Specific tetramethylammonium recognition drives general anion positioning in tandem sites of a deep cavitand

Article abstract of DOI:10.1039/c0nj00224k

A new cavitand bearing four 2-benzylbenzimidazole moieties binds tetramethylammonium, surrounding it in a synthetic binding site with a single opening that comprises a second binding site. Ion pairing couples the binding sites, driving general anion posit

Full text of DOI:10.1039/c0nj00224k

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LETTER
www.rsc.org/njc | New Journal of Chemistry
Specific tetramethylammonium recognition drives general anion
positioning in tandem sites of a deep cavitandw
Miroslav Kvasnica and Byron W. Purse*
Received (in Montpellier, France) 24th March 2010, Accepted 29th March 2010
First published as an Advance Article on the web 13th April 2010
DOI: 10.1039/c0nj00224k
A new cavitand bearing four 2-benzylbenzimidazole moieties
binds tetramethylammonium, surrounding it in a synthetic
binding site with a single opening that comprises a second
binding site. Ion pairing couples the binding sites, driving general
anion positioning in this second site, which is defined by
geometry rather than specific anion-recognition motifs.
Ion pairing is the strongest supramolecular interaction, but it
has been underexploited in designed systems because it lacks
the strong orientational disposition of, for example, the
hydrogen bond. Recent interest in the molecular recognition
of ion pairs has focused on the design, synthesis, and
characterization of heteroditopic receptor molecules comprising
known anion-binding motifs and known cation-binding
motifs.1 These motifs can be close enough to allow for
cooperative contact ion pair binding2 or they can be separated
and thus suitable for the binding of dissociated ion pairs,3 the
former typically offering higher affinity because of maximized
coulombic attraction. While these types of receptors offer the
possibility for important applications,4 they do not directly use
ion pairing to induce binding: each ion is bound separately
using molecular recognition motifs that are classics of
supramolecular chemistry.5 We now report on a reductionist
approach that obviates the need for specific recognition motifs
at one of two tandem sites: a tetramethylammonium is
recognized selectively and only ion pairing drives anion
placement in a tandem site.
Fig. 1 Structure of cavitand 1 and its vase-shaped conformation,
stabilized by hydrogen bonding to four molecules of methanol.
Fig. 2 ORTEP plot (50% probability) of the X-ray structure of
cavitand 1 with four molecules of methanol and one bound molecule
of chloroform. Inset: cartoon showing the predicted mode of ion pair
binding.
For our study we designed a resorcinarene-based cavitand
with four 2-benzylbenzimidazole moieties 1, which was
prepared in a short, gram-scale synthesis (Fig. 1; see the
ESIw).6 The cavitand has a single-sided opening and a high
affinity for tetramethylammonium, which is bound in the deep
part of the cavity.7 It has been previously shown that hydrogen
bonding anions (e.g. acetate) can interact with the upper rim
of a related cavitand.8 We hypothesized that in nonpolar
solvents, based on the geometry of the cavitand, we
could instead use ion pairing to direct the anion into an
unfunctionalized site adjacent to the tetramethylammonium:
the open top site of the cavitand, surrounded by the benzyl
substituents (inset cartoon, Fig. 2).
Slow evaporation of a chloroform–methanol solution of
cavitand 1 afforded single crystals suitable for X-ray analysis.
The X-ray structure revealed a bound molecule of chloroform
and the stabilization of the cavitand’s folded conformation by
four molecules of methanol that complete a seam of hydrogen
bonds between the imidazole groups (Fig. 2).9
To study ion pair recognition, we carried out binding studies
1
using H-NMR (0.5% CD3OD in CDCl3, 23 1C), a series of
tetramethylammonium salts, and cavitand 1 (Fig. 3). Salts
with good solubility (NMe4OAc, NMe4SAc, NMe4F,
NMe4BH(OAc)3, and NMe4(CH2NO2)) almost completely
displaced chloroform from the cavity when present at a 1 : 1
ratio to the cavitand at mM concentrations (Ka > 103 MÀ1).
Some salts have limited solubility in chloroform, but were
bound to the cavitand when present in excess as a suspension
(NMe4BF4, NMe4NO3, NMe4Cl, NMe4Br, and NMe4I).
Department of Chemistry and Biochemistry, University of Denver,
Denver, USA. E-mail: bpurse@du.edu; Fax: +1 303 871 2254;
Tel: +1 303 871 2937
w Electronic supplementary information (ESI) available: Cavitand synth-
esis, crystallographic information, and EXSY measurement description.
CCDC reference numbers 762896. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0nj00224k
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Table 1 Binding constants Ka of selected tetramethylammonium salts
determined from 1H NMR and EXSY experiments, and exchange rate
constants for guest entry k1 and egress k (0.5% CD3OD in CDCl3)
À1
Ka
Ka
k1/
k /
À1
1
Salt
(from H NMR) (from EXSY) MÀ1 sÀ1 sÀ1
NMe4SAc
NMe4F
NMe4BH(OAc)3 8900
NMe4OAc 6800
3600
4700
4400
4100
6400
—
12 000
11 000
30 000
—
2.7
2.8
4.7
—
nature of the anion has only a small effect on the rate of
tetramethylammonium exchange. The anion is present in the
upper site of the cavitand, but it does not act significantly as a
cap or plug, slowing or preventing cation exchange. Cavitand
guest exchange is mechanistically coupled to unfolding13—
ring flip of at least one nine-membered bis-ether ring—and
these results show that the anion has only a minimal effect on
this process. This result is again consistent with the predictions
from molecular modeling that the anion will be held in a
relatively open site, from which it can undergo rapid exchange.
The slower tetramethylammonium exchange does not
require separation of the ion pair nor does it necessitate the
interruption of any strongly attractive interactions between
the anion and the cavitand. The relative insensitivity of both
thermodynamics and kinetics of ion pair binding to the nature
of the anion is a special consequence of the absence of classical
anion binding motifs.
Fig. 3 1H NMR binding studies (0.5% CD3OD in CDCl3, 23 1C) of
cavitand 1 with selected tetramethylammonium salts (left) and mole-
cular model (Spartan ’04; PM3) showing the binding mode of cavitand
1 and tetramethylammonium acetate. Carbons of NMe4OAc are
orange and the ethyl groups have been truncated for clarity (right).
*Spectrum shown without CD3OD.
Others were completely insoluble, and the cavitand did not
extract them into chloroform (NMe4BPh4). The solubility of
the tetramethylammonium salt seems to be the primary factor
governing binding, as opposed to any incompatibility between
cavitand and anion. Cation recognition, in contrast, is specific:
+
NBu4 is too large to fit in the deep part of the cavity and
consequently NBu4F is not bound.
The nature of the anion influences the NMR chemical shift
of neighboring hydrogens,10 confirming the predicted ion pair
binding mode (Fig. 3). Both the bound tetramethylammonium
and the cavitand’s benzylic hydrogens have chemical shifts
that are strongly influenced by the anion (tabulated in
the ESIw). Cavitand hydrogens far-removed from the
predicted anion binding site, such as the resorcinarene methine
hydrogens, are unaffected by the nature of the anion, showing
that the anions do not have a significant presence at these
locations. These data strongly support the formation of a
bound contact ion pair that is consistent with the molecular
modeling. Tetramethylammonium salts typically have high
(Ka > 105 MÀ1) association constants in nonpolar solvents,11
so this result is consistent with known ion pairing energies.
To further characterize this mode of ion pair recognition, we
quantified the effects of the anion on the thermodynamics and
kinetics of guest binding and exchange. While the addition of
methanol (0.5%) to chloroform lowers somewhat the binding
affinity, this solvent mixture offers improved solubility and is
therefore better suited to these measurements. The resolved
signals for free and bound tetramethylammonium in the 1D
NMR spectra show that, for all of the tested ammonium salts
and solvents, guest exchange is slow on the NMR timescale.
The binding equilibrium defines the association constant Ka
according to the substitution of bound solvent for tetramethyl-
ammonium salt (see the ESIw). For all anions measured, the
binding constants are very similar (Table 1). Importantly,
these results show that the anion-binding site is equally
competent to host a diverse set of anions, which is very difficult
or impossible to achieve using classical recognition motifs.
We used the EXSY NMR method to measure the effect of
the nature of the anion on the kinetics of guest exchange
(Table 1).12 Like in the thermodynamic measurements, the
We have reported the synthesis and characterization of a
new cavitand that acts as a heteroditopic receptor for ion
pairs. The results of this study show that artificial receptor
molecules can be designed to bind to ion pairs by using specific
recognition motifs for only one of the ions, provided that there
are sufficient geometric constraints. This approach offers a
Table 2 Crystal data and structure refinement for 1
Empirical formula
Formula mass
Temperature
C98H90Cl6N8O12
1784.44
100(2) K
0.71073 A
Wavelength
Crystal system
Space group
Unit cell dimensions
Monoclinic
P21/n (No 14)
a = 12.3804(2) A; a = 901
b = 24.7338(4) A; b = 91.996(10)1
c = 29.2318(5) A; g = 901
8945.8(3) A3
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
4
1.321 g cmÀ3
0.259 mmÀ1
3708
Crystal size
y range for data collection
Index ranges
0.51 Â 0.25 Â 0.10 mm
1.08–26.731
À15 r h r 15, À31 r k r 31,
À36 r l r 36
Total reflections collected
Independent reflections
Completeness to y
Absorption correction
Max./min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R indices (all data)
178 241
14 292 [Rint = 0.0669]
y = 26.731; 100%
Multi-scan
0.9746/0.8792
Full-matrix least-squares on F2
19 012/0/1129
0.89
R1 = 0.0669, wR2 = 0.1856
R1 = 0.0900, wR2 = 0.2111
Peak/hole 2.308/À1.127 e AÀ3
Largest difference
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promising way to use ionic attractions as a design element,
overcoming their limitation of little intrinsic directional
disposition. We are currently preparing chiral versions of these
cavitands for use as asymmetric hosts for anions, with a view
towards applications in asymmetric catalysis.
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Experimental
Single crystals of 1 were grown from a mixture of methanol–
chloroform. A pale yellow crystal was mounted on MiTeGen
MicroMounts with MiTeGen LV Cryo Oil to prevent
evaporation of enclosed solvents and measured on a Bruker
D8 APEX II Diffractometer using monochromatized MoKa
radiation (l = 0.71073 A) at 100(2) K. High values of R and
wR are due to disordered solvent molecules present in the unit
cell (Table 2). The structure was refined by full-matrix least
squares based on F2 (SHELXL97).14
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Acknowledgements
The authors gratefully acknowledge Alyssa Roche and Grant
Ruehle for their contributions to the cavitand synthesis and
the University of Denver for financial support.
Notes and references
1 G. J. Kirkovits, J. A. Shriver, P. A. Gale and J. L. Sessler,
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B. D. Smith, in Macrocyclic Chemistry: Current Trends and
Future Perspectives, ed. K. Gloe and B. Antonioli, Kluwer,
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¨ ¨
14 G. M. Sheldrick, SHELXL97, University of Gottingen, Gottingen,
Germany, 1997.
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