Measurements of weak halogen bond donor abilities with tridentate anion receptors

Article abstract of DOI:10.1039/c0cc03347b

The chelate effect of a tridentate receptor is exploited to determine halogen bonding association constants that vary by several orders of magnitude, including interactions of weak donors for which thermodynamic data were not previously available. Free en

Full text of DOI:10.1039/c0cc03347b

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Measurements of weak halogen bond donor abilities with tridentate anion
receptorsw
´
Elena Dimitrijevic, Olga Kvak and Mark S. Taylor*
Received 19th August 2010, Accepted 14th October 2010
DOI: 10.1039/c0cc03347b
The chelate effect of a tridentate receptor is exploited to
determine halogen bonding association constants that vary by
several orders of magnitude, including interactions of weak
donors for which thermodynamic data were not previously
available. Free energy relationships with computed and
experimental properties hold over this wide range of donors.
The strengths of iodine- and bromine-based halogen bonds,
CH–anion and anion–arene interactions are compared.
contribution of XB to the functions of halogen-containing
pharmaceuticals and biomolecules,16 the thermodynamics of
the relatively weak halogen bonds proposed to be involved in
such systems have not been studied by experiment. Computational
studies of XB would also benefit from experimental data for a
diversity of interaction strengths.
Here, we employ tridentate anion receptors to determine, in
acetone solution with the tetrabutylammonium counterion,
XB association constants that vary by almost four orders of
magnitude. The chelate cooperativity exhibited by these
receptors enables quantitative studies of the XB donor ability
Halogen bonding (XB), the class of noncovalent interactions
in which covalently bound halogen atoms function as electro-
philic species, has attracted widespread recent interest from
fundamental and applied perspectives.1 The majority of
applications of XB—including crystal engineering,2 chemical
separations,3 magnetic and conductive materials,4 and liquid
crystal assembly5—have been carried out in condensed phases.
While studies of XB in solution are at a less advanced stage, a
handful of applications in anion recognition,6 catalysis,7 and
pseudorotaxane formation8 suggest that XB will be a valuable
addition to the arsenal of noncovalent interactions available
for molecular recognition.
of modestly electron-deficient iodoarenes,
a
class of
compounds for which thermodynamic data were not previously
available. The data are used to construct relationships of XB
strength with computationally and empirically derived
quantities. The tridentate receptor scaffold also enables direct
comparisons of the strengths of iodine-based halogen bonds
with other weak interactions, including a bromine-based
halogen bond, CH–anion hydrogen bond, and anion–p
interaction.
The starting point for our study was triester 4a, a halogen-
bonding receptor that displays high affinity for anions in
organic solution. The 4a–ClÀ association constant (acetone,
298 K) is 1.9 Â 104 MÀ1, with all four signals in the 19F-NMR
spectrum of 4a displaying characteristic upfield changes in
chemical shift upon halogen bond formation. This observation
suggested that the synthesis of partially fluorinated derivatives
of 4a would represent a unique opportunity to determine, by
19F-NMR titrations, the strengths of halogen bonds involving
electronically diverse donors. Likewise, variation of the donor
atom (iodine in 4a) would enable measurements of association
constants involving bromine-based halogen bonding,
CH–anion hydrogen bonding, and anion–arene interactions.
Mono-, di- and trifluorinated variants (1–3), as well as
receptors in which the iodine donor atom of 4a was replaced
with a bromine, fluorine, and hydrogen substituent (4b–d) were
prepared from tri(bromomethyl)mesitylene (Fig. 1; see the ESIw).
Methyl esters of the benzoic acids used to construct receptors 1–4
vary markedly in electron density at iodine: representative
molecular electrostatic potential surfaces (B3LYP/6-31+G**-
LANL2DZdp)17 are depicted (Fig. 1). The ‘s-hole’ model of
XB characterizes the interaction as an electrostatic attraction
between a Lewis base and the region of electron deficiency at the
halogen atom:18 accordingly, these compounds should vary
appreciably in donor ability. In particular, the mono- and
difluorinated iodobenzoates, and the bromine-substituted
derivative, are significantly less electron-deficient than the donors
employed in previous quantitative studies of XB.13
A significant challenge to implementation of XB in solution
is the paucity of thermodynamic data available in comparison
to other noncovalent interactions such as hydrogen bonding,9
ion-pairing,10 and interactions of p systems.11 Data of this
type are essential for advancing understanding of the
fundamental properties of supramolecular interactions.12
Studies of the strengths of halogen bonds have been restricted
to perfluoroalkyl, perfluoroaryl, or alkynyl iodides, which
possess among the highest donor abilities of neutral
compounds studied to date.13 The weak nature of XB inter-
actions involving less electron-deficient halocarbon donors
renders determinations of such association constants
a
challenge. Indirect approaches are promising in this regard,
but only two such studies have been published: cleft receptors
were employed to estimate the strength of ClÁ Á ÁN and BrÁ Á ÁN
halogen bonds,14 and (repulsive) arene–halogen interactions
were studied using chemical double-mutant cycles.15 Quantitative
data regarding the donor ability of a wide range of halo-
carbons are not currently available, and would be of value,
particularly from the standpoint of developing a quantitative
understanding of the importance of XB in biological and
medicinal chemistry. Despite speculation regarding the
Department of Chemistry, University of Toronto, 80 St. George St.,
Toronto, ON M5S 3H6, Canada. E-mail: mtaylor@chem.utoronto.ca;
Fax: +1 416 978-8775; Tel: +1 416 946-0571
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, representative 19F-NMR titration
data, and computational details. See DOI: 10.1039/c0cc03347b
Association constants of 1–4 with tetra-n-butylammonium
chloride (Bu4N+ClÀ) were determined by 19F-NMR titrations
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9025–9027 9025

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Table 1 Association constants (Ka) of receptors 1–4 with Bu4N+XÀ
Entry Receptor XÀ
Kaa/MÀ1
VS ,max/kcal molÀ1
b
1
2
3
4
5
6
7
8
1a
1b
1c
2a
2b
2b
2b
2b
2b
2c
3
ClÀ
ClÀ
ClÀ
ClÀ
ClÀ
BrÀ
IÀ
18 Æ 4
15.8
16.1
16.5
17.9
18.4
3 Æ 1
7 Æ 1
38 Æ 8
(2.2 Æ 0.2) Â 102
91 Æ 18
44 Æ 9
À
PhCO2À 22 Æ 4
9
H2PO4
ClÀ
2 Æ 0.5c
10
11
12
13
14
15
15 Æ 3
18.8
21.4
ClÀ
(2.8 Æ 0.3) Â 102
4a
4b
4c
4d
ClÀ
(1.9 Æ 0.2) Â 104 d 22.7
ClÀ
o10 (decomp.)
12.2
—
16.7
ClÀ
o5
o5
ClÀ
a
Association constant (acetone, 298 K) by 19F-NMR titration.
Calculated (B3LYP/6-31+G**-LANL2DZdp) molecular electrostatic
Fig. 1 Structures of tridentate halogen bonding receptors and
electrostatic potential surfaces (B3LYP/6-31+G**-LANL2DZdp) of
representative XB donor groups studied here. Blue indicates regions of
partial positive charge and red regions of partial negative charge.
Maximum values of the electrostatic potential at iodine are indicated
below each structure.
b
c
potential at the donor atom. In acetonitrile. Data from ref. 6a.
d
This wide range of free energies of interaction represents an
opportunity to evaluate relationships between XB thermo-
dynamics and computed quantities. Relationships of this type
represent useful tools for probing the mechanisms of binding
events and for guiding structural optimization.
Calculated molecular electrostatic potentials are employed
extensively in linear free energy relationships involving
noncovalent interactions. In a study of para-substituted
iodoperfluorobenzene derivatives, we observed a relationship
between free energies of XB and the maximum electrostatic
potential calculated at iodine (VS,max).13 It was unclear whether
this relationship would extend to the wide range of XB association
constants explored here. Values of VS,max for the methyl ester
analogs of 1–4 (B3LYP/6-31+G**-LANL2DZdp: see above)
are assembled in Table 1. A linear relationship between
log(Ka) and VS,max is evident (Fig. 2b);19 the relationship
may be stronger than the correlation coefficient (r2 = 0.79)
might indicate, since receptors not having a 3-fluoro substituent
(1b, 1c, 2c, and 3) are grouped below the trendline in Fig. 2.
Calculations suggest that the 3-fluoro substituent serves to
gear the ester group, promoting a conformation that favors
tridentate binding. We conclude that relationships between
electrostatic potential and XB strength hold for iodoarenes
varying significantly in electron density, in agreement with
computational predictions.
A plot of log(Ka) against d13C, the chemical shift of the
carbon atom bound to iodine, also reveals a modest correlation
(see the ESIw). The direction of this trend (the strongest XB
donors having lowest values of d13C) is perhaps counter-
intuitive;20 we speculate that increased shielding of the
ipso carbon arises from polarization of the C–I bond in
response to increased substitution of the arene by fluoro
substituents.21 We note that studies of iodoalkynes have
revealed unusual substituent effects on d13C,13 as well as
unexpected, downfield changes in d13C upon halogen
bonding.22 The latter have been modeled computationally.
The observation that moderately electron-deficient iodo
compounds display measurable anion affinities confers a
practical benefit: while highly fluorinated 4a underwent
decomposition in the presence of the basic anions benzoate
Fig. 2 (a) 19F NMR titration data for the interactions of Bu4N+ClÀ
with 1c, 2a, 3 and 4a ([receptor] = 0.5–1.0 mM in acetone). Curves of
best fit to a 1 : 1 binding model are shown. (b) Correlation between
log(Ka) and calculated electrostatic potential at I for 1a–1c, 2a–2c,
3 and 4a.
(acetone, 298 K) and curve fitting to 1 : 1 binding models
(Fig. 2a and Table 1). Analysis by the method of continuous
variation (Job plot) was consistent with 1 : 1 stoichiometry for
each complex. The effect of the number and position of
fluorine substituents on the receptor’s affinity for chloride is
striking (entries 1–5, 10–12): the 1b–ClÀ association constant
is almost four orders of magnitude lower than that of 4a–ClÀ.
c
9026 Chem. Commun., 2010, 46, 9025–9027
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and dihydrogenphosphate, clean 1 : 1 binding of these anions
À
3 P. Metrangolo, Y. Carcenac, M. Lahtinen, T. Pilati, K. Rissanen,
A. Vij and G. Resnati, Science, 2009, 323, 1461–1464.
by 2b was observed. The low affinity of 2b for PhCO2 and
À
4 M. Fourmigue
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and P. Batail, Chem. Rev., 2004, 104, 5379–5418;
P. Palvadeauc and
B. Schollhorn, Tetrahedron Lett., 2006, 47, 1249–1252.
H2PO4 relative to the halides (entries 5–9) is unusual, as it
K. Boubekeur, J.-L. Syssa-Magale
´
,
does not follow the trend of anion hydration enthalpies. The
preferential binding of the spherical halides over oxygen-based
anions may be a useful feature of XB from the standpoint of
receptor design.6b
¨
5 H. L. Nguyen, P. N. Horton, M. B. Hursthouse, A. C. Legon and
D. W. Bruce, J. Am. Chem. Soc., 2004, 126, 16–17.
6 (a) A. Mele, P. Metrangolo, H. Neukirch, T. Pilati and G. Resnati,
J. Am. Chem. Soc., 2005, 127, 14972–14973; (b) M. G. Sarwar,
B. Dragisic, S. Sagoo and M. S. Taylor, Angew. Chem., Int. Ed.,
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The low anion affinities of receptors 4b–4d, in which the
iodine group involved in the interaction is replaced by other
substituents, are revealing (entries 12–15). Decomposition of
bromine-based XB donor 4b was evident at high Bu4N+ClÀ
concentrations. However, the upper limit of the binding
constant is three orders of magnitude lower than the value
of Ka for 4a–ClÀ in acetone. Given that halogen bonds of
organobromine donors are proposed to play roles in drug–
receptor interactions and biomolecule conformations, it is
noteworthy that an attractive BrÁ Á ÁClÀ interaction was not
observed in the context of this optimized receptor system. This
result suggests that the stabilization gained from close contacts
of the lighter halogen atoms may be modest.23
7 A. Bruckmann, M. A. Pena and C. Bolm, Synlett, 2008, 900–902.
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8 C. J. Serpell, N. L. Kilah, P. J. Costa, V. Felix and P. D. Beer,
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9 C. Laurence and M. Berthelot, Perspect. Drug Discovery Des.,
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11 J. C. Ma and D. A. Dougherty, Chem. Rev., 1997, 97, 1303–1324;
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13 C. Laurence, M. Queignec-Cabanetos and B. Wojkowiak, Can. J.
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Perfluorobenzoic acid-derived receptor 4c shows no
detectable affinity for chloride. This result is consistent with
studies of anion–arene interactions involving neutral hosts,
which indicate that these are weak in moderately polar organic
solvents.24 Similarly, receptor 4d, designed to probe the
relative magnitudes of CH–anion hydrogen bonding and
XB, interacts with ClÀ with an association constant at least
one thousand times less than that of 4a. Competition between
hydrogen bonding and XB has been the subject of crystal
engineering studies.25 Our data indicate that direct replacement
of a given proton with an iodine substituent increases donor
ability significantly, presumably due to the high polarizability
of iodine in comparison to hydrogen.
16 P. Auffinger, F. A. Hays, E. Westhof and P. S. Ho, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 16789–16794; A. R. Voth,
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5061–5084.
In conclusion, tridentate receptors have proved to be a
powerful platform for probing the strengths of halogen bonds
involving weak donors. This study demonstrates that species
other than the exotic perfluorinated iodo compounds studied
previously are capable of attractive halogen bonding inter-
actions with anions in solution. The ability to tune halogen
bonds by systematic variation of electronic structure may
prove useful in future applications in molecular recognition
or medicinal chemistry.
17 DFT calculations were carried out with Gaussian ’03 (Revision
C.02: M. J. Frisch et al.) using the B3LYP functional and the
6-31+G** basis set for all atoms except iodine. The LANL2DZ
effective core potential, with polarization functions of d symmetry
and diffuse functions of p symmetry was employed for iodine:
C. E. Check, T. O. Faust, J. M. Bailey, B. J. Wright, T. M. Gilbert
and L. S. Sunderlin, J. Phys. Chem. A, 2001, 105, 8111–8116.
See the ESIw for details.
18 T. Clark, M. Hennemann, J. S. Murray and P. Politzer, J. Mol.
Model., 2007, 13, 291–296.
This work was supported by the NSERC (Discovery Grants
program, graduate fellowship to E.D.), the Canadian Foundation
for Innovation, and the Ontario Ministry of Research and
Innovation.
19 For plots of log(Ka) versus calculated Mulliken charge at iodine
(r2 = 0.74) and energy of the s*C–I orbital (r2 = 0.87), see the ESIw.
20 W. F. Reynolds, Prog. Phys. Org. Chem., 1973, 19, 165–202.
21 This trend in d13C is correctly modeled by DFT (GIAO) calculations.
See the ESIw for details. For a computational study of complex
effects of XB on d13C of haloarenes, see R. Glaser, N. Chen, H.
Wu, N. Knotts and M. Kaupp, J. Am. Chem. Soc., 2004, 126,
4412–4419.
22 J. A. Webb, J. E. Klijn, P. A. Hill, J. L. Bennett and N. S. Goroff,
J. Org. Chem., 2004, 69, 660–664; W. N. Moss and N. S. Goroff,
J. Org. Chem., 2005, 70, 802–808.
23 A. Gavezzotti, Mol. Phys., 2008, 106, 1473–1485.
24 O. B. Berryman, A. C. Sather, P. B. Hay, J. S. Meisner and
D. W. Johnson, J. Am. Chem. Soc., 2008, 130, 10895–10897.
See ref. 6b for a related control experiment in the context of a
bidentate receptor.
Notes and references
1 Halogen Bonding: Fundamentals and Applications, ed.
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305–311.
2 T. Caronna, R. Liantonio, T. A. Logothetis, P. Metrangolo,
T. Pilati and G. Resnati, J. Am. Chem. Soc., 2004, 126,
4500–4501; A. Sun, N. S. Goroff and J. W. Lauher, Science,
2006, 312, 1030–1034.
25 P. Metrangolo and G. Resnati, Science, 2008, 321, 918–919.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9025–9027 9027