Halogen bonding between anions and iodoperfluoroorganics: Solution-phase thermodynamics and multidentate-receptor design

Article abstract of DOI:10.1002/chem.201202689

The interactions of iodoperfluoroarenes and -alkanes with anions in organic solvent were studied. The data indicates that favorable halogen-bonding interactions exist between halide anions and the monodentate model compounds C₆F₅I an

Full text of DOI:10.1002/chem.201202689

FULL PAPER
DOI: 10.1002/chem.201202689
Halogen Bonding between Anions and Iodoperfluoroorganics:
Solution-Phase Thermodynamics and Multidentate-Receptor Design
Mohammed G. Sarwar, Bojan Dragisic´, Elena Dimitrijevic´, and Mark S. Taylor*[a]
Abstract: The interactions of iodoper-
fluoroarenes and -alkanes with anions
in organic solvent were studied. The
data indicates that favorable halogen-
bonding interactions exist between
halide anions and the monodentate
model compounds C6F5I and C8F17I.
These data served as a basis for the de-
velopment of preorganized multiden-
tate receptors capable of high-affinity
anion recognition. Several new recep-
tor architectures were prepared, and
ated in more detail. Computation was
employed to better interpret the struc-
ture–activity relationships arising from
these studies. Investigations of the ther-
modynamics of anion binding (by
vanꢁt Hoff analysis) and solvent effects
reveal details of these halogen bonding
interactions.
the
multidentate-iodoperfluoroben-
zoate-ester design, as described in a
preliminary communication, was evalu-
Keywords: anions · molecular rec-
ognition · noncovalent interactions ·
perfluoroarenes · thermodynamics
Introduction
XB in medicinal chemistry,[15] self-assembly,[16] and cataly-
sis[17] are emerging rapidly.[18]
Halogen bonding (XB) occurs “when there is evidence of a
net attractive interaction between an electrophilic region on
a halogen atom X belonging to a molecule or molecular
fragment R–X and a nucleophilic region of a molecule, or
molecular fragment, Y–Z.”[1] R—X···Y–Z interactions are
most thermodynamically favorable when X is a heavy halo-
gen atom (I>Br>Cl>F) and R is either an electronegative
or polarizable substituent, and display a pronounced prefer-
ence for 1808 noncovalent R-X-Y angles.[2] Both charge-
transfer[3] (donation of electron density to low-lying s*R-X or-
bitals) and electrostatic models[4] (interaction with the ꢀs-
holeꢁ region of electron deficiency centered on X) have
been advanced to account for these interactions. The utility
of XB for directing self-assembly in condensed phases is es-
tablished,[5] and includes applications in crystal engineer-
ing,[6] liquid crystals,[7] chiral discrimination,[8] topochemical
polymerization,[9] and organic materials design.[10] Applica-
tions of XB in solution have been developed more slowly;
the scarcity of thermodynamic data for interactions of or-
ganic donors (as opposed to inorganic donors RX, where R
is also a halogen atom[11]) has likely been a contributing
factor. In recent years, the body of data of this type for in-
teractions of haloalkynes,[12] haloarenes,[13] and haloal-
Our research group has explored anion recognition using
multidentate XB donors. The crystallographic literature in-
dicates that halogen bonds to anionic acceptors are highly
directional and that a single anion may accept multiple halo-
gen bonds in the solid state.[19] Evidence that XB interac-
tions of anions are thermodynamically favorable in solution
includes the formation of trihalide anions, for example, the
interaction of I2 with KI to form KI3, an interaction that is
exothermic by 4 kcalmolÀ1 in water,[20] and the handful of
reported association constant (Ka) values for interactions of
anions with organic XB donors.[21] Iodoperfluoroarene-func-
tionalized podand 1a stands as a pioneering example of the
incorporation of XB donor groups into molecular receptors;
C—I···IÀ halogen bonding was estimated to contribute
roughly 1.8 kcalmolÀ1 to the free energy of interaction with
NaI in CDCl3, as judged by Ka values determined for 1a
and control receptor 1b (Figure 1).[22] The geometry of this
receptor precludes bi- or tridentate halogen bonding with
anions, a conclusion supported by X-ray crystallography of
the 1a–NaI complex and by the modest estimated contribu-
tion of XB to the thermodynamics of binding. In compari-
ACHTUNGTRENNUNG
kanes[13b,14] has grown, and demonstrations of the utility of
´
´
[a] M. G. Sarwar, B. Dragisic, E. Dimitrijevic, Prof. M. S. Taylor
Department of Chemistry, Lash Miller Laboratories
University of Toronto
80 St George St., Toronto ON M5S 3H6 (Canada)
Fax : (+1)416-978-8775
E-mail: mtaylor@chem.utoronto.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202689.
Figure 1. Structures of iodoperfluoroarene-based halogen-bonding recep-
tors for NaI (1a, Ref. [22]) and Bu4NCl (2, Ref. [26]).
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son to hydrogen bonding,[23] Lewis acid–Lewis base[24] and
anion–arene[25] interactions, XB interactions have arguably
been underexploited in the design of synthetic anion recep-
tors.
bonding for uncharged donor/acceptor pairs in alkane sol-
vent.[35]
Noncovalent bond distances and angles were calculated at
the B3LYP and MP2 levels of theory for each of the com-
plexes studied (Table 1). In all cases, the calculated I—XÀ
distances are significantly shorter than the sums of van der
Waals radii (SvdW =3.73 ꢄ for I/Cl, 3.83 ꢄ for I/Br, and
3.96 ꢄ for I/I). The calculated C-I-XÀ angles are close to
We thus set out to design hosts bearing XB donor groups
oriented appropriately for multidentate anion recognition,
and in 2010 reported that tris(iodoperfluorobenzoate) ester
2 acts as a tridentate anion receptor, with Ka value of 1.9ꢃ
104 mÀ1 for nBu4N+ClÀ in acetone solvent at 295 K.[26] Values
of Ka for interactions of 2 with tetra-n-butylammonium
halide salts, nBu4N+XÀ, decreased in the order ClÀ >BrÀ >
Table 1. Calculated, gas-phase halogen bond lengths (I···XÀ) and angles
(C-I-XÀ) for complexes of C6F5I and C4F9I with halides.
À
À
IÀ, and oxoanions (HSO4 , TsOÀ, NO3 ) did not interact
with 2 to a measurable extent under these conditions. We
have since employed partially fluorinated variants of 2 to
obtain quantitative data for XB interactions of weak
donors[27] and have prepared urea-based iodoperfluoroben-
zoate receptors that interact with anions through combina-
tions of halogen bonding and hydrogen bonding.[28] Studies
of haloimidazolium- and halotriazolium-based receptors
have demonstrated that XB may be employed for anion rec-
ognition in either polar or protic solvents.[29,30,31] The interac-
tions have been employed to template the assembly of cate-
nanes and rotaxanes,[16] to mediate anion transport across
lipid bilayers,[32] and to accelerate Ritter-type reactions of
benzylic halides.[33]
Complex
B3LYP[a]
MP2[a]
XB distance
XB distance
XB angle
XB angle
[ꢄ]
[8]
[ꢄ]
[8]
C4F9I···ClÀ
C4F9I···BrÀ
C4F9I···IÀ
2.82
3.02
3.24
2.83
3.02
3.25
177.2
177.0
177.0
180.0
180.0
180.0
2.85
3.04
3.28
2.84
3.02
3.26
177.7
177.6
177.6
180.0
180.0
180.0
C6F5I···ClÀ
C6F5I···BrÀ
C6F5I···IÀ
[a] Calculations carried out using the 6-31+GACTHNUTRGNEUGN(d,p)-LANL2DZdp basis
set (see text).
1808, in accordance with previous experimental and compu-
tational results. This preference appears to be slightly stron-
ger for halide complexes of C6F5I relative to those of C4F9I.
The B3LYP and MP2 levels of theory resulted in similar op-
timum geometries, although the noncovalent bond lengths
that were calculated using the former were shorter. The
counterpoise-corrected energies of interaction (DE, along
with the BSSE values) for each complex were calculated at
the two levels of theory employed (Table 2). Among the
trends evident from these data is the greater calculated hal-
Here, we present a full account of our studies of the influ-
ence of iodoperfluoroorganic halogen-bond-donor structure
on solution-phase association constants with anionic ac
tors. Association constants of simple monodentate donors,
iodoperfluorobenzene (C6F5I) and 1-iodoperfluoroooctane
ACHTUNGTNERcNUNG ep-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(C8F17I), with salts, Bu4N+XÀ, in a range of solvents are re-
ported, along with thermodynamic data obtained by
vanꢁt Hoff analysis. Computational modeling of such interac-
tions in the gas phase is also presented. The evaluation of
various multidentate anion-receptor architectures is de-
Table 2. Calculated gas-phase energies of interaction (DE, kcalmolÀ1
)
and basis set superposition errors (BSSE, kcalmolÀ1) for complexes at
the B3LYP and MP2 levels of theory.
ACHTUNGTRENNUNGscribed, and implications of these results for the design of
selective and high-affinity receptors are discussed.
Complex
B3LYP[a]
MP2[a]
DE
BSSE
DE
BSSE
C4F9I···ClÀ
C4F9I···BrÀ
C4F9I···IÀ
À24.4
À23.3
À20.3
À22.6
À21.6
À18.6
0.27
0.88
0.27
0.30
0.89
0.28
À19.2
À18.6
À16.0
À18.1
À17.6
À15.0
2.76
6.18
4.49
2.89
6.26
4.55
Results and Discussion
Thermodynamics of halogen-bonding interactions of anions
with iodoperfluorobenzene and iodoperfluorooctane: As
preliminary steps towards developing multidentate recep-
tors, we undertook computational modeling and experimen-
tal determinations of binding constants for interactions of
commercially available perfluoroiodooctane and perfluoro-
C6F5I···ClÀ
C6F5I···BrÀ
C6F5I···IÀ
[a] Calculations carried out using the 6-31+GACTHNUTRGNEUGN(d,p)-LANL2DZdp basis
set; basis set superposition errors estimated by the counterpoise method
(see text).
ACHTUNGTRENNUNG
ogen-bond donor ability of C4F9I relative to C6F5I towards
the halide anions and the higher acceptor ability of the light-
er more charge-dense halides (IÀ <BrÀ <ClÀ). Whereas sim-
ilar trends hold for the B3LYP and MP2 methods, the latter
level of theory generally results in lower interaction energies
and higher basis-set superposition errors.
AHCTUNGTRENNUNG
except iodine, for which the LANL2DZdp effective core po-
tential was employed. The basis set superposition error
(BSSE) was estimated by the counterpoise method.[34] To
simplify the calculations, complexes of iodoperfluorobutane
C4F9I rather than C8F17I were modeled. We have found that
gas-phase calculations of this type provide useful levels of
correlation with experimental free energies of halogen
Ka values of C6F5I and C8F17I with Bu4N+ salts of various
anions were determined by 19F NMR titrations in acetone
solvent at 295 K (Table 3). Upon addition of halogen-accept-
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Halogen Bonding between Anions and Iodoperfluoroorganics
FULL PAPER
dictions of electrostatic models,[11,13b,35] and are supported by
Table 3. Association constants (Ka) for interactions of C6F5I and C8F17I
with Bu4N+XÀ in acetone at 295 K.
computational studies.[38]
C6F5I donor
Ka [MÀ1
C8F17I donor
Ka [MÀ1
]
We studied the temperature dependence of the Ka values
of C6F5I and C8F17I with Bu4N+ClÀ in acetone to obtain en-
thalpies and entropies of interaction using vanꢁt Hoff plots.
To obtain accurate thermodynamic parameters, we investi-
gated as wide a temperature range as was experimentally ac-
cessible (238–308 K, Figure 2). Several features of the data
[a,b]
[a]
XÀ
]
XÀ
ClÀ
BrÀ
IÀ
1.5ꢃ102
1.0ꢃ102
4.4ꢃ101
ClÀ
BrÀ
IÀ
2.2ꢃ103
1.0ꢃ103
3.3ꢃ102
TsOÀ
<0.5ꢃ101
<0.5ꢃ101
<0.5ꢃ101
TsOÀ
–
–
–
–
–
À
À
NO3
NO3
À
À
HSO4
HSO4
[c]
AcOÀ
–
–
AcOÀ
À
[c]
À
H2PO4
H2PO4
[a] Ka values were determined by fitting changes in 19F NMR chemical
shift to a 1:1 binding isotherm. Experiments were carried out in dupli-
cate; uncertainties in Ka values estimated to be Æ10%. [b] Ka values for
interactions of C6F5I with Bu4N+XÀ were previously reported in the Sup-
porting Information of Ref. [26]. [c] The halogen-bond donor decom-
posed upon addition of Bu4N+XÀ.
ing anions, the resonances corresponding to the 2-fluoro
groups of C6F5I and the CF2I group in iodoperfluorooctane
underwent significant upfield shifts; the maximum values of
the complexation-induced changes in chemical shift, Dd, as
determined by nonlinear curve fitting to a 1:1 binding iso-
therm, were roughly 1.2 ppm for the C6F5I···ClÀ interaction
and 12 ppm for that of C8F17I···ClÀ. The halogen-bond
donors decomposed in the presence of basic anions such as
fluoride and dihydrogenphosphate under the conditions of
the NMR titrations. The Ka values for interactions of C8F17I
with halides are roughly consistent with those determined
recently for 1,6-diiodoperfluorohexane, IACHTNUGTRNEG(UN CF2)6I in acetoni-
trile solvent, the latter values being determined using UV/
Vis absorbance spectroscopy (Ka =250, 150, and 80mÀ1 for
ClÀ, BrÀ and IÀ, respectively, as their Bu4N+ salts).[36] In our
hands, addition of Bu4N+ halides to C8F17I in acetone did
not lead to UV/Vis spectral changes that would be suitable
for determining Ka values.
In agreement with the gas-phase calculated results, the ex-
perimental solution-phase data show that C8F17I interacts
more favorably with halides relative to C6F5I. Similarly, the
relative affinities for the halides, ClÀ >BrÀ >IÀ, are in line
with the computationally predicted trend. However, the
Figure 2. vanꢁt Hoff plots (ln(Ka) versus 1000/T) for interactions of C6F5I
(top) and C8F17I (bottom) with Bu4N+ClÀ in acetone. Values of Ka were
determined by 19F NMR titrations at temperatures ranging from 238 to
308 K.
oxoACHTUNGTRENNUNGanions for which binding constants could be determined
showed only weak interactions with C6F5I, despite that such
species are often good hydrogen-bond acceptors (for exam-
ple, the enthalpy of transfer of NO3 from water to acetoni-
are noteworthy (Table 4). The interactions are entropically
favorable (that is, DS>0), a result that is in contrast to the
complexation of group 10 fluorides by C6F5I in toluene, as
studied by Perutz, Brammer, and co-workers and for which
DS values ranged from À10 to À17 calmolÀ1 KÀ1.[13c] Several
examples of positive entropies of interaction for anion bind-
ing by neutral receptors have been reported; receptor desol-
À
trile is higher than that of IÀ).[37] It has also been noted that
a bromoimidazolium-based receptor displays high levels of
discrimination for halides over oxoanions in aqueous metha-
nol.[29b] In another study, a monodentate iodoimidazolium
compound was found to bind more tightly to dihydrogen-
phosphate and acetate than to halides in [D6]DMSO, thus
indicating that XB of oxoanions is favorable in certain in-
stances.[30] In any case, we speculate that the high affinities
of the perfluorinated donors towards halide anions, as evi-
dent herein, reflect either significant charge-transfer contri-
butions, dispersion contributions, or both, to their interac-
tions. Such proposals have been advanced to rationalize
other trends in XB thermodynamics that do not follow pre-
Table 4. Enthalpies (DH) and entropies (DS) of interaction between
Bu4N+ClÀ and C6F5I or C8F17I in acetone, as determined by vanꢁt Hoff
plot analysis. Values of Ka were determined by 19F NMR titrations at
temperatures ranging from 238 to 308 K.
XB donor
DH [kcalmolÀ1
]
DS [calmolÀ1 KÀ1
]
C6F5I
C8F17I
À2.7
À3.0
1.7
4.8
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M. S. Taylor et al.
vation is among the phenomena that have been invoked to
rationalize such behavior.[39] In particular, Huber and co-
workers have used isothermal titration calorimetry to obtain
thermodynamic data for charge-assisted XB interactions of
bis(imidazolium) receptors with halides in a variety of or-
ganic solvents, and have found faACTHUNRGTNNEUGvorAHCTUNGTRENNaUGN ble (in certain cases,
dominant) entropic contributions to the thermodynamics of
binding.[31] Interestingly, the data herein shows that the dif-
ferent halogen bond donor ability of C8F17I and C6F5I to-
wards Bu4N+ClÀ in acetonitrile appears to arise from both
modest enthalpic (DDH=À0.3 kcalmolÀ1) and entropic
(TDDS=0.9 kcalmolÀ1 at 298 K) contributions, with the
magnitude of the latter being perhaps slightly greater.
Whereas the more favorable enthalpy of interaction for the
iodoperfluoroalkane–chloride complex is consistent with the
computational data discussed above, the difference in en-
tropic contributions is somewhat surprising and highlights
the dangers of neglecting entropy when interpreting struc-
ture-activity relationships for noncovalent interactions.
Scheme 1. Synthesis of bidentate halogen-bond donors 3 and 4.
Multidentate halogen-bond donors as anion receptors: De-
spite the lower halide affinity of C6F5I relative to C8F17I, we
felt that the former could be chemically modified more
readily for the purpose of preorganized receptor design.
While SNAr reactions of C6F5I provide ready access to para-
substituted C6F4I donor groups,[40] this substitution pattern
may not be ideal for orienting donors to bind to an anion in
a convergent fashion: for example, receptor 1a described
above does not act as a multidentate halogen bond donor.
C6F5I (Table 2) shows that both 3 and 4 act as bidentate
anion receptors: for a given anion, the Ka values for interac-
tions of the diiodo compounds are roughly an order of mag-
nitude higher than those of C6F5I. Geometry optimizations
of 3···ClÀ and 4···ClÀ complexes in the gas phase (B3LYP/6-
Table 5. Association constants (Ka) for interactions of receptors 3 and 4
We
instead
elected
to
pursue
ortho-substituted
with Bu4N+XÀ in acetone at 295 K.
iodoperfluoroACHTUNGTRENNUNGarenes.
Receptor 3
Ka [MÀ1
Receptor 4
Ka [MÀ1
]
[a]
[a]
XÀ
]
XÀ
Ethynylene and diynylene-linked iodoperfluoroarenes as bi-
dentate halogen-bond donors: Drawing on the structures of
hydrogen-bonding dimerization motifs developed by Duch-
arme and Wuest,[41] we investigated ethynylene and buta-
ClÀ
BrÀ
IÀ
NO3
HSO4
1.7ꢃ103
ClÀ
BrÀ
IÀ
NO3
HSO4
1.2ꢃ103
8.5ꢃ102
1.0ꢃ103
–
–
–
3.5ꢃ102
À
À
<0.5ꢃ101
<0.5ꢃ101
À
À
ACHTUNGTRENNUNGdiynylene groups as linkers for 2-iodoperfluoroarene halo-
[a] Ka values were determined by fitting changes in 19F NMR chemical
shift to a 1:1 binding isotherm. Experiments were carried out in dupli-
cate; uncertainties in Ka values estimated to be Æ20%.
gen-bond donors. Among the attractive features of these
linker groups are their low steric demand, electron-with-
drawing ability, which is beneficial for halogen bond dona-
tion, and their conformational rigidity. The syntheses of re-
ceptors 3 and 4 from 1,2-diiodotetrafluorobenzene are de-
picted in Scheme 1. A modified Sonogashira coupling using
copper(I) chloride in DMF to promote alkynylsilane activa-
31+GACTHNUTRGENU(GN d,p)-LANL2DZdp) revealed the expected bidentate
coordination (Figure 3). The calculated geometry of the
3···ClÀ complex was characterized by an average I···ClÀ dis-
tances of 3.18 ꢄ, C-I-ClÀ angles of 1668, and a I-ClÀ-I angle
of 768. For 4···ClÀ, the calculations revealed halogen bonds
tion[42] en
ACHTUNGTRENNUNGabled the synthesis of 3 in a single step from C6F4I2
and bis(trimethylsilyl)acetylene. Receptor 4 was prepared
by conventional Sonogashira coupling of C6F4I2 with
trimethylsilyl
N
that were shorter (dI···Cl =3.14 ꢄ) and more linear (qC-I-Cl =
A
1748), with a less acute I-ClÀ-I angle of 948. Similar trends
were observed for geometry optimizations of the 3···BrÀ and
4···BrÀ complexes in the gas phase: the bromide complex of
4 was calculated to possess shorter I···Br distances (3.25
versus 3.29 ꢄ), more linear C-I-BrÀ angles (1748 versus
1678) and a less acute I-BrÀ-I angle (928 versus 748). The
calculated geometries also indicate that bidentate coordina-
tion of ClÀ by 4 is accompanied by bending of the buta-
diethynylation of C6F4I2 in the presence of the Pd catalyst,
and the resulting challenging purification of the products.
However, the synthetic route shown in Scheme 1 enabled
relatively rapid access to sufficient quantities of material for
anion-binding studies.
Ka values of 3 and 4 with anions were determined by
19F NMR titrations with Bu4N+ salts as described above
(Table 5). Comparing this data with that for interactions of
À
A
&
4
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Halogen Bonding between Anions and Iodoperfluoroorganics
FULL PAPER
Figure 4. Plot of calculated energy versus I···ClÀ···I angle for the bifurcat-
ed halogen bond shown. Calculations were carried out at the B3LYP/6-
31+GACTHNUTRGENUG(N d,p)-LANL2DZdp level of theory.
Figure 3. Calculated gas-phase geometries of the 3–ClÀand 4–
ClÀcomplexes, as depicted by ball-and-stick (top) and space-filling
models (bottom). Calculations were carried out with the B3LYP func-
tional using the 6-31+GACHTUNGTRENNUNG(d,p)-LANL2DZdp split basis set.
and 2-iodobenzaldehyde (6). The synthesis of 5 was accom-
plished using a reported protocol;[47] reduction of 5 with
borane followed by Swern oxidation yielded the volatile al-
dehyde 6 (Scheme 2). Receptors 7–11 and 13 were synthe-
The ability of alkyne and diyne groups to undergo distor-
tions of this type is established.[44]
Although the preference for halogen-bonding systems to
adopt noncovalent bond angles of 1808 is known to be strin-
gent, the question of the preferred I-XÀ-I angle was less
clear. An analysis of the Cambridge Crystallographic Date
Centre Structural Database (CSD) by Beer and co-workers
suggested that bifurcated halogen bonds of chloride and
bromide tend to adopt I-XÀ-I angles of 1808, whereas those
of iodide tends to show a larger range (70–1808).[45] As the
I-XÀ-X angle becomes smaller, it appears that steric interac-
tions between iodine atoms destabilize the bifurcated
system, an effect that is more pronounced for smaller hal-
ides XÀ. Examination of space-filling models of the calculat-
ed 3···ClÀ and 4···ClÀ complexes supports this idea, with the
iodo groups incurring a significantly closer approach in
3···ClÀ. To further probe this issue, we have carried out gas-
phase computational modeling of the bifurcated halogen
bond C6F5I···ClÀ···IC6F5 while constraining the I-ClÀ-I angle
to values from 708 to 1708 in ten-degree increments
(Figure 4).[46] The calculations suggest that bifurcated com-
plexes having angles less than 80 degrees are significantly
destabilized.
Scheme 2. Synthesis of iodoperfluoroarenes 5 and 6. DMF=N,N-dimeth-
AHCTUNGTRENGNyUN lformamide, TMS=trimethylsilyl.
sized from 5, by condensations mediated by diisopropylcar-
bodiimide and catalytic 4-(dimethylamino)pyridine
(Figure 5). Condensation of 6 with trans-1,2-diaminocyclo-
hexane (toluene, 1058C) generated bis(imine) 12 in 67%
AHCTUNGTRENNUNG
yield. Triesters 14 and 15 were prepared by alkylation of 5
with the corresponding tris(bromomethyl)arene.
The anion-recognition properties of receptors 7–14 (as-
sessed by Ka values determined in acetone solvent as de-
AHCTUNGTREGsNNUN cribed above) are summarized in Table 6. Benzyl ester 7
displayed chloride affinity that was marginally higher than
that of amide 8. Ester-based receptors capable of acting as
bidentate halogen-bond donors (9–11) had Ka values with
Bu4N+ClÀ ranging from 1.1–1.8ꢃ103 mÀ1, affinities similar to
those of the ethynylene- and butadiynylene-based bidentate
receptors 3 and 4 discussed in the previous section. Dramat-
ic effects of the linker length and flexibility on Ka were not
evident in this series of compounds. On the other hand, bis-
Computational modeling thus appears to indicate that
butaACHTUNGTRENNUNGdiynylene-linked receptor 4 is better suited than 3 to ac-
commodate the distance and angle preferences of bifurcated
halogen bonds involving ClÀ and BrÀ. However, this trend
was not borne out in the experimental binding data in ace-
tone: the Ka values of 3 and 4 for a given anion were found
to differ by less than a factor of two, with 3 interacting more
tightly with both ClÀ and BrÀ under the conditions of the
19F NMR titration.
AHCTUNGTERG(NNUN imine) 12 displayed a relatively low Ka value with chloride.
DFT modeling of the 12···ClÀ complex in the gas phase re-
vealed a bifurcated halogen bond having a I-ClÀ-I angle of
838; we speculate that the suboptimal angle combined with
the flexibility of 12 (in comparison to 3) may be contributing
factors.
Multidentate halogen-bond donors based on 2-iodoperfluoro-
benzaldehyde and 2-iodoperfluorobenzoic acid: In search of
donor groups that could lend themselves to rapid evaluation
of multidentate XB receptor architectures, we turned to per-
fluorinated derivatives of 2-iodoperfluorobenzoic acid (5)
Esters 13–14 and 2, which are capable of donating three
halogen bonds, displayed Ka values for chloride that were
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M. S. Taylor et al.
creased down the group (ClÀ >
BrÀ >IÀ) and the oxoanion af-
finities were low. Because the
Ka values of 2 with halides are
significantly higher than those
of C6F5I and C8F17I, the triden-
tate donor provides a better in-
dication of the magnitude of
this effect. The observation of
similar trends for the mono-
and tridentate donors suggests
that the geometry of triester 2
does not play a major role in
influencing its selectivity as an
anion receptor.
The thermodynamics of the
2···ClÀ interaction were further
probed using a vanꢁt Hoff plot,
Figure 5. Structures of anion receptors 7–14.
from which
a
DHbinding of
À3.9 kcalmolÀ1 and DSbinding of
+6.1 calmolÀ1 KÀ1 were inferred
Table 6. Association constants (Ka) for interactions of receptors 7–14 and
(Figure 6). The positive DSbinding is consistent with the data
described above for the C6F5I···ClÀ interaction, and its mag-
nitude is roughly three times that of the latter. We note that
this quantitative comparison is an approximation, given that
C6F5I is not an ideal substitute for the iodoperfluoroben-
zoate groups of 2. Subject to a similar qualification, compar-
ision of DHbinding for 2···ClÀ and C6F5I···ClÀ suggests that the
enthalpy contributions of each successive halogen bond are
not additive.
2 with Bu4N+XÀ in acetone at 295 K.
[a,b]
XB donor
XÀ
Ka [MÀ1
]
7
8
9
10
11
12
13
14
2
2
2
2
2
ClÀ
ClÀ
ClÀ
ClÀ
ClÀ
ClÀ
ClÀ
ClÀ
ClÀ
BrÀ
IÀ
7.0ꢃ101
4.0ꢃ101
1.2ꢃ103
1.1ꢃ103
1.8ꢃ103
2.0ꢃ102
8.0ꢃ103
3.0ꢃ103
1.9ꢃ104
3.8ꢃ103
7.6ꢃ102
1.0ꢃ101
<1.0ꢃ101
<1.0ꢃ101
TsOÀ
À
NO3
HSO4
À
2
[a] Ka values were determined by fitting changes in 19F NMR chemical
shift to a 1:1 binding isotherm. Experiments were carried out in dupli-
cate; uncertainties in Ka values estimated to be Æ20%. [b] Ka values for
interactions of 7, 10, 11 and 2 were previously reported in Ref. [26].
higher than those of the bidentate receptors. The chloride
affinity of triethanolamine triester 13 was intermediate be-
tween those of the tris(hydroxymethyl)arene derivatives, 14
and 2. The Ka value of hexasubstituted benzene derivative 2
with chloride was six times higher than that of its trisubsti-
tuted congener 14, thus suggesting that the methyl substitu-
ents provide a degree of preorganization consistent with
previous studies of related hexasubstituted benzene-based
receptors.[48] As discussed in our preliminary report,[26] com-
putational modeling of the 2···ClÀ adduct in the gas phase
revealed a binding mode in which the anion accepts a halo-
gen bond from each of the three iodoperfluorobenzoate
groups. Ka values of 2 with various Bu4N+XÀ salts indicated
the same trends that were observed for the simple mono-
dentate donors, C6F5I and C8F17I, that is, halide affinities de-
Figure 6. vanꢁt Hoff plot (ln(Ka) versus 1000/T) for the interaction of tri-
dentate receptor 2 with nBu4N+ClÀ in acetone. Values of Ka were deter-
mined by 19F NMR titrations at temperatures ranging from 268 to 298 K.
Solvent effects on halogen bonding of iodoperfluoroorganics
with anions: The Ka value of 2 with Bu4N+ClÀ showed con-
siderable variation as
a function of solvent identity
(Table 7). Whereas the Ka value for chloride binding in ace-
tonitrile was within a factor of five of that for acetone, those
for chlorinated solvents (CH2Cl2 and CHCl3) and for di-
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Halogen Bonding between Anions and Iodoperfluoroorganics
FULL PAPER
Table 7. Association constants (Ka) for interactions of receptor 2 and
ically favorable; both entropic and enthalpic factors appear
to contribute to the differences in behavior observed in the
two classes of iodoperfluoroorganic donors.
C8F17I with Bu4N+ClÀ in various solvents at 295 K.
[a]
XB donor
Solvent
Ka [MÀ1
]
2
2
2
2
acetone
acetonitrile
dichloromethane
dimethylsulfoxide
chloroform
acetone
acetonitrile
dimethylsulfoxide
dichloromethane
1.9ꢃ104
5.0ꢃ103
3.1ꢃ101
1.3ꢃ101
0.6ꢃ101
2.2ꢃ103
1.3ꢃ102
3.2ꢃ101
3.1ꢃ101
Several multidentate receptor architectures based on
ortho-substituted iodoperfluoroarene donors have been
evaluated. Solution-phase binding data indicate that ethyny-
lene, butadiynylene, imine, and ester linking groups are
useful for the construction of iodoperfluoroarene-derived bi-
dentate anion receptors. Tridentate receptors show still
higher Ka values with halides: structure-activity relationships
suggest that the preorganized nature of the hexasubstituted
benzene-based triester 2 contributes to its high chloride af-
finity in organic solvent. Studies of both tridentate 2 and
C8F17I reveal significant solvent effects on halogen bonding
interactions with anions, including a surprising deleterious
effect of chlorinated solvents such as dichloromethane and
chloroform.
2
C8F17I
C8F17I
C8F17I
C8F17I
[a] Ka values were determined by fitting changes in 19F NMR chemical
shift to a 1:1 binding isotherm. Experiments were carried out in dupli-
cate; uncertainties in Ka values estimated to be Æ10–20%.
methyl sulfoxide were suggestive of significant deleterious
effects on binding.[49] Similar effects were observed for the
monodentate iodoperfluoroalkane donor C8F17I.
The bi- and tridentate receptors described in this study
display the same trends in anion affinity as were observed
for the simple monodentate model compounds; it is likely
that more rigid iodoperfluoroarene-based architectures
would be needed to overcome the intrinsic preferences of
the donor groups that underlie this behavior. Beer and co-
workersꢁ observations that the levels of anion selectivity of
conformationally restricted haloimidazoliophanes and cate-
nanes are influenced by receptor geometry indicate that this
goal is achievable. Computational studies suggest that sever-
al features of the halogen-bonding interaction should be
taken into account when considering the design of multiden-
tate receptors: in addition to the generally recognized pref-
erence for linear C–I···XÀ noncovalent bonds, the I-XÀ-I
angle is likely to contribute meaningfully to the strength of
bifurcated interactions with anions. The predicted destabili-
zation of complexes having small I-XÀ-I angles (apparently
a result of steric interactions between iodo groups) is con-
The data for chlorinated solvent are particularly striking
because most scales of solvent polarity and polarizability, in-
cluding Kosowerꢁs Z scale, ET(30), and p*, place both di-
chloromethane and chloroform lower than acetone and ace-
tonitrile.[50] Competition with hydrogen-bond donation by
the chlorinated solvents is possible, although values of a, a
measure of solvent hydrogen-bond donor ability, are not en-
tirely consistent with this proposition; for example, acetoni-
trile possesses a value of a that is higher than that of di-
chloromethane. Halogenated solvents, particularly CHCl3,
are also known to act as halogen-bond donors.[51] Given the
complexity of receptor–anion interactions in solution (desol-
vation, ion pairing, etc.), the significant entropic contribu-
tions to the interactions in acetonitrile, as revealed by vanꢁt
Hoff plot analysis, and the relatively small number of sol-
vents examined in the present study, our ability to interpret
these data is somewhat limited. Interesting solvent effects
were also evident in studies of halogen bonding between
ACHUTNGERNsNUG istAHCTUNGTRNENeUGN nt with previous crystallographic studies, and may be a
iodo
amine,[13b] and between anions and bis(haloimidazolium) re-
ceptors.[31]
perfluorocarbons and the neutral acceptor, triethyl-
productive line of investigation in terms of developing selec-
tive anion receptors. Identifying new halogen bond donor
groups either that give rise to strong interactions with
anions (especially in competitive solvents), that are readily
incorporated into modular architectures, or both, and apply-
ing halogen bonding of anions in functional contexts (e.g. in
the development of synthetic ion transporters and catalysts)
represent interesting directions for future study.
ACHTUNGTRENNUNG
Conclusion
Halogen-bonding interactions between halide anions and
iodoperfluoroalkanes and iodoperfluoroarenes are of appre-
ACHTUNGTRENNUNGciable strength in moderately polar organic solvents such as
A
R
ACHTUNGTRENNUNG
acetone and acetonitrile, and they may be employed as the
basis for the development of multidentate anion receptors.
The monodentate donors, C8F17I and C6F5I, display Ka
values for anions in acetone solvent ranging from 40–
2200mÀ1; trends include the interactions of the iodoperfluor-
oalkane with a given anion being characterized by higher Ka
values than those of the corresponding arenes, a preference
for binding to the lighter halides (ClÀ >BrÀ >IÀ), and rela-
tively weak binding of oxoanions. Analysis of the tempera-
ture dependence of the C8F17I···ClÀ and C6F5I···ClÀ Ka values
reveals several noteworthy features: anion binding is entrop-
Experimental Section
General considerations: Reactions were carried out in oven-dried glass-
ware fitted with rubber septa under an atmoACTHNUTRGNEsNUG phere of dry argon, unless
otherwise indicated. Toluene (HPLC grade) and tetrahydrofuran were
purchased from Caledon Laboratories and purified by passing through
two columns of activated alumina under argon (Innovative Technology,
Inc.). Stainless steel syringes were used to transfer air- and moisture-sen-
sitive liquids.
1H and 19F NMR spectra were obtained using either a Varian Mercury
400 MHz or Agilent 500 DD2MHz spectrometer, with an HX 5 mm
OneNMR probe. 1H NMR spectra are reported in parts per million
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M. S. Taylor et al.
(ppm) relative to tetramethylsilane and referenced to residual protium in
the solvent. Chemical shifts for fluorine were recorded in parts per mil-
lion (ppm) relative to CFCl3 using trifluorotoluene (d 63.72 ppm) as an
internal standard. High-resolution mass spectra (HRMS) were obtained
on a VS 70–250S (double focusing) mass spectrometer at 70 eV. Infrared
(IR) spectra were obtained on a PerkinElmer Spectrum 100 instrument
equipped with a single-reflection diamond/ZnSe ATR accessory, either in
the solid state or as neat liquids, as indicated.
Synthesis: 2-Iodoperfluorobenzoic acid 5[47] and receptors 2, 7, 10, and
11[26] were prepared as previously reported. Receptors 8–9 and 13–14
were prepared in analogy to the procedures for 10–11 and 2, respectively,
and their characterization data are provided in the Supporting Informa-
tion.
hexane (0.084 mmol. 10 mL), 2,3,4,5-tetrafluoro-6-iodobenzaldehyde
(2 equiv, 0.17 mmol, 51 mg) and dry toluene (1 mL). The tube was sealed
and the solution heated to 1058C for 20 h. Solvent was removed in vacuo
and the resulting crude product crystallized from cyclohexane affording
the title compound (39 mg, 67%). 1H NMR (400 MHz, CDCl3): d=8.13
(s, 2H), 3.56 (m, 2H), 1.89 (m, 6H), 1.52 ppm (m, 2H); {1H}13C NMR
(100 MHz, CDCl3): d=157.0, 74.9, 32.7, 24.3 ppm; {19F}13C NMR
(100 MHz, CDCl3): d=157.0, 147.2, 147.1, 145.9, 140.9, 139.9 ppm;
19F NMR (376 MHz, CDCl3): d=À114.6 (m, 2F), À139.0 (m, 2F), À151.0
(m, 2F), À153.3 ppm (m, 2F); IR (powder): n˜ =2931 (m), 2963 (m) 1639
(m), 1618 (m), 1494 (s), 1469 (s), 1358(m), 1149 (m), 1129 (m), 1071 (s),
958 (m) 802 cmÀ1(m); HRMS (ESI): m/z calcd for C20H13F8I2N2:
686.90403; found: 686.90135.
Anion-binding titrations: 19F NMR titrations were carried out as de-
1,2-Bis(2,3,4,5-tetrafluoro-6-iodophenyl)ethyne (3): To an oven-dried
Schlenk tube equipped with a stir bar and cooled under an atmosphere
of argon were added 1,2-bis(trimethylsilyl)ethyne (1 equiv, 0.9 mmol,
AHCTUNGTRENNUNG
scribed previously.[28] Representative plots of 19F NMR chemical shift
versus concentration of nBu4N+XÀ are provided in the Supporting Infor-
mation.
205 mL), [PdACHTUNGTRENNUNG(PPh3)2Cl2], (5 mol%, 0.045 mmol, 32 mg), PPh3 (10 mol%,
Computational details: Calculations were carried out with the Gaussian
ꢀ09 software package,[52] on a Linux workstation equipped with two quad-
core AMD Shanghai processors. Cartesian coordinates of all calculated
structures are provided in the Supporting Information.
0.09 mmol, 24 mg), 1,2-diiodo-3,4,5,6-tetrafluorobenzene (2.5 equiv,
2.25 mmol, 905 mg), and CuCl (0.5 equiv, 0.45 mmol, 45 mg) in dry DMF
(0.5 mL). After stirring for 6 h at 808C, the solvent was evaporated and
the residue was subjected to flash column chromatography (silica gel,
pentane), affording
a white solid. (92 mg, 0.16 mmol, 18% yield).
19F NMR (376 MHz, CDCl3): d=À113.4 (m, 2F), À128.8 (m, 2F), À149.2
(m, 2F), À153.6 ppm (m, 2F); IR (powder):n˜ =1620 (s), 1498 (s), 1473 (s),
1412 (s), 1376 (s), 1082 (s), 986 (s), 799 (s), 608 cmÀ1 (m); HRMS (EI):
m/z calcd for C14F8I2: 573.7962; found: 573.7952.
Acknowledgements
1,4-Bis(2,3,4,5-tetrafluoro-6-iodophenyl)buta-1,3-diyne (4): To an oven-
dried Schlenk tube equipped with a stir bar and cooled under an atmos-
phere of argon were added 1-iodo-2-[(trimethylsilyl)ethynyl]-3,4,5,6-tetra-
fluorobenzene[43] (1 equiv, 0.48 mmol, 177 mg) and CuCl (0.48 equiv,
1.25 mmol, 190 mL) in 0.5 mL DMF. After stirring for 6 h at 808C, the
solvent was evaporated and the residue was subjected to flash column
chromatography (silica gel, pentane), affording a white solid. (48 mg,
0.19 mmol, 30% yield). 19F NMR (376 MHz, CDCl3): d=À113.5 (m, 2F),
À129.0 (m, 2F), À148.6 (m, 2F), À153.4 ppm (m, 2F); IR (powder): n˜ =
1618 (s), 1491 (s) 1460 (s), 11363 (s), 948 (s), 797 cmÀ1(s); HRMS (EI):
m/z calcd for C16F8I2: 697.79616; found: 697.79686.
This work was funded by NSERC (Discovery Grants Program, Graduate
Fellowship to E. D.), the Canada Foundation for Innovation and the
Province of Ontario. NMR experiments were carried out at the Centre
for Spectroscopic Investigation of Complex Organic Molecules and Poly-
mers, funded by the Canada Foundation for Innovation (project #19119)
and the Ontario Ministry of Research and Innovation. The authors thank
Mike Chudzinski for his assistance with computational modeling of halo-
gen-bonding interactions.
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Received: July 27, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

M. S. Taylor et al.
Halogen Bonding
M. G. Sarwar, B. Dragisic,
´
´
E. Dimitrijevic,
M. S. Taylor* .................. &&&& — &&&&
Halogen Bonding between Anions and
Iodoperfluoroorganics: Solution-Phase
Thermodynamics and Multidentate-
Receptor Design
Halogen-bonding interactions between
halide anions and iodoperfluoro-
AHCTUNGTRENGNaUN lkanes and iodoperfluoroarenes in
moderately polar organic solvents,
such as acetone and acetonitrile, are of
appreciable strength (see figure). Sev-
eral multidentate-receptor architec-
tures were also evaluated. Structure-
activity relationships, computational
studies, thermodynamics from vanꢁt
Hoff plot analysis, and solvent effects
are presented.
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www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!