Anion receptors composed of hydrogen- and halogen-bond donor groups: Modulating selectivity with combinations of distinct noncovalent interactions

Article abstract of DOI:10.1021/ja202096f

Studies of a series of urea-based anion receptors designed to probe the potential for anion recognition through combinations of hydrogen and halogen bonding are presented. Proton- and fluorine-NMR spectroscopy indicates that the two interactions act in concert to achieve binding of certain anions, a conclusion supported by computational studies. Replacement of the halogen-bond donating iodine substituent by fluorine (which does not participate in halogen bonding) enables estimation of the contribution of this interaction to the free energy of anion binding. Evidence for attractive contacts between anions and electron-deficient arenes arising from the use of perfluoroarene-functionalized ureas as control receptors is also discussed. The magnitude of the free energy contribution of halogen bonding depends both on the geometric features of the group linking the hydrogen- and halogen-bond donor groups and on the identity of the bound anion. The results are interpreted in relation to fundamental features of the halogen-bonding interaction, including its directionality and unusual preference for halides over oxoanions. Cooperation between two distinct noncovalent interactions leads to unusual effects on receptor selectivity, a result of fundamental differences in the interactions of halogen- and hydrogen-bond donor groups with anions.

Full text of DOI:10.1021/ja202096f

ARTICLE
pubs.acs.org/JACS
Anion Receptors Composed of Hydrogen- and Halogen-Bond Donor
Groups: Modulating Selectivity With Combinations of Distinct
Noncovalent Interactions
Michael G. Chudzinski, Corey A. McClary, and Mark S. Taylor*
Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6 Canada
S Supporting Information
b
ABSTRACT: Studies of a series of urea-based anion receptors
designed to probe the potential for anion recognition through
combinations of hydrogen and halogen bonding are presented.
Proton- and fluorine-NMR spectroscopy indicates that the two
interactions act in concert to achieve binding of certain anions, a
conclusion supported by computational studies. Replacement
of the halogen-bond donating iodine substituent by fluorine
(which does not participate in halogen bonding) enables estimation of the contribution of this interaction to the free energy of anion
binding. Evidence for attractive contacts between anions and electron-deficient arenes arising from the use of perfluoroarene-
functionalized ureas as control receptors is also discussed. The magnitude of the free energy contribution of halogen bonding
depends both on the geometric features of the group linking the hydrogen- and halogen-bond donor groups and on the identity of
the bound anion. The results are interpreted in relation to fundamental features of the halogen-bonding interaction, including its
directionality and unusual preference for halides over oxoanions. Cooperation between two distinct noncovalent interactions leads
to unusual effects on receptor selectivity, a result of fundamental differences in the interactions of halogen- and hydrogen-bond
donor groups with anions.
’ INTRODUCTION
geometries when interacting with a common guest and carried
out calculations suggesting that the two interactions may be
energetically independent of each other (that is, that the forma-
tion of halogen bonds may not significantly weaken existing
hydrogen bonds and vice versa).4c,10 Small-molecule receptors
capable of guest binding using these two interactions in solution
might serve as models for such situations and provide informa-
tion regarding the extent of stabilization possible. Second,
research from our laboratories led to the development of the
first receptors capable of high-affinity anion recognition by XB
alone and revealed unusual differences in the intrinsic selectiv-
ities of HB and XB for anionic guests: XB hosts show a preference
for halide anions over oxoanions (phosphate, nitrate, sulfate),
perhaps due to a greater contribution of charge-transfer or dis-
persion contributions to XB in comparison to HB.8c This latter
observation suggested that it might be possible to create recep-
tors in which selectivity arises not from size and shape matching
with a particular anionic guest (a well-precedented strategy in
anion recognition)11 but rather from the combined intrinsic
anion preferences of two distinct noncovalent interactions. We
are aware of only a single example of an anion receptor that
employs both XB and HB: Beer and co-workers recently
reported the synthesis and the preliminary anion binding proper-
ties of an iodotriazolium-derived rotaxane.9b The preference of
Halogen bonding (XB) between electron-deficient halogen
compounds and Lewis bases is gaining widespread recognition as
a useful class of noncovalent interactions.1 Applications of XB in
condensed phases are extensive, including the assembly of
functional materials, supramolecular polymers and crystalline
assemblies.2 Proposed roles for XB in medicinal chemistry,3 as
well as in controlling the structure and the function of
biomolecules,4 are also emerging at a rapid pace. Similarities
are often invoked between XB and hydrogen bonding (HB):5
Both are directional interactions for which a dominant electro-
static contribution to the binding enthalpy is generally pro-
posed.6 While applications of HB in solution phase molecular
recognition are abundant, only a handful of instances in which
XB has been employed for this purpose have been reported. A
growing body of thermodynamic data suggests that certain
halogen bonds are sufficiently strong to drive molecular recogni-
tion processes in solution,7 and recently developed anion
receptors8 and interlocked supramolecular architectures9 de-
monstrate that this goal is indeed achievable.
Here, we describe the development of receptors capable of
anion binding by combinations of XB and HB interactions. We
were interested in pursuing this goal for two reasons: First, Ho
and co-workers recently pointed out numerous instances in
which a basic site (often a carbonyl group in a biomolecule)
simultaneously participates in XB and HB in the solid state; they
observed that XB and HB donors often adopt orthogonal
Received: March 7, 2011
Published: June 13, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis and Structures of Anion Receptors
1aꢀ3b
Table 1. Association Constants (Ka) of Receptors 1aꢀ3a and
1bꢀ3b with Halide Anions and Free Energy Contributions of
the XB Interaction (ΔΔGXB
)
receptor
anion
Ka (Mꢀ1
)
ΔΔGXB (kcal/mol)
ꢀ0.2 ( 0.1
1a
1b
1a
1b
1a
1b
2a
2b
2a
2b
2a
2b
3a
3b
3a
3b
3a
3b
Clꢀ
Clꢀ
Brꢀ
Brꢀ
Iꢀ
8.5 ꢁ 103 a
6.5 ꢁ 103 a
1.7 ꢁ 103 b
1.4 ꢁ 103 b
1.3 ꢁ 102 b
1.0 ꢁ 102 b
8.0 ꢁ 103 a
1.7 ꢁ 103 a
2.4 ꢁ 103 b
3.7 ꢁ 102 b
2.2 ꢁ 102 b
55b
4.9 ꢁ 103 a,b
3.1 ꢁ 103 b
9.4 ꢁ 102 b
5.0 ꢁ 102 b
1.1 ꢁ 102 b
61b
ꢀ0.1 ( 0.1
ꢀ0.2 ( 0.1
ꢀ0.9 ( 0.1
ꢀ1.1 ( 0.1
ꢀ0.9 ( 0.1
ꢀ0.3 ( 0.1
ꢀ0.4 ( 0.1
ꢀ0.3 ( 0.1
Iꢀ
Clꢀ
Clꢀ
Brꢀ
Brꢀ
Iꢀ
Iꢀ
Clꢀ
Clꢀ
Brꢀ
Brꢀ
Iꢀ
Iꢀ
this system for iodide over the other halide anions was rationa-
lized in terms of size matching of the binding site and solvation
effects in protic medium. Here, we present detailed anion binding
studies of a series of urea receptors that incorporate either one or
two iodoperfluorobenzoate groups as halogen-bond donors and
demonstrate that the incorporation of these groups results in a
significant alteration of the anion selectivity of the urea functional
group. The origin of this effect is the selective stabilization of
halides by the XB donor groups, as revealed by evaluation of the
free energy contributions of XB to the overall thermodynamics of
binding. Experiments probing the directionality of halogen
bonds in solution and evidence for attractive anionꢀarene
interactions of oxoanions with perfluoroaryl groups are also
described.
a Determined by fitting changes in solution absorbance as a function of
anion concentration to a 1:1 binding isotherm (n-Bu4Nþ cation,
acetonitrile solvent, carried out in duplicate: uncertainty in Ka values
estimated to be (20%). b Determined by fitting changes in 1H- and 19F-
NMR chemical shift as a function of anion concentration to a 1:1 binding
isotherm (n-Bu4Nþ cation, d3-acetonitrile solvent, carried out in dupli-
cate: uncertainty in Ka values estimated to be (20%). The reported
values are the averages of Ka determinations using changes in chemical
shift for one urea NꢀH signal and one fluoro substituent. See the
Supporting Information.
’ UREA-BASED RECEPTORS BEARING A SINGLE
HALOGEN-BOND DONOR: EFFECTS OF LINKER
STRUCTURE
The urea functional group, well-known for its ability to
interact with anions through HB interactions,12 was chosen as
a scaffold for the construction of combined HB/XB receptors.
2-Iodoperfluorobenzoic acid, the XB subunit used in our pre-
vious study of multidentate anion receptors, was coupled to
amino alcohol-derived ureas to yield receptors 1aꢀ3a, which
differ by the nature of the linker that connects the XB donor to
the urea moiety (Scheme 1). Perfluorinated receptors 1bꢀ3b,
which lack the 2-iodo substituent participating in the proposed
halogen bond, were synthesized to provide a measure of the
contribution of the XB interaction to the anion affinities of
1aꢀ3a. Strictly speaking, control receptors 1bꢀ3b provide
measures of the relative contributions of XB and anionꢀarene
interactions13 in this system; this point is discussed in greater
detail below.
1
Figure 1. Changes in H- (red, b) and 19F-NMR (blue, () chemical
shift (Δδ) of receptor 1a upon addition of n-Bu4NþBrꢀ (d3-aceto-
nitrile). Curves represent equations of best fit to a 1:1 binding model.
of both NꢀH resonances as well as the 19F-NMR chemical shifts
of all magnetically distinct fluorine substituents. Figure 1 depicts
the changes in 1H- and 19F-NMR chemical shift upon addition of
n-Bu4NþBrꢀ to 1a: the significant downfield shift of the urea
NꢀH NMR signal, along with the upfield change in δ19F of the
four fluorine substituents, are consistent with anion binding
through a combination of XB and HB. The association constants
The association constants of receptors 1aꢀ3a and 1bꢀ3b
with halide anions (tetrabutylammonium cation, acetonitrile
solvent) are assembled in Table 1. Addition of halide anions to
each receptor resulted in changes in the 1H-NMR chemical shifts
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(for example, for receptors 1a and 1b ΔΔGXB = ΔGbinding(1a)
ꢀ
ΔGbinding(1b)) provides a rough estimate of the contribution of
the XB interaction to the overall thermodynamics of binding.15
Based on previous observations from our laboratories, we
anticipated negative values of ΔΔGXB for the halide anions,
which are good acceptors of halogen bonds. The data reveal a
significant influence of the structure of the amino alcohol linker
group on the strength of the halogen bond formed. Receptor 1a
shows a barely measurable contribution of the XB interaction to
anion affinity, while receptor 2a binds to each of the halide anions
with association constants an order of magnitude higher than
those of receptor 2b, corresponding to values of ΔΔGXB of
approximately 1 kcal/mol. Receptor 3a, in which the HB and XB
donor groups are linked by a flexible hexamethylene spacer, gave
values of ΔΔGXB lower than those of 2a for each anion.
Presumably, the low value of ΔΔGXB for 3a in comparison to
2a reflects the increased entropic cost for chloride binding of the
former, due to the flexible linker tethering the urea and iodoper-
fluorobenzoate groups. Effects of this type are well precedented
and underlie the use of rigid, preorganized scaffolds in receptor
design. The differences in behavior between receptors 1a and 2a,
on the other hand, are less clear; computational modeling of their
chloride complexes was undertaken to probe this issue. For this
purpose, simplified models 1a0ꢀ3a0(which lack the 4-nitro
substituent) were considered. The gas-phase geometries of the
receptorꢀClꢀ complexes were optimized using density func-
tional theory (DFT), employing the B3LYP functional.16 The
6-31þþG(d,p) basis set was used for C, H, N, O, F, and Cl
atoms, and the LANL2DZ effective core potential,17 augmented
with polarization functions of d symmetry and diffuse functions
of p symmetry (LANL2DZdp),18 was employed for iodine. For
each receptor, the chloride anion interacts with both hydrogen-
and halogen-bond donor groups in the energy-minimized struc-
ture (Figure 3). However, a difference in the halogen-bond
Figure 2. (a) UVꢀvis absorption spectra of 2a upon addition of n-
Bu4NþClꢀ (acetonitrile) and (b) absorbance of 2a (λ = 362 nm) as a
function of [n-Bu4NþClꢀ]. Curve represents the equation of best fit to a
1:1 binding model.
angles is evident, with the CꢀI Clꢀ angle in 1a0 (155°)
3 3 3
distorted from the preferred 180° geometry by 15° more than
that of 2a0 (170°). Receptor 3a0 is predicted to accommodate a
near-linear halogen bond (179.6°).
of the chloride anion, which exceed those of Brꢀ and Iꢀ, were
determined by UVꢀvis absorption spectroscopy, taking advan-
tage of the 4-nitroaniline chromophore present in these recep-
tors. The spectroscopic changes accompanying binding of
chloride by 2a are shown in Figure 2a. In each case, analysis by
the method of continuous variation (Job plot) was consistent
with a 1:1 host:guest binding stoichiometry. Values of Ka were
determined by fitting the changes in NMR chemical shift or
absorbance as a function of anion concentration to 1:1 binding
isotherms by standard methods.14 When NMR was employed,
the average of the values of Ka determined by 1H NMR (the urea
NꢀH signal) and by 19F-NMR (the 3-F signal) is reported. Each
determination was carried out in duplicate or triplicate, and an
uncertainty of (20% is estimated for all reported Ka values. In
cases where the magnitude of the association constant was
appropriate for determination by either method (NMR or
UVꢀvis spectroscopy), data obtained using the two techniques
were in good agreement, for example, NMR yielded values of
Whilꢀe the differences in XB angle between 1a0ꢀClꢀ and
2a0ꢀCl might seem to be modest, data from X-ray
crystallography,1a,19 gas-phase microwave spectroscopy,20 and
computation21 indicate that halogen bonds show a more strin-
gent preference for linearity than do hydrogen bonds. To probe
the potential magnitude of this effect in the current system, we
carried out calculations of the gas-phase binding energy of the
C6F5IꢀClꢀ halogen-bonded complex as a function of the Cꢀ
I
Clꢀ angle. These calculations were conducted at the MP2
3 3 3
level of theory: The complex geometry was optimized (MP2/
aug-cc-pVDZ, with the aug-cc-pVDZ-PP effective core potential
for iodine),22 and the single-point energy calculations (MP2/
aug-cc-pVTZ, with the aug-cc-pVTZ-PP effective core potential
for iodine) were carried out while incrementally altering the
halogen-bond angle. Two limiting cases were investigated: (1)
The chloride anion was held in the plane of the perfluoroaryl
group (a CꢀCꢀI Clꢀ dihedral angle of 180°); and (2) the
3 3 3
chloride anion was held in the plane perpendicular to that of the
(10.4 ( 2.1) ꢁ 103 Mꢀ1 and (6.5 ( 1.3) ꢁ 103 Mꢀ1
,
perfluoroaryl group (a CꢀCꢀI Clꢀ dihedral angle of 90°), as
3 3 3
respectively, for the 1aꢀClꢀ and 1bꢀClꢀ association constants
compared to (8.5 ( 1.7) ꢁ 103 Mꢀ1 and (6.5 ( 1.3) ꢁ 103 Mꢀ1
as determined by UVꢀvis spectroscopy.
the CꢀI Clꢀ angle was varied. The electronic energy of the
3 3 3
complex is plotted as a function of halogen-bond angle for each of
these two limiting dihedral angles in Figure 4. For comparison,
the energy of the pyrroleꢀClꢀ hydrogen-bonded complex
(which has a similar calculated gas-phase energy of interaction
The difference ΔΔGXB between the free energies of interac-
tion of the iodinated and fluorinated receptors with a given anion
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Figure 3. Structures of the 1a0ꢀClꢀ, 2a0ꢀClꢀ, and 3a0ꢀClꢀ com-
plexes calculated by DFT (B3LYP/6-31þþG(d,p)-LANL2DZdp, gas-
phase: see the text). Values of the I Clꢀ halogen-bond distance and
3 3 3
CꢀI Clꢀ halogen-bond angle are listed beneath each structure.
3 3 3
Figure 4. Calculated gas-phase energies of the iodoperfluorobenzeneꢀ
chloride and pyrroleꢀchloride complexes (MP2/aug-cc-pVTZ//MP2/
aug-cc-pVDZ) as a function of CꢀI Clꢀ and NꢀH Clꢀ angle,
as the C6F5IꢀClꢀ complex at this level of theory)23 as a function
of NꢀH Clꢀ angle, for each of these two limiting dihedral
3 3 3
ꢀ3 3 3
3 3 3
respectively. Graphs for dihedral angles (CꢀCꢀI Cl and CꢀNꢀ
angles, is shown on the same graphs.
3 3 3
H
Clꢀ, respectively) ϕ = 180° (top) and ϕ = 90° (bottom) are
3 3 3
The data indicate that the halogen-bonded complex incurs a
significantly higher energetic penalty than does the hydrogen-
bonded complex upon distortion from the ideal linear geometry,
for example, a bond angle of 155° destabilizes the halogen-
bonded complex by roughly 5 kcal/mol, in comparison to
1 kcal/mol for the hydrogen-bonded complex. (As an aside,
the two systems differ in terms of the dihedral angle that incurs
the smallest energetic penalty: For the C6F5IꢀClꢀ complex, the
90° dihedral angle (which allows for a potentially attractive
anionꢀarene interaction as the Clꢀ is brought closer to the
electron-deficient π face of the arene) is preferred over the 180°
dihedral (in which the anion approaches the electronegative
fluorine substituents). The reverse is predicted for the pyrroleꢀ
Clꢀ complex: In this case, the contact between the anion and
the electron-rich π face of the heterocycle is predicted to be a
repulsive interaction, and the calculations indicate that the 180°
shown. Calculated molecular electrostatic potential energy surfaces of
C6F5I (top right) and pyrrole (bottom right) (MP2/aug-cc-pVDZ) are
shown for comparison: blue indicates regions of partial positive charge.
arises when it is bound to a sufficiently electronegative group;24
calculated molecular electrostatic potentials (Figure 4) indicate
that this region is spatially restricted in C6F5I relative to pyrrole.
The differences in solution-phase binding data for 1a and 2a
complement previous gas- and solid-phase studies of the angular
preference of XB and suggest that this feature must be considered
carefully when designing rigid receptors based on XB.
’ UREA-BASED RECEPTORS INCORPORATING TWO
HALOGEN-BOND DONOR GROUPS
We anticipated that the more balanced combination of two
HB and two XB donor groups could give rise to significant
alterations in receptor selectivity as a result of the increased
contribution of the XB interaction to guest binding. Serinol-
derived receptor 4a presents such an ensemble of binding groups,
with perfluorinated 4b serving as a control. The affinities of these
receptors for a range of halides and oxoanions, determined by
NMR or absorption spectroscopy titrations, are assembled in
dihedral (which may benefit from a stabilizing CH anion
3 3 3
hydrogen bond) is preferred. In any case, the magnitude of these
differences is relatively minor, and the halogen bond is predicted
to be the more directional interaction regardless of the dihedral
angle chosen). Electrostatic models of XB interpret its pro-
nounced directionality as arising from the localized nature of
the ‘σ-hole’, the region of partial positive charge at a halogen that
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Table 2. Association Constants (Ka) of Receptors 4aꢀ4c with
Anions and Estimated Free Energy Contributions of the XB
(ΔΔGXB) and Anionꢀarene Interactions (ΔΔGAA
)
ΔΔGXB
ΔΔGAA
receptor
anion
Ka (Mꢀ1
)
(kcal/mol)
(kcal/mol)
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
BzOꢀ
BzOꢀ
BzOꢀ
Clꢀ
Clꢀ
Clꢀ
Brꢀ
Brꢀ
Brꢀ
TsOꢀ
TsOꢀ
TsOꢀ
Iꢀ
1.9 ꢁ 105 a
1.4 ꢁ 105 a
6.6 ꢁ 104 a
2.1 ꢁ 104 a
2.5 ꢁ 103 a
2.3 ꢁ 103 a
6.5 ꢁ 103 b
4.9 ꢁ 102 b
4.6 ꢁ 102 b
1.1 ꢁ 103 b
9.6 ꢁ 102 b
5.5 ꢁ 102 b
5.6 ꢁ 102 b
60b
ꢀ0.2 ( 0.1
ꢀ0.5 ( 0.1
ꢀ1.3 ( 0.1
ꢀ1.5 ( 0.1
ꢀ0.1 ( 0.1
ꢀ1.4 ( 0.1
ꢀ0.1 ( 0.1
ꢀ0.1 ( 0.1
ꢀ0.1 ( 0.1
ꢀ0.1 ( 0.1
ꢀ0.3 ( 0.1
0 ( 0.1
Iꢀ
Iꢀ
55b
HSO4ꢀ
HSO4ꢀ
HSO4
4.4 ꢁ 102 b
3.8 ꢁ 102 b
2.3 ꢁ 102 b
2.9 ꢁ 102 b
2.6 ꢁ 102 b
1.6 ꢁ 102 b
ꢀ
Figure 5. (a) Plot of ꢀΔGbinding of 4a against ꢀΔGbinding of 4b for the
series of anions tested. The dotted line represents y = x. (b) Bar graph
illustrating the differences in anion selectivity between receptors 4b and
4a (gray and red bars, respectively).
ꢀ0.3 ( 0.1
ꢀ0.3 ( 0.1
ꢀ
NO3ꢀ
NO3ꢀ
NO3
respectively) than for the oxoanions TsOꢀ, HSO4ꢀ, and
NO3ꢀ (Δδmax = ꢀ0.32, ꢀ0.34, and ꢀ0.27, respectively). These
data are consistent with the idea that receptor 4a interacts with
halide anions through combinations of HB and XB, while the
latter interaction is weak or absent in the case of the oxoanions. A
contribution of dispersion or charge transfer to the XB interac-
tions of halides is a possible explanation for this behavior; high-
level computational studies suggest that halogen bonds cannot
be modeled as purely electrostatic interactions. Figure 5 illus-
trates the alteration of the anion selectivity of the urea receptor
resulting from selective stabilization of the halide anions by the
XB donor groups in 4a.
a Determined by fitting changes in solution absorbance as a function of
anion concentration to a 1:1 binding isotherm (n-Bu4Nþ cation,
acetonitrile solvent, carried out in duplicate: uncertainty in Ka values
estimated to be (20%). b Determined by fitting changes in 1H- and, for
4a and 4b, 19F-NMR chemical shift as a function of anion concentration
to a 1:1 binding isotherm (n-Bu4Nþ cation, d3-acetonitrile solvent,
carried out in duplicate: uncertainty in Ka values estimated to be (20%).
The reported values are the averages of Ka determinations using changes
in chemical shift for one urea NꢀH proton and one fluoro substituent in
4a and 4b. See the Supporting Information.
Table 2, along with the contribution of the halogen bonds to the
free energy of binding ΔΔGXB (as defined above).
AnionꢀArene Interactions in Perfluorinated Receptor 4b.
As alluded to earlier, the perfluoroaryl moieties present in the
“control” receptors 1bꢀ4b are not innocent with respect to
noncovalent interactions; these electron-deficient aryl groups are
capable of anionꢀarene interactions.25 Despite significant interest in
the fundamental nature and the potential applications of anionꢀ
arene interactions, definitive evidence for attractive contacts of
this type in solution is rare.26 To estimate the magnitude of putative
anionꢀarene interactions in complexes of 4b, we prepared
benzoate ester 4c and determined the difference in binding
energies ΔΔGAA (ΔΔGAA = ΔGbinding(3b) ꢀ ΔGbinding(3c)).27
Estimation of the strength of anionꢀarene interactions in
receptor 4b by this approach revealed surprising results. Previous
publications suggested that interactions between anions and
Comparison of the association constants of 4a and 4b for the
series of anions reveals the pronounced preference of the
halogen-bond donor groups to interact with the halides over
oxoanions, an observation consistent with our previous work.
The oxygen-based anions tested, which vary widely in Brønsted
basicity, do not show a significant stabilizing interaction with the
halogen-bond donor groups in 4a, while the values of ΔΔGXB for
the halide anions are each greater than 1 kcal/mol. The magni-
tudes of the 19F-NMR chemical shift changes of 4a upon anion
binding are considerably higher for the halides Brꢀ and Iꢀ (the
maximum changes in chemical shift Δδmax obtained from curve
fitting of the NMR titration data are ꢀ1.7 and ꢀ1.9 ppm,
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Table 3. Association Constants (Ka) of Receptors 5a and 5b
with Halide Anions and Free Energy Contributions of the XB
Interaction (ΔΔGXB
)
receptor
anion
Ka (Mꢀ1 a
)
ΔΔGXB (kcal/mol)
ꢀ0.7 ( 0.1
5a
5b
5a
5b
5a
5b
5a
5b
5a
5b
5a
5b
5a
5b
5a
5b
BzOꢀ
BzOꢀ
Clꢀ
3.3 ꢁ 103
1.0 ꢁ 103
2.4 ꢁ 103
86
8.3 ꢁ 102
2.0 ꢁ 102
7.0 ꢁ 102
24
1.4 ꢁ 102
8.5
54b
38b
ꢀ
Figure 6. Structure of the 4b0ꢀNO3 complex calculated by DFT
ꢀ2.0 ( 0.1
ꢀ0.8 ( 0.1
ꢀ2.0 ( 0.1
ꢀ1.7 ( 0.1
ꢀ0.2 ( 0.1
ꢀ0.3 ( 0.1
ꢀ0.2 ( 0.1
(B3LYP/6-31þþG(d,p), gas phase). Hydrogen-bond distances and
nitrateꢀperfluoroarene contact distances are indicated.
Clꢀ
ꢀ
H2PO4ꢀ
H2PO4
Brꢀ
Brꢀ
Iꢀ
Iꢀ
TsOꢀ
TsOꢀ
HSO4ꢀ
30b
19b
ꢀ
HSO4
ꢀ
NO3ꢀ
21
NO3
14
1
a Determined by fitting changes in H NMR and 19F-NMR chemical
shift as a function of anion concentration to a 1:1 binding isotherm (n-
Bu4Nþ cation, d3-acetonitrile solvent, carried out in duplicate: uncer-
tainty in Ka values estimated to be (20%). The reported values are the
averages of Ka determinations using changes in chemical shift for one
urea NꢀH proton andꢀone fluorine substituent. b Association constants
for TsOꢀ and HSO4 were determined by 19F-NMR because of
significant broadening of the signals corresponding to the NꢀH protons
in the 1H NMR spectrum.
Figure 7. Structure of the 4a0ꢀClꢀ and 5aꢀClꢀ complexes calculated
by DFT (gas-phase, B3LYP/6-31þþG(d,p)-LANL2DZdp: see text).
Values of the I Clꢀ halogen-bond distance and CꢀI Clꢀ halogen-
3 3 3
3 3 3
bond angle are listed beneath each structure.
interactions of the perfluoroarene group with this series of
anions. The former would seem to be more consistent with
existing computational data.28
uncharged, substituted phenyl groups would be weak in a
moderately polar solvent, such as acetonitrile,26c,d and the
binding data for the halides are consistent with this notion
(ꢀΔΔGAA e 0.1 kcal/mol for Clꢀ, Brꢀ, and Iꢀ). However,
appreciable values of ΔΔGAA (ꢀ0.3 to ꢀ0.5 kcal/mol) were
observed for the oxoanions BzOꢀ, TsOꢀ, HSO4ꢀ, and NO3ꢀ. A
significant change in 19F-NMR chemical shift upon oxoanion
binding (Δδmax ∼ ꢀ0.7 ppm for the fluoro substituent para to
the carboxyl group) and a relatively short nitrateꢀperfluoroarene
Achieving Halide Selectivity in Combined HB/XB Recep-
tors. Continued evaluation of the effects of the geometry and
strength of the XB and HB donor groups led us to explore
symmetrical, ethanolamine-based receptor 5a. Computational
modeling of 4a0ꢀClꢀ and 5aꢀClꢀ complexes (Figure 7: 4a0 is a
simplified model of 4a lacking the nitro group) suggested that the
halogen bonds in the latter are closer to linearity than in the
former, and the four donor groups presented by 5a more
efficiently surround the anion than do those of 4a. In addition,
the hydrogen-bond donor ability of dialkylurea 5a was antici-
pated to be weaker than that of nitroaniline-based 4a, offering the
possibility that the halogen bonds might contribute in a more
balanced way to the observed order of anion affinities. These
predictions were borne out by the anion binding data for 5a and
its perfluorinated analog 5b (Table 3).
contact distance (dO C = 3.25 Å) in the calculated structure of
3 3 3
ꢀ
the 4b0ꢀNO3 complex (Figure 6: 4b0 lacks the nitro substi-
tuent present in 4b) are consistent with the proposed an-
ionꢀarene interaction. This result represents an addition to
the small set of experimental data supporting such interactions
in solution and is noteworthy because interactions of oxoanions
with arenes are particularly poorly documented in the solution
state. It is not clear whether the difference in behavior between
the halides and the oxoanions is the result of the geometry of
receptor 4b or a reflection of an intrinsic trend in the strength of
Of the receptors studied, 5a shows the most significant effect
of XB on the overall thermodynamics of anion binding. The
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Journal of the American Chemical Society
ARTICLE
’ CONCLUSIONS
Studies of anion receptors equipped with both halogen- and
hydrogen-bond donor functional groups demonstrate that it is
indeed possible to employ these interactions cooperatively in
molecular recognition. Several types of evidence—including the
1
nature of the anion-induced H- and 19F-NMR spectroscopic
changes, the association constants of control receptors lacking
the XB donor functional group, and calculated geometries of
receptorꢀanion complexes—indicate that the two interactions
occur simultaneously upon binding of XB acceptor anions, such
as halides. Among the key findings to emerge from this study are:
(1) The free energy contribution of the halogen bonds
formed is dependent on the identity of the spacer group
linking the HB and XB donor groups. Calculations
suggest that this dependence is a manifestation of the
strong preference of halogen bonds to adopt a linear
EWGꢀX B geometry, a property inferred from solid-
3 3 3
state and gas-phase studies but not previously explored
in solution. The stringent directionality of XB will likely
be an important feature to consider when developing
applications of the interaction in solution-phase molec-
ular recognition.
(2) An anion participating in two HB interactions with a urea
functional group is able to engage in attractive halogen
bonds with iodoperfluoroaryl groups. Control experi-
ments provide a rough estimate of the contribution of
the XB interactions to the overall thermodynamics of
binding in acetonitrile solvent. The estimated incremen-
tal free energy per halogen bond is negligible for
ꢀ
most oxoanions (< 0.2 kcal/mol for NO3ꢀ, HSO4
Figure 8. (a) Plot of ꢀΔGbinding of 5a against ꢀΔGbinding of 5b for the
series of anions tested. The dotted line represents y = x. (b) Bar graph
illustrating the differences in anion selectivity between receptors 5b and
5a (gray and red bars, respectivley).
and TsOꢀ), is small for BzOꢀ and H2PO4ꢀ (0.3 and
0.4 kcal/mol, respectively), and approaches 1 kcal/mol
for the halide anions. These results are consistent with
conclusions regarding the intrinsic anion selectivity of the
XB interaction reached through studies of XB receptors
in moderately polar organic solvent and highlight the
significant distinctions between the XB and HB interac-
tions that have emerged from several studies by our
research group.
association constants for the halides are nearly 30 times higher
for 5a than for the control receptor 5b. We also note that the
binding data for dihydrogenphosphate (H2PO4ꢀ) and benzoate
indicate that these anions participate in stabilizing XB interac-
tions with the iodoperfluoraryl groups in 5a and that the
magnitude of these effects is higher than those observed for
the less basic oxoanions. Halogen bonding involving phosphate
oxygens has been proposed to play a role in controlling the
secondary structure of modified DNA oligomers,29 but reliable
estimates for the strengths of such interactions have proved to
be elusive. The current work indicates that these interactions are
indeed attractive in acetonitrile solution, although weak (roughly
0.4 kcal/mol per halogen bond).
The overall effect of incorporating halogen-bond donors to a
urea receptor is to confer a significant level of halide selectivity to
a class of compounds known to interact tightly with Y-shaped
anions (Figure 8). Conventionally, tuning of receptor selectivity
has been accomplished by varying the number of donor groups
(generally HB donors) and their orientation in space;30 taking
advantage of differences in the intrinsic preferences of two
distinct noncovalent interactions to achieve this result repre-
sents an unusual approach. As our fundamental understand-
ing of “exotic” noncovalent interactions (that is, those other
than HB, such as anionꢀarene,13 cation-π,31 XB and related
interactions)32 continues to improve, new opportunities to
exploit this second approach, and to combine it with the first,
may emerge.
(3) Comparisons of the anion affinities of urea receptors
bearing pendant perfluorobenzoate functional groups
with those bearing unsubstituted benzoate groups pro-
vide evidence for attractive anionꢀarene interactions
with perfluoroaryl groups in acetonitrile solution. The
observation of weakly attractive contacts with oxoanions
ꢀ
(ꢀΔΔGAA roughly 0.3ꢀ0.5 kcal/mol for NO3ꢀ, HSO4
,
TsOꢀ and BzOꢀ), but not with halide anions, was
unexpected and represents one of only a handful of
studies enabling a quantitative estimate of the magnitude
of such interactions in solution.
(4) Receptors composed of both halogen- and hydrogen-
bond donor groups display anion selectivities that represent
a “compromise” between the distinct preferences of the
two interactions. Incorporating iodoperfluoroaryl groups
into a urea receptor selectively boosts its affinity for
halide anions, while having a minor to negligible effect on
its interactions with oxoanions. This represents an uncon-
ventional approach to modulating receptor selectivity,
and one that may become more prevalent as new infor-
mation regarding poorly understood noncovalent inter-
actions emerges.
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Journal of the American Chemical Society
ARTICLE
’ ASSOCIATED CONTENT
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S
Supporting Information. Complete experimental proce-
b
dures, representative binding curves and Job plots, methods of
data analysis, and computational details. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mtaylor@chem.utoronto.ca
’ ACKNOWLEDGMENT
This work was supported by NSERC (Discovery Grants
Program), the Canadian Foundation for Innovation (Leaders
Opportunity Fund), the Ontario Ministry of Research and
Innovation (Research Infrastructure Program), the University
of Toronto, and Merck Research Laboratories (Canadian Aca-
demic Development Program).
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