DOI: 10.1002/chem.

201302162

Supramolecular Hierarchy among Halogen-Bond Donors

Christer B. Aakerçy,*[a] Michele Baldrighi,[b] John Desper,[a]

Pierangelo Metrangolo,[b] and Giuseppe Resnati[b]

Abstract: Through a combination of
structural chemistry, vibrational spec-
troscopy, and theory, we have systemat-
ically examined the relative structure-
directing importance of a series of di-
topic halogen-bond (XB) donors. The
molecular electrostatic potential surfa-
ces of six XB donors were evaluated,
which allowed for a charge-based rank-
ing. Each molecule was then co-crystal-
lized with 21 XB acceptors and the re-
sults have made it possible to map out
Keywords: crystal engineering · do-
nor–acceptor systems · halogen
bonding · self-assembly · supra-
molecular chemistry
the supramolecular landscape describ-
ing the competition between I/Br–eth-
ynyl donors, perfluorinated I/Br
donors, and I/Br–phenyl based donors.
The results offer practical guidelines
for synthetic crystal engineering driven
by robust and directional halogen
bonds.

Introduction The halogen bond (XB)[1] is currently receiving considera-

The concept of hierarchy has long been recognized as being
of key importance in many aspects of chemistry. For exam-
ple, a hierarchy of chemical reactivity of different moieties
makes it possible for a synthetic chemist to make a choice
among different substrates and alternative pathways in
order to reach a molecular target. Regioselective and metal-
catalyzed reactions provide many examples where our un-
derstanding of the relative difference in reactivity makes it
possible to devise sophisticated reaction schemes that allow
us to navigate between alternative synthetic outcomes.
The importance of establishing a ranking of moieties with
similar chemical behavior also has a fundamental role to
play in supramolecular chemistry, where a detailed knowl-
edge of intermolecular interactions, and therefore the pref-
erence of one chemical moiety for interaction when con-
fronted with several possible partners, is crucial for the ra-
tional preparation of a material with desired structure and
properties. Such knowledge can be used to select partners
with the most favorable interactions in order to obtain a par-
ticular arrangement of molecules in the crystal lattice or to
drive the interaction topology by using complementary func-
tionalities.
[a] Prof. Dr. C. B. Aakerçy, Dr. J. Desper
Department of Chemistry, Kansas State University
211 CBC Building, Manhattan, KS 66506 (USA)
Fax: (+ 1) 785-532-6666
E-mail: aakeroy@k-state.edu
[b] Dr. M. Baldrighi, Prof. Dr. P. Metrangolo, Prof. Dr. G. Resnati
Department of Chemistry, Materials and Chemical Engineering
“Giulio Natta”, Politecnico di Milano, via L. Mancinelli 7
20133 Milan (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302162.
ble attention in supramolecular chemistry. Such interactions
where halogen atoms (the XB donors) act as electron densi-
ty acceptors are driven by a region of positive electrostatic
potential, the so-called s-hole,[1f, 2] resulting from the aniso-
tropic distribution of electrons in the heavier halogen atoms.
XB characteristics have been examined extensively in the
last 10–15 years, and halogen bonds have found numerous
practical applications[3] such as in the separation of a,w-diio-
doperfluoroalkane mixtures,[4] in organic reactions[5] , as well
as in the discovery and development of active pharmaceuti-
cal ingredients.[6]
The performance of a halogen-bond donor depends on
the degree of polarization of the halogen atom, that is, the
greater the positive electrostatic potential of the s-hole, the
more effective the XB donor will be.[1f] This means that the
magnitude of the positive potential of the s-hole depends
on the ability of the halogen atom to be polarized, as well as
on the presence of electron-withdrawing moieties that en-
hance the anisotropy of the electron distribution on the ad-
jacent halogen atom. Based upon this information, it has
been possible to establish some primary guidelines that
allow for a ranking of XB donor moieties in terms of donor
ability: (i) the power of the XB donor moiety decreases in
the order I > Br > Cl @ F;[7] (ii) the greater the electron-with-
drawing ability of the backbone of the XB donor molecule
is, the more effective the XB donor moiety is expected to
be.[8] A few studies have tried to link the degree of hybridi-
zation of the carbon atom to which the halogen atom is
bonded to its XB-donor effectiveness, but here the evidence
is both sparse and conflicting.[9] Furthermore, there have
been no systematic comparisons of the relative structural ef-
fects that can be imparted by halogen-bond donors as
a result of the presence of electron-withdrawing substituents
versus the degree of hybridization on the XB donor. To fur-
ther develop the practical applications of supramolecular

16240  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 16240 – 16247
 FULL PAPER
chemistry and crystal engineering, it is essential to establish solids that produced single crystals of sufficient quality. By
robust and reliable rankings of competing intermolecular in- combining the theoretical data with the frequency of occur-
teractions. This is particularly true in the case of halogen rence of co-crystal formation for each XB donor, we hoped
bonding as this interaction may be employed simultaneously to establish an XB donor ranking within this group of six
with hydrogen-bond strategies for the assembly of complex, compounds. It can be readily assumed that the iodo-substi-
multicomponent architectures of desired stoichiometry and tuted molecule within each of the three pairs of com-
connectivity.[10] pounds would be more effective than the bromo analogue,
Herein, we examine the relative donor strength of the ar- but it was much less clear how the two ethynyl and the two
omatic XB donors by using a combination of structural fluorinated species would perform with respect to each
chemistry, vibrational spectroscopy, and theory, with the other.
focus on the ability of haloethynylbenzenes to compete with
other better-known aromatic halogen-bond donor moieties
in co-crystallization reactions. Results and Discussion
The iodo/bromo-ethynyl moiety is a known XB donor,[11]
but it has not yet been subjected to systematic studies with The molecular structures were investigated by computation-
a view to determine its ranking in the library of XB donors al studies, by minimizing the molecular geometry and calcu-
of potential use in crystal engineering. Such information can lating the electrostatic potential energy surface Vs(r) of
form the basis for more reliable noncovalent synthetic strat- each molecule (Figure 2). These calculations were per-
egies in the assembly of more complex supramolecular tar-
gets.[6f, 11f,g]
The new molecules chosen for this study were 1-iodoe-
thynyl-4-iodobenzene (IEIB) and 1-bromoethynyl-4-iodo-
benzene (BEIB), where each compound carries two signifi-
cantly different XB donor functionalities. The molecular
electrostatic properties of these two compounds, as well as
their ability to form co-crystals with a library of suitable XB
acceptor molecules, were compared with the corresponding
properties of four well-known XB donors (Figure 1).

Figure 2. From left to right and from top to bottom: the molecules under
study in order of decreasing surface electrostatic potential associated
with the s-hole of the best XB donor atom in the molecule. The electro-
static potential surfaces were calculated at 0.002 IsoValue. Potential
values are in kJ mol 1.
Figure 1. Chemical structures of the six XB donors examined. From left
to right: Csp-bonded XB donors (IEIB, BEIB); activated Csp2-bonded
donors (DITFB = 1,4-diiodotetrafluorobenzene, DBTFB = 1,4-dibromote-
formed by using DFT at the B3LYP/6-311 + G** level with
trafluorobenzene); nonactivated Csp2-bonded donors (DIB = 1,4-diiodo-
benzene, DBB = 1,4-dibromobenzene).
Spartan software[12] for the geometry optimization and for
displaying the electrostatic potential energy surface. The
maximum value of the potential, V(r), corresponding to the
A premise for this study is the assumption that most con- depth of the s-hole on each halogen atom, was determined
ventional halogen bonds are dominated by electrostatics, for the six donors (Figure 3).
a premise that means that (i) a more pronounced s-hole
would produce a more effective XB donor and (ii) a better
XB donor should be more efficient at forming co-crystals
with a suitable XB acceptor.
Initially, we calculated the molecular electrostatic poten-
tial surfaces around each relevant halogen-bond donor
atom, and subsequently we allowed each XB donor to react
with 21 XB acceptor molecules (through solvent-drop grind-
ing reactions) to establish the supramolecular yield for each
donor, that is, the successful formation of the X-bonded Figure 3. From left to right: the six XB donor molecules in order of de-
creasing electrostatic potential associated with the most positive s-hole
adduct. Finally, to determine the exact nature of the molecu- among the halogen atoms in these molecules. Maximum values associated
lar recognition events that drove the formation of the co- with each XB donor are reported near the corresponding atom. Values
crystal in each case, we report single-crystal data for all are in kJ mol 1.

Chem. Eur. J. 2013, 19, 16240 – 16247  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 16241
 C. B. Aakerçy et al.

The results show strong similarity between the s-holes on component of our examination as this directly probes the
DITFB and IEIB with maximum values for V(r) of 169 and practical structure-directing ability of each donor and, thus,
172 kJ mol 1, respectively. can offer robust and transferable guidelines for crystal engi-
These numbers demonstrate that the hybridization of the neering.
carbon atom adjacent to the iodine atom can compensate The six ditopic XB donor molecules were mixed in a 1:1
for the electron-withdrawing influence of fluorine atoms. ratio with each of the 21 different XB acceptor molecules
Despite the fact that the iodine atom directly attached to (Figure 4) by using solvent-drop grinding, a technique that is
the sp2 carbon atom of the aromatic ring benefits strongly commonly used for screening co-crystal formation among
from the electron-withdrawing influence of the four fluorine a variety of compounds.[14]
atoms, the strong polarizing
effect of the sp carbon atom
allows the ethynyl-based iodine
atom to display a s-hole of
comparable magnitude. Our re-
sults are consistent with recent
findings by Le Questel et al.[13]
who examined the V(r) associ-
ated with the s-hole of differ-
ently substituted iodoacetylenes
(H CC I and NC CC I)
with several fluorine-substituted
iodobenzenes. A similar conclu-
sion can be drawn by examining
the V(r) maximum positive
value for the bromine atoms in
DBTFB and BEIB:
140 kJ mol 1 for the former and
147 kJ mol 1 for the latter. A
less polarizable bromine atom
(as compared with the iodine Figure 4. Chemical structures of the monotopic (1–11) and symmetric ditopic (12–21) XB acceptor molecules
atom) is even more strongly af- used in the solvent-drop grinding co-crystallization studies.
fected by an sp triple bond
moiety than it is by the proxim-
ity of an sp2-perfluorinated ring; the s-holes of iodine atoms The resulting solid from each of the 126 reactions was an-
are separated by 3 kJ mol 1, whereas those of the bromine alyzed by using attenuated total reflectance (ATR) FTIR
atoms are separated by 7 kJ mol 1. As expected, the weakest spectrometry. As the fundamental C I and C Br bond
XB donors, DIB and DBB, have substantially lower values stretching bands were outside the detection range of our in-
for the positive regions on their respective electrostatic po- strument, the formation of a multicomponent product (as
tential surfaces, 108 and 82 kJ mol 1, respectively. The ab- opposed to a physical mixture of the two reactants) had to
sence of electron-withdrawing moieties means that the halo- be established through a careful comparison of the whole
gen atoms on these molecules do not display electrostatic IR spectrum of each reaction mixture with the IR spectrum
potential surfaces significantly depleted of charge. of each individual component. For reactions involving the
To summarize, the calculations have identified the iodoe- fluorinated molecules, DITFB and DBTFB, the changes in
thynyl moiety in IEIB as the top-ranked XB donor, immedi- the C=C stretching bands (1400–1500 and 1200–1300 cm 1)
ately followed by the two iodine atoms in DITFB. The bro- and in the C F stretching bands (900–1000 cm 1) were par-
mine atom of BEIB occupies a position between DITFB ticularly helpful, whereas for IEIB, BEIB, DIB, and DBB,
and DBTFB with the ranking again based upon the calculat- the C=C stretching bands (1400–1500 and 1200–1300 cm 1),
ed electrostatic potential associated with its s-hole. Finally, the C H in-plane bending (900–1000 cm 1), and the C H
as expected, the iodine atoms of DIB are second to last out-of-plane bends (750–850 cm 1) proved to be very useful
whereas the bromine atoms in DBB display the smallest diagnostic tools. In addition, for IEIB and BEIB, the CC
positive potential, well below 100 kJ mol 1. (2150–2200 cm 1) bond stretch was also analyzed as it is di-
The next phase in our investigation involved using co- rectly influenced by the presence or absence of a halogen
crystallizations as a way of probing the structural impor- bond.
tance of intermolecular interactions. The expectation was The results were tabulated (see the Supporting Informa-
that the ability of the six XB donors to form co-crystals tion) and used as the basis for determining which grinding
should, to some extent, reflect the theoretically derived elec- experiments produced a co-crystal, and which did not lead
trostatic hierarchy that we obtained. This is an important to a reaction. Our systematic analysis of the IR spectra from

16242 www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 16240 – 16247
Supramolecular Hierarchy among Halogen-Bond Donors
FULL PAPER
the 126 reactions reveals that co-crystal formation results in Table 1. Results of solvent-drop co-crystallization grinding experiments
significant shifts in the modes associated with the C=C, C F, based on the comparison of the ATR-FTIR spectra of the XB donors
and of the products.[a]
and C H bonds, even though the magnitude of these shifts
are relatively small, and they also lack consistency in terms Acceptor IEIB DITFB BEIB DBTFB DIB DBB

of the direction of the change (blue/red shift). This observa- 1 + + +

2 + + +
tion is not too surprising as the C=C, C F, and C H bonds
3 +
are not directly involved in the C X···N/O halogen bond, 4
but are instead indirectly affected as a result of changes in 5 +
crystal packing and nearest neighbors that arise in the co- 6 + +
crystal as compared with the solid-state arrangement of the 7 +
8
molecule by itself. Nevertheless, co-crystal formation was 9 + + +
only deemed to have happened when bands from both com- 10 + + +
pounds were present in the resulting IR spectrum and sever- 11 + + + + +
al significant shifts could be observed (Figure 5). 12 + + + + +
13 + + + + +
14 + + + + +
15 + + +
16 + + +
17 + + + +
18 + + + +
19 + + + +
20
21 + + +
Yield[b] [%] 81 76 52 43 24 0
[a] Donors are listed from left to right in order of their decreasing effi-
ciency for co-crystal formation. Band positions, shifts, and the criteria
adopted to determine the occurrence of co-crystal formation are provid-
ed in the Supporting Information. [b] Supramolecular yields are ex-
pressed as % of positive results.

ing that there is a significant difference between donor affin-

Figure 5. A sample comparison between the ATR-FTIR spectra of an ities for the acceptor. Although some aspects of the yields
XB donor as a pure sample (IEIB, top line) and of the product of a suc- for each donor could have a steric component, the final
cessful co-grinding experiment (IEIB:12 co-crystal, bottom line). The po- trends and behaviors are likely to be just marginally affect-
sition of relevant peaks of the XB donor and the corresponding peaks in
the spectrum of the product are reported.
ed, leaving the proposed hierarchy in place.
The results from the co-crystallization experiments reflect
the hierarchy of expected XB capability order as deter-
The results from the 126 co-crystallizations are summar- mined by the electrostatic potential calculations remarkably
ized in Table 1 and lead to the following hierarchy: IEIB  well, as shown in Figure 6. IEIB and DITFB show very simi-
DITFB > BEIB  DBTFB > DIB > DBB. IEIB and DFTFB lar supramolecular yields (and their maximum electrostatic
both have supramolecular yields above 75 %, whereas BEIB potential surface values are similar), and the supramolecular
and DBTFB formed co-crystals in approximately 45–50 %
of cases. The nonactivated XB donors were far less effective
with only 5/21 reactions producing co-crystals with DIB,
whereas no co-crystals were obtained with DBB.
It is worth commenting on the possible steric influence of
the synthetic outcome in these reactions, notably for accept-
or molecules 3, 6, 7, 8, and 17. The large size of the atoms
involved on the halogen-bond donor site can potentially
make halogen bonding sensitive to the presence of sterically
encumbered groups in close proximity of the acceptor sites.
This may, in principle, penalize a perfluorinated donor
molecule, in which fluorine atoms can hamper the self-as-
sembly process. For example, IEIB forms a co-crystal with 7
whereas DITFB does not, and BEIB forms a co-crystal with Figure 6. Histogram representation of the results deriving from both the
3, whereas DBTFB does not, an observation that could be computational analysis and the solvent-drop grinding experiments. XB
donors are listed in order of bonding efficiency (decreasing from left to
explained through geometric, as opposed to charge-related right) as a function of the computed s-hole electrostatic potential (grey
factors. However, BEIB, which is less sensitive to steric hin- bars) and of the supramolecular yield obtained from solvent-drop grind-
drance than DITFB, cannot form a co-crystal with 7, indicat- ing experiments (black bars).

Chem. Eur. J. 2013, 19, 16240 – 16247  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 16243

yields for the next pair (ranking determined by their respec-
tive maximum potential values) reflect their theoretically es-
tablished hierarchical raking. It is clear that a reduction in
the positive electrostatic potential energy value of the s-
hole is accompanied by a corresponding decrease in reaction
success; DBB, ranked as the weakest XB donor in this
study, did not produce any co-crystals in 21 attempts.
Although vibrational spectroscopy provides reliable evi-
dence for establishing whether co-crystallization takes place
or not, single-crystal structural data are needed to determine
the precise driving force for co-crystal formation. IEIB and
BEIB both contain two different potential XB donors, one
of which is activated by an adjacent ethynyl moiety. We at-
tempted to grow single crystals of co-crystals of IEIB and
BEIB and all acceptors listed in Figure 4, a process that pro-
duced three crystal structures. Additionally, we obtained the
crystal structure of BEIB by itself (see the Supporting Infor-
mation).
The crystal structure determination of IEIB:4-phenylpyri-
dine, IEIB:2, shows that the 1:1 co-crystal is assembled by
an I···N halogen bond (I···N 2.730(2) ; Figure 7), which
Figure 7. Crystal structure of the IEIB:2 co-crystal. In evidence, the pri-
mary intramolecular contacts (black dotted lines), represented by the
I···N XB and the type I contact between the two Csp2-bonded iodine
atoms. The iodoethynyl moiety is interacting with the major electron-
donor site (the pyridyl-based nitrogen atom), driving the formation of
the co-crystal.
links adjacent molecules into dimers. The iodine atom par-
ticipating in this key XB, is the activated XB donor, the io-
doethynyl moiety. The second halogen atom on the mole-
cule participates in a type I halogen–halogen contact, which
is typically viewed as a close-packing interaction[9b, 15]
(Figure 7). Clearly, the most prominent XB acceptor in this
system is occupied by the halogen atom with the highest
positive charge on the s-hole.
The crystal structure determination of IEIB:11 also shows
the product to be a 1:1 co-crystal. The co-crystal synthesis is
driven by a short I···N halogen bond between the activated
iodine atom and the benzimidazole nitrogen atom (I···N,
2.760(3) ). This behavior is also consistent with the best
donor – best acceptor guidelines for hydrogen bond-driven
supramolecular synthesis that have been promoted by the
research groups of Etter and Aakerçy,[16, 17] as the nonacti-
vated iodine atom is involved in a halogen–p interaction
with the benzoimidazole portion of the acceptor. Finally, the
bromo substituent on 11 forms a type I contact with a bro-
mine atom from a neighboring XB acceptor (Figure 8).
In the crystal structure of IEIB:19 there is one unique XB
donor molecule for every half XB acceptor molecule result-
16244 www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
C. B. Aakerçy et al.
Figure 8. Intermolecular contacts (dotted black lines) in the IEIB:11 co-
crystal. a) The supramolecular adduct formed by the interaction of the
XB donors of IEIB and the acceptors of compound 11. b) Type I halo-
gen–halogen contacts among Br atoms of compound 11 and the halogen
bond between the most activated iodine atom of IEIB and the nitrogen
atom of compound 11.
ing in a 2:1 stoichiometry (despite the fact that the reactants
were combined in equimolar ratios in the solution). The as-
sembly is driven by halogen bonds between the activated
iodine atoms and both N-benzimidazole acceptor sites
(Figure 9), resulting in supramolecular trimers (I···N
2.814(1) ). The weaker XB donor, the nonactivated iodine
atom, is located in close proximity to the p-cloud of a neigh-
boring phenyl ring (of 19) in a near perpendicular manner,
indicating that this also represents a real halogen bond.
Consistently with the previous two crystal structures, the
better acceptor site in this molecule (based upon electrostat-
ic charge) is preferentially interacting with the iodoacety-
lene (the better XB donor), whereas the second-best XB
donor, the other iodine atom, has to settle for the electron-
density in the vicinity of an sp2-hybridized carbon atom. Fi-
nally, the combination of the primary I···N and the secon-
dary I···p XBs results in a remarkable 2D 5-fold interpene-
trated network of 63 nets composed of alternating IEIB and
compound 19 molecules (Figure 9).
Notably, in all the three crystal structures, the geometries
of the halogen bonds involving the iodoethynyl moieties are
very close to linear (C I···N; 173.8–178.58) accompanied by
a very short distance between the donor and the acceptor
moieties (around 78 % of the sum of the van der Waals radii
for the N and I atoms when the donor is the iodoethynyl
moiety).
We also grew single crystals of pure BEIB (from metha-
nol) to gather more information about the preferred interac-
tions involving haloethynyl species. The intermolecular in-
teractions found in the structure of BEIB give further evi-
dence that a bromoethynyl moiety is structurally more im-
portant than a nonactivated aromatic iodine atom. The pri-
mary short contact involves the s-hole on the bromoethynyl
moiety forming a halogen bond with the p-cloud of the CC
(an XB acceptor) of an adjacent molecule (Figure 10).
Chem. Eur. J. 2013, 19, 16240 – 16247
Supramolecular Hierarchy among Halogen-Bond Donors
FULL PAPER
the molecular recognition pro-
cess is also confirmed by the
geometric parameters for each
short contact (Table 2).
Based upon these crystallo-
graphic data, it is clear that the
activated and nonactivated hal-
ogen-bond donors operate at
significantly different energy/
strength levels, a fact that in
turn means that there is no
synthon crossover[19] between
these XB donor sites and they
can therefore, in principle, be
employed simultaneously in
a crystal engineering strategy,
where to each moiety is as-
signed an independent structur-
al task.

Conclusion

We have shown that IEIB and

BEIB are XB donor molecules
Figure 9. Crystal structure of the halogen-bonded supramolecular adduct IEIB:19. a) The primary I···N halo- with considerable potential in
gen bond and the secondary C I···p halogen bond (black dotted lines) are shown. b) A space-filling represen-
crystal engineering and molecu-
tation of the interpenetration between the different nets. Each color corresponds to a different net. c) A sim-
plified representation of the interpenetrating networks; the topological analysis and the picture were obtained lar recognition-based events.
by using TOPOS 4.0.[18] The co-crystallizations have es-

Table 2. Geometric parameters of halogen bonds involving the haloe-

thynyl moieties in the crystal structures presented.
Donor Acceptor X···D Distance Distance[a] C X···D
[] [%] [8]
IEIB 2 2.730 77.3 178.52
IEIB 11 2.760 78.2 176.53
IEIB 19 2.814 79.7 173.08
BEIB – 3.340 94.1 173.86
Figure 10. Crystal structure of pure BEIB. A linear halogen bond (black [a] With respect to the sum of van der Waals radii of the donor and the
dotted lines) between the Br atom and the p-cloud of the alkyne, almost acceptor atoms.
perpendicular to the CC axis, represents the major noncovalent interac-
tion among BEIB molecules.
tablished that IEIB and DITFB are XB donors of almost
equal power, and the remaining four XB donors in this
The Br···C distance, 3.34 , is slightly shorter than the study can be ranked correctly by using the assumption that
combined van der Waals radii and almost perfectly perpen- halogen bonds are primarily electrostatic in nature. The
dicular to the triple bond axis (88.78). Notably, the C single-crystal X-ray diffraction studies demonstrate that the
Br···CC angle is almost linear (173.868), thus suggesting best donor – best acceptor concept, well known from hydro-
that the s-hole of the halogen atom is a key element for the gen-bonded systems, is also applicable to halogen-bonded
formation of the interaction. The major difference in the in- systems with multiple and competitive XB donors; the two
teraction pattern between this structure and the previous types of interactions have many parallel features and func-
three is that the nonactivated halogen atom in this case is tions.
not involved in any short-range interaction. Merging the results obtained in the theoretical, statistical,
As expected, in almost all the structures obtained, the and crystallographic studies, the halogenated ethynyl moiet-
iodine atom directly connected to the aromatic ring plays ies appear as robust, selective, and extremely powerful XB
a structural role in the final crystal packing by means of sec- donor moieties. In fact, IEIB has been found to be very
ondary weaker interactions spanning type I and halogen–p comparable to the better known XB donor DITFB. Further-
interactions. The primary role of the haloethynyl moiety in more, the bromoethynyl moiety, which has been neglected

Chem. Eur. J. 2013, 19, 16240 – 16247  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 16245

as a possible XB donor in crystal engineering, is shown to
display structural capability which lies half way between
DITFB and DBTFB.
The ability to rank intermolecular interactions—and
therefore the interacting preference of one chemical moiety
when confronted with several possible partners—is crucial
for the effective recognition and sequestration of specific
targets, and for the preparation of selective sensors or, in
fact, for any chemical device that relies on an intermolecular
binding event for function and performance. As halogen
bonds are relatively weak and reversible, it is particularly
difficult to identify trends and patterns and to establish a hi-
erarchy of molecular-recognition efficiency in a competitive
situation. However, we have shown that a systematic ap-
proach utilizing complementary probes can allow for a relia-
ble and robust ranking of strength and structural influence,
a ranking that can subsequently be utilized in supramolec-
ular synthesis of complex architectures by using a targeted
application of hierarchical self-assembly.
Experimental Section
All starting reagents and solvents were purchased in high-purity grade
from commercial vendors and used without any further purification. 1,4-
diiodobenzene, bis(triphenylphosphine)palladium(II) dichloride, cop-
per(I) iodide, and silica gel (70–230 mesh, 60  pore size) were pur-
chased from Sigma–Aldrich; triethylamine, methanol, magnesium sulfate,
sodium bisulfite, hexanes, and n-heptane were purchased from Fisher Sci-
entific. N-bromosuccinimide was purchased from Acros Organics. 13C
and 1H NMR spectra were acquired on a Varian Mercury 400 MHz; IR
experiments were performed on a Thermo Nicolet 380 FTIR spectrome-
ter equipped with a Smart Performer ATR device, using a Ge or ZnSe
crystal (the latter being used to enhance the sensitivity in the 2000–
2300 cm 1 region).
Synthesis of 4-iodo-1-(trimethylsilyl)ethynyl iodobenzene (A):[20] To 1,4-
diiodobenzene (2 g, 6.06 mmol) were added triethylamine (350 mL) and
bis(triphenylphosphine)palladium(II) dichloride (25.5 mg, 0.072 mmol).
The mixture was stirred and deoxygenated, then copper(I) iodide (14 mg,
0.144 mmol) was added, and the mixture was again deoxygenated. A so-
lution of trimethylsilylacetylene (148.8 mg, 3.03 mmol) in triethylamine
(15 mL) was then added dropwise over 5 h, and the mixture was stirred
overnight at 25 8C under a nitrogen atmosphere. After removal of the
solvent under vacuum, the solid product was dissolved in chloroform (20
mL) and washed with water (2  40 mL) and brine (20 mL). The organic
phase was collected, dried over MgSO4, and the solvent removed under
vacuum. The solid residue was purified by column chromatography by
using silica gel (60 , 70–230 mesh) and n-heptane as the eluent, afford-
ing 517.8 mg of A (2.27 mmol, 37 %) as a white solid. m.p. 51–52 8C;
1
H NMR (400 MHz, CDCl3): d = 7.63 (d, J = 8.2 Hz, 2 H), 7.18 (d, J =
8.2 Hz, 2 H), 0.24 (s, 9 H) ppm; 13C NMR (101 MHz, CDCl3): d = 137.48,
133.54, 122.71, 104.09, 96.00, 94.64, 0.03 ppm.
Synthesis of 4-iodo-1-ethynylbenzene (B):[19] To a stirred solution of A
(517.8 mg, 2.27 mmol) in chloroform (20 mL), were added methanol
(20 mL) and potassium carbonate (627 mg, 4.54 mmol). The mixture was
deoxygenated and stirred for 4 h at 25 8C, then water (30 mL) was added.
The mixture was stirred for an additional 15 min, then the organic phase
was separated, and the aqueous phase extracted three times with chloro-
form (20 mL). The combined organic phases were collected and dried
over MgSO4 and evaporated under vacuum, affording 383.5 mg
(1.681 mmol, 97.5 %) of a white solid. m.p. 57–58 8C; 1H NMR (400 MHz,
CDCl3): d = 7.67 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 8.5 Hz, 2 H), 3.13 ppm (s,
1 H); 13C NMR (101 MHz, CDCl3): d = 137.61, 133.71, 121.68, 95.04,
82.82, 78.77 ppm.
16246 www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
C. B. Aakerçy et al.
Synthesis of 4-iodo-1-iodoethynylbenzene (IEIB):[21] To a solution of B
(147 mg, 0.644 mmol) in methanol (30 mL), were added, simultaneously
and dropwise over 30 min, an almost saturated solution of iodine
(215.7 mg, 0.85 mmol) in methanol and a 10 % water solution of sodium
hydroxide (59 mg, 1.47 mmol), while the mixture was maintained under
vigorous stirring. The mixture was stirred overnight and then water was
added until a white precipitate formed, which was filtered and washed
first with water (20 mL), then with a saturated solution of sodium bisul-
fite (10 mL), then with water (20 mL) again. The solid was dried under
a flow of nitrogen and collected without need of further purification, af-
fording 161.3 mg of a slightly yellow powder (0.456 mmol, 71 %). m.p.
101.5–103 8C; 1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 2 H),
7.14 ppm (d, J = 8.4 Hz, 2 H); 13C NMR (101 MHz, CDCl3): d = 137.50,
133.86, 122.90, 95.07, 93.24, 8.61 ppm; IR (ATR FTIR; selected bands):
ñ = 2169, 1910, 1477, 1464, 1387, 1228, 1213, 1057, 1003, 816 cm 1.
Synthesis of 4-iodo-1-bromoethynylbenzene (BEIB):[22] To a stirred solu-
tion of B (173 mg, 0.759 mmol) in acetone (30 mL) was added silver(I)
nitrate (13 mg, 0.076 mmol). The mixture was stirred for 30 min, then N-
bromosuccinimide (406 mg, 2.276 mmol) was added. The mixture was
stirred for 1 d, protected from light, then the acetone was evaporated
under vacuum and the solid mixture was purified by column chromatog-
raphy over a short pad of silica gel, eluting with hexanes, affording
230 mg (0.750 mmol, 99 %) of a white crystalline powder. m.p. 102–
104 8C; 1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 8.6 Hz, 1 H),
7.16 ppm (d, J = 8.6 Hz, 1 H); 13C NMR (101 MHz, CDCl3): d = 137.62,
133.56, 122.27, 94.90, 79.29, 51.68 ppm; IR (ATR FTIR; selected bands):
ñ = 2196, 1896, 1478, 1455, 1386, 1261, 1232, 1055, 1006, 810 cm 1.
Solvent-drop grinding synthesis of co-crystals with IEIB: 4-Iodo-1-iodoe-
thinylbenzene (5 mg, 0.014 mmol) was mixed with 0.014 mmol of the XB
acceptor, then a drop of methanol (ca. 10 mL) was added and the mixture
was ground until dryness or for 5 min. IR spectra of the samples were
collected for the resulting powders.
Solvent-drop grinding synthesis of co-crystals with DIB: 1,4-Diiodoben-
zene (5 mg, 0.015 mmol) was mixed with 0.015 mmol of the XB acceptor,
then a drop of methanol (ca. 10 mL) was added and the mixture was
ground until dryness or for 5 min. IR spectra of the samples were collect-
ed for the resulting powders.
Solvent-drop grinding synthesis of co-crystals with DITFB: 1,4-Diiodote-
trafluorobenzene (5 mg, 0.012 mmol) was mixed with 0.012 mmol of the
XB acceptor, then a drop of methanol (ca. 10 mL) was added and the
mixture was ground until dryness or for 5 min. IR spectra of the samples
were collected for the resulting powders.
Solvent-drop grinding synthesis of co-crystals with BEIB: 4-Iodo-1-bro-
moethinylbenzene (5 mg, 0.016 mmol) was mixed with 0.016 mmol of the
XB acceptor, then a drop of methanol (ca. 10 mL) was added and the
mixture was ground until dryness or for 5 min. IR spectra of the samples
were collected for the resulting powders.
Solvent-drop grinding synthesis of co-crystals with DBB: 1,4-Dibromo-
benzene (5 mg, 0.021 mmol) was mixed with 0.021 mmol of the XB ac-
ceptor, then a drop of methanol (ca. 10 mL) was added and the mixture
was ground until dryness or for 5 min. IR spectra of the samples were
collected for the resulting powders.
Solvent-drop grinding synthesis of co-crystals with DBTFB: 1,4-Diiodote-
trafluorobenzene (5 mg, 0.016 mmol) was mixed with 0.016 mmol of the
XB acceptor, then a drop of methanol (ca. 10 mL) was added and the
mixture was ground until dryness or for 5 min. IR spectra of the samples
were collected for the resulting powders.
Synthesis of the IEIB:2 co-crystal: IEIB (5 mg, 0.014 mmol) was mixed
in a vial with 4-phenylpyridine (2.2 mg, 0.014 mmol) and ground with the
aid of a drop of methanol. The resulting solid product was then dissolved
in methanol (1.5 mL) and the solution was allowed to evaporate slowly.
Crystals appeared in the solution after 2 d. m.p. 108–110 8C. IR (ATR
FTIR; selected bands): ñ = 2155, 1476, 1461, 1386, 1177, 1055, 1002,
821 cm 1.
Synthesis of the IEIB:11 co-crystal: IEIB (5 mg, 0.014 mmol) was mixed
in a vial with acceptor 11 (4.1 mg, 0.014 mmol) and ground with the aid
of a drop of methanol. The resulting solid product was then dissolved in
Chem. Eur. J. 2013, 19, 16240 – 16247
Supramolecular Hierarchy among Halogen-Bond Donors
methanol (1.5 mL) and the solution was allowed to slowly evaporate.
Crystals appeared in the solution after 2 d. IR (ATR FTIR; selected
bands): ñ = 2157, 1479, 1468, 1388, 1174, 1057, 1004, 819 cm 1.
Synthesis of the IEIB:19 co-crystal: IEIB (5 mg, 0.014 mmol) was mixed
in a vial with 19 (4.8 mg, 0.014 mmol) and ground with the aid of a drop
of methanol. The resulting solid product was then dissolved in methanol
(1.5 mL) and the solution was allowed to slowly evaporate. Crystals ap-
peared in the solution after 1 d. m.p. 99–100 8C. IR (ATR FTIR; selected
bands): ñ = 2161, 1479, 1458, 1396, 1055, 1006, 815 cm 1.
Synthesis of BEIB single crystals: BEIB (5 mg, 0.014 mmol) was dis-
solved in methanol (1.5 mL) and the solution was allowed to slowly evap-
orate. Crystals appeared in the solution after 4 d. m.p. 102–104 8C. IR
(ATR FTIR; selected bands): ñ = 2196, 1478, 1455, 1386, 1054, 1005,
810 cm 1.
Acknowledgements
We thank NSF (CHE-0957607) and Fondazione Cariplo (projects 2009–
2550 and 2010–1351) for financial support.
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Received: June 6, 2013
Published online: October 15, 2013
www.chemeurj.org 16247