Selective anion binding by a macrocycle with convergent hydrogen bonding functionality

Full text of DOI:10.1021/ja005772+

2456
J. Am. Chem. Soc. 2001, 123, 2456-2457
Selective Anion Binding by a Macrocycle with
Convergent Hydrogen Bonding Functionality
Kihang Choi and Andrew D. Hamilton*
Department of Chemistry, Yale UniVersity
New HaVen, Connecticut 06520
ReceiVed NoVember 8, 2000
A key problem in supramolecular chemistry is the design of
synthetic receptors with convergent binding groups that are
arranged to match the functionality of the guest molecule.1 Such
receptors should have not only high affinity but also the improved
selectivity that is important for sensing applications. In particular,
many anions have diverse geometries that offer a possible route
to the development of shape-selective anion receptors.2 Although
we and others3 have made extensive use of hydrogen bonding to
recognize anions, rarely have the binding groups been arranged
in a convergent and rigid manner. Notable exceptions include
the bicylic cyclophane4 of Anslyn that binds planar anions and
the calix[4]pyrrole5 of Sessler that exploits four hydrogen bond
donors to bind the spherical fluoride anion. To expand the type
of anions that can be targeted by this strategy we have prepared
a novel macrocyclic anion receptor with C3 symmetry that binds
tetrahedral anions such as sulfate and phosphate with high affinity.
Although several artificial receptors for these important2a anions
have been reported,6,7 few have the combined features of rigid,
convergent, and geometrically optimal binding groups.
Figure 1. The calculated structure of the 1:1 complex between 1 and
p-tosylate anion: (a) a side view and (b) a bottom view with CPK
representation. The lowest energy conformation of the macrocycle was
used as an initial structure for the calculation with the MM2 force field.
R groups are omitted for clarity.
Macrocycle 1 was synthesized starting from 5-substitutied-3′-
nitro-3-biphenylcarboxylic acid, which in turn was prepared from
the coupling reaction between 3-nitrophenylboronic acid and the
corresponding 3-iodobenzoic acid. Functional group manipulation
and stepwise coupling of the monomeric unit gave the linear
trimer that was cyclized to the corresponding macrocycle 1.8 This
design projects into the center of the cavity three amide groups
that serve as hydrogen bonding donors for anion binding. A Monte
Carlo conformational search9 showed that the lowest energy
conformer has a central hole ≈5 Å in diameter, lined only with
hydrogen atoms, three from the amides and six from the aryl
groups. The size of the hole and skewed arrangement of three
amide protons are nicely matched to the size and shape of
tetrahedral oxyanions, such as p-tosylate (Figure 1).
To determine the anion binding properties of the macrocycle,
NMR titration experiments10 were performed in 2% DMSO-d6/
CDCl3 and the chemical shift data were analyzed by EQNMR, a
nonlinear regression curve fitting program.11 Titration of 1 with
tosylate anion as its tetrabutylammonium salt gave 1:1 binding
isotherms for the amide and aryl protons of 1 (Figure 2). The
aryl protons of the anion showed ≈0.3 ppm upfield shifts upon
binding due presumably to the ring current effect of the macro-
cycle. The 1:1 binding ratio was confirmed by a Job’s plot.10 The
complexation induced chemical shift changes (∆δ) of the mac-
rocycle protons projecting into the central cavity (C2H, C2′H)
are much larger than those of the externally directed protons. 1a
and 1b showed similar binding affinities indicating the overall
anion binding properties are not affected significantly by the
functional groups outside the central cavity.
(1) (a) Lehn, J. M. Supramolecular Chemistry; VCH: Weinheim, 1995.
(b) Schneider, H. J.; Yatsimirski, A. Principles and Methods in Supramolecular
Chemistry; Wiley: Somerset, 2000. (c) Rojas, C. M.; Rebek, J., Jr. J. Am.
Chem. Soc. 1998, 120, 5120-5121.
The other anions tested showed more complex binding
behavior, which was characterized by initial upfield shifts
(2) For recent reviews, see: (a) Supramolecular Chemistry of Anions;
Bianchi, A., Bowman-James, K., Garcia-Espana, E., Eds.; VCH: Weinheim,
1997. (b) Gale, P. A. Coord. Chem. ReV. 2000, 199, 181-233. (c) Antonisse,
M. M. G.; Reinhoudt, D. N. Chem. Commun. 1998, 443-448. (d) Schmidtch-
en, F. P.; Berger, M. Chem. ReV. 1997, 97, 1609-1646.
(3) (a) Fan, E.; Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am.
Chem. Soc. 1993, 115, 369-370. (b) Linton, B. R.; Goodman, M. S.; Hamilton,
A. D. Chem. Eur. J. 2000, 6, 2449-2455. (c) Kavallieratos, K.; De Gala, S.
R.; Austin, D. A.; Crabtree, R. H. J. Am. Chem. Soc. 1997, 119, 2325-2326.
(d) Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem. Soc. 1997, 119,
1793-1794. (e) Bu¨hlmann, P.; Nishizawa, S.; Xiao, K. P.; Umezawa, Y.
Tetrahedron 1997, 53, 1647-1654. (f) Andrievsky, A.; Ahuis, F.; Sessler, J.
L.; Vo¨gtle, F.; Gudat, D.; Moini, M. J. Am. Chem. Soc. 1998, 120, 9712-
9713. (g) Black, C. B.; Andrioletti, B.; Try, A. C.; Ruiperez, C.; Sessler, J. L.
J. Am. Chem. Soc. 1999, 121, 10438-10439. (h) Sasaki, S.; Mizuno, M.;
Naemura, K.; Tobe, Y. J. Org. Chem. 2000, 65, 275-283.
(4) (a) Bisson, A. P.; Lynch, V. M.; Monahan, M. C.; Anslyn, E. V. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2340-2342. (b) Snowden, T. S.; Bisson, A.
P.; Anslyn, E. V. J. Am. Chem. Soc. 1999, 121, 6324-6325.
(5) (a) Gale, P. A.; Sessler, J. L.; Kra´l, V.; Lynch, V. J. Am. Chem. Soc.
1996, 118, 5140-5141. (b) Gale, P. A.; Sessler, J. L.; Kra´l, V. Chem. Commun.
1998, 1-8. (c) Anzenbacher, P., Jr.; Jurs´ıkova´, K.; Lynch, V. M.; Gale, P.
A.; Sessler, J. L. J. Am. Chem. Soc. 1999, 121, 11020-11021.
(6) (a) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Cecchi, M.; Escuder, B.;
Fusi, V.; Garcia-Espan˜a, E.; Giorgi, C.; Luis, S. V.; Maccagni, G.; Marcelino,
V.; Paoletti, P.; Valtancoli, B. J. Am. Chem. Soc. 1999, 121, 6807-6815 and
references therein. (b) Kra´l, V.; Furuta, H.; Shreder, K.; Lynch, V.; Sessler,
J. L. J. Am. Chem. Soc. 1996, 118, 1595-1607 and references therein.
(7) For neutral phosphate receptors with C3 symmetry, see: (a) Valiyaveet-
til, S.; Engbersen, J. F.; Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int.
Ed. Engl. 1993, 32, 900-901. (b) Beer, P. D.; Chen, Z.; Goulden, A. J.;
Graydon, A.; Stokes, S. E.; Wear, T. J. Chem. Soc., Chem. Commun. 1993,
1834-1836. (c) Raposo, C.; Pe´rez, N.; Almaraz, M.; Mussons, L.; Caballero,
M. C.; Mora´n, J. R. Tetrahedron Lett. 1995, 36, 3255-3258. (d) Ishida, H.;
Suga, M.; Donowaki, K.; Ohkubo, K. J. Org. Chem. 1995, 60, 5374-5375.
(e) Xie, H.; Yi, S.; Wu, S. J. Chem. Soc., Perkin Trans. 2 1999, 2751-2754.
(8) The synthesis and characterization of the macrocycles are described in
the Supporting Information.
(9) (a) MacroModel9b version 6.5 was used. 2000 separate search steps
were followed by energy minimization using the MM2* force field and CHCl3
solvation parameters. (b) Mohamadi, F.; Richards, N. G.; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W.
C. J. Comput. Chem. 1990, 11, 440-467.
(10) Connors, K. A. Binding Constants; John Wiley: New York, 1987.
(11) Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311-312.
10.1021/ja005772+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/20/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2457
Table 1. Association Constants (M-1) of 1 with
Tetrabutylammonium Salts at 296 Ka
anion
I-
1ab
1bb
1bc
2
120b
1.3 × 105
1.2 × 105
(9.0 × 103)
7.6 × 103
(1.9 × 103)
d
<10
(1.1 × 104)
Cl-
8.8 × 103
<10
d
(1.7 × 103)
NO3
4.6 × 105
20
620b
-
(2.1 × 103)
pTsO-
2.6 × 105
2.1 × 105
780
d
d
-
HSO4
slow equilibriume
d
d
1.7 × 103
H2PO4
slow equilibriume
1.5 × 104 f
500c
-
a Determined by titrating a 0.5-1.0 mM macrocycle solution with
salt solution. The salt solution contains macrocycle at its initial
concentration to account for dilution effects. The association constant
of the 2:1 complex (MI + M h M2I) is included in parentheses when
it is applicable. Estimated errors are within (20%. b In 2% DMSO-
d6/CDCl3. c In DMSO-d6. d Not determined. e Slow equilibrium among
free macrocycle; a 1:1 complex and a 2:1 complex were observed at
Figure 2. Change in 1H chemical shift of 1b with increasing pTsO-
concentration in 2% DMSO-d6/CDCl3 (b, amide NH; 9, C2′H; 1, C2H;
0, C4′H; 3, C4H; O, C6H; [, BocNH). C5′H and C6′H, which overlap
each other, showed little change (≈0.03 ppm). The assignment was done
using COSY and NOESY experiments. The countercation was tetrabu-
tylammonium, and the concentration of 1b was 0.75 mM at 296 K.
f
room temperature. The association constants were not calculated. Slow
equilibrium was observed.
them to bind two equivalent macrocycles in a sandwich complex.
This accounts for the large upfield shifts of the macrocycle protons
in the M2I complex from ring current effects in the π-stacked
structures. I- showed much higher binding affinity than Cl-,
which has higher charge density. This selectivity can be explained
by the large size and rigidity of the binding site. In the case of
-
HSO4 and H2PO4-, binding equilibria were slow on the NMR
1
time scale and separate sets of H peaks were observed for the
M, MI, and M2I complexes. In contrast, a linear analogue 2
showed much weaker binding to all anions tested.
The ∆δ values of the interior protons in the macrocycle are
sensitive to the shape of the bound anion. While the tetrahedral
anion complexes showed a large ∆δ (0.8-1.1 ppm) of the amide
proton, the other anion complexes showed small or negative ∆δ
(-0.35 to 0.05 ppm). In addition, the relative ratio between ∆δ
of C2H and C2′H (∆δ2/∆δ2′) was much larger for the planar
(3.0) and spherical (2.2-2.8) anion complexes than the tetrahedral
anion complexes (1.1-1.2), indicating a different binding mode
for the different anions.
Figure 3. (a) Changes in the amide 1H chemical shift of 1b with
increasing I- concentration. The data (b) were curve-fitted11 to the
multiple-equilibrium model involving 1:1 and 2:1 complexes of 1 with
I-. Conditions as in Figure 2 were used. (b) The multiple-equilibrium
model used for the curve fitting. M2I and MI structures were calculated
by using the MM2 force field. The iodide anion of the M2I complex is
located between two macrocycles.
In a more competitive hydrogen bonding solvent such as 100%
DMSO-d6, the association constants decreased significantly and
M2I complex formation was not observed. The stability of the
complexes with halide and nitrate anions decreased dramatically
even in 50% DMSO-d6/CDCl3. However, tetrahedral anions such
-
as pTsO-, HSO4 , and H2PO4- retained strong binding in DMSO-
(especially of the amide protons) up to 0.5 equiv addition of
anionic substrate. Above 0.5 equiv, the direction of the shift
changed to downfield (Figure 3a). The binding isotherms of the
amide and aryl protons fit a model of M2I and MI complex
formation (Figure 3b, M:macrocycle, I:ion) and the association
constants of each equilibrium step were obtained.12 Spherical
halide, planar nitrate, and tetrahedral hydrogen sulfate and
dihydrogen phosphate anions all showed this mode of binding
(Table 1).13 The even distribution of charge on these anions allows
d6 with the H2PO4- complex still showing slow exchange on the
NMR time scale.
In conclusion, we have synthesized a novel anion receptor
based on the rigid disposition of hydrogen bonding groups in the
interior of a macrocyclic scaffold. This convergent projection of
dipoles enables the macrocycle to bind anions with size and shape
selectivity and stable complexes were formed even in polar
solvent. We are currently using this novel macrocycle as a
building block in the formation of functionalized and more
complex molecular receptors.
(12) Due to the directionality of macrocycle 1, two diastereomers of the
M2I complex could be formed: parallel and antiparallel isomers. However,
only single isomer formation was assumed for the association constant
calculation. This assumption is supported by the observation of only a single
Acknowledgment. This work was supported by the National Institute
of Health (GM35208).
1
set of H signals for the M2I complex under slow exchange conditions.
(13) For examples of 2:1 host-guest complexes, see: (a) Dodziuk, H.;
Ejchart, A.; Lukin, O.; Vysotsky, M. O. J. Org. Chem. 1999, 64, 1503-
1507. (b) Haino, T.; Yanase, M.; Fukazawa, Y. Angew. Chem., Int. Ed. Engl.
1997, 36, 259-260. (c) Berg, U.; Gustavsson, M.; Åstro¨m, N. J. Am. Chem.
Soc. 1995, 117, 2114-2115. (d) Andersson, T.; Westman, G.; Wennerstro¨m,
O.; Sundahl, M. J. Chem. Soc., Perkin Trans. 2 1994, 1097-1101. (e) Manka,
J. S.; Lawrence, D. S. J. Am. Chem. Soc. 1990, 112, 2440-2442.
Supporting Information Available: Synthetic schemes for 1, selected
NMR titration data, and a Job’s plot (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA005772+