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Current Opinion in Solid State and Materials Science 13 (2009) 3645

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Current Opinion in Solid State and Materials Science


journal homepage: www.elsevier.com/locate/cossms

Halogen bonding: Recent advances


Marc Fourmigu *
Sciences Chimiques de Rennes, Universit Rennes 1, UMR CNRS 6226, Campus de Beaulieu, 35042 Rennes, France

a r t i c l e

i n f o

Article history:
Received 15 April 2009
Accepted 4 May 2009

Keywords:
Halogen bond
Hydrogen bond
Crystal engineering
Crystallography
Molecular materials

a b s t r a c t
Halogen bonding (XB), as a directional interaction between covalently bound halogen atoms (XB donor)
and Lewis bases (A, XB acceptor), has been recently intensively investigated as a powerful tool in crystal
engineering. After a short review on the origin and general features of halogen bonding, current developments towards (i) the elaboration of three-dimensional networks, (ii) the interaction with anionic XB
acceptors, (iii) its identication in biological systems and (iv) the formation of liquid crystal phases will
be described. Theoretical analyses, statistical studies and experimental electron density determinations
converge to describe halogen bonding as a relatively weak structure directing tool, when compared with
hydrogen bonding. However, when the halogen atom is strongly activated as in iodoperuorinated molecules or cationic aromatic systems can halogen bonding act as an efcient and reliable structure directing tool.
2009 Elsevier Ltd. All rights reserved.

1. Introduction
Halogen bonding describes a directional interaction between
covalently bound halogen atoms (X) and Lewis bases (A). The
halogen atom is typically bonded to a carbon or another halogen.
Halogen atoms themselves can act as Lewis bases in halogen  halogen interactions. The strong observed preference for linear
DAX  A interaction parallels that known for DAH  A hydrogen
bonds (HB) and preferences for the geometries at the acceptor (Lewis base) are also consistent with those observed in hydrogen
bonding. This analogy has led to dene the halogen atom as XB donor, the Lewis base as XB acceptor even if the latter is the electron
density donor in these interactions. While Hassel was one of the
very rst to realize that halogen atoms could form attractive interactions with Lewis bases [1], the following studies concentrated on
adducts of dihalogen molecules with Lewis bases [2]. The role of
chlorochloro interactions reported by Schmidt in crystal engineering [3,4], the preference for two distinct geometries, identied
as type I and type II by Parthasarathy [5] and Jeffrey [6], further
discussions on the geometry and nature of XB by Desiraju [7] are
important landmarks in this domain, soon followed in the last
10 years by the extensive contributions of Resnati and Metrangolo
who highlighted the potential of aliphatic and aromatic iodoperuorocarbons such as CnF2n+1AI or F5C6AI to act as strong XB donor
molecules [8]. Several excellent reviews on halogen bonding are
now available [9], some of them specically dedicated to metal
complexes as XB acceptors [10,11] together with a recent book
on halogen bonding [12]. In the following, we will therefore con* Tel.: +33 23 23 52 43; fax: +33 23 23 67 32.
E-mail address: marc.fourmigue@univ-rennes1.fr
1359-0286/$ - see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cossms. 2009.05.001

centrate on the most recent contributions without pretending for


exhaustiveness, but highlighting, from a personal perspective, the
most appealing results.
2. Origin and general features of halogen bonding
If we restrict ourselves to carbon-bound halogen atoms, halogen
bonding can be separated into two groups which were often investigated separately (i) the halogen  halogen CAX  X0 AC interactions
in the one hand and (ii) the CAX  A where A is a Lewis base in the
other hand. In these systems, halogen bonds are characterized by
X  X0 or X  A distances signicantly shorter than the sum of van
der Waals radii. Furthermore, for the X  X interactions, two preferred geometries were identied, noted type I and type II in
Scheme 1, while the CAX  A interaction with Lewis bases is characterized by its strong linearity (Scheme 1). Despite some earlier controversies, there is now a general agreement to consider that halogen
bonding is essentially controlled by electrostatic factors [13], even if
dispersion forces and charge-transfer might also contribute to the
observed structural motifs.
Statistical analysis of X  X contacts in crystal structures have
shown that an halogen atom can actually be described with two different radii rather than a single van der Waals radius, a shorter one
along the CAX axis, a longer one perpendicular to it, a behavior
known as polar attening [14]. Theoretical calculations [15] and
experimental high resolution X-ray determinations [16] have shown
that indeed the electron density around a bonded halogen atom is
not spherical but anisotropically distributed, with a charge concentration in the equatorial area, and charge depletion along the polar
CAX axis, the so-called r-hole (Fig. 1). This polarization is strongly
enhanced in the order Cl < Br < I [13], varies with the carbon atom

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M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

-
-
X +

X +
-

+
X -

2
+ X

(a)

X +

type II

C interactions

I
F

A (Lewis base)
X
interaction

Scheme 1. Geometrical preferences (i) for the halogen  halogen interactions: type
I: h1  h2; type II: h1  90 involving the XB acceptor, h2  180 involving the XB
donor; (ii) for the CAX  A interaction where A is a Lewis base and h  180.

C
and

type I

-
C

Br
Br

(b)
F

Me2N
N

hybridization in the following order: CCAI > C@CAI > R3CAI and is
also strongly accentuated in the presence of electron withdrawing
atoms as in iodoperuorocarbons such as F2n+1CnAI or F5C6AI [17].
As a consequence, the type II geometry (Scheme 1) offers two
different roles for the halogen atoms; one of them provides the
Lewis base site situated orthogonal to its CAX bond, and aligned
in a linear arrangement with the r-hole of the other halogen. This
picture is reinforced by the geometry and nature of CAX  X0 AC
interactions with X X0 where the heavier halogens are much
more likely to play the XB donor [7].
3. A crystal engineering tool: from 1D chains to 3D
interpenetrated networks, from organic to coordination
chemistry
The remarkable strength and high directionality of halogen bonds
formed by activated iodo- or bromoperuorocarbons has been the
basis for the crystallization of numerous 1D systems, either based
on ditopic XB donor and ditopic XB acceptor (Scheme 2a) or from single molecules bearing both a XB donor and acceptor moieties
(Scheme 2b and c) [19,20]. Note also the recently reported structures
derived from asymmetric porphyrins shown in Scheme 2c [21,22] or
other chain systems (Scheme 2d) obtained as powders through
mechanochemical synthesis [23,24].
This very successful approach has been extended to layered
structures involving tridentate XB donors with tridentate XB
acceptors, planar tetradentate XB donors with tetradentate XB
acceptors, etc. [25]. Of particular note are also the adamantoid
architectures formed from the self assembly of tetrahedral polydentate XB donor or acceptors, as shown beautifully in Fig. 2 for

(c)

Br
F

N
H
N

N
H
N

H
N

H
N

N
I

I
F

(d)

F
F

A'
I

A, A' = O, S, NH
A'
I

I
A'
A

F
F

Scheme 2. Heteromolecular (a and d) or monomolecular (b and c) halogen-bonded


systems.

[Et4N+Cl,CBr4] [26]. Other similar adamantane structures were


obtained from a self complementary tetradentate molecule
(Scheme 3a) [27], a tetradentate XB acceptor with a bidentate XB
donor (Scheme 3b) [28], or tetradentate XB donor and acceptor
molecules (Scheme 3c) [28].
Other three-dimensional networks of unusual 4,5-connected
didecahedron cells (each containing an encapsulated cation) were
also obtained from the tetratopic CBr4 neutral molecule, halogen
bonded to the ditopic and linear CuBr2 anion [29]. Competition
between the formation of halogen-bonded networks rather than
coordination networks was recently illustrated by Brammer et al.
in various associations of the Cu2(3-iodobenzoate)4 paddle-wheel
with simple short linkers such as dioxane or diazabicyclo(2.2.2)octane (dabco) through CAI  O XB [30].
4. Halogen-bonded anionic assemblies
Fig. 1. Electron-decient (+d, blue) and rich (d, red) regions observed around Clatoms in chloranil C6O2Cl4, as deduced from an experimental high resolution X-ray
crystallography investigation [18] (Courtesy of Pr. E. Espinosa, Nancy, France.). (For
interpretation of the references to color in this gure legend, the reader is referred
to the web version of this paper.)

Most of the recent developments of halogen-bonded supramolecular systems were based on neutral donor (haloperuorocarbons, iodoalkenes, and alkynes, . . .) and acceptor moieties of

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M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

Fig. 2. The elementary adamantane-like cage in the structures of [Et4N+Cl,CBr4]


complexes supported from within the cavity by NEt4+ counter ion. XB are shown as
black thin lines (adapted from Ref. [26]).

Lewis base character such as pyridines, dioxane, tetramethyethylenediamine, . . .), as illustrated above in Part 2. However, because
of the essentially electrostatic nature of the XB interaction, charged
systems, where at least the halogen bond acceptor is anionic, can
be expected to provide much stronger interactions than neutral
assemblies. In that respect, I3, IBr2 or Br3 can be considered as
very strong halogen-bonded systems between the neutral dihalogen and one halide anion. Calculations for the HACCAI  F
I

(a)

NO2

O2N

system afforded for example an interaction energy as high as


153 kJ mol1 [31]. As a consequence, anion coordination and
anion-templated assembly under XB control has developed extensively in the latter years and has been very recently reviewed
[11,32]. Therefore we will only highlight in the following several
a few selected recent examples which demonstrate the rich potential of this approach.
In two-component systems, the anion functions as XB acceptor
and the cation as XB donor. Such systems are the basis for molecular conductors based on halogenated tetrathiafulvalenes (TTF)
such as EDT-TTF-I or EDT-TTFI2 (Scheme 4) [33]. Upon oxidation
of the TTF core, the formed radical cations have a strong tendency
to associate into mixed-valence conducting systems, where the
overlap between radical molecules into 1D or 2D systems leads
to the formation of partially lled conduction bands. Furthermore,
oxidation of the TTF core activates the halogen atom(s) as a
stronger XB donor, which then interacts strongly through XB, at
the organic/inorganic interface, with the counter ion used during
the electrocrystallization experiments, which acts then as Lewis
base.
All possible anions have been used to act as XB acceptors in such
conducting salts [34], from the simple halides [35] (Fig. 3) and polyhalides (I3, IBr2, . . .), polyhalometallates, polycyanometallates,
polythiocyanatometallates [36] (Fig. 4) to more elaborate dithiolene
complexes such as [Ni(mnt)2] [37,38], or cluster anions such as
[Re6Se6(CN)6]4 [39,40] or [Mo3S7Cl6]2 [41]. Polymeric anionic networks can also act as efcient XB acceptors when associated with
iodinated TTFs, for example with the one-dimensional edge-sharing
PbI6 octahedra in [PbI3]1 [42], the layered [Pb5/6h1/6I2] system
with a PbI2 structure [43] or complex cadmium thiocyanate lacunar
networks such as [Cd3(NCS)8]2 and [Cd5(SCN)14]4 [44].
One example of a three-component system where the cation
only plays a spectator role (at least in the XB structure) is provided
by the anionic complexes formed by the three-fold symmetry molecule 1,3,5-triuoro-2,4,6-triiodobenzene (TFTIB), which offer a
rich palette of anionic network structures. Faced with various neutral bipyridyl XB acceptors which were expected to act as bidentate
spacers to afford (6,3) trigonal networks, TFTIB was invariably acting as a bidentate spacer affording 1D innite chains rather than
2D honeycomb structures [45]. DFT calculations demonstrated that
the halogen bond donor character of TFTIB was decreasing upon
successive Lewis base molecules coordinating to the iodine atoms.
This drawback was successfully circumvented when using anionic
halogen bond acceptors such as Cl or Br as n-Bu4N+ or PPh4+ salts

I
(b)

N
O
O

F F
+

TTF

I
FF

F F

S
S
EDT-TTF-I

S
S

S
S
EDT-TTFI2

Scheme 4.

FF

O
N

(c)

I
F4

N
O
O
N

F4

N
O

O
O

+
I

O
N

I
O

F4

F4

Scheme 3. Molecular associations giving rise to 3D adamantoid structures.

Fig. 3. Halogen bonding in the conducting mixed-valence salt (EDT-TTF-I)2Br


formed upon oxidation of iodo(ethylenedithio)tetrathiafulvalene in the presence of
Br [35]. Note also the CAH  Br interactions.

M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

Fig. 4. Halogen bonding in the conducting mixed-valence salt (EDT-TTFI2)2+[(isoq)2Cr(NCS)4] [36], showing the CAI  SAC halogen bonds (dotted lines)
involving the sulfur atoms of the N-coordinated thiocyanate anions.

[46]. In these salts, each iodine atom is now engaged in XB interaction (Fig. 5), while each halide anion is surrounded by three iodine
atoms with acute I  X  I angles (X = Cl, Br), a general feature
among XB halide complexes [47]. The large size of the cations hindered however the formation of honeycomb lattices but afforded
layered systems with a recurrent motif shown in Fig. 5. Working
with the larger I anion as XB acceptor and the smaller SMe3+,
NEt4+, NiPr4+ or PEt4+ cations allowed for the isolation of the
sought-after (6,3) topology with the cations in the centers of the
hexagonal frames (Fig. 5) [48].
A beautiful three-component system where now two different
halide anions act as XB donors in the very same crystal has been recently reported by Yamamoto and Kato [49]. In their earlier works
[50], these authors had described the electrocrystallization of TTF
derivatives in the presence of halide anions and neutral XB donor
molecules such as diiodoacetylene, tetraiodoethylene or 1,4-diuoro-tetraiodobenzene to afford layered conducting materials
characterized by partially oxidized cationic TTF-based layers alternating with halogen bonded two-dimensional anionic lattices

Fig. 5. Top: corrugated layers formed by [sym-C6F3I3nBu4NBr], the large nBu4N+


cations are represented by large blue cycles [46]. Bottom: honey-comb layers
formed in [sym-C6F3I3Et4NI] [48].

39

encompassing the halide anions and neutral XB donor molecules.


When using a mixture of Br and I anions together with tetraiodoethylene (TIE), the electrocrystallization of smaller TTF derivatives less prone to the formation of layered materials afforded a
supramolecular sheathing of the 1D TTF stacks involving two I,
one Br for ve TIE molecules. As shown in Fig. 6, each Br anion
forms XB with eight surrounding TIE molecules while each I anion
is surrounded by six TIE molecules. An extended series of similar
compounds was isolated which consist of a single chain of donor
molecules isolated by a 3D network of halide anions connected
by the XB with the iodine containing neutral molecules [49].
5. Quantitative investigations of XB strength: beyond
qualitative geometrical evidences
As illustrated above, the numerous crystal engineering approaches using XB as a building tool have shown a strong efciency, particularly with activated iodine XB donors such as
those found in iodoperuorocarbons. These studies have been
complemented by several theoretical investigations which showed
the primarily electrostatic nature of this interaction, though second
order contributions such as polarization, dispersion, and charge
transfer have been demonstrated to be non-negligible [51]. These
studies have been recently complemented by physical chemistry
investigations, in solution and in the solid state, aimed at a better
understanding of the origin and strength of halogen bonding.
Based on an electrostatic solvent competition model, quantitative 1H, 19F and 31P NMR studies of the association constants of
1:1 complexes formed between peruorohexyliodide F13C6AI and
various Lewis bases in different solvents, have conrmed the
strong electrostatic component of the XB interaction without
excluding the possibility for charge-transfer with strongest Lewis
bases [52].
EPR on nitroxyde radicals has appeared as a powerful tool to
investigate the strength of intermolecular interaction between
the O atom of the R2NO group and an HB or XB donor molecules
in solution, through the evolution of the nitrogen hyperne splitting aN, which indeed increases upon interaction (Scheme 5)
[53,54]. This effect is essentially based on the enhanced contribution of the polar structure II of nitroxyde radicals, when engaged
in a HB or XB bond (form IV vs. form III in Scheme 5). The trends
of binding energies and aN evolution are the same: derivatives with

Fig. 6. Projection view along c of the unit cell of (EDT-TTF)4BrI2(TIE)5 [49]. The size
of the Br and I anions has been increased. Dotted lines indicate the XB
interactions.

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M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

N O

N O

II

N O

I
III

N O

IV

Scheme 5. Mesomeric forms of a nitronyl radical, when engaged in XB.

F > derivatives without F; peruoroalkyl > peruoroaromatic; alcohol complexes > iodo complexes. Theoretical calculations show
that the interaction energy of R2NO with the strongest XB donors
such as C3F7AI or C6F5AI is half the values found with the strongest
HB donor molecules such as phenol or C3F7OH, demonstrating that,
at least with this specic acceptor molecule, the HB interaction is
always stronger than the XB one.
The interaction of such stable radicals has also been
investigated by 19F NMR. Indeed, since the uorination of aliphatic
or aromatic iodinated molecules strongly enhances their ability
XB to Lewis bases, 19F NMR is an extremely useful tool to investigate intermolecular interactions such as XB [55,56]. With
iodoperuoroalkanes, the signal of the CF2AI uorine atom(s) geminal to the iodine invariably shows a high-eld shift on XB formation as large as 1020 ppm while in peruoroiodoaromatics, the
uorine atom(s) ortho to the iodine also shows albeit to a lesser
extend a similar high-eld shift. When now radical molecules
such as 2,2,6,6-tetramethyl(piperidin-1-oxyl) (TEMPO) are halogen
bonded to iodoperuoroalkanes, an opposite, much larger paramagnetic downeld shift of the signal of the CF2I uorine atoms
is observed [57], which has been attributed to a transfer of some
of the unpaired spin density from the nitroxidic moiety to the peruorinated chain through the heavy halogen atom. Paramagnetic
19
F NMR appears therefore as a simple, effective and powerful tool
to detect and establish qualitatively the strength of the XB interaction. Theoretical investigations of this strong and specic paramagnetic shift were performed on the model TEMPOIACF3 complex. It
was found that the formation of the XB is accompanied by a significant charge polarization of both molecules, and in particular, of
the most polar resonance structure IV (Scheme 5). The best estimation of the gas-phase binding energy of the complex, obtained at
the MP2/aug-cc-pVTZ level, is about 36, and 29 kJ mol1 in CHCl3.
The origin of the down eld shift has been clearly ascribed to paramagnetic contributions determined by Fermi contact interactions
and to spin transfer from TEMPO to the ICF3 uorine atoms.
Solid state NMR has been also recently used as a new spectroscopic ngerprint to determine precisely the intermolecular N  I
distances of microcrystalline halogen-bonded systems [58],
through the analysis of the dipolar interactions between the spins
of the 15N and 127I nuclei, since hetero-nuclear dipolar couplings
provide indeed precise information on inter-nuclear distances.
The one dimensional 15N CP-MAS spectrum of powder sample of
benzyl-bis(4-iodobenzyl)amine revealed two magnetically non
equivalent and crystallographically distinct 15N sites in the unit
cell. The magnitudes of the dipolar 15NA127I couplings correspond
to inter-nuclear distances of 2.7 and 2.9 , in very good agreement
of the known range of N  I XB lengths.
Perhaps the most reliable experimental method to quantitatively estimate the strength of halogen bonding in the solid state
is the electron density distribution determined from high resolution X-ray diffraction studies (multipole renements) and analyzed
through the Baders quantum theory of atoms in molecules (AIM)
theory [59]. Applied to these systems, this theoretical analysis
demonstrated [60] that the electron densities at the halogen bond
critical points correlate with the interaction energies, exactly in the
same way shown before on HB [61,62]. When a pairwise interatomic interaction is established, a topological saddle conformation of the electron density distribution q(r) is observed at the
inter-atomic surface, where the electron distribution exhibits a

local minimum along the interaction direction (the bond path)


and a local maximum in the perpendicular plane to that direction.
The position where the bond path crosses the inter-atomic surface
is called the bond critical point (rBCP) and, because of the saddle
distribution, rq(r) = 0 at r = rBCP. All the topological and energetic
properties of q(r) at rBCP, permit to deeply characterize the interatomic interaction, offering signicant valuable information about
both its nature and strength. Those properties are: (i) the magnitude of the electron density qBCP, (ii) the three main curvatures
of the distribution q(r) at rBCP (two negative k1BCP, k2BCP < 0 that
are perpendicular to the bond path, and one positive k3BCP > 0
along the bond path direction), (iii) the Laplacian r2qBCP = RkiBCP
(indicating if the electron distribution is locally depleted
r2qBCP > 0, or concentrated r2qBCP < 0), as well as and (iv) the
local electron kinetic, potential and total energy densities
(GBCP, VBCP and HBCP, respectively).
Only four detailed investigations of this type have been reported to
date for halogen-bonded systems (Scheme 6), and concern the (E)-1,2bis(4-pyridyl)ethylene1,4-diiodotetrauorobenzene complex (bpeC6F4I2) [63], the 4,40 -dipyridyl-N,N0 -dioxide1,4-diiodotetrauorobenzene
complex (bpNOC6F4I2) [64], and most recently the (E)-1,2-bis(4-pyridyl)ethylene1,4-dibromotetrauorobenzene (bpeC6F4I2) and 4,40 dipyridyl1,4-dibromotetrauorobenzene (dpC6F4I2) complexes [65].
In (bpeC6F4I2), the relation successfully used by Espinosa for
the calculation of the HB energy EHB, EHB = Vb [61], where Vb is
the potential energy density at the BCP gives the strength of the
XB as 37.3 kJ mol1. A value of 31 kJ mol1 was deduced for
(bpNOC6F4I2) while smaller values of 28.0(8), 22.6(4) and 16.3(4)
kJ mol1 were deduced for (bpeC6F4Br2) and the two non equivalent dimers of (dpC6F4Br2), respectively, conrming the weaker
interaction with the bromo derivatives when compared with the
analogous iodo ones. In all these compounds, the determination
of the atomic charges from integration over the atomic basins
showed that the charge transfer contribution to the XB energy is
not particularly signicant, conrming the predominantly electrostatic character of the interaction [51].
6. Halogen bond vs. hydrogen bond: competition, collaboration
or orthogonality?
The striking similarities between hydrogen and halogen, the
search for evaluation of their comparative bonding strengths, led
Resnati and Metrangolo to investigate already in 2000 competitive
experiments with p-diiodotetrauorobenzene or 1,2-diiodotetrauoroethane [8]. For example, while the separate mixing of 1,2bis(4-pyridyl)ethane with either diiodotetrauorobenzene as XB

F4

N
N

(bpe)(C6F4I2)

(dpNO)(C6F4I2)

Br

(bpe)(C6F4Br2)

Br

(dp)(C6F4Br2)

F4
O

F4

N
N

Br
F4

Br

Scheme 6. Complexes and molecules investigated by high resolution X-ray


diffraction.

41

M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

H
O

N
N

O
N

N
N

F
N

N
H

O
F

I
n

H
H

O
n

Scheme 7. Co-existence of XB and HB in the 1:1 iodineiso-nicotinamide and the 1:2 tetrauorodiiodobenzeneiso-nicotinamide complexes [66].

ditopic donor, or with hydroquinone as analogous HB ditopic


donor afforded in both cases the anticipated chain systems in a
crystalline form, the mixing in equimolar quantities of 1,2-bis(4pyridyl)ethane with both the XB and the HB donor molecules afforded exclusively the halogen-bonded system.
Other co-crystallization experiments reported by Aakery with
iso-nicotinamide faced with I2 (Scheme 7) or p-C6F4I2 as XB donors
[66], or with a ditopic XB acceptor containing both a pyridine and a
benzimidazole moieties faced with various halogenated oximes
[67] have shown that XB could co-exist with HB in the same structure while the halogen bond interaction was also capable of competing with weaker CAH  O,N hydrogen bonds, as also observed
by Dutremez with iodoalkenes and alkynes [68]. Halometallate
salts described by Brammer et al. provide another series to compare the relative strength of hydrogen and halogen bonding
[69,70].
This co-existence/collaboration of both hydrogen and halogen
bonds has been specically addressed in biochemistry following
evaluation of the possible role of halogen bonding to control macromolecular conformations [71]. Although halogens are widely
used in drug design and to probe molecular interactions, XB has
only recently been recognized as a distinct interaction in the
assembly of proteins and nucleic acids (Fig. 7) [72,73]. For example,
thyroid hormones represent a class of naturally iodinated molecules where I  O halogen bonds appear to play a crucial role in
their recognition by their cognate proteins [74]. A database survey
of short halogen  oxygen interactions involving 66 different protein structures and six different nucleic acid structures has shown
that, if the general features of halogen bonding in small molecules are maintained, some specic deviations reect the more
complex environment found in biomolecular systems [75]. In the
one hand, the generally restrictive geometric criteria in small-molecule crystal structures need to be relaxed in macromolecules. In
the other hand, in most cases where the halogen interacts with a
carboxyl or amide group, it is the p system of the C@O group rather
than the lone pairs of the oxygen atoms that serves as halogen
bond acceptor. This observation led the same authors to describe
halogen bonds as orthogonal molecular interactions to hydrogen
bonds [76], at least in most peptide structures where a carbonyl

3
Fig. 7. Examples of short X  O contacts in a ligandprotein complex and nucleic
acids. (a) The 2.2- structure (PDB ID code 1P5E) of phospho-CDK2/cyclin A in
complex with the inhibitor 4,5,6,7-tetrabromobenzotriazole [77]. The inhibitor is
shown with three bromine halogen bonds to peptide carbonyl oxygen atoms of the
protein. Two interactions (middle) involve the lone pairs of the oxygen atom and
one (right) involves the p system of the C@O group. In addition, one halogen bond to
a water molecule (w) is seen (left). (b) Intramolecular halogen bond identied as
stabilizing a DNA junction (PDB ID code 1P54) in the 1.9- structure of
d(CCAGTACbr5UGG) [78]. (c) View of the packing interactions involving three short
I  O contacts in a unique six-stranded DNA structure (PDB ID code 1UE2; 1.4 ) of
the sequence d(Gi5CGAAAGCT) (i5C, 5-iodocytosine) [79]. Reproduced from Ref.
[75] with permission of Proc Natl Acad Sci USA.

42

M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

crystals using both hydrogen and halogen bonding, or in purely XB


bent-core liquid crystals involving the meta disubstituted 1,3-diiodo-peruorobenzene. In the former case (Scheme 10a) [85], two
stilbazole molecules are linked to the heteroditopic para-iodoperuorophenol, affording thermotropic behavior (nematic phase) in
a 1020 temperature range. The small clearing enthalpies
(23 kJ mol1) were taken as evidence that clearing is not accompanied here by dissociation. In the second case, a chiral nematic
phase was observed with a phase sequence arising from the lability
of the halogen-bonded complex [86].
Similar molecules were also used for the preparation of
polymers exhibiting thermotropic behavior (Scheme 11a) [87].
Compared with the analogous hydrogen-bonded supramolecular
liquid crystalline polymers [88], the halogen-bonded polymers
showed less stable nematic phases and crystal mesophases. Furthermore, the temperature range of liquid crystals, particularly,
for the nematic phase was very narrow. These different thermal
behaviors were possibly attributed to the strong linearity of the
halogen bond and the lack for side CAH  O@C hydrogen bonds
which would facilitate the formation of a coplanar geometric structure and subsequently stabilize the mesogenic core [89]. Another
use of polymers bounded through XB is the elaboration of layerby-layer lms of controlled composition and architecture (Scheme

preferred out-of-plane
halogen bonding
C
H

N
C

preferred in-plane
hydrogen bonding

Scheme 8. Statistical geometrical preferences for simultaneous H- and X-bond on


carbonyl oxygen atom in peptides.

oxygen atom acts simultaneously as a hydrogen bond acceptor and


a halogen bond acceptor. In these situations, the relative angle of
approach of H- and X-bonds to a shared Lewis base oxygen atom
is close the 90. Furthermore, the HB appears to concentrate in
the amidic plane towards the oxygen lone pairs while the XB are
most often directed above or below that plane (Scheme 8). These
results indicate that amide oxygen, in the context of the strong steric requirements of a polypeptide chain, present two perpendicular
electronegative interaction surfaces to potential H- or X-bond
donors. Also, the halogen bond was shown not to perturb the
energy of the primary hydrogen bonds in the folded protein. These
observations should have important consequences in the current
molecular dynamics simulation protocols which do not take into
account halogen bonding interactions.

(a)

7. Halogen bond in soft matter science: liquid crystals, polymers

The pioneering work of halogen bonded liquid crystals [80] was


reported by Bruce et al. and was based on the XB interaction
between a range of nonmesomorphic 4-alkoxystilbazoles and the
volatile iodopentauorobenzene (Scheme 8a) [81]. Comparison of
the transition temperatures of similar hydrogen-bonded systems
(phenol or benzoic acid derivatives) suggested that the halogen
bond in the uid, liquid crystal phase of these systems had an
appreciable strength, similar to that seen in hydrogen-bonding systems. The avoidance of volatile halogen bonding molecules in such
complexes led researchers in this eld to investigate trimeric systems such as those shown in Scheme 9bd, which afford indeed
monotropic thermotropic mesophases, based on a,x-diiodoperuoroalkanes (Scheme 9b) [82], p-diiodoperuorobenzene
(Scheme 9c) [83] or more exible derivatives (Scheme 9d) [84].
In some cases however, the large enthalpy changes associated with
the clearing temperatures (typically 89 kJ mol1) has been taken
as an indication of partial de-coordination and XB breaking at the
clearing temperature.
Recent extension of this work involved symmetry breaking of
the above-mentioned linear arrangements, either in trimeric liquid

(a)

CnH2n+1O
I

O
H
F

F
N

(b)

CnH2n+1O
N

F
F

I
N

CnH2n+1O

CnH2n+1O
Scheme 10. Bent-core complexes.

(b)
F5

CnH2n+1O
N

FF

CnH2n+1O

I
I

FF

OCnH2n+1

(c)
F

CnH2n+1O
N

N
OCnH2n+1

(d)
F

CnH2n+1O
N

m O

N
OCnH2n+1

Scheme 9. Molecular structures of the dimeric (a) or trimeric (bd) complexes giving rise to thermotropic phases (see text).

M. Fourmigu / Current Opinion in Solid State and Materials Science 13 (2009) 3645

(a)
F
N

n
O

F
(CH2)4

m
O

O
F

(b)

I
F

F
I

N
n

PIPBA

PVPy

Scheme 11. Polymer-based halogen-bonded systems. S in (a) stands for various


spacers.

11b) through alternated deposition of a polyacrylate bearing a


AOAC6F4AI aryl ring (PIPBA) and poly(4-vinyl)pyridine (PVPy) [90].
8. Conclusions and perspectives
Besides the AIM theory [59] evoked above in Part 5, older models of atomatom potential methods, involving a pixelisation of the
charge density distribution (PIXEL approach) [91,92], have been
also recently used by Gavezzotti to investigate halogen bonding
[93]. These statistical and theoretical investigations conrmed that
the strength of the XB increases in the order Cl < Br < I, and with
peruoro substitution at the XB donor. They also indicate that in
most cases, the total stabilization is in the order 115 kJ mol1,
that is lower than that in the weak alcohol O  HO HB (25 kJ mol1)
or in the carboxylic acid dimer (40 kJ mol1). Only those situations
described above involving peruoroiodocarbons as XB donors are
able to compete with relatively weak hydrogen bonds. Furthermore, even when short intermolecular distances appear, they
may not always be the outcome of binding stabilization but rather
the results of secondary effects under the tolerance of at energy
surfaces. In other words, some conclusions on halogen bonding
based only on geometrical evidence should be often be reconsidered more carefully in energy terms, for example when compared
with pp stacking energies [16,94], when as to decide of the primary origin of a given crystal structure.
Nevertheless, it is important to stress than, even if halogen
bonding, as the weak CAH  O,N hydrogen bonds [95,96], spans a
continuum from van der Waals contacts to normal HB, and might
not be, in most cases, the primary cohesive energy of a crystal,
its predictability and efciency as a crystal engineering tool is
unambiguously demonstrated today, particularly with strongly
activated XB donor molecules through peruoro substitution or
cationic activation, and/or with anionic XB acceptors. Under those
specic circumstances, it provides novel attractive possibilities toward self-assembled architectures, in the crystalline solid state, in
soft matter or even in biological systems.
Acknowledgements
Financial support from CNRS, University Rennes 1 and ANR contract no. ANR-08-BLAN-0091-02) is gratefully acknowledged. We
warmly thank Pr. J. Meinnel (Rennes, France) and Pr. E. Espinosa
(Nancy, France) for enlightening discussions on the topic of halogen bonding.
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