:1 interactions were observed in solution for halides and symmetrical oxoanions. The crystal structure of the [Pt(30)4]
SO4 complex shows that the metal coordination directs all eight NH donors from the four urea functional groups toward the
454 Metal Complexes as Receptors

Figure 33 Schematic representation of the preorganization of the second sphere by the first-sphere coordination. Adapted from Mercer, D. J.;
Loeb, S. J. Chem. Soc. Rev. 2010, 39, 3612–3620.

Figure 34 X-ray crystal structure of [Pt(30)4]SO4. Adapted from Bondy, C. R.; Loeb, S. J.; Gale, P. A. Chem. Commun. 2001, 729–730.

incoming anion which is nestled into the binding pocket (Fig. 34).94–96 The X-ray crystal structure of the complex [Pt(30)4]SO4
shows that eight independent NH/O urea–anion interactions in the second sphere of coordination are shown as dashed lines.
Another example of this approach was reported by Wu and coworkers.97 The authors synthesized the simple pyridylurea ligand
31 that assembles into a hexameric capsule, directed by the coordination of six Cu2 þ ions, which can encapsulate sulfate anions
with six urea groups. The sulfate inclusion complex was generated by the reaction of CuSO4$5H2O with 3 equiv. of 31 in N,N-
dimethylformamide (DMF). The resulting complex provided single crystals suitable for X-ray analysis. The crystal structure contains
two kinds of Cu2 þ environments, designated as [Cu1] and [Cu2]. The [Cu1] moieties are octahedrally coordinated by six ligand
molecules forming two inversion-related C3-symmetric clefts. The sulfate anion is positioned within a cavity formed by two
such complex units and coordinated by six urea groups, and the capsules further extend into a 1D chain (Fig. 35). Meanwhile,
the [Cu2] moieties are chelated by two ligands and two DMF molecules, and adopt a Jahn–Teller distorted octahedral geometry.

3.19.3 Binuclear Complexes

3.19.3.1 Macrocyclic Complexes
3.19.3.1.1 Metal complexes of polyazamacrocycles and cryptands as anion receptors
As mentioned in the general introduction, the use of more than one metal center is the preferred choice of many metallobiomo-
lecules. In this way, both metal ions can complement each other to achieve better performances not only in recognition but also
in activation, signaling, or transport properties.
 Metal Complexes as Receptors 455

Figure 35 Chemical structure of 31. Schematic crystal structure of the [Cu1] fragment in the Cu2 þ complex of 31. Adapted from Yang, Z.; Wu, B.;
Huang, X.; Liu, Y.; Li, S.; Xia, Y.; Jia, C.; Yang, X.-J. Chem. Commun. 2011, 47, 2880–2882.

Figure 36 Representation of the cascade complex formation for a binuclear complex. Adapted from Lehn, J.-M. Supramolecular Chemistry, Concepts
and Perspectives; VCH: Weinheim, 1995.

The term cascade was coined by Lehn to describe systems in which the substrate binding steps are not commutative but follow
a given sequence. For instance, if a receptor takes up two metal ions and a bridging ligand, the metal ions should bind first to allow
the bridge to be established between them.31,98 Cascade systems oppose to cosystems in which the binding of several substrates is
commutative, namely, it does not require a given sequence (Fig. 36).
The assistance of the second metal can have important implication in selection. The distance between the metal centers can be
regulated by the design of the ligand generating bite discrimination (vide infra). Several examples of this behavior are described in
the next paragraphs.

3.19.3.1.2 Monocyclic binuclear complexes

Binuclear complexes of monocyclic ligands have been extensively used to recognize substrates connected to the metal centers either
as monodentate or as bridging ligands. Pioneering works in the field regard the macrocycle bisdien,99,100 in which two diethylenetri-
amine subunits (dien) are separated by diethyl ether spacers (32) (Scheme 5).
Each dien subunit binds one metal ion leaving vacant positions in the coordination sphere so that the metal centers are able to
lodge guest species. The Cu2 þ–Cu2 þ distance in the binuclear complex along with the possibility of the ether oxygen atom to make
hydrogen bonds makes this complex particularly prone to bind a hydroxo anion as a bridging ligand with a high stability constant
(log K ¼ 7.27). On the other hand, the flexibility of the macrocycle permits the interaction of its binuclear complexes with other
substrates as imidazolate which is also bound as a bridging ligand. The crystal structures of both these system are shown in
Fig. 37.101,102 Some other examples of X-ray crystal structures of binuclear complexes of monocyclic ligands containing hydroxo
bridges are mentioned in Refs. [103–105].
To modulate the distance between the metal centers to make recognition sites for substrates as phosphates, a,u-dicarboxylates,
mononucleotides, etc., the diethyl ether spacers in 32 were replaced by different aryl spacers.28,106 Other approaches to change the
stability of the binuclear complexes and their affinity for the guest species have consisted in either the methylation of the amine
groups of dien or the replacement of this subunit by dipropylenetriamine units (Scheme 6).

Scheme 5 Chemical structure of 32.

456 Metal Complexes as Receptors

Figure 37 X-ray crystal structure of [Cu2(32)(m-OH)(m-ClO4)]2 þ and [Cu2(32)(m-im)(im)2](ClO4)2. Adapted from Coughlin, P. K.; Lippard, S. J.
J. Am. Chem. Soc. 1981, 103, 3228–3229; Coughlin, P. K.; Dewan, J. C.; Lippard, S. J.; Watanabe, E.; Lehn, J. M. J. Am. Chem. Soc. 1979, 101, 265–
266.

Scheme 6 Chemical structure of several 32 derivatives.

An example of coordination of sulfate as a monodentate anion to each one of the Cu2 þ centers of a binucleating ligand was
reported for the ligand having m-xylene spacers (33) (Fig. 38).107
An interesting example described by Bianchi, García-España et al. regards the ditopic macrocyclic receptor 34, which forms
binuclear Cu2 þ complexes with coordinatively unsaturated sites (Fig. 39). Due to the presence of the reinforcing piperazine rings,
34 is a quite rigid receptor that has a fixed distance between the coordination centers. This characteristic was used for discriminating
between long and short a,u-dicarboxylates.108
The five carbon atoms in the chain of pimelic acid seemed to be appropriate for permitting a nonstressed bridging coordination
of the dianion between both metal sites as shown by the crystal structure collected in Fig. 39.
In this system, a clear switch from supramolecular interaction mode (Fig. 40A) of the carboxylate with the extensively proton-
ated demetallated macrocycle to coordinative interactions (Fig. 40C) with the binuclear metal complex going through a mixed
supramolecular/coordinative mode (Fig. 40B), in which both situations are present when the mononuclear species prevail in
solution, occurred on increasing the pH.
Discrimination between glutamic and aspartic amino acids using monocyclic ligands by means of their complexation was
reported by García-España et al.109 A detailed analysis of the potentiometric studies revealed that the binuclear Cu2 þ complex
of this hexaza pyridinophane macrocycle (35) could accommodate better L-glutamate than L-aspartate as a bridging ligand between
the metal centers, forming cascade complexes (Fig. 41). The paramagnetic 1H NMR studies supported the amino acid binding
through the two carboxylate groups (Cu–O–O–Cu ligation mode). Moreover, the alteration of the voltammetric response of the
Cu2 þ complex in the presence of glutamic acid permitted its electrochemical sensing.
More recently, these authors synthesized a new pyridinophane containing a complete sequence of propylenic chains
(Scheme 7).110 The acid–base behavior and Cu2 þ and Zn2 þ coordination of this and other related receptors were analyzed by
potentiometric titrations and UV–Vis spectroscopy. The number of nitrogen donor atoms in these receptors allows the coordination
of two metal ions with unsaturated coordination sites. This contributes to the recognition and/or activation of additional guests as
 Metal Complexes as Receptors 457

Figure 38 X-ray crystal structure of [Cu2(33)](SO4)2. Adapted from Nation, D. A.; Reibenspies, J.; Martell, A. E. Inorg. Chem. 1996, 35, 7246–7252.

Figure 39 X-ray crystal structure of the cation [(Cu2(34)(H2O)2)Pim]2 þ. Adapted from Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Fusi, V.; García-
España, E.; Giorgi, C.; Llinares, J. M.; Ramírez, J. A.; Valtancoli, B. Inorg. Chem. 1999, 38, 620–621.

Figure 40 Representation of the different interaction modes operating as a function of pH in the system Cu2 þ-34-pim. Adapted from Bazzicalupi,
C.; Bencini, A.; Bianchi, A.; Fusi, V.; García-España, E.; Giorgi, C.; Llinares, J. M.; Ramírez, J. A.; Valtancoli, B. Inorg. Chem. 1999, 38, 620–621.

exogen ligands in mixed complexes. In fact, solution studies revealed the formation of homo- and heterobinuclear Cu2 þ and Cu2 þ–
Zn2 þ ternary complexes with imidazole. Paramagnetic NMR data suggested that imidazole coordinates to the metal ions as
a bridging ligand in a wide pH range. Furthermore, SOD activity for Cu2 þ–Cu2 þ and Cu2 þ–Zn2 þ complexes with the different hex-
aazapyridinophane receptors was measured by nitro blue tetrazolium (NBT) assay at pH 7.4, obtaining some of the lowest values
reported in the literature for Cu–SOD mimics. This behavior was related to the coordination modes of the metal ions and with the
flexibility of the aliphatic chains of the receptor that would permit the molecular rearrangements along the catalytic pathway.
Another relevant example of this behavior is the recognition of imidazolate as a bridging ligand by a binuclear complex of the
terpyridinophane receptor 40.111 Thus, the homo- and heterobinuclear Cu2 þ and Cu2 þ–Zn2 þ complexes of this receptor have
458 Metal Complexes as Receptors

Figure 41 Discrimination of L-glutamate over L-aspartate by addition of 2 equiv. of Cu2 þ per mole of 35. Adapted from Verdejo, B.; Aguilar, J.;
Doménech, A.; Miranda, C.; Navarro, P.; Jiménez, H. R.; Soriano, C.; García-España, E. Chem. Commun. 2005, 3086–3088.

Scheme 7 Chemical structure of 36, 37, 38, and 39.

shown great ability for incorporating imidazole as a bridging anionic ligand, with a high constant for the interaction of this anion
with the Cu2 þ complexes. pH-metric titrations showed that the ternary complexes prevail in solution above pH 4. Moreover, the
crystal structure obtained for the complex [Cu2(40)(im)(Br)(H2O)](CF3SO3)2$3H2O shows the imidazole acting as bridging ligand
between the metal centers (Fig. 42). Thus, for this system the different coordination modes of the metal ions and the presence of
noncoordinated amino groups in the proximity of the metal site are in line with relevant features of the native Cu2Zn2-SOD.
Kersting et al. reported the end-on binding of azide in a binuclear Ni2 þ complex of a 28-membered hexaaza-dithiophenolate
macrocycle (41),112 [Ni2(41)(m1,1-N3)][ClO4] (Fig. 43). Conversely, the end-to-end coordination is observed in a related azido
complex of a smaller 24-membered macrocycle, [Ni2(42)(m1,3-N3)][ClO4].113 The analysis of the different crystal structures

Figure 42 X-ray crystal structure of the [Cu2(40)(im)(Br)(H2O)]2 þ cation. Adapted from Verdejo, B.; Blasco, S.; García-España, E.; Lloret, F.; Gav-
iña, P.; Soriano, C.; Tatay, S.; Jiménez, H. R.; Doménech, A.; Latorre, J. Dalton Trans. 2007, 4726–4737.
 Metal Complexes as Receptors 459

Figure 43 Schematic representation of the binuclear complex [Ni2(41)(m1,1-N3)][ClO4]. Adapted from Jeremies, A.; Gruschinski, S.; Meyer, M.;
Matulis, V.; Ivashkevich, O. A.; Kobalz, K.; Kersting, B. Inorg. Chem. 2016, 55, 1843–1853; Hausmann, J.; Klingele, M.-H.; Lozan, V.; Steinfeld, G.;
Siebert, D.; Journaux, Y.; Girerd, J.-J.; Kersting, B. Chem. Eur. J. 2004, 10, 1716–1728.

Scheme 8 Chemical structure of the ligand 42.

indicated that the end-on coordination mode of azide in [Ni2(41)(m1,1-N3)][ClO4] was due to the different conformation of the
complexes and to the presence of a channel-like binding pocket which accommodates the azide anion via repulsive CH/p
interactions.
Kersting had previously reported the fixation of carbon dioxide by the related complex with 42 (Scheme 8). The binuclear Ni2 þ
complexes of this permethylated macrocycle present a great affinity for the activation and subsequent transformation of atmo-
spheric CO2 inside the hydrophobic macrocyclic cavity.114 The hydroxo-bridged Ni2 þ complex fixed carbon dioxide in MeOH
from air in the form of methyl carbonate in quantitative yield and the final product was identified through its X-ray crystal structure.
An analogous result was obtained from the m-Cl complex, but this process occurred under unusual conditions (neutral/slightly
acidic medium) for this type of reaction.
Hossain and coworkers have recently reported the polyazamacrocyclic receptor 43 whose metal complexes are capable of detect-
ing cyanide in water up to values much lower than the acceptable limit set by Environmental Protection Agency (EPA) for drinking
water.115 Selective binding of cyanide over a wide range of inorganic anions (F, Cl, Br, I, NO3  , HCO3  , ClO4  , SO4 2 , and
PO4 3 ) has been analyzed through an indicator displacement assay using different commercially available dyes (Fig. 44). Although

Figure 44 Synthetic pathway to 43 and its binding mechanism for cyanide in the presence of an external dye. Adapted from Rhaman, M.; Alamgir,
A.; Wong, B. M.; Powell, D. R.; Hossain, A. RSC Adv. 2014, 4, 54263–54267.
460 Metal Complexes as Receptors

no crystal structures have been obtained, results from DFT calculations suggest that the cyanide anion is bridged between the two
metal ions.

3.19.3.1.3 Monocyclic binuclear complexes with pendant arms

Similarly to the mononuclear complexes, pendant arms can be introduced in binuclear complexes to add auxiliary groups for
substrate binding and/or activation.
Adopting this strategy, Fabbrizzi et al. reported a bisdien macrocyclic derivative containing two 2-picolyl pendant arms as
specific receptor for imidazole (44).116 This ligand formed binuclear Cu2 þ complexes by coordination of each metal ion through
the triamine moieties. The auxiliary pycolyl groups were able to block each metal center, so that the imidazole acts as bridge
between the two prepositioned metal ions, with the simultaneous release of a proton. Thus, the binuclear Cu2 þ complex was
able to recognize L-histidine in aqueous solution in the presence of any other amino acid. In fact, the histidine binding can be visu-
ally perceived and can be quantitatively determined through a simple spectrophotometric titration experiment (Fig. 45).
Li, Tang, and coworkers reported different homo- and heterobinuclear imidazolate-bridged complexes, [(Cu(im)
Cu)(45)](ClO4)3$0.5H2O and [(Cu(im)Zn(H 245))-(Cu(im)Zn(H 145))](ClO4)3 of a macrocyclic ligand containing two flexible
hydroxyethyl pendant arms (45) as possible models for Cu2Zn2-SOD (Fig. 46).117,118 In fact, this heterobinuclear complex was the
first example of a imidazolate-bridged Cu2 þ–Zn2 þ complex in a single macrocyclic ligand. Interestingly, the X-ray structures of the
Cu–Zn and Cu–Cu complexes were significantly different with the stereochemical inversion of at least one of the two tertiary
nitrogen atoms of the macrocyclic ligand in the formation of the complexes. On the other hand, the SOD-like activities of the
two complexes were investigated by the NBT assay and the good activities obtained for the two complexes were attributed to the
flexible macrocyclic ligand.
Receptors with imidazolate pending functions and the ability of their binuclear Cu2 þ–Cu2 þ and Cu2 þ–Zn2 þ complexes to
mimic SOD activity have been reported by Sun et al.119,120

Figure 45 Schematic representation of binuclear complex [Cu2(44)(im)]3 þ. Adapted from Fabbrizzi, L.; Pallavicini, P.; Parodi, L.; Perotti, A.;
Taglietti, A. J. Chem. Soc. Chem. Commun. 1995, 2439–2440.

Figure 46 Chemical structure of 45. X-ray crystal structure of (A)[(Cu(im)Cu)(45)]3 þ and (B) [(Cu(im)Zn)(H45)]4 þ. Adapted from Li, S.; Li, D.;
Yang, D.; Li, Y.; Huang, J.; Yu, K.; Tang, W. Chem. Commun. 2003, 880–881; Li, D.; Li, S.; Yang, D.; Yu, J.; Huang, J.; Li, Y.; Tang, W. Inorg. Chem.
2003, 42, 6071–6080.
 Metal Complexes as Receptors 461

Figure 47 Schematic representation of the molecular reorganization of the binuclear copper complex of 46 in the presence of imidazole. Adapted
from Fabbrizzi, L.; Foti, F.; Patroni, S.; Pallavicini, P.; Taglietti, A. Angew. Chem. Int. Ed. 2004, 43, 5073–5077.

Figure 48 Schematic representation of the binuclear Zn2 þ complex of 47. Adapted from Mesquita, L. M.; André, V.; Esteves, C. V.; Palmeira, T.;
Berberan-Santos, M. N.; Mateus, P.; Delgado, R. Inorg. Chem. 2016, 55, 2212–2219.

Fabbrizzi et al. reported the first example of a new kind of molecular machine capable of performing a molecular reorganization
in the presence of imidazole.121 The macrocyclic 46 has two different binding sites for metal ions, the first one is formed by the
pyridine and the secondary amines (site 1) while the second one (site 2) is constituted by the secondary amines and completed
by the deprotonated amide groups. At acidic pH predominates the first binding arrangement (site 1) while at pH above 10 the
second one (site 2) occurs. However, these authors proved that the addition of imidazole at pH 10 yields a change of the Cu2 þ
ions from site 2 to site 1 since deprotonated imidazolate binds to the metal ions as a bridging ligand forcing the metal ions to
complete their first coordination sphere with the pyridine and secondary amine nitrogens (Fig. 47). Interestingly, just substrates
having an imidazole moiety such as histidine and histamine give rise to this site exchange. The color change associated with this
process would permit the optical detection of imidazole containing substrates.
A new dien-derived macrocycle bearing 2-methylquinoline arms and containing m-xylyl spacers was prepared by the group of
Delgado et al. (Fig. 48).122 The binuclear Zn2 þ complex of this macrocycle (47) exhibits only weak fluorescence in aqueous solu-
tion, but the addition of 1 equiv. of PPi causes a 21-fold enhancement of the fluorescence intensity. The receptor behaves as a highly
selective sensor for PPi as other anions, including phosphate, phenylphosphate, AMP, ADP, and ATP, fail to induce any fluorescence
change and practically do not affect the fluorescence intensity of the sensor in the presence of HPPi3 . Competition titrations carried
out in aqueous solution at pH 7.4 revealed a high association constant value of 6.22 log units for the binding of PPi by the binuclear
Zn2 þ receptor while association constant values for binding of the other phosphorylated substrates are in the 5.5–4.0 log unit range.
An interesting example of a purple acid phosphatase (PAP) mimic was reported by Comba et al.123 The ligand 48 was built
appending two tridentate coordination sites to the well-known cyclam structure (Scheme 9). The [(H2(48)){FeIII2(O)}(X)n]m þ
behaves as a PAP mimic hydrolyzing MP esters although with low activity in comparison with the pure enzyme. However, the
similar catalytic efficiency with the monoester and diester substrates supports well the catalytic mechanism proposed for PAP
enzymes consisting of a monodentate coordination of the phosphoester followed by a nucleophilic attack of a terminal or free
hydroxide. The diprotonated cyclam platform provides secondary interactions, which are also clue in the observed mechanism
(Fig. 49).

3.19.3.1.4 Tren-derived cryptands

Cryptands derived from the polyamine tris-(2-aminoethyl)amine (tren) can also act, after coordination of two metal ions (M), as
anion receptors through a cascade-type complexation mechanism. The close cavity of this kind of receptors allows for a better
462 Metal Complexes as Receptors

Scheme 9 Chemical structure of [H2(48)]2 þ.

Figure 49 Proposed reaction mechanism for the hydrolysis of BDNPP and DNPP. Adapted from Comba, P.; Gahan, L. R.; Hanson, G. R.; Mereacre,
V.; Noble, C. J.; Powell, A. K.; Prisecaru, I.; Schenk, G.; Zajaczkowski-Fischer, M. Chem. Eur. J. 2012, 18, 1700–1710.

removal of the solvent sphere of the encapsulated substrates. Furthermore, increasing the rigidity of a cryptate can improve its selec-
tivity to anions, as the M/M distance can be fixed within a narrower range.124 In this sense, some interesting reviews focused on the
metal complexes of this type of ligands were reported previously.18,20,28
An early example of a metal-containing anion receptor is the dicopper cryptate 49 (Fig. 50). In this and structurally related crypt-
ates, each tren subunit coordinates to a Cu2 þ ion in a trigonal bipyramidal binding mode leaving one axial position available for
anion binding to form a cascade complex.
The stability of such complexes can be expected to depend on the complementarity between the shape and size of the anion and
the host cavity. Indeed, work by the Fabbrizzi group demonstrated that 49 interacts with various anions such as N3  , OCN, SCN,
SO4 2 , HCOO, CH3COO, HCO3  , and NO3  .125 Complex formation can easily be detected by the color change of an aqueous
solution of the receptor from blue in the absence of these anions to green in their presence. Compound 49 forms the most stable
complex with N3  (log K ¼ 4.78) followed by OCN (log K ¼ 4.60) and HCO3 ; (log K ¼ 4.56), a result that was rationalized by the
almost perfect fit of azide and, to a lesser extent, hydrogen carbonate and cyanate between the two copper centers. All other anions
studied, even the twofold charged sulfate or the strongly coordinating thiocyanate, are bound considerably less tightly leading to the
conclusion that the host does not recognize the donor tendencies or the shape, but the bite length of the anionic guest (Fig. 51).
More recently, the dicopper cryptand complex 50 (Fig. 50) was described by the same group, which was shown to preferentially
recognize guanosine monophosphate (GMP) over other nucleotide MPs.126 This discriminating behavior of 50 was ascribed to the
capability of GMP to bridge, with its phosphate group and carbonyl oxygen atoms on the nucleobase, the distance between the two
metal ions inside the cryptate. Moreover, Nelson and coworkers studied azide recognition by the binuclear copper complex (49)
obtaining suitable X-ray crystal structures that confirmed the existence of collinear Cu–NNN–Cu geometry.127
 Metal Complexes as Receptors 463

Figure 50 Schematic representation of 49 and 50 binuclear complexes. Adapted from Fabbrizzi, L.; Pallavicini, P.; Parodi, L.; Taglietti, A. Inorg.
Chim. Acta 1995, 238, 5–8; Amendola, V.; Bergamaschi, G.; Buttafava, A.; Fabbrizzi, L.; Monzani, E. J. Am. Chem. Soc. 2010, 132, 147–156.

Figure 51 Representation of the distance between two consecutive donor atoms of an anion X acting as an ambidentate ligand. Peak selectivity
for the stability of the [Cu2(49)(X)]3 þ complex with respect to the bite distance of the anion. Adapted from Fabbrizzi, L.; Pallavicini, P.; Parodi, L.;
Taglietti, A. Inorg. Chim. Acta 1995, 238, 5–8.

Fabbrizzi and coworkers have synthesized an anthracene bis-tren cage system (51) containing two Cu2 þ or Zn2 þ metal ions as
potential fluorescent sensors for anions in aqueous solution (Fig. 52).128 The dicopper complex forms a cascade complex with
ambidentate anions (N3  , NCO) bound between the two metal ions. However, the fluorescence of this complex is quenched
by the copper ions via an electron or energy transfer mechanism. Binuclear Zn2 þ complex proved to be a better candidate as a -
fluorescent sensor. The fluorescence of this complex is not quenched by the zinc ions but rather by ambidentate anions such as
N3  that bind between the two zinc centers. It is speculated that quenching is caused by electron transfer from the electron-rich
azide anion to the anthracene moiety.
An interesting example of this behavior is the binuclear metal cryptate [M2(52)]4 þ (M ¼ Cu and Zn) developed by Lu and
coworkers that can cleave the CeC bond of nitriles to generate cyanide-bridged complexes [M2(52)(CN)]3 þ due to the high recog-
nition of [M2(51)]4 þ toward CN, an anion with the appropriated size and shape (Fig. 53).129,130 Further investigations indicate
that the binuclear Zn2 þ cryptate [Zn2(52)]4 þ can also cleave the C–C bond of nitriles, including acetonitrile, propionitrile, and
benzonitrile at room temperature, resulting in the cyano-bridged cryptate [Zn2(52)(CN)]3 þ and corresponding alcohol.130 The
observed rate constant and half-time are 3.0  10 4 s 1 and 39 min, respectively, indicating that the cleavage rate of
[Zn2(52)]4 þ is faster than that of [Cu2(52)]4 þ. High-performance Liquid Chromatography (HPLC) measurements have shown
that the C–C bond cleavage of (S)-(þ)-2-methylbutyronitrile by [Zn2(52)]4 þ produces (R)-()-2-butanol only, revealing that
the cleavage reaction proceeds through an SN2 pathway (Walden inversion).
Moreover, these authors studied the formation of binuclear Cu2 þ complexes and the interaction with imidazolate anion within
its cavity.131 Related with the ability of this ligand to form ternary complexes, the same group prepared the cryptate [Co2(52)]4 þ
that can recognize Cl and Br but not F and I.124
The different substitution of the aromatic spacer was employed to analyze the mechanism of CO2 fixation by the binuclear
complexes (Ni2 þ, Co2 þ, Zn2 þ, and Cu2 þ) 52132 and 49.133 Surprisingly, the binuclear Cu2 þ cryptate [Cu2(49)](ClO4)4 can easily
take up atmospheric CO2 even under weakly acidic conditions at room temperature and convert it from bicarbonate into carbonate
monoesters in alcohol solution.
464 Metal Complexes as Receptors

Figure 52 Schematic illustration of the quenching effect of the azide recognition by the Zn2(51) complex. Adapted from Fabbrizzi, L.; Faravelli, I.;
Francese, G.; Licchelli, M.; Perotti, A.; Taglietti, A. Chem. Commun. 1998, 971–972.

Figure 53 X-ray crystal structure of (A) [Cu2(52)(CN)]3 þ, (B) [Co2(52)Br]3 þ, and (C) [Cu2(52)(Im)]3 þ. Adapted from Yang, L.-Z.; Li, Y.; Zhuang,
X.-M.; Jiang, L.; Chen, J.-M.; Luck, R. L.; Lu, T.-B. Chem. Eur. J. 2009, 15, 12399–12407; Zhuang, X.-M.; Lu, T.-B.; Chen, S. Inorg. Chim. Acta 2005,
358, 2129–2134; Chen, J. M.; Zhuang, X. M.; Yang, L. Z.; Jiang, L.; Feng, X. L.; Lu, T. B. Inorg. Chem. 2008, 47, 3158–3165.

Xie et al. have reported the selective recognition and encapsulation of fumarate over its cis-isomer maleate in aqueous solution at
physiological pH, due to the size- and shape-matching effect of the binuclear Cu2 þ complex of a rigid cryptand containing 2,6-
naphthyl units as spacers (53) (Fig. 54).134 The extended and rigid conformation of this new cryptand, the right size of fumarate,
as well as the p–p stacking interactions allows the coordination of this anion by two metal ions in [M2(53)]4 þ.
Another example of these cascade cryptand complexes has been recently described by Mateus and Delgado (54).135 This
cryptand binds, in aqueous solution, dicarboxylate anions with remarkably high association constants (7.3–10.0 logarithmic units).
In fact, a maximum in selectivity was found for substrates with four carbon atoms separating the carboxylate groups (adipate
 Metal Complexes as Receptors 465

Figure 54 X-ray crystal structure of [(Cu2(53))(fum)]2 þ. Adapted from Xie, G.-Y.; Jiang, L.; Lu, T.-B. Dalton Trans. 2013, 42, 14092–14099.

Figure 55 X-ray crystal structure of (A) [Cu2(54)(m-adi)]2 þ and (B) [Cu2(54)(m-tph)]2 þ. Adapted from Mateus, P.; Delgado, R.; André, V.; Duarte,
M. T. Inorg. Chem. 2015, 54, 229–240.

(adi2 ) and therephtalate (tph2 ) anions). The X-ray crystal structures obtained for these two complexes (Fig. 55) show that this
cryptand is able to adjust the size and form of the substrate. Additionally, the establishment of van der Waals and C–H/p
interactions between the substrates and the walls of the receptor also contribute to the stability of the ternary complex and to
the observed selectivity. Other examples from these authors are included in Refs. [136,137].

3.19.3.2 Open-Chain Ligands

For some purposes, particularly in relation to catalytic aspects, complexes of open-chain ligands are very interesting since the
auxiliary groups may be disposed in a more flexible or self-adaptive way onto the ligand structure. As a matter of fact, many acyclic
ligands have been used in processes related to oxygen activation followed by hydroxylation of C–C bonds.138,139
A series of open-chain receptors in which two bis(dipicolyl)amine scaffolds have been connected through benzylic or phenolic
moieties have been prepared for the recognition of different oxoanions (Scheme 10).140–143 While the binuclear Zn2 þ complex of
the ligand 55 having a 4-methyl-phenolate spacer binds phosphate anions selectively, the corresponding Zn2 þ complexes of 56 and

Scheme 10 Chemical structure of 55, 56, and 57.

466 Metal Complexes as Receptors

Figure 56 Schematic illustration for the binding mode between 58 and 59 with Cu2 þ and acetate. Adapted from Striegler, S.; Dittel, M. J. Am.
Chem. Soc. 2003, 125, 11518–11524; Striegler, S.; Gichinga, M. G. Chem. Commun. 2008, 5930–5932.

Figure 57 Schemetatic representation of the AMP binding by the [Eu2(60)]6 þ. Adapted from Sahoo, J.; Arunachalam, R.; Subramanian, P. S.;
Suresh, E.; Valkonen, A.; Rissanen, K.; Albrecht, M. Angew. Chem. Int. Ed. 2016, 55, 9625–9629.

57 having a phenolate spacer modified with different chromophores in para-position have shown to be very effective metallorecep-
tors for the recognition and optical sensing of PPi anions.
Striegler et al. have worked in the synthesis and binuclear Cu2 þ complexes of N0 -1,3-bis[(pyridin-2-ylmethyl)amino]propan-2-
ol (58) as well as with related derivatives with the goal to recognize sugars144 and disaccharides (Fig. 56).145 They studied the
coordination of various natural, underivatized sugars to the binuclear complex [Cu2(H 158)(m-ac)]2 þ in aqueous solution at
highly alkaline pH. The binding strengths of the ternary complexes with D-mannose and D-glucose differ in about 1.5 orders of
magnitude. Moreover, depending on the studied saccharide, a blue or a red shift of the absorption maximum of the metal complex
occurs during carbohydrate binding, highlighting the sugar discrimination ability of [Cu2(H 158)(m-ac)]2 þ. This phenomenon is
related to the specific number of hydroxyl groups of the particular monosaccharide involved in chelation to the binuclear metal
complex.
Later studies of the same group indicated that sugar recognition is highly dependent on subtle modifications in the ligand and,
thereby in the structure of the binuclear complex that could not be predicted only from the intermetallic Cu–Cu distances.
Recently, the same authors have also studied the interaction between the chiral binuclear complex 59 and galactonoamidines
that had been identified as potent inhibitors of glycosidases.146 The different contributions of the hydroxyl groups in the glycon
led to significantly different binding strengths of the resulting galactonoamidine–metal complex assemblies.
Albrecht and Subramanian have shown that coordinative saturated double-stranded helicates can be easily formed from (60)
and the corresponding lanthanide(III) salts.147 The coligands at the metal site can be easily replaced by appropriate anions. The
authors report the selective recognition of AMP in presence of ADP/ATP and other anions. AMP produces a specific luminescence
answer because it bridges perfectly between the metal centers replacing the quenching coligands in the coordination sphere of the
metal ions (Fig. 57).
Metal-based receptors with an open ligand structure have also offered good results in dicarboxylate sensing. Kim et al. developed
a binuclear Cu2 þ complex (61) that selectively binds oxalate over malonate, succinate, and glutarate in water (Fig. 58).148 The asso-
ciation constants determined by using the indicator displacement method showed that the value for oxalate (K ¼ 1.3  105 M 1)
was 4, 50, and 200-fold higher than those obtained for malonate, succinate, and glutarate, respectively. Moreover, an increase in
the oxalate concentration resulted in an increase of the fluorescence, and could be associated with the successful competitive
binding of the oxalate ion and displacement of the indicator from the receptor.
 Metal Complexes as Receptors 467

Figure 58 Chemical structure of 61 and X-ray crystal structure of the [Cu2(61)Cl(ox)(H2O)]þ cationic complex. Adapted from Tang, L.; Park, J.;
Kim, H.-J.; Kim, Y.; Kim, S. J.; Chin, J.; Kim, K. M. J. Am. Chem. Soc. 2008, 130, 12606–12607.

3.19.4 Trinuclear Complexes

3.19.4.1 Trinuclear Complexes of Macrocyclic Ligands
While binuclear Cu2 þ complexes are usually employed in the recognition and binding of anionic species, only few complexes of
macrocyclic ligands with three metal ions within the cavity have been described. In fact, Luo et al. reported the first example of a tri-
nuclear Cu2 þ cryptate (62) bridging an imidazole anion. In this case, the X-ray crystal structure of the trinuclear complex
[Cu3(62)(im)(Br)2](ClO4)3$H2O showed that each metal ion is coordinated to a pyridyl moiety of the ligand. However, only
two metal ions are directly implicated in coordination with the imidazole anion.149 Electrospray Ionisation Mass Spectrometry
(ESI-MS) studies confirmed the stability of the trinuclear species in solution.
Alfonso, García-España et al. reported one the first examples in which a Cu3(OH)2 cluster is formed within a macrocyclic frame-
work.150 The high number of nitrogen donor atoms around a macrocyclic cavity in 63 allows the simultaneous coordination of
several metal ions. In fact, a X-ray crystal structure of the trinuclear complex was obtained, [Cu3(63)(OH)2](ClO4)2Cl2$5H2O
(Fig. 59). Furthermore, the anti-Curie behavior observed can be related to the existence of a magnetically coupled [Cu3(OH)2]4 þ
system. Similar ligands were developed by the group of Lisowski.151
Delgado and Lloret analyzed the synthesis and Cu2 þ coordination studies of a hexaaminic macrobicycle containing pyridyl
spacers (64).152 The potentiometric studies revealed that this receptor was able to coordinate three metal ions within its cavity.
Thus, trinuclear species predominated in solution from pH 5.0, being the hydroxo complexes the main species. Furthermore,
the X-ray crystal structure obtained, [Cu3(64)(m3-CO3)]$(ClO4)4, showed a carbonate bridged by three Cu2 þ as a result of the atmo-
spheric CO2 fixation. This example was considered as the first m3-CO3-bridged trinuclear Cu2 þ complex located in the interior of
a macrobicyclic cavity (Fig. 60).

Figure 59 Schematic representation of the structure of the cation [Cu3(63)(OH)2]4 þ. Adapted from González-Alvarez, A.; Alfonso, I.; Cano, J.; Díaz,
P.; Gotor, V.; Gotor-Fernández, V.; García-España, E.; García-Granda, S.; Jiménez, H. R.; Lloret, F. Angew. Chem. Int. Ed. 2009, 48, 6055–6058.
468 Metal Complexes as Receptors

Figure 60 X-ray crystal structure of [Cu3(64)(m3-CO3)]4 þ cation. Adapted from Mateus, P.; Delgado, R.; Lloret, F.; Cano, J.; Brandão, P.; Felix, V.
Chem. Eur. J. 2011, 17, 11193–11203.

Figure 61 X-ray crystal structure of the [Cu3(52)(OH)2(ox)]2 þ complex cation. Adapted from Esteves, C. V.; Mateus, P.; Andres, V.; Bandeira, N. A.
G.; Calhorda, M. J.; Ferreira, L. P.; Delgado, R. Inorg. Chem. 2016, 55, 7051–7060.

Furthermore, Delgado et al. reported an exhaustive analysis of the Cu2 þ complexes of the well-known cryptand 52, as an approx-
imation for the selective binding of oxalate or malonate by bridging the two copper centers of the [Cu2(52)(H2O)2]4 þ receptor.
Surprisingly, the solution studies revealed the unexpected formation of a 3:1:1 Cu:52:anion stoichiometry for the cascade species
with oxalate and malonate. In fact, the X-ray crystal structure confirmed the presence of tricopper complexes, with an unusual
binding mode for the dicarboxylate anion (Fig. 61). Each one of the two metal ions binds four nitrogen donor atoms of the
cryptand and one additional hydroxide group, which bridges to the third copper.153
An analogous analysis for this receptor has been recently reported by Qi et al. that obtained a X-ray crystal structure of the
trinuclear complex, [Cu3(52)(CO3)(m-OH)2](NO3)2$6H2O (Fig. 62), in which the three metal ions possessed two different coor-
dination environments, and are bridged by two hydroxyl groups and one carbonate group formed by fixation of atmospheric
CO2.154

3.19.4.2 Trinuclear Complexes of Open-Chain Ligands

Several interesting cases of trinuclear complexes of open-chain ligands behaving as substrate receptors can be found in the literature.
In order to develop trinuclear metal complexes as synthetic models of trimetallic enzymes, Cao et al. reported a tribenzylamine
scaffold able to dispose three pendant arms together creating the adequate space to accommodate different oxoanions (65).155
These authors isolated the trinuclear Zn2 þ complexes [Zn3(65)(CF3SO3)6], [Zn3(CF3SO3)3(m3-HPO4)(65)](CF3SO3), and
[Zn3(CF3SO3)3(m3-CO3)(65)](CF3SO3) (Fig. 63) that were identified also in solution by nuclear magnetic resonance and high-
resolution mass spectrometry (HRMS). Interestingly, the complex [Zn3(CF3SO3)3(m3-HPO4)(65)](CF3SO3) was considered as
the first example of a synthetic {Zn3(m3-PO4)} core stabilized in a single ligand framework mimicking natural zinc enzyme cores.
Moreover, the activity of the triply bridging carbonate could be controlled sterically to provide good models for studying bridging
carbonates.156
 Metal Complexes as Receptors 469

Figure 62 X-ray crystal structure of the [Cu3(52)(CO3)(m-OH)2]2 þ. Adapted from Qi, Z.-P.; La, Y.-S.; Li, P.-Y.; Xu, W.; Qin, C.-G. Polyhedron 2016,
119, 216–222.

Figure 63 X-ray crystal structure of [Zn3(CF3SO3)3(m3-HPO4)(65)]þ. Adapted from Liu, X.; Du, P.; Cao, R. Nat. Commun. 2013, 4, 2375.
doi:10.1038/ncomms3375.

More recently, these authors synthesized two new trinucleating ligands and analyzed their Cu2 þ complexes as catalysts for the
hydrolysis of 4-nitrophenyl phosphate (NPP).157 The identification of the NPP-bound intermediate [(CuCl)3(NPP)(66)]þ by
HRMS was related to the fact that the NPP binding by the complex take place first for substrate activation. Remarkably, the complex
[(CuCl)3(HPO4)(67)](PF6) was isolated from NPP hydrolysis assay and was characterized by single crystal X-ray diffraction. As can
be seen in Fig. 64, a triply bridging phosphate is coordinated after hydrolysis by the three metal ions. The author proposed a nucle-
ophilic attack of NPP by water molecules from the bottom of the plane defined by the three metal ions, which supported the
proposed biological phosphate hydrolysis at the trimetallic active site of pyrophosphatases.
Neves et al. have synthesized a new multidentate N,O-donor ligand and the structure of the trinuclear Cu2 þ complex
[Cu3(68)(m-OAc)](ClO4)2 was determined by X-ray crystallography (Fig. 65).158 This complex shows a significant catalytic activity
toward the hydrolysis of the substrate bis(2,4-dinitrophenyl)phosphate. In fact, the calculated catalytic constant (kcat) is approxi-
mately 30 times higher than the one obtained for the analogous binuclear complex. This behavior is associated with the higher
nucleophilic reactivity of the Cu2 þ-bound OH group in the trinuclear complex (pKa ¼ 6.9) versus the binuclear complex
(pKa ¼ 5.7). Moreover, the catechol oxidase activity is analyzed since it efficiently catalyzes the oxidation of 3,5-di-tert-butylcatechol
to 3,5-di-tert-butyl-o-benzoquinone by dioxygen.

3.19.5 Metallocages as Receptors

In the last section of this article, we describe several examples of metallocages in which substrate coordination occurs through a coor-
dinative pathway. The host–guest properties of these metallosupramolecular assemblies have been exploited for a variety of
proposes,159 including molecular storage of reactive species,160 the binding of environmental pollutants,161 catalysis,162 and the
delivery of biologically relevant molecules, including drugs.163
470 Metal Complexes as Receptors

Figure 64 Structure of [(CuCl)3(HPO4)(67)]þ. Adapted from Ning, Y.; Gao, M.; Zheng, K.; Zhang, Z.; Zhoub, J.; Hao, X.; Cao, R. J. Mol. Catal. A:
Chem. 2015, 403, 43–51.

Figure 65 X-ray crystal structure of the cation [Cu3(68)(m-OAc)]2 þ. Adapted from Osório, R. E. H. M. B.; Neves, A.; Pacheco Camargo, T.; Mireski,
S. L.; Bortoluzzi, A. J.; Castellano, E. E.; Haase, W.; Tomkowicz, Z. Inorg. Chim. Acta 2015, 435, 153–158.

A water-soluble calix[6]arene-based tris(imidazole) ligand (69) was developed by Reinaud et al.164 These authors synthesized
a highly selective Zn2 þ receptor for primary amines in water near physiological pH. It is well-known that upon binding to a metal
cation, the conformational freedom of 69 is restricted and the cone conformation is favored. The geometry of the system constrains
the metal center in a tetrahedral environment, orienting the fourth labile coordination sites toward the interior of the cavity
provided by the calixarene macrocycle. The primary amine occupies the fourth position of the tetrahedral coordination of the metal
ion. The hydrophobicity of the cavity contributes to stabilize the binding of hydrophobic amines as heptylamine, tyramine,
serotonine, and dimethyldopamine in the cage (Fig. 66).
Reinaud et al. have also worked with calix[6]arene-based Cu2 þ complex to bind anions in water.165 They found a strong and
selective fluoride binding in the pH range of 6–7 by the copper complex. Although the complex also binds chloride ions, the
 Metal Complexes as Receptors 471

Figure 66 Illustration of the synergistic interaction of calix[6]arene 69, heptylamine, and Zn2 þ for the complex formation. Adapted from Bistri, O.;
Colasson, B.; Reinaud, O. Chem. Sci. 2012, 3, 811–818.

Figure 67 (A) Macrocyclic ligand 70, (B) binuclear Ag(I)-complex [Ag2(70)X2](SbF6)2, and (C) schematic representation of binding modes of the
inclusion complexes. Adapted from Omoto, K.; Tashiro, S.; Kuritani, M.; Shionoya, M. J. Am. Chem. Soc. 2014, 136, 17946–17949.

interaction is 1000 times less efficient. The authors concluded that the combination of the calix[6]arene hydrophobic cavity with the
Cu2 þ complex, presenting its labile site in the endo position, is the reason for the selective recognition process.
Host–guest metal cavities where the metal is different from those of Werner type can be developed when the metal is binding
with aromatic p-planes. This interaction provides unique structural and electronic characteristics to the metal complexes.166,167 In
this regard, the Agþ ion is well-known to bind to the periphery of many types of aromatic hydrocarbons through Ag–p interac-
tions168 and the coordinatively labile nature of the Agþ ion in host compounds possibly provides a platform for guest-binding sites
to construct thermodynamically stable assemblies.169,170
Shionoya et al. firstly developed a diamond-shape macrocyclic ligand with two phenanthroline metal-binding sites providing
binuclear metal complexes with Cuþ, Zn2 þ or Pd2 þ.171,172 Based on this macrocyclic skeleton, they synthesized later a cyclo-
phane-type macrocyclic ligand 70 and its binuclear Agþ complex (Fig. 67).173 The binuclear Agþ complex of 70 forms a highly
stable inclusion complex with a ditopic guest, [2.2]paracyclophane (pCp), through multipoint Ag–p interactions in the cavity
(Fig. 67C). Ferrocene (FeCp2), a sandwich-shape metal complex, was also included into the cavity, and thereby its redox behavior
was significantly influenced. By the inclusion of pCp and FeCp2, they demonstrated that the Ag–p bonding is a useful structural
motif for host–guest chemistry and has great potential to control the electronic properties and reactivity of guest molecules possibly
leading to cooperative functions with photoreactive anthracene walls of the cavity.
Nitschke et al. synthesized a cationic cubic structure (71) where the coordinatively unsaturated molybdenum centers located on
each face of the cube were envisioned to serve as binding sites for coordinating species (Fig. 68A).174 The high positive charge (þ 16)
of the framework and the observation of triflate anion coordination at the molybdenum sites encouraged them to further investigate
the 71 as an anion receptor. They performed 19F NMR and studied the addition of tetra-n-butylammonium fluoride, chloride,
bromide, or iodide to the cage 71, observing a change in the broad triflate signal that sharpens considerably and a movement of
its chemical shift, both of them associated with the release of the triflate counter-ions from the cage structure into the solution.
In addition to halide encapsulation in 71, these authors had previously discovered that neutral molecules, such as ammonia,
could coordinate to the molybdenum centers.175 The crystal structure of the NH3 adduct of the cubic host 71 (Fig. 68B) was consis-
tent with the ligation of 12 NH3 molecules to the molybdenum centers. From all the experiments performed with both cages, they
inferred that in all ternary host–guest complexes incorporating neutral ligands, the neutral ligand’s displacement of a weakly coor-
dinating triflate anion from the host framework enhanced the halide binding affinity as a result of the steric effects and an increase in
472 Metal Complexes as Receptors

Figure 68 (A) Iron(II) triflate, 2-formylpyridine, and tetrakis(para-aminobenzoato)dimolybdenum(II) self-assembled to form the cubic structure 71.
(B) The X-ray crystal structure of the Heterometallic Supramolecular Cube 71 with 12 equiv. of ammonia (shown as space-filling representations)
saturating the molybdenum coordination sites. Adapted from Ramsay, W. J.; Ronson, T. K.; Clegg, J. K.; Nitschke, J. R. Angew. Chem. Int. Ed. 2013,
52, 13439–13443.

Figure 69 (A) Space-filling representation of the X-ray crystal structure, where two OTf ions (shown in space-filling model) occupy the two binding
pockets of [Cd5(72)6](CO3)(OTf)2]6 þ (shown as a framework). (B) View down the long axis of the structure showing coordination of a carbonate ion
to the equatorial Cd2 þ centers (apical metal centers are omitted for clarity). Adapted from Browne, C.; Ramsay, W. J.; Ronson, T. K.; Medley-Hallam,
J.; Nitschke, J. R. Angew. Chem. Int. Ed. 2015, 54, 11122–11127.

favorable Coulomb forces between the host and halide. Most importantly, they provided a method to regulate iodide binding based
on the modulation on steric and electronic interactions instead of the use of allosteric effects.176
More recently, Nitschke and coworkers designed a rigid ligand 72 which metal complexes derived in a new class of trigonal bypir-
amidal structures in which a central guest is exposed directly to three dicationic metal centers, allowing for selective transformations
and substrate stabilization.177 72 was also found to generate a new M4(72)6 molecular rectangle with different templates.
Regarding the M5(72)6 structures, the spatially constrained arrangement of the three equatorial metal ions was found to induce
small-molecule transformations. Atmospheric carbon dioxide was fixed as carbonate and bound to the equatorial metal centers in
both the Zn5(72)6 and Cd5(72)6 assemblies. From the crystal structure obtained from Cd5(72)6 (Fig. 69), they have shown that the
octahedral coordination sphere of the equatorial Cd2 þ centers is satisfied by a carbonate dianion, which forms three bonds to the
equatorial metal centers with its oxygen atoms. As no carbonate was added to the solution during the self-assembly, they inferred
that the anion was generated from atmospheric carbon dioxide.
Wu and coworkers have isolated and structurally characterized a family of anion-templated tetragonal metallocages of general
formula [(Gn)3{Cu2(73)}](8 n)þ (73 ¼ Hdpmaþ; Gn ¼ NO3  , ClO4  , SiF6 2 , BF4  , SO4 2 ) (Fig. 70), a complex double salt,
and a 1D-coordination polymer.178 The formation of the anion-templated metallocage depends on the shape of the anion, and the
ability of the anionic guest to coordinate and form hydrogen-bonding interactions with the cationic [Cu2(73)4]8 þ.
Domasevich et al. reported a related ligand made up of two pyridinazine units connected by a meta-benzene moiety (74). The
formation of [Cu274]4 þ metallocages is templated by octahedral anions as AsF6  , PF6  , SiF6 2 , GeF6 2 , SnF6 2 , TiF6 2 , GaF6 3 ,
and AlF6 3 .179 The crystal structure of the [SiF63[Cu274]]2 þ cage shows that the axial fluorides of the octahedral anion are bound
to the Cu2 þ ions, while the equatorial ones form a total of 12 C–H∙∙∙∙∙F hydrogen bonds (Fig. 70B).
 Metal Complexes as Receptors 473

Figure 70 (A) X-ray crystal structure of [(SO4)2 3{Cu2(73)4}(CH3SO4)2]4 þ. Adapted from Wu, J.-Y.; Zhong, M.-S.; Chiang, M.-H.; Bhattacharya,
D.; Lee, Y.-W.; Lai, L.-L. Chem. Eur. J. 2016, 22, 7238–7247. (B) Structure of [(SiF6)2 3{Cu2(74)4}(H2O)2]2 þ cations. Adapted from Degtyarenko, A.
S.; Rusanov, E. B.; Bauzá, A.; Frontera, A.; Krautscheid, H.; Chernega, A. N.; Mokhire A. A.; Domasevitch, K. V. Chem. Commun. 2013, 49, 9018–
9020.

Figure 71 Schematic representation for the selective binding of heteroaromatic compounds by a supramolecular bisporphyrin tweezer 75. Adapted
from Ikbal, S. A.; Dhamija, A.; Rath, S. P. Chem. Commun. 2015, 51, 14107–14110.

Until now, we have shown examples of metallosupramolecular structures made by the interaction of one type of ligand.
However, structures formed by utilizing diverse intermolecular interactions and multiple molecular components are still very
rare,180 maybe because the fabrication of a multicomponent aggregate as a single species requires specific molecular binding pref-
erences and competitive self-sorting.
Rath et al. were able to covalently connect two octaethylporphyrin units with diethyl pyrrole spacer leading to the formation of
cofacial Mg(II) bisporphyrin (75) which provides a Pacman pocket with high vertical flexibility.181 Addition of 2-aminopyrimidine,
pyrazine, or 1,4-dioxane to the dichloromethane solution of 75 produces a 1:1 sandwich complex in solution, which after coordi-
nation with pyrazine or 1,4-dioxane forms a 1D polymer that leads to precipitation of the mixed ligand complex (Fig. 71).
Interestingly, when heterogeneous guest pairs are used, guest ligands are encapsulated selectively between the inside and the outside
of the bisporphyrin cavity.
Binding constants were measured and they found that 2-aminopyrimidine strongly binds with 75 to form a 1:1 sandwich
complex which, upon addition of pyrazine/1,4-dioxane, is transformed into a six-coordinate mixed ligand complex. It is interesting
to note here that the addition of pyrazine/1,4-dioxane followed by 2-aminopyrimidine also produces the same mixed ligand
complex and, thus, guest ligands bind selectively between the inside and the outside of the bisporphyrin cavity.
The ability of metallosupramolecular assemblies to selectively bind guest molecules within their internal cavities is clearly
extremely important. However, just as useful as guest encapsulation, but harder to attain, is the ability to controllably release
the guest from the cavity when required.
474 Metal Complexes as Receptors

Figure 72 Scheme showing the molecular structure (A) of 76, (B), cage, [Pd2(76)4](BF4)4, and (C) the chloride induced conversion of the cage
[Pd2(76)4](BF4)4 into a metallo-macrocycle [Pd2(76)2Cl4] using [NBu4]Cl as stimuli and reversible conversion with AgBF4. (D) Encapsulation of cis-
platin in the cage and reversible conversion into a metallo-macrocycle using [NBu4]Cl and AgBF4 as stimuli. Adapted from Preston, D.; Fox-Charles,
A.; Lo, W. K. C.; Crowley, J. D. Chem. Commun. 2015, 51, 9042–9045.

Yam et al. aborded this topic and studied the release of the guest by UV irradiation.182 On the other hand, Nitschke et al. used
transmetallation as stimuli for anionic croconate release.183 Another example related to the release of the guest molecule by altering
the host’s binding ability has been developed by Crowley et al.184 They synthesized a diglyme substituted tripyridil ligand (76) and
form a [Pd2(76)4]2 þ cage. This new system can be reversibly toggled between the cage and its corresponding [Pd2(76)2Cl4] metallo-
macrocycle by the sequential addition of tetrabutylammonium chloride ([NBu4]Cl) and AgBF4 as stimuli. Additionally, it was
demonstrated that the guest molecules, bound either endo- (within the cage cavity) or exo-hedrally on the exterior face of the
Pd2 þ cage, were released into solution on chloride-triggered cage dis-assembly and taken up a new on reassembly (Fig. 72). The
authors showed that two molecules of cis-platin could be inserted in the cage. While the addition of (NBu4)Cl disrupts the cage
liberating the cis-platin molecule, the cage will be re-formed upon addition of AgBF4.

3.19.6 Conclusions and Outlook

Molecular recognition chemistry has evolved spectacularly since the pioneering work and conceptual ideas developed by Pedersen,
Cram, and Lehn on this topic. Many synthetic receptors that able to interact strongly and selectively with a variety of substrates
through intermolecular forces have been designed, synthesized, and studied over the past years. However, the ability of metal
ions, in particular of transition metal ions with unfilled d orbitals, to organize the space around them in a programmed or predict-
able manner is in many instances crucial for the achievement of sophisticated receptors with improved selection and/or catalytic
properties. Metal sites compete more efficiently with the solvation (hydration) energy of the substrates than nonmetallic sites
and thereby are interesting for achieving recognition in highly polar solvents such as water. However, metal sites usually require
additional binding sites to better interpret the recognition event. These additional binding sites might be another metal ion giving
rise to the so-called cascade complexes, hydrogen-bond donor or acceptor sites, or sites providing other kinds of intermolecular
interactions such as p-stacking, cation, or anion–p interaction. The use of metal ions with vacant coordination positions forming
part of metallocages has revealed very attractive recognition motifs in the last years. This article has intended to provide several
examples highlighting this chemistry of still unidentifiable borders.

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 3.20 Endofullerenes and Carboranes
Y Zhu and B Zhiyu, Institute of Chemical and Engineering Sciences (ICES), Singapore, Singapore
V Kalavakunda, Pachaiyappa’s College, Chennai, India; and Northern Illinois University, DeKalb, IL, United States
NS Hosmane, Northern Illinois University, DeKalb, IL, United States
Ó 2017 Elsevier Ltd. All rights reserved.

3.20.1 Introduction 479

3.20.2 Endofullerenes 479
3.20.3 Carboranes 480
3.20.4 Structure of Carboranes 480
3.20.4.1 Ortho-, Meta-, and Para-Carboranes 481
3.20.4.2 Closo-, Nido-, Arachno-, Hypho-, and Klado-Carboranes 481
3.20.5 Synthesis of Carboranes 481
3.20.6 Applications of Carboranes and Endofullerenes 482
3.20.6.1 Biomedical Applications of Carboranes 482
3.20.6.1.1 Boron Neutron Capture Therapy 482
3.20.6.1.2 Analogs of Biomolecules 482
3.20.6.2 Electrochemical Applications and Molecular-Level Motions 483
3.20.6.3 Semiconductor Applications and Materials 483
3.20.6.4 Applications in Nanovehicles 484
3.20.6.4.1 First Generations of Nanovehicle: Nanotrucks 484
3.20.6.4.2 C60–Motor Hybrid and Introduction of p-Carborane Wheels 485
3.20.7 Summary 486
References 486

3.20.1 Introduction

In this article, we will be looking into the supramolecular properties of endofullerenes and carboranes. We will discuss their properties,
synthesis, and novel applications. An introduction to the carboranes and their isomers along with a detailed account of the recent
developments and their applications is given attention. Many reviews of the synthesis and structures have already been put forth
by leading researchers in the field of boron science. This article is intended to bring out the latest developments in the application
of carboranes, including their potential use in modern materials. The chemical reactivity and stability of the carboranes make them
a prominent molecule when a choice of boron compounds arises for drug design and development, boron neutron capture therapy
(BNCT), enzyme inhibitors, or semiconductor devices. Another recent application that we will be examining involves a molecular
vehicle that could be used to move along metallic surfaces.

3.20.2 Endofullerenes

A fullerene is a molecule of carbon in the form of a hollow sphere, ellipsoid, tube, and many other shapes. Spherical fullerenes are
also called buckminsterfullerene (buckyballs), and they resemble the balls used in football (soccer) such as C60 shown in Fig. 1.1
Cylindrical ones are called carbon nanotubes or buckytubes. Fullerenes are similar in structure to graphite, which is composed
of stacked graphene sheets of linked hexagonal rings, but they may also contain pentagonal rings and, sometimes, heptagonal rings.
Buckminsterfullerene, C60, is the smallest fullerene molecule containing pentagonal and hexagonal rings in which no two
pentagons share an edge. It is also the most common in terms of natural occurrence, as it can often be found in carbon soot.
The structure of C60 is a truncated icosahedron, which resembles an association football of the type made of 20 hexagons and 12
pentagons, with a carbon atom at the vertices of each polygon and a bond along each polygon edge. The C60 molecule has two bond
lengths. The 6:6 ring bonds (between two hexagons) can be considered “double bonds” and are shorter than the 6:5 bonds
(between a hexagon and a pentagon). The average bond length is 1.4 angstroms (Å).
Another fairly common fullerene is C70, but fullerenes with 72, 76, 84, and even up to 100 carbon atoms are commonly
obtained. In geometric terms, the structure of a fullerene is a trivalent convex polyhedron with pentagonal and hexagonal faces.
In graph theory, the term fullerene refers to any 3-regular, planar graph with all faces of size 5 or 6 (including the external face).
It follows from Euler’s polyhedron formula, V
E þ F ¼ 2 (where V, E, and F are the numbers of vertices, edges, and faces), that there
are exactly 12 pentagons in a fullerene and (V/2
10) hexagons.

Comprehensive Supramolecular Chemistry II, Volume 3 http://dx.doi.org/10.1016/B978-0-12-409547-2.12524-7 479

480 Endofullerenes and Carboranes

Figure 1 Buckminsterfullerene. https://en.wikipedia.org/wiki/Fullerene.

Figure 2 Endohedral metallofullerene. Reproduced from Chai, Y.; Guo, T.; Jin, C.; Haufler, R. E.; Chibante, L. P. F.; Fure, J.; Wang, L.; Alford, J. M.;
Smalley, R. E. J. Phys. Chem. 1991, 95, 7564–7568, with permission of American Chemical Society.

Endohedral fullerenes, also called endofullerenes, are fullerenes that have additional atoms, ions, or clusters enclosed within
their inner spheres. The first lanthanum C60 complex was synthesized in 1985 and called La@C60.2 Two basic types of endohedral
complexes exist: endohedral metallofullerenes (Fig. 2) and nonmetal doped fullerenes.

3.20.3 Carboranes

Carboranes, also known as carbaboranes, are polyhedral clusters or molecules of carbon and boron stabilized by electron, delocalized
covalent bonding in a skeletal framework.3 Hence, these classes of compounds can be considered as derivatives of boron hydrides with
carbon atoms replacing isoelectronic B or BH groups. Mixed hydrides or heteroboranes are borane cages that contain heteroatoms such
as carbon, nitrogen, silicon, phosphorus, arsenic, and selenium. In these species, the boron atoms occupy the vertices of ‘deficient’
cages.4 Carboranes are the class of borane cages that contain carbon as the heteroatom. When the heteroatoms are metals, then
these compounds are referred to as metallacarboranes.5 Compounds with the general formula C2BnHnþ 2 (n ¼ 3–10) are the most
widely used carborane ligands. Ortho-carborane (Fig. 3) is the most commonly studied polyhedron molecule, and it has promising
applications in polymer and medicinal chemistry.6

3.20.4 Structure of Carboranes

The syntheses by Stock and coworkers of several boron hydrides such as B2H6, B4H10, B5H9, B5H11, B6H10, and B10H14 led to an
understanding of the multicentered bonding in the structures of the boron hydrides.7 Subsequent to the Second World War,
 Endofullerenes and Carboranes 481

Figure 3 Ball and stick model of ortho-carborane (1,2-C2B10H12). The hydrogen bound to the boron atoms is not shown in the image on the right.
https://en.wikipedia.org/wiki/Carborane.

Figure 4 Ortho-carboranes undergo aromatic electrophilic substitution reactions to form the corresponding meta- and para-forms. https://en.
wikipedia.org/wiki/Carborane.

research with the intention of producing high-energy liquid boron hydrides led to the identification of polyhedral borane ions
(Bn Hn 2
, where n ¼ 10–12) and the carboranes (C2B10H12).8

3.20.4.1 Ortho-, Meta-, and Para-Carboranes

Ortho-carborane undergoes aromatic electrophilic substitution reactions. On heating, it rearranges to form meta- and para-carboranes
(Fig. 4). These three isomeric forms of icosahedral closo-carboranes differ in their stability. The naming as closo-dicarbadodecaborane is
following the IUPAC nomenclature. For these polyhedral compounds, they are commonly known as ortho-, meta-, and para-carboranes.

3.20.4.2 Closo-, Nido-, Arachno-, Hypho-, and Klado-Carboranes

The carboranes are classified based on their structural characteristics into five groups. Suitable prefixes such as closo-, nido-, arachno-,
hypho-, and klado- are added to the carborane in naming them. A closo-carborane is a “closed-cage” structural arrangement of the carbon
and boron atoms where all boron and carbon atoms occupy all vertices of the polyhedron. The nido-carboranes are structures with
a “nest” like appearance. The structure is similar to a closo-carborane of the same number of components in the geometry, except
for a missing vertex, or, in other words, the n boron atoms occupy the vertices of an n þ 1 closo-polyhedron. The closo-carboranes
are more stable than the other isomeric forms. On heating, the isomers rearrange to a stable closo-form. A closo-polyhedron with
two missing vertices and a “spiderweb” -like appearance is known as the arachno-carborane. In an arachno-isomer, the n boron atoms
occupy vertices of an n þ 2 closo-polyhedron. The term hypho- is prefixed before carboranes to indicate “netlike” open clusters where the
boron atoms occupy n vertices in an n þ 3 closo-polyhedron and klado- meaning “a branch,” indicating that these carboranes have the
boron atoms occupy n vertices of an n þ 4 closo-polyhedron.
Two or more polyhedral borane clusters linked together are indicated by the prefix conjuncto- meaning “together.” The carboranes
are electron-deficient molecules in which the bonding electrons are shared by three or more atoms. The structural geometries of
various closo-carboranes and nido-carboranes are given in Tables 1 and 2, respectively.

3.20.5 Synthesis of Carboranes

The carboranes can be synthesized by a reaction of boron hydrides with acetylene and its derivatives. Early in the 1950s, using an
electric discharge technique, the first carboranes (1,5-C2B3H5, 1,2 and 1,6 isomers of C2B4H6, and 2,4-C2B5H7) were synthesized in
low yields. In the early years of carborane syntheses, the cage compounds were reported to have formed from a reaction of
482 Endofullerenes and Carboranes

Table 1 Molecular formulas of a few closo-carboranes

and their corresponding structural geometry

Molecular formula Structural geometry

C2B3H5 Trigonal bipyramid

C2B4H6 Octahedron
C2B5H7 Pentagonal bipyramid
C2B6H8 Dodecahedron
C2B7H9 Tricapped square antiprism
C2B8H10 Bicapped square antiprism
C2B9H11 Octahedron
C2B10H12 Icosahedron

Table 2 Molecular formulas of a few nido-carboranes

and their corresponding structural geometry

Molecular formula Structural geometry

CB5H9 Pentagonal pyramid

C2B3H7 Square pyramid
C2B4H8 Pentagonal pyramid
C2B7H13 Icosahedral
C3B3H7 Pentagonal pyramid
C4B2H6 Pentagonal pyramid

unsaturated hydrocarbons with boranes in the vapor phase. It was observed that alkynes more readily led to the formation of
carboranes than alkenes. Under high-energy conditions, the reaction favored the formation of closed-cage carboranes, whereas
open-cage carboranes resulted from milder reaction conditions:7,9
B10 H14 þ C2 H2 / C2 B10 H12 þ2H2
decaborane acetylene carborane

Diethyl sulfide (C2H5)2S can be used as a catalyst in the earlier reaction. Derivatives of the carboranes are synthesized by the
substitution of the hydrogen atoms by other groups. The closo-carboranes can be decapitated to form a nido-carborane, as shown
in the succeeding text:
C2 B10 H12 þ RONa þ ROH/NaC2 B9 H12 þ BðOR Þ3 þ H2

Several types of reactions are currently employed for the synthesis of carboranes, and the predominant methods include the
following:
(a) Borane–alkyne reactions
(b) Alkyl borane–alkyne reactions
(c) Pyrolysis of alkyl boranes
(d) Hydroboration of alkynyl boranes
(e) Reaction involving alkyl haloboranes and alkynyl boranes

3.20.6 Applications of Carboranes and Endofullerenes

3.20.6.1 Biomedical Applications of Carboranes
3.20.6.1.1 Boron Neutron Capture Therapy
Recently, the synthesis of dendritic polyethylene glycosylated (PEG) Au-nanoparticle–carborane assemblies through click chemistry
has been reported.10 The reaction involves azido-terminated Au nanoparticles and alkyne derivatives of carborane and PEG alkyne.
These nanostructures contain an adequate number of carborane cages so as to be useful as the boron source in BNCT, a promising
cancer therapy involving slow moving neutrons.10 Since carboranes contain high boron content clusters, a convenient vehicle is
provided for attaching biomolecules like carbohydrates, amino acids, lipids, nucleic acids, and vitamins to the carbon atoms of
the polyhedron. These carborane-containing biomolecules are promising compounds for BNCT procedures.11

3.20.6.1.2 Analogs of Biomolecules

Analogs of biologically active peptides with carborane-derived amino acids have been synthesized, and several of them have been
reported to have a multifold increase in their biological activity.12 Numerous carborane analogs of retinoic acid receptor ligands
and modulators provide a new class of therapeutic agents in the retinoid-mediated chemotherapy.13,14 Estrogen, a steroid
 Endofullerenes and Carboranes 483

hormone, is the primary sex hormone in females, and it is also an important hormone in males for the development of
secondary sexual characteristics. The steroid hormone 17b-estradiol is an endogenous estrogen and a prominent member of the
class of estrogens. An analog of 17b-estradiol, 1-hydroxymethyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane, has
been reported to have a 10-fold increase in activity.15
Tuberculosis is considered a major threat among the infectious diseases with millions reported to have being infected. Ethambutol
is a widely used drug to treat such patients and thousands of analogs of this drug have been synthesized to achieve increased
effectiveness. The SQ109 is a Mycobacterium tuberculosis growth inhibitor, and a series of analogs involving a 1,2-carborane have
been synthesized.16,17 Although not much potential was observed on Mycobacterium tuberculosis, these compounds have exhibited
cell inhibition among the Gram-negative E. coli. Oldfield and coworkers have reported this interesting observation, which might
pave the way for further investigations on the mechanism behind the antibacterial property of these carborane-containing analogs.18
Dihydrofolate reductase, an enzyme in cell growth and proliferation, is key among folates. Compounds derived using carboranes
have been shown to inhibit the folate in M. tuberculosis.19 A number of enzyme-mimetic systems are being developed, by constructing
prism-like metallacages, using carborane-based metallacycles.20
Carborane-based dendrimers are widely synthesized and they are expected to evolve into nanomedicines in the future. The
properties of the dendrimers can be tuned to obtain the desired biomedical application. Dendrimers of 2,20 -bis(hydroxymethyl)
propanoic acid containing carboranes have been synthesized, and their potential use in BNCT has been identified and reported
by several groups. Many biodegradable dendrimers have been used for the attachment of carboranes, followed by use in the delivery
of boron-10 atoms for BNCT procedures.21
Androgen is a key male reproductive hormone. Androgen antagonists with a 1,12-dicarba-closo-dodecaborane cage, replacing the
C, D rings of the steroid hormone testosterone, can be synthesized, and their biological potency in mouse fibroblast cell lines has
been found to be superior to that of the clinically proved androgen antagonist hydroxyflutamide. Hence, this complex could find
potential use in prostate cancer.22,23 Similarly, a thyroxine transport protein, transthyretin, is found in the blood of amyloid-related
disease conditions, which need to be treated. Several carborane analogs of nonsteroidal anti-inflammatory drugs have been
evaluated for inhibition of amyloid fibril formation. Thus, carboranes are frequently very attractive pharmacophores in the designed
synthesis of new classes of pharmaceuticals.
The HIV protease is a crucial enzyme for the progression of the viral infection, and potential inhibitors of these enzymes are
designed to act as specific anti-HIV drugs. Metallacarborane derivatives were investigated for their anti-HIV activity and were found
to show promising results. Carboranes such as the dicarba-closo-dodecarboranes are reported to inhibit the viral proteases.24–26

3.20.6.2 Electrochemical Applications and Molecular-Level Motions

The development of indirect electrolysis has led to investigations of electrooxidation reactions, where fullerenes and carboranes
have been reported to have promising outcomes.27 Molecular propellers derived using carboranes have been demonstrated to
be driven at GHz rates in an electric field or during gas flow.28,29 Metallacarboranes derived from a dicarbollide ligand and nickel
have a propensity for rotation around the metal–ligand axis. These complexes find potential applications as electrochemically
controlled rotator switches (Fig. 5).30–32
The photoisomerization of four- and three-wheeled fluorescent molecules of varying sizes using p-carborane as wheels has been
identified to show a better photoisomerization than with fullerene wheels.33–35

3.20.6.3 Semiconductor Applications and Materials

Achieving improved performance with reduction in dimensions and costs is the need of the hour in the semiconductor industry.36
Better fabrication of silicon-based devices is obtained by doping the silicon crystal lattice with heteroatoms.37 Liang Ye and

Figure 5 Nickel- and dicarbollide-derived metallacarboranes as potential electrochemical switches. https://en.wikipedia.org/wiki/Carborane.

484 Endofullerenes and Carboranes

coworkers have reported a novel strategy of doping silicon, using carboranes as a source of boron atoms. The report indicates a better
conductivity with the carborane-doped silicon material.38
Polyhedral carboranes are found to be useful molecules in electronics.39 They might also be useful as luminescent materials.40
The o-carboranes act as potential electron-withdrawing groups in oligothiophene-based organic solar cells. Kang and coworkers
have synthesized a series of carboranes containing oligothiophenes and evaluated their potential in heterojunction cells.41
Cyclometalated iridium (III) complexes are established as efficient phosphorescent emitters, and they are widely used as
organic light-emitting diodes and in solid-state lighting.42,43 Homoleptic tris-cyclometalated iridium complexes with substituted
o-carboranes were identified as a good phosphorescent dopant in organic light-emitting diodes.44

3.20.6.4 Applications in Nanovehicles

Nanovehicle is a new class of molecular machine that consists of a molecular-scale chassis and an axle and wheels that can roll on
a solid surface in a defined direction. The strategy adopted is the “top-down” approach to achieve miniaturization. This strategy
is very commonly used in the semiconductor industry. This approach is to continuously shrink a macroscopic entity using
photolithography and other relevant techniques. However, scaling in this manner is nearing its limit.
Miniaturization can be pushed beyond the limit set by the top-down approach if the functional micro- or nanoscopic entities can
be constructed using individual molecules, and this is known as the “bottom-up” approach. Instead of scaling it down, one can
build it up from a molecular foundation. However, due to the complexity of the process, it is very difficult to obtain results that
are comparable with what a biological system is capable. Thus, the attention turned to simpler systems where it is possible to
construct and understand. For useful nanomachines with functional mechanical properties, the machines need to be integrated
into devices that interface with the surrounding system. This step adds extra difficulties to the designing process. Nanomachines
are currently designed to operate in a crystalline solid and to be mounted and operated on a surface or to be moved around
and operated on a surface.
Due to limitations of current tools available for nanoscience, a detailed single-molecular study on a surface is limited. The most
conventional and intuitive machinery for controlled translations on flat surfaces would be a nanovehicle with molecular wheels.
The basic concept is similar to that of the wheelbarrow that we see in our daily life. Although quantum mechanics might not predict
wheels to be the most efficient for nanoscale development, it is also difficult to prove that it will be inefficient. The development of
nanomachines aims to be able to move and operate the machine on a surface by converting energy input into a controlled motion
on a surface. Such input can be heat or electrical energy. The evolution of the nanovehicles could prove to be the future direction of
nanotechnology.

3.20.6.4.1 First Generations of Nanovehicle: Nanotrucks

The first generation of nanovehicles begins with the nanotrucks. This original nanocar does not contain a molecular motor. It was
designed based to understand how fullerenes move about on metal surfaces.45 The molecule consists of an H-shaped chassis with
fullerene groups attached at the four corners to act as wheels as shown in Fig. 6.45 The full chassis was synthesized in the laboratory.
Fullerene wheels were chosen as fullerene has a perfectly spherical shape. However, the synthesis of fullerene derivatives seemed to
be a demanding process. The insolubility of a structure, similar to that shown in Fig. 6, makes the isolation of pure product
somewhat difficult to achieve.

Figure 6 Nanotruck. Reproduced from Shirai, Y.; Osgood, A. J.; Zhao, Y.; Yao, Y.; Saudan, L.; Yang, H.; Yu-Hung, C.; Sasaki, T.; Morin, J.-F.;
Guerrero, J. M.; Kelly, K. F.; Tour, J. M. J. Am. Chem. Soc. 2006, 128, 4854–4864, with permission of American Chemical Society.
 Endofullerenes and Carboranes 485

Figure 7 Nanotruck on gold surface. Reproduced from Morin, J.-F.; Shirai, Y.; Tour, J. M. Org. Lett. 2006, 8, 1713–1716, with permission of
American Chemical Society.

When dispersed on a gold surface, the molecules attach themselves to the surface via their fullerene groups (Fig. 7), and they are
detected via scanning tunneling microscopy.45,46 One can deduce their orientation because the frame length is a little shorter than
its width.

3.20.6.4.2 C60–Motor Hybrid and Introduction of p-Carborane Wheels

A unidirectional synthetic molecular rotor, also known as Feringa motor,47 was first incorporated into the nanocar model with
a fullerene–motor hybrid. However, the incorporation of the two molecular components, the fullerene wheel and the motor,
proved to be incompatible. The rapid intramolecular quenching of the photoexcited state of the motor moiety by the fullerene
wheels mitigated the operation of the motor. Thus, there is a need for the molecular wheels to be photochemically inert in order
to further develop the nanomachines.
The p-carborane structure was later chosen to replace the photoactive fullerene molecular wheels. It has proved to be an excellent
replacement, as it does not have a strong absorption at 365 nm, which is the operational wavelength of the molecular motor. Thus,
this would not quench the motor’s photochemical rotary process. The p-carborane was chosen as it shares similar properties with
fullerenes. Both are highly symmetrical and spherically aromatic; these are two important factors to take into account when designing
a molecular wheel.46 However, p-carborane is highly robust, making it easier to synthesize more elaborated surface-rolling
nanomachines. Furthermore, p-carborane contains carbon atoms that are easily substituted; thus, it is possible to construct molecular
wheels with functionalized “hubcaps.” Hence, the incorporation of the p-carborane wheel not only solved the photoactive fullerene-
wheel incompatibility problem but also provided a better, logical continuation of the development of the surface-capable functional
molecular vehicle.
The structure of the first motorized nanocar (Fig. 846) is a simpler one, since the carborane structure has a better solubility, and
thus, the auxiliary solubility groups of OC12H25 in the previous fullerene-wheeled structure are no longer necessary. The synthetic

Figure 8 p-Carborane nanocar. Reproduced from Morin, J.-F.; Shirai, Y.; Tour, J. M. Org. Lett. 2006, 8, 1713–1716, with permission of American
Chemical Society.
486 Endofullerenes and Carboranes

Figure 9 The p-carborane molecular structures. Arrows indicate expected direction of rolling motion on surfaces. Reproduced from Shirai, Y.;
Morin, J.-F.; Sasaki, T.; Guerrero, J. M.; Tour, J. M. Chem. Soc. Rev. 2006, 35, 1043–1055, with permission of The Royal Society of Chemistry 2006,
All rights reserved.

process gives an  5% overall yield. Considering the extra steps required for the motor, the synthetic advantage gained by using the
p-carborane wheels is large. The thermodynamic and kinetic parameters of the thermal conversion of the unstable to stable isomer
were similar to those obtained by Feringa.47 The bulky p-carborane wheels do not alter the rotation of the motor. This means that
the chassis and axle-bearing alkynyl moieties are long enough to prevent steric hindrance. A number of other carborane-wheeled
nanovehicles (Fig. 9) were synthesized.48

3.20.7 Summary

There is much more to develop in the design, synthesis, and utilization of carborane-based compounds. This article summarizes
research aiming to demonstrate the usefulness of closo-carboranes as biologically and electrochemically active molecules. Active
compounds derived from closo-carboranes act as antagonists, due to their hydrophobic nature, and facilitate protein inhibition,
thereby facilitating treatment of diseases, such as in the case of HIV proteases. Fullerenes and carboranes also show high potential
in constructing nanovehicles based on extensions of the macroscopic concepts. It should be pointed out that current artificial
nanovehicles are still primitive; it could take a long time to find useful applications.

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