Tetrahedron Letters 57 (2016) 5416–5425

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Digest paper

Recent advances in molecular recognition with tetrathiafulvalene-based

receptors
Vladimir A. Azov
University of Bremen, Institute of Applied and Physical Chemistry, Department of Biology and Chemistry, Leobener Strasse UFT, D-28359 Bremen, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Tetrathiafulvalenes (TTFs) are popular building blocks on the scene of supramolecular chemistry, where
Received 28 August 2016 they play various roles ranging from electron rich guest moieties in interlocked supramolecular architec-
Revised 15 October 2016 tures to structural elements of ion sensors. In this review, we discuss so far rather neglected role of TTFs
Accepted 21 October 2016
as active elements of binding sites in molecular receptors. We consider several recent design concepts of
Available online 22 October 2016
molecular receptors with architectures of molecular tweezers, macrocycles, and metal-coordinated cages
that contain two or more TTF, extended TTF, or pyrrolo-TTF moieties. High affinity to electron-deficient
Keywords:
guests and redox activity allowed their use for the construction of functional supramolecular materials
Tetrathiafulvalenes
Molecular receptors
and sensors, as well as pave the way for other practical applications.
Molecular recognition Ó 2016 Elsevier Ltd. All rights reserved.
Macrocycles
Molecular tweezers
Calixpyrroles
Calixarenes
Coordination cages
Functional materials
Charge-transfer complexes

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5416
Tetrathiafulvalenes in molecular recognition as electron-rich guest molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5417
Molecular receptors with tetrathiafulvalenes as building blocks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5417
Receptor concept. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5417
Tetrathiafulvalene-calix[4]pyrroles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5418
Rigid glycolurile-based receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5420
Calixarene-based molecular tweezers and tripodal receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5421
ExTTF tweezers and macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5421
TTF metal coordination cages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5423
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5424
Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5424
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5424

Introduction first a stable radical cation and then a dication (Fig. 1). Initially,
tetrathiafulvalene (TTF) and its derivatives were extensively stud-
Tetrathiafulvalene [1] 1 is redox active electron rich hetero- ied in the context of organic electronics due to the ability to form
cyclic compound that can be oxidized in a stepwise manner giving conductive, semiconductive, and superconductive solid-state
phases [2]. Later, due to their unique electron-donating [3] and
electrochemical properties, TTFs found use as building blocks in
E-mail addresses: vazov@uni-bremen.de, vlazov@gmail.com

http://dx.doi.org/10.1016/j.tetlet.2016.10.082
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
Fig. 1. Stepwise reversible oxidation of TTF to its stable radical-cationic and
dicationic states.
Fig. 2. Structures of modified tetrathiafulvalenes exemplified by directly-substi-
tuted TTFs 2 and 3 and extended TTFs derived by side extension of the p-system 4
and insertion of a p-spacer between two heterocycles 5, respectively.
diverse molecular and supramolecular systems [4], ranging from
polymers [5], dendrimers [4], and ion sensors [4] to Langmuir-
Blodgett films [4] and charge-transfer systems [6], commonly play-
ing the role of redox-switchable groups [7].
Flexibility of TTF chemistry [8] allowed attachment of different
substituents R in a symmetric and asymmetric manner, allowing
integration of TTF moieties in various molecular architectures
and fine tuning of their oxidation potentials and electron-donating
properties (Fig. 2). Attachment of alky substituent leads to the
decrease of the first oxidation potential (like in tetramethyl-TTF
2), whereas thioalkyl substituents (like in tetrathiomethyl-TTF 3)
affect the first oxidation potential in the opposite manner, leading
to its increase [2a]. Direct extension of the p-systems via the two
neighboring carbon atoms of one or both 1,3-dithiole
heterocycles is another possibility to alter the properties of TTFs.
Pyrrolo-annealed tetrathiafulvalenes [9] 4 represent one of the
examples that feature an extended p-systems, low oxidation
potentials and convenient possibility to attach substituents to N-
atom of pyrroles using simple nucleophilic substitution reactions.
Another commonly used strategy to create new TTF derivatives is
to expand the backbone of TTF by the insertion of diverse vinyl,
ethynyl, and p-quinoid (such as 9,10-dihydroanthracene moiety
in 5) p-spacers between the two 1,3-dithiole rings. This methodol-
ogy has been successfully employed for the construction of the
cyclic and acyclic p-extended TTF (exTTF) derivatives [10].
Tetrathiafulvalenes in molecular recognition as electron-rich
guest molecules
One of the most exciting applications of tetrathiafulvalenes
belongs to the realm of so-called interlocked supramolecular archi-
Fig. 3. Reversible formation of 1:1 complex between CBPQT4+ and TTF by inclusion
of electron-rich TTF moiety into electron-poor CBPQT4+ cavity. Complex stability
strongly depends on the nature of the TTF substituents R.
5417
tectures, such as catenanes and rotaxanes [11]. In these interlocked
systems, electron-rich TTF guest is stacked between two positively
charged electron deficient viologen units of the host cyclobis(-
paraquat-p-phenylene) (CBPQT4+) macrocycle. After the first
reports on the synthesis of TTF-containing rotaxanes [12] and cate-
nanes [13,14], this very potential type of host–guest system was
widely used in construction of redox-switchable molecular
devices, supramolecular assemblies on surfaces and on nanoparti-
cles [15]. One particularly impressive feature of the TTF-containing
interlocked systems is the possibility to switch them between two
or more states by reversible altering of the electron-donating prop-
erties of TTFs by their oxidation and reduction. In the non-oxidized
state, electron-rich TTF moiety resides inside the electron deficient
CBPQT4+ macrocycle. Upon oxidation, TTF loses its electron donat-
ing properties and slips out of CBPQT4+ cavity, being usually
replaced by an aromatic moiety, and returns back after its reduc-
tion. Thus, TTF plays a role of the redox-controllable molecular
motor, which drives positional displacement of supramolecular
components upon its reversible oxidation and reduction.
Self-assembly between CBPQT4+ and TTF groups [16] (Fig. 3)
proceeds spontaneously upon mixing of two species. Binding stud-
ies between CBPQT4+ macrocycle and various TTF derivatives have
shown that binding affinity strongly depends on the nature of TTF
substituents, with thiolakyl-substituted TTFs being the weakest
binders and alkyl-substituted TTFs and pyrrolo-TTFs being the
strongest binders. Direct correlation between the first oxidation
potential of TTF derivatives and their binding affinity to CBPQT4+
macrocycle has been reported [17]. The binding process between
TTF and CBPQT4+ is fast on the NMR timescale, but can be slowed
down or even precluded by the attachment of bulky substituents
on both sides of TTF group.
Molecular receptors with tetrathiafulvalenes as building blocks
Receptor concept
In the well-studied host–guest systems discussed above, single
electron-rich TTF unit served as a guest for an electron-deficient
positively charged macrocylcle. On the other hand, host–guest sys-
tems, employing the reverse binding principle, i.e. host molecule
with a binding site comprising two or more TTF moieties arranged
for the binding of electron-deficient guests (Fig. 4), are much less
common. In this review, we discuss recently developed TTF-based
receptors with multiple TTF groups, tailored for the binding of dif-
ferent types of electron-deficient guests. Several types of such
receptors were designed during the last decade, including tetrathi-
afulvalene-calix[4]pyrrole, rigid glycolurile-based receptors with
two parallel TTF arms, calixarene-based receptors with TTF arms,
cyclic and acyclic receptors employing exTTFs, and TTF-based
metal coordinated cages. All these receptor classes showed high
binding affinity to electron deficient guests, which varied from
Fig. 4. Paradigm shift in receptor design: from being a guest, tetrathiafulvalene
becomes a part of the binding cavity of a host molecule.
5418 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
planar aromatic molecules to fullerenes. Guest selectivity (planar
vs. spherical guests) was achieved by the fixation of the appropri-
ate geometry of molecular recognition centers. Various types of
molecular clips and tweezers for binding of neutral guests have
been discussed before [18]; this review will focus on receptor sys-
tems comprising two or more tetrathiafulvalene building blocks.
Additionally, TTF-containing molecular tweezers that were not
employed as molecular receptors [19] will not lie in the focus of
this review.
Initial attempts to construct tetrathiafulvalene-based molecular
receptors were focused on the use of TTF cyclophanes and cage
molecules [20]. Most of them fell short of the expected goal, with
binding affinity below the initial expectations. Although such com-
pounds formed mixed donor–acceptor phases in the solid state,
binding affinity in solution was relatively weak and usually not
reported. TTF cyclophane 6 and pyrrolo-tetrathiafulvalene ‘‘belt”
7 can serve as illustrative examples (Fig. 5a). Receptor 6 formed
charge-transfer (CT) complexes with 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ) and fullerene C60 in the solid state. X-ray
analysis of the co-crystals showed the location of the guest mole-
cules in the cavity of the receptor between two TTF units, whereas
6 formed self-inclusion ‘‘hand-in-hand” complexes in the pure
form [21]. In the cocrystal of belt 7 with tetracyanoquin-
odimethane (TCNQ), one TCNQ molecule is located between two
TTF-containing macrocycles and not within a molecular cavity
(Fig. 5b), as it could have been expected [22]. TTF-belt is collapsed
due to direct intramolecular TTF-TTF contacts, leaving no space
between the two TTF units for a guest molecule.
Fig. 5b clearly demonstrates the common problem pertinent to
all flexible bis-TTF molecular structures: they tend to collapse due
to the stacking of the neighboring TTF groups. Tendency to form
the stacks is well-known and is of advantage for the formation of
conductive phases in the solid state, but should be precluded in
the structures of molecular receptors. Tetrathiafulvalenes favor
Fig. 5. (a) Structures of TTF-containing cyclophanes 6 and 7. (b) Crystal packing of
7
TCNQ that distinctly shows intramolecular slipped stacking of TTF moieties with
each other. (Reprinted with permission from Ref. [22]. Copyright 2002 the American
Chemical Society.)
formation of parallel-displaced stacks (slipped stacking), as seen
in Fig. 5. Thus, if a receptor with two parallel-aligned TTF groups
does not allow their mutual relative displacement, TTF propensity
to stack is also significantly reduced. Taking into account these
construction principles, several ingenious TTF-based receptor
architectures have been designed and successfully implemented.
All of them feature well-defined binding cavity and rigid backbone,
which preclude the formation of tight intramolecular parallel-dis-
placed TTF stacks.
Tetrathiafulvalene-calix[4]pyrroles
TTF-calix[4]pyrrole receptor (TTF-C[4]P) 8 (Fig. 6a) was first
reported in 2004 by Sessler/Jeppesen [23a] and represents the
most successful and universal class of TTF-based receptors
designed to date. It is prepared by the four-fold condensation of
mono-pyrrolo-TTF 9 with acetone under acidic conditions. Its
architecture is based on the structure of calix[4]pyrrole anion
receptor [24], with four pyrrole units being replaced by their
mono-pyrrolo-TTF (MPTTF) analogues. Due to the unique design,
TTF-C[4]P 8 can serve both as the receptor for small inorganic
anions, as well as for electron-deficient aromatic molecules. Bind-
ing of an anion, such as Cl , triggers conformational switching from
1,3-alternate to cone conformation of the receptor [23b,c], whereas
rigid framework of calix[4]pyrrole backbone prevents TTF moieties
from intramolecular stacking with each other in both of these
conformations. In the 1,3-alternate double-sided tweezer-like
conformation, TTF-C[4]P can serve as a binder of planar electron
deficient molecules (Fig. 6b). Common classes of planar guests
include nitroaromatic derivatives, such as 1,3,5-trinitrobenzene
10, and fluorenone derivatives, such as methyl 2,5,7-
trinitrodicyanomethylenefluorene-4-carboxylate (MTNDMFC) 11.
Driving force of the complex formation are the p–p stacking and
charge-transfer (CT) interactions between electron-rich MPTTF
moieties of the receptor and electron-deficient guests, as well as
H-bonding between the HN-groups of pyrroles and nitro-groups
of the guests. In the cone vase-shaped conformation, TTF-C[4]P
binds fullerenes C60 12, its derivatives, and C70, which also
represent electron-deficient guest species. Due to the formation
of CT complexes, host–guest binding is always accompanied by
spectral changes and is commonly visible with a naked eye.
Fig. 7 illustrates switching between the two binding conforma-
tions of TTF-C[4]P using the complexation of Cl anion accompa-
nied by selective binding of either a planar guest in the 1,3-
alternate and of a spherical guest (fullerene) in the cone conforma-
tion. Binding of Cl and of electron-deficient guests can be moni-
tored using methods of optical and NMR spectroscopy, as well as
cyclic voltammetry [23c]. Ambivalent guest 13 is bound by both
conformations of TTF-C[4]P receptor 8.
In a later study the binding stoichiometry between TTF-C[4]P
receptor 8 and fullerene was revised on the basis of several X-ray
structures (Fig. 8) and job Plot experiments [25]. It has been shown
that the 1:1 binding stoichiometry between buckyballs and TTF-C
[4]P receptors best describes receptor-fullerene interactions, than
the previously reported 1:2 host–guest stoichiometry.
Due to its four-fold symmetry, structural modification of the
TTF-calix[4]pyrroles is possible in symmetric and asymmetric
manner. Symmetric modification of 8 can be performed in a
straightforward way by using the same one-pot four-fold conden-
sation of MPTTF building blocks with different substitution pat-
terns and acetone. Different MPTTF derivatives, for example,
benzene- or thiophene-annealed MPTTFs [26], and can be used to
tune the solubility profile and electron-donating properties of the
TTF-C[4]P receptors. Asymmetric modification is more tedious,
since it demands separation of complex product mixtures derived
from co-cyclization of two different MPTTF building blocks [27].
 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
Fig. 6. (a) Synthesis of tetra-TTF-calix[4]pyrrole (TTF-C[4]P) receptor 8 by the four-fold condensation of mono-pyrrolo-TTF 9 with acetone. Formed receptor is shown in 1,3-
alternate conformation. (b) Typical guests of receptor 8.
Fig. 7. Change of the binding modes between TTF-C[4]P receptor 8 and its guests:
quasi-planar electron-deficient aromatic guests are bound in the 1,3-alternate
conformation, whereas the receptor in the cone conformation induced by Cl
complexation preferentially binds electron-deficient spherical guests. (Reprinted
after modifications with permission from Ref. [23c]. Copyright 2002 Elsevier.)
TTF-calix[4]pyrroles with one and two MPTTF units and three or
four non-substituted pyrroles in the backbone, respectively, have
also been synthesized, but were less effective in comparison with
the symmetric receptors comprising four MPTTF moieties [28].
Excellent guest binding properties, which are accompanied by
the changes of optical and NMR spectra as well as of electrochem-
ical properties, paved the way for several practical applications for
TTF-C[4]P receptors. One of the applications lies in the field of
detection of nitroaromatic derivatives, which are broadly used as
commercial explosive materials and are subject of strict control
in the environment. Binding of nitroaromatic explosives, such as
1,3,5-trinitrobenzene (TNB, 10), 2,4,6-trinitrotoluene (TNT) or pic-
5419
Fig. 8. X-ray structure of (TBA) [C60(2
F)]. TBA = tetrabutylammonium. (Rep-
rinted after modifications with permission from Ref. [25]. Copyright 2014 the
American Chemical Society.)
ric acid (2,4,6-trinitrophenole, TNP) with receptor 8 or its symmet-
rically substituted analogues leads to formation of charge-transfer
complexes, easily detectable using spectroscopic methods. Inter-
estingly, positive homotropic allosteric effect is observed, when
TTF-C[4]P 8 is titrated with the test compounds TNB, TNP, and
TNT. It was explained by the rigidification of the receptor structure
and favorable inductive polarization of the opposite binding site
after the binding of the first molecular guest. Receptor 8 and its
symmetric derivatives with an altered TTF substitution pattern
can operate in an aqueous environment, although their sensitivity
is not sufficient for practical applications. Later it was demon-
strated that asymmetric TTF-C[4]P s can be employed as colorimet-
ric chemosensors either for nitroaromatic explosives or anions
depending on the substituent attached to one of the MPTTF arms.
Another promising application for tetrathiafulvalene–calix[4]
pyrroles lies in the field of so-called functional materials, i.e. self-
5420 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
Fig. 9. Schematic representation of the proposed supramolecular polymer formed
from TTF-C[4]P 8 and di-2,5,7-trinitrodicyanomethylene-fluorene-4-carboxylate
(di-TNDCF) 14. Addition of TNB 10 or Cl leads to decomposition of the polymer due
to competitive complexation or conformational change of TTF-C[4]P, respectively.
Chemical structure of the linker molecule TNDCF 14 is shown below.
assembled supramolecular aggregates that can undergo reversible
stimuli-induced assembly and disassembly. In their cooperative
work, groups of Sessler/Jeppensen designed a number of
supramolecular polymeric systems comprising two hetero-com-
plementary components, one of which was TTF-C[4]P 8 that inter-
acted with a hetero-complementary monomer to form a polymeric
structure. Two general system types have been designed. In the
first type, binding of the second ditopic component occurs in the
1,3-alternate conformation of the receptor. As the second mono-
meric components that interlinks TTF-C[4]Ps with each other serve
molecules with two electron-deficient nitro-aromatic groups, such
as dinitrophenyl-functionalized calix[4]pyrrole [29a], bis-3,5-
Fig. 10. Glycoluril-based molecular clips 15, 16, and 17 with several different types of TTF arms prepared in the groups of Chiu and Hudhomme.
dinitrobenzoates [29b], and a glycol diester-linked bis-2,5,7-
trinitrodicyanomethylenefluorene-4-carboxylate [29c] 14 (bis-
TNDCF). The resulting functional supramolecular polymers are
held together by a combination of donor–acceptor and hydrogen
bonding interactions. They undergo dynamic, reversible
structural transformations upon exposure to very different types
of external chemical stimuli, namely chloride anion Cl or 1,3,5-
trinitrobenzene 10 (Fig. 9), which exert their function through
two different mechanisms. In the former case, decomposition of
the polymer is due to conformational change of TTF-C[4]P from
binding 1,3-alternate conformation to non-binding cone
conformation, whereas in the latter case it is due to competitive
complexation of TNB with TTF-C[4]P, while remaining in the
same 1,3-alternate conformation.
The second type of redox- and pH-responsive supramolecular
polymeric system based on TTF-C[4]P 8 employs phenyl C61 buty-
ric acid (PCBA) as a second heteroditopic monomer [30]. Self-
assembly of these monomers is initiated by the conformational
switching of TTF-C[4]P to cone conformation upon its interaction
with deprotonated carboxylic group of PCBA followed by its com-
plexation with the fullerene moiety of the second PCBA molecule.
The chemistry, properties and applications of tetrathiaful-
valene-calix[4]pyrroles have been comprehensively reviewed in a
very recent review of Sessler and co-workers [31].
Rigid glycolurile-based receptors
Several structurally similar molecular clips [32] (i.e. molecular
receptors with an open cavity that function by stapling a guest
molecule between two ‘‘arms” or ‘‘wings”) 15–17 with tetrathiaful-
valene arms were built on the base of concave glycolurile scaffold
by rigid attachment of two TTF units using two short CH2-spacers.
(Fig. 10).
Molecular clips 15 were first synthesized by the group of Chiu
[33] and were reported to bind positively charged electron defi-
cient macrocycle containing a cation-recognition domain. This
macrocycle/molecular-clip system functions as a molecular switch
controllable by several different pairs of external stimuli. Upon the
use of K+/[2.2.2]cryptand (complexation-decomplexation with the
macrocycle), NH+4/Et3N (complexation-decomplexation with the
macrocycle), (p-BrPh)3NSbCl6/Zn (oxidation–reduction of TTF
arms) reactant pairs, as well as of heating/cooling cycles, control
of the movement of this molecular switch between its threaded
and unthreaded states can be achieved. The association/dissocia-
tion processes leads to formation/destruction of the CT complex
and color changes that are observable by the naked eye.
 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
Fig. 11. Calixarene-based molecular tweezers 18 and 19 and tripodal receptors 20
comprising two or three MPTTF units as a binding center, respectively.
The concept of glycoluril-based molecular clips with TTF arms
has been later expanded in the group of Hudhomme [34], which
reported the synthesis of structurally similar receptors 16 and 17
with shortened and extended arms, respectively. In addition to
binding of planar electron-deficient guests, molecular clips 15–17
displayed complex electrochemical behavior, featuring self-com-
plexation and formation of mixed-valence and radical cation dimer
states upon their partial oxidation in a solution [33c,34b]. This
behavior manifested itself in the splitting of the first oxidation of
TTF and by the absorption in the near-IR region, pertinent to
elusive mixed-valence and radical cation dimer of TTFs, usually
not observable in a solution.
Calixarene-based molecular tweezers and tripodal receptors
Calixarenes represent a universal and flexible backbone widely
used in supramolecular chemistry. Despite that, only few cal-
ixarene-TTF conjugates have been reported to date, with most of
them being designed as ion-binders with TTF groups playing the
role of electrochemical relay. Only recently, several calixarene-
based bis-TTF molecular architectures aimed at binding of elec-
tron-deficient guest were reported. The first reported calixarene-
based molecular tweezers employed tetrathio-substituted TTFs
and displayed only modest binding properties [35]. Therefore,
monopyrrolo-TTFs (MPTTFs) were chosen as the follow-on build-
ing blocks due to their better electron-donating properties and
more extended p-systems. Using MPTTFs, calixarene-based molec-
ular tweezers 18 and 19 (Fig. 11) were constructed in the group of
Fig. 12. (a) Molecular model of the host–guest complex of 18 with TCNQ (R = H).
Propyl groups on the lower calix[4]arene rim are replaced with methyls. (b) Binding
titration of 18 with TCNQ showing formation of the charge-transfer bands.
5421
Fig. 13. Schematic illustration of complex formation between the host H and G
showing plausible double-decker structure of [G
(H)2]. Depending on the oxidation
state of H (neutral or double positively charged), the overall charge of the complex
can be either 2 or 2+. The host H 20 is shown in yellow, green icosahedron
represents the guest G closo-dodecaborate dianion [B12C12]2 . (For interpretation of
the references to colour in this figure legend, the reader is referred to the web
version of this article.)
Azov [36]. Receptors 18 and 19 differed from each other by the way
of attachment of MPTTF units to the calix[4]arene scaffold:
whereas more rigid receptors 18 feature direct Ar-TTF bond, in
more flexible receptors 19 Ar-TTF contained an additional –CH2–
link. Receptor 18 were prepared using the direct copper-catalyzed
N-arylation of the upper-rim brominated calixarenes with MPTTF
units, whereas 19 was prepared using nucleophilic substitution
of the bromomethylated calixarene derivative under basic condi-
tions. Moreover, structurally related tripodal receptors [37] com-
prising three MPTTF units attached to the 1,3,5-substituted-2,4,6-
triethylbenzene scaffold were prepared in a similar manner to 19.
Addition of planar electron-deficient guests, such as TCNQ or
2,5,7-trinitro-9-dicyanomethylenefluorene, to a receptor solution
leads to formation of deeply-colored charge-transfer complexes.
In general, rigid receptors 18 were found to be more efficient bin-
ders than the flexible ones 19, what can be rationalized by the good
match between the guest and the binding cavity of the receptors
(Fig. 12a). UV/vis binding titrations (Fig. 12b) allowed determina-
tion of the binding constants, which reached as high as
2  105 m 1 in CH2Cl2 for Me-substituted rigid receptor [38] 18
(R = Me; Fig. 11). All TTF-based receptors displayed reversible oxi-
dation/reduction processes.
Tripodal receptors were found to be efficient binders of ionic
species in the gas phase. As it was proven by ESI-MS experiments,
these molecular hosts displayed high affinity not only to posi-
tively-charged pyridinium derivatives [37] but also to dianionic
icosahedral closo-dodecaborate [39] [B12C12]2 , which cannot be
considered per se electron deficient species due to delocalized neg-
ative charge (Fig. 13). Formation of host–guest complexes with 1:1
and 2:1 stereochemistry was observed in the latter case. As
expected, receptor 20 also formed host–guest complexes after its
partial chemical oxidation due to electrostatic attraction between
the positively charged receptors and negatively charge dodecabo-
rate. Thus, the overall charge of this supramolecular complex can
be switched between -2 and + 2 without its decomposition.
ExTTF tweezers and macrocycles
Whereas ‘‘parent” tetrathiafulvalene 1 and its derivatives with
peripheral substituents are planar or exhibit only very slight devi-
ation from planarity in their energy minimum, some extended TTFs
derived by insertion of a p-spacer between two rings are not planar
in their ground state. This corresponds also to exTTF 5 (Fig. 2),
derived from 1 by the insertion of 9,10-dihydroanthracene unit,
which features curved geometry in its non-oxidized state. The
shape complementarity between the concave aromatic surface
exTTF 5 and the curved exterior of fullerenes and carbon nanotubes
leads to attractive non-covalent interactions between these species
5422 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425

Fig. 14. (a) Tweezers-type 21a and cyclic 22 fullerene receptors based on curved exTTF building blocks. (b) Side and top views of the energy-minimized (AMBER) model of the
22
C60 (n = 2, spacer = p-xylyl) associate. The macrocycles are depicted in stick representation, whereas fullerenes are shown as space-filling models. (Reprinted with
permission from Ref. [43]. Copyright 2002 the American Chemical Society.)

and allowed construction of exTTF-containing molecular receptors

with architectures of molecular tweezers, macrocycles, and den-
drimers [40]. Additionally, curvature of the exTTF backbone pre-
vents their direct stacking, allowing to keep flexible architecture
of molecular receptors.
Molecular tweezers 21a (Fig. 14a) represent the first synthetic
receptor for fullerene C60 employing the exTTF building block
[41]. Despite its relatively simple design, 21a efficiently binds full-
erene in chlorobenzene and CHCl3/CS2 mixtures, with binding con-
stant Ka, determined using the UV-vis binding titrations, reaching
as high as 3.00  103 M 1 in PhCl. Additionally, receptor 21a dis-
played uncommon solvent-controlled positive homotropic cooper-
ative binding behavior, which manifested itself in CHCl3/CS2
mixtures by the formation of a tetrameric complex with two units
of C60 sandwiched between two molecules of receptor 21a. Further
development of this structural design led to dendrimer structures
containing up to 24 exTTF moieties [42]. These redox-active den-
drimers also displayed affinity to C60 in solution, and the binding
process occurred in a positive cooperative manner similar to
molecular tweezers 21a.
As the further project development, macrocycles 22 containing
the same exTTF building block have been synthesized and tested as
fullerene hosts [43]. To rigidify their structure, these macrocycles
contained two additional rigid fragments, an aromatic and a vinyl
spacers (Fig. 14a). Several macrocycles with o-xylyl and p-xylyl as
well as naphthyl spacers and with the alkene tether of variable
length were prepared. Their binding properties toward two differ-
ent fullerenes, C60 and C70, were compared in chlorobenzene. The
best binder 22 (n = 2, spacer = p-xylyl) bound C60 with log Ka = 6.5 -
M 1 in PhCl at room temperature (Fig. 14b), demonstrating the
superiority of macrocyclic design over the acyclic one. Extended
macrocycles with naphthyl spacers were better suited for binding
of the larger C70 guests, whereas the smaller macrocycles with
xylyl spacers and short tethers (n = 0) demonstrated 2:1 binding
with C70. Fig. 15. (a) Stricture of the water-soluble exTTF-based molecular tweeter 21b and
(b) of its complex with nanotube depicting the process of electron transfer from TTF
Ex-TTF-based nanotweezers 21b with a polar solubilizing den- to CNT upon photon absorption. (Reprinted with permission from Ref. [44].
dron in the m-position have (Fig. 15) been employed for binding Copyright 2002 the American Chemical Society.)
 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
of carbon nanotubes (VNT) in the aqueous media [44]. The curved
ex-TTF group is known for its affinity to CNT through p–p stacking
and electron donor–acceptor interactions. In the case of nan-
otweezers, synergetic effect of two tetherd exTTF groups lead to
enhanced stability of the supramolecular aggregates. Steady-state
as well as time-resolved spectroscopy investigation gave evidence
for efficient electronic communication between the exTTF nan-
otweezers and CNTs in the ground and excited states. In the elec-
tronic ground state electronic communication results in a shift of
electron density from exTF to CNT, and in the excited electronic
state a full separation of electron density was observed, leading to
oxidized exTTF and reduced CNT. Lifetimes of the exited states were
determined to be in the range of several hundred picoseconds.
TTF metal coordination cages
Metal coordination cages are supramolecular assemblies that
usually possess well-defined structures with good spatial separa-
Fig. 16. Formation of the Pt-coordinated molecular trigonal prism 23 from three
pyridine-modified MPTTF units 24.
Fig. 17. Formation of the Pd-coordinated molecular cage 25a–c by four-fold coordination of two exTTF units 26a,b.
5423
tion between the rigid components comprising their structures.
The inner cavity is delineated by the ligands bound with each other
via coordinated metal atoms at their apexes. Due to these design
principles precluding intramolecular ligand stacking, metal coordi-
nation cages are well suited for the preparation of TTF-containing
supramolecular hosts. Nevertheless, the first examples of TTF-
based metal coordination cages was reported only within the last
five years by the group of Salle.
Coordination cage 23 (Fig. 16) has the form of molecular prism
and self-assemble upon coordination of four tetra-dentate bis-pyr-
rolo-TTF ligands 24 by six Pt centers [45]. Although formation of
several different structures can be expected upon mixing of 24 with
the 2-fold excess of cis-(PEt3)2Pt(OTf)2 complex, the reaction in
dimethyl sulfoxide converged to a single product 23, as it was
shown first by ESI-MS and NMR, and then by X-ray crystallography.
UV-vis titration of the solution of 23 with tetrafluorotetracyano-p-
quinodimethane (TCNQF4) gave evidence for the formation of the
charge-transfer complexes with 1:1 stoichiometry.
Using the same principle of Pt- or Pd-coordination with pyri-
dine-containing ligands, a family of coordination cages 25a–c with
the side panels based on the exTTF groups has been synthesized
[46]. Due to intrinsic curvature of the exTTF moiety, such cages
form by the coordination of only two tetra-dentate exTTF-contain-
ing ligands 26a,b (Fig. 17) with M4L8+
2 stoichiometry/charge. Struc-
ture of coordination cages 25b was proven by X-ray, both in the
pure form as well as the inclusion complex with [B12F12]2 guest
with 1:2 host/guest stoichiometry. In the complex, each
[B12F12]2 anion is located in the cavity between two palladium
metal centers, whereas the cavity shape is slightly distorted in
comparison to the free cage 25b.
Using metal-coordinated cages 25, the first example of redox-
triggered guest release process from a coordination cage has been
demonstrated [46b]. Four triethyleneglycol (TEG) chains attached
to each of the ligands 26b increase the solubility of the cages as
well as, more importantly, tune the redox properties of the
5424 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
Fig. 18. (a) Side and (b) top views of the X-ray crystal structures of the
[coroneneM4
25c2] complex; R = O(CH2CH2O)3CH3. Colors used: green for exTTF
skeleton, blue for PEG chains, orange for Pd complex, gray for coronene. (Reprinted
with permission from Ref. [46c]. Copyright 2016 Royal Society of Chemistry.) (For
interpretation of the references to colour in this figure legend, the reader is referred
to the web version of this article.)
coordination cages. Due to the electron-donating mesomeric effect
of the four TEG substituents, oxidation potential of substituted
exTTFs is suitably separated from the one of ferrocenyl co-
ligands, allowing the selective oxidation of the exTTF moieties of
the coordination cage 25b. The oxidation of ex-TTF groups is
accompanied by a drastic change of the molecular shape from a
bent butterfly-like structure to an extended shape with two
aromatic positively charged 1,3-dithiolium rings located in one
plane and appended to the anthracene moiety. Due to shape
change, selective oxidation of the TTF moieties of cage 25b leads
to its immediate disassembly into components. It was shown
that the cage 25b disassembles upon chemical oxidation with the
thianthrenium radical cation, releasing the complexed guest out
of the cavity, and subsequently reassembles upon reduction with
tetrakis(dimethylamino)ethylene.
In a subsequent paper, it was reported that guest binding can be
tuned by altering the total charge of the coordination cage [46c],
what can be achieved by the variation of the ligands of the four
metal atoms holding the cage together. Modified neutral M4L2
cage 25c exhibits a good ability to bind planar polyaromatic
guests, such as coronene, perylene, and pyrene, with the 1:1
stoichiometry, showing much better binding affinity in
comparison with the charged M4L8+ 2 capsules 25a,b, and affording
evidence that neutral guests prefers binding by neutral molecular
cages. The binding constant for the coronene complex (Fig. 18)
was 1.1  105 M 1, almost three orders of magnitude higher in
comparison with the positively charged coordination cage. Thus,
metal coordination cages with TTF panels represent a novel
highly promising class of redox-controllable molecular capsules
for electron-deficient molecular guests.
Conclusions
To summarize, recent advances in the field of tetrathiaful-
valene-based receptors convincingly demonstrate that TTFs pos-
sess significant potential as an electron-rich building block for
the receptor construction. In the course of the last decade, several
efficient molecular receptor types employing TTF building blocks
have been designed and successfully tested. Although their molec-
ular architectures are diverse, comprising acyclic and cyclic struc-
tures, as well as metal coordination cages, all of them feature well-
separated TTF moieties, which prevent their intramolecular stack-
ing and allow easy guest access to the binding center. TTF-based
molecular receptors offer broad perspective for their application
in the field of sensorics and functional materials. Although TTFs
represent redox-active building blocks, this aspect of their chemi-
cal activity still remains almost unexploited in the context of
receptor function. In future, the ability to control electron-donating
properties of tetrathiafulvalenes by their reversible oxidation and
reduction can be used to create redox-controllable functional
materials and molecular Velcro.
Acknowledgement
The author is grateful to Dr. S. Bähring (University of Southern
Denmark) and Prof. M. Sallé (University of Angers) for their help
with the preparation of illustrations.
References and notes
[1] (a) J.L. Segura, N. Martín, Angew. Chem. Int. Ed. 40 (2001) 1372–1409;
(b) TTF Chemistry. Fundamentals and Applications of Tetrathiafulvalene,
Yamada, J., Sugimoto, T., Eds.; Springer: Heidelberg, 2004.
[2] (a) F. Wudl, Acc. Chem. Res. 17 (1984) 227–232;
(b) M. Bendikov, F. Wudl, D.F. Perepichka, Chem. Rev. 104 (2004) 4891–4945.
[3] M.R. Bryce, Adv. Mater. 11 (1999) 11–23.
[4] (a) M.R. Bryce, J. Mater. Chem. 10 (2000) 589–598;
(b) M.B. Nielsen, C. Lomholt, J. Becher, Chem. Soc. Rev. 29 (2000) 153–164;
(c) J. Becher, J.O. Jeppesen, K. Nielsen, Synth. Met. 133–134 (2003) 309–315.
[5] S. Inagi, K. Naka, Y. Chujo, J. Mater. Chem. 17 (2007) 4122–4135.
[6] J. Guasch, L. Grisanti, M. Souto, V. Lloveras, J. Vidal-Gancedo, I. Ratera, A.
Painelli, C. Rovira, J. Veciana, J. Am. Chem. Soc. 135 (2013) 6958–6967.
[7] D. Canevet, M. Sallé, G. Zhang, D. Zhang, D. Zhu, Chem. Commun. (2009) 2245–
2269.
[8] (a) G. Schukat, E. Fanghänel, Sulfur Rep. 18 (1996) 1–278, For reviews on
synthetic chemistry of tetrathiafulvalenes, see:;
(b) J.M. Fabre, Chem. Rev. 104 (2004) 5133–5150.
[9] J.O. Jeppesen, J. Becher, Eur. J. Org. Chem. (2003) 3245–3266.
[10] (a) J. Roncali, J. Mater. Chem. 7 (1997) 2307–2321;
(b) M.B. Nielsen, F. Diederich, Chem. Rev. 105 (2005) 1837–1867;
(c) Y. Zhao, G. Chen, K. Mulla, I. Mahmud, S. Liang, P. Dongare, D.W. Thompson,
L.N. Dawe, S. Bouzan, Pure Appl. Chem. 84 (2012) 1005–1025.
[11] (a) A.R. Pease, J.O. Jeppesen, J.F. Stoddart, Y. Luo, C.P. Collier, J.R. Heath, Acc.
Chem. Res. 34 (2001) 433–444;
(b) N.N.P. Moonen, A.H. Flood, J.M. Fernández, J.F. Stoddart, Top. Curr. Chem.
262 (2005) 99–132.
[12] P.R. Ashton, R.A. Bissell, N. Spencer, J.F. Stoddart, M.S. Tolley, Synlett (1992)
923–926.
[13] Z.-T. Li, P.C. Stein, N. Svenstrup, K.H. Lund, J. Becher, Angew. Chem. Int. Ed.
Engl. 34 (1995) 2524–2528.
[14] Z.-T. Li, P.C. Stein, J. Becher, D. Jensen, P. Moerk, N. Svenstrup, Chem.-Eur. J. 2
(1996) 624–633.
[15] (a) J.F. Stoddart, Chem. Soc. Rev. 38 (2009) 1802–1820;
(b) R. Klajn, J.F. Stoddart, B.A. Grzybowski, Chem. Soc. Rev. 39 (2010) 2203–
2237.
[16] (a) D. Philp, A.M. Slawin, N. Spencer, J.F. Stoddart, D.J. Williams, J. Chem. Soc.,
Chem. Commun. (1991) 1584–1586;
(b) W. Devonport, M.A. Blower, M.R. Bryce, L.M. Goldenberg, J. Org. Chem. 62
(1997) 885–887.
[17] (a) M.B. Nielsen, J.O. Jeppesen, J. Lau, C. Lomholt, D. Damgaard, J.P. Jacobsen, J.
Becher, J.F. Stoddart, J. Org. Chem. 66 (2001) 3559–3563;
(b) S. Nygaard, C.N. Hansen, J.O. Jeppesen, J. Org. Chem. 72 (2007) 1617–1626.
 V.A. Azov / Tetrahedron Letters 57 (2016) 5416–5425
[18] M. Hardouin-Lerouge, P. Hudhomme, M. Sallé, Chem. Soc. Rev. 40 (2011) 30–
43.
[19] (a) H. Fujiwara, E. Arai, H. Kobayashi, J. Mater. Chem. 8 (1998) 829–831;
(b) C. Simao, M. Mas-Torrent, V. André, M.T. Duarte, J. Veciana, C. Rovira,
Chem. Sci. 4 (2013) 307–310;
(c) V.A. Azov, R. Gómez, J. Stelten, Tetrahedron 64 (2008) 1909–1917.
[20] J.O. Jeppesen, M.B. Nielsen, J. Becher, Chem. Rev. 104 (2004) 5115–5131.
[21] (a) T. Tachikawa, A. Izuoka, T. Sugawara, J. Chem. Soc., Chem. Commun. (1993)
1227–1229;
(b) A. Izuoka, T. Tachikawa, T. Sugawara, T. Saito, S. Shinohara, Chem. Lett.
(1992) 1049–1052.
[22] K. Nielsen, J.O. Jeppesen, N. Thorup, J. Becher, Org. Lett. 4 (2002) 1327–1330.
[23] (a) K.A. Nielsen, W.-S. Cho, J.O. Jeppesen, V.M. Lynch, J. Becher, J.L. Sessler, J.
Am. Chem. Soc. 126 (2004) 16296–16297;
(b) K.A. Nielsen, G.H. Sarova, L. Martín-Gomis, F. Fernández-Lázaro, P.C. Stein,
L. Sanguinet, E. Levillain, J.L. Sessler, D.M. Guldi, Á. Sastre-Santos, J.O. Jeppesen,
J. Am. Chem. Soc. 130 (2008) 460–462;
(c) K.A. Nielsen, L. Martín-Gomis, G.H. Sarova, L. Sanguinet, D.E. Gross, F.
Fernández-Lázaro, P.C. Stein, E. Levillain, J.L. Sessler, D.M. Guldi, Á. Sastre-
Santos, J.O. Jeppesen, Tetrahedron 64 (2008) 8449–8463.
[24] For reviews on calix[4]pyrrole-based anion receptors, see: (a) S.K. Kim, J.L.
Sessler Acc. Chem. Res 47 (2014) 2525–2536;
(b) D.S. Kim, J.L. Sessler, Chem. Soc. Rev. 44 (2015) 532–546.
[25] C.M. Davis, J.M. Lim, K.R. Larsen, D.S. Kim, Y.M. Sung, D.M. Lyons, V.M. Lynch, K.
A. Nielsen, J.O. Jeppesen, D. Kim, J.S. Park, J.L. Sessler, J. Am. Chem. Soc. 136
(2014) 10410–10417.
[26] J.S. Park, F. Le Derf, C.M. Bejger, V.M. Lynch, J.L. Sessler, K.A. Nielsen, C. Johnsen,
J.O. Jeppesen, Chem. Eur. J. 16 (2010) 848–854.
[27] (a) K.A. Nielsen, S. Bähring, J.O. Jeppesen, Chem. Eur. J. 16 (2010) 848–854;
(b) K.A. Nielsen, Tetrahedron Lett. 53 (2012) 5616–5618.
[28] K.A. Nielsen, W.-S. Cho, J. Lyskawa, E. Levillain, V.M. Lynch, J.L. Sessler, J.O.
Jeppesen, J. Am. Chem. Soc. 128 (2006) 2444–2451.
[29] (a) J.S. Park, K.Y. Yoon, D.S. Kim, V.M. Lynch, C.W. Bielawski, K.P. Johnston, J.L.
Sessler, Proc. Natl. Ac. Sci. USA 108 (2011) 20913–20917;
(b) S. Bähring, D.S. Kim, T. Duedal, V.M. Lynch, K.A. Nielsen, J.O. Jeppesen, J.L.
Sessler, Chem. Commun. 50 (2014) 5497–5499;
(c) S. Bähring, L. Martín-Gomis, G. Olsen, K.A. Nielsen, D.S. Kim, T. Duedal, Á.
Sastre-Santos, J.O. Jeppesen, J.L. Sessler, Chem. Eur. J. 22 (2016) 1958–1967.
[30] D.S. Kim, J. Chang, S. Leem, J.S. Park, P. Thordarson, J.L. Sessler, J. Am. Chem.
Soc. 137 (2015) 16038–16042.
[31] A. Jana, M. Ishida, J.S. Park, S. Bähring, J.O. Jeppesen, J.L. Sessler, Chem. Rev. doi:
10.1021/acs.chemrev.6b00375.
5425
[32] There is no strictly defined distinction between the terms ‘‘molecular clips”
and ‘‘molecular tweezers”. Both terms can be used in parallel for the same
molecular receptor system.
[33] (a) P.-N. Cheng, P.-T. Chiang, S.-H. Chiu, Chem. Commun. (2005) 1285–1287;
(b) K.-W. Cheng, C.-C. Lai, P.-T. Chiang, S.-H. Chiu, Chem. Commun. (2006)
2854–2856;
(c) P.-T. Chiang, N.-C. Chen, C.-C. Lai, S.-H. Chiu, Chem. Eur. J. 14 (2008) 6546–
6552.
[34] (a) Y. Cotelle, M. Allain, S. Legoupy, P. Hudhomme, Org. Lett. 16 (2014) 2590–
2593;
(b) Y. Cotelle, M. Hardouin-Lerouge, S. Legoupy, O. Alévéque, E. Levillain, P.
Hudhomme, Beilstein J. Org. Chem. 11 (2015) 1023–1036.
[35] M.H. Düker, R. Gómez, C.M.L. Vande Velde, V.A. Azov, Tetrahedron Lett. 52
(2011) 2881–2884.
[36] M.H. Düker, H. Schäfer, M. Zeller, V.A. Azov, J. Org. Chem. 78 (2013) 4905–
4912.
[37] M.-L.L. Watat, T. Dülcks, D. Kemken, V.A. Azov, Tetrahedron Lett. 55 (2014)
741–744.
[38] K.R. Korsching, H. Schäfer, J. Schönborn, A. Nimthong-Roldán, M. Zeller, V.A.
Azov, RSC Adv. 5 (2015) 82699–82703.
[39] J. Warneke, C. Jenne, J. Bernarding, V.A. Azov, M. Plaumann, Chem. Commun.
52 (2016) 6300–6303.
[40] E.M. Pérez, B.M. Illescas, M.Á. Herranz, N. Martín, New J. Chem. 33 (2009) 228–
234.
[41] E.M. Pérez, L. Sánchez, G. Fernández, N. Martín, J. Am. Chem. Soc. 128 (2006)
7172–7173.
[42] G. Fernández, L. Sánchez, E.M. Pérez, N. Martín, J. Am. Chem. Soc. 130 (2008)
10674–10683.
[43] D. Canevet, M. Gallego, H. Isla, A. de Juan, E.M. Pérez, N. Martín, J. Am. Chem.
Soc. 133 (2011) 3184–3190.
[44] C. Romero-Nieto, R. García, M.Á. Herranz, C. Ehli, M. Ruppert, A. Hirsch, D.M.
Guldi, N. Martín, J. Am. Chem. Soc. 134 (2012) 9183–9192.
[45] S. Bivaud, J.-Y. Balandier, M. Chas, M. Allain, S. Goeb, M. Sallé, J. Am. Chem. Soc.
134 (2012) 11968–11970.
[46] (a) S. Bivaud, S. Goeb, V. Croué, P.I. Dron, M. Allain, M. Sallé, J. Am. Chem. Soc.
135 (2013) 10018–10021;
(b) V. Croué, S. Goeb, G. Szalýki, M. Allain, M. Sallé, Angew. Chem. Int. Ed. 55
(2016) 1746–1750;
(c) G. Szalýki, V. Croué, M. Allain, S. Goeb, M. Sallé, Chem. Commun. 52 (2016)
10012–10015.