New "cholapod" anionophores; high-affinity halide receptors derived from cholic acid

Full text of DOI:10.1021/ja016796z

12716
J. Am. Chem. Soc. 2001, 123, 12716-12717
cholapods which show exceptional affinities for chloride and
bromide anions.
New “Cholapod” Anionophores; High-Affinity Halide
Receptors Derived from Cholic Acid
The new receptors 4-10 feature the following developments:
(i) the introduction of urea/thiourea groups in positions 7 and 12
of the steroid, raising the number of H-bond donors to 4 (for
4-7) and 5 (for 8-10); (ii) the use of electron-withdrawing
substituents to raise donor power; and (iii) the C20 side chains,
which increase solubility and lipophilicity. The urea/thiourea
groups are axially disposed which, as noted previously for 2,5
aids preorganization by restricting rotation about the C(7/12)-N
bonds. The favored planar, all-anti-urea conformation transmits
this effect, so that all four (thio)urea N-H groups are positioned
for anion binding. Equally, intramolecular H-bonding is sup-
pressed. Modeling7 indicates that no such interactions are possible
for 4-7. In 8-10 the sulfonamide oxygens can make hydrogen
bonds to the NHAr groups, but these involve distortion of ureas
from planarity and are probably intrinsically weak.8
Alan J. Ayling,† M. Nieves Pe´rez-Paya´n,‡ and
Anthony P. Davis*,†
School of Chemistry, UniVersity of Bristol
Cantock’s Close, Bristol BS8 1TS, UK
Department of Chemistry, Trinity College
Dublin 2, Ireland
ReceiVed August 8, 2001
The study of anion recognition is one of the more active areas
of supramolecular chemistry.1 An important subset of anion
receptors are designed to operate in organic solvents through
H-bond donation by electroneutral functional groups.2 These
neutral, organic hosts may be seen as the anion-binding coun-
terparts of the classical cation-binding crown ethers, cryptands,
and spherands. However, in terms of affinity, the anionophores
have yet to match the cationophores. While association constants
g1010 M-1 are not uncommon for cryptands and spherands,3
reported binding constants to neutral organic anionophores rarely
exceed 105 M-1 4
.
Recently, we described the synthesis and binding properties
of the steroid-based tripodal receptors 1 and 2, both derived from
cholic acid 3.5 The steroidal framework preorganizes the H-bond
Receptors 4-10 were synthesized from 3 via protected
aminosteroids 11 and 12,9 as described in the Supporting
Information. Despite their arrays of polar functionality, all were
freely soluble in CHCl3. The 1H NMR spectra of 4 and 5 in CDCl3
were well-resolved, while those of 6-10 were broadened.
However, all receptors gave well-resolved spectra after addition
of excess bromide or chloride (as tetraethylammonium or tetra-
phenylphosphonium salts). In a titration of 5 with Et4N+Cl-, the
NH resonances broadened initially then sharpened after addition
of 1 equiv, having moved downfield by 1.6-2.1 ppm. Although
the signals could not be followed accurately, their motions
appeared to be roughly linear with [Et4N+Cl-]. Additional halide
(up to 10 equiv) produced little further change (∆δ < 0.09 ppm,
no evidence of saturation). In titrations of 9 and 10 with the same
substrate, spectra again sharpened at 1 equiv with minor changes
thereafter.
donor groups, largely prevents intramolecular hydrogen bonding,
and promotes solubility in nonpolar media. 1 and 2 were found
to bind tetrabutylammonium chloride with Ka ) 7200 and 92 000
M-1 in CDCl3 respectively. These initial “cholapods”6 had clear
potential for improvement; further H-bond donors could be added,
and stronger (more acidic) donor groups could be used. We have
now incorporated such changes and report a new series of
† University of Bristol.
The above NMR data supported complex formation with
predominantly 1:1 stoichiometry and receptor NH groups acting
as H-bond donors. However, this technique was clearly unsuitable
for determining binding constants in CDCl3. While measurements
might have been possible in more polar solvents, CHCl3 provides
a better model for certain media of interest, for example, biological
‡ Trinity College Dublin.
(1) Bianchi, A.; Bowman-James, K.; Garcia-Espan˜a, E. Supramolecular
Chemistry of Anions; Wiley-VCH: New York, 1997. Schmidtchen, F. P.;
Berger, M. Chem. ReV. 1997, 97, 1609. Beer, P. D.; Gale, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 487.
(2) Gale, P. A.; Sessler, J. L.; Kra´l, V. Chem. Commun. 1998, 1. Antonisse,
M. M. G.; Reinhoudt, D. N. Chem. Commun. 1998, 443.
(3) ComprehensiVe Supramolecular Chemistry; Gokel, G. W., Ed.; Mo-
lecular recognition: receptors for cationic guests; Pergamon: Oxford, 1996;
Vol. 1.
(6) We propose to use this term for podand structures based on bile acid
scaffolds. For other cholapods, see: Davis, A. P.; Lawless, L. J. Chem.
Commun. 1999, 9. De Muynck, H.; Madder, A.; Farcy, N.; De Clercq, P. J.;
Pe´rez-Paya´n, M. N.; O¨ hberg, L. M.; Davis, A. P. Angew. Chem., Int. Ed.
2000, 39, 145. Boyce, R.; Li, G.; Nestler, H. P.; Suenaga, T.; Still, W. C. J.
Am. Chem. Soc. 1994, 116, 7955. Venkatasan, P.; Cheng, Y.; Kahne, D. J.
Am. Chem. Soc. 1994, 116, 6955. Li, C. H.; Budge, L. P.; Driscoll, C. D.;
Willardson, B. M.; Allman, G. W.; Savage, P. B. J. Am. Chem. Soc. 1999,
121, 931. Potluri, V. K.; Maitra, U. J. Org. Chem. 2000, 65, 7764.
(7) MacroModel 7.0, Amber* force field, GBSA solvation (CHCl3):
Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Caufield, C.;
Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
(8) Gennari, C.; Gude, M.; Potenza, D.; Piarulli, U. Chem. Eur. J. 1998,
4, 1924.
(4) For neutral organic anionophores exhibiting high affinities, see for
example: (a) Bu¨hlmann, P.; Nishizawa, S.; Xiao, K. P.; Umezawa, Y.
Tetrahedron 1997, 53, 1647. (b) Andrievsky, A.; Ahuis, F.; Sessler, J. L.;
Vo¨gtle, F.; Gudat, D.; Moini, M. J. Am. Chem. Soc. 1998, 120, 9712. (c)
Nissink, J. W. M.; Boerrigter, H.; Verboom, W.; Reinhoudt, D. N.; van der
Maas, J. H. J. Chem. Soc., Perkin Trans. 2 1998, 2623. (d) Jagessar, R. C.;
Shang, M. Y.; Scheidt, W. R.; Burns, D. H. J. Am. Chem. Soc. 1998, 120,
11684. (e) Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org. Chem.
1999, 64, 1675. (f) Kubik, S.; Goddard, R. J. Org. Chem. 1999, 64, 9475. (g)
Anzenbacher, P.; Jursikova, K.; Sessler, J. L. J. Am. Chem. Soc. 2000, 122,
9350. (h) Choi, K. H.; Hamilton, A. D. J. Am. Chem. Soc. 2001, 123, 2456.
(5) Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem. Soc. 1997, 119,
1793.
(9) Davis, A. P.; Pe´rez-Paya´n, M. N. Synlett 1999, 991.
10.1021/ja016796z CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/17/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 50, 2001 12717
Table 1. Extraction Data, Derived Association Constants, and Binding Free Energies of Receptors 4-10 to Et4N+Cl- and Et4N+Br- in
a
Water-Saturated CHCl3
Et4N+Cl-
Et4N+Br-
[substrate]aq
(M)
equivalents
-∆G°
[substrate]aq
(M)
equivalents
-∆G°
c
c
receptor
extractedb
Ka (M-1
)
(kJ mol-1
)
extractedb
Ka (M-1
)
(kJ mol-1
)
4
5
6
7
8
9
10
0.07
0.02
0.019
0.01
0.005
0.001
0.001
0.50
0.59
0.69
0.57
0.59
0.45
0.56
1.62 × 107
2.83 × 108
4.77 × 108
1.05 × 109
4.58 × 109
6.60 × 1010
1.03 × 1011
-41.84
-49.05
-50.37
-52.36
-56.07
-62.79
-63.92
0.03
0.66
0.50
0.64
0.53
0.59
0.56
0.57
9.79 × 106
1.84 × 108
2.26 × 108
3.24 × 108
2.63 × 109
1.68 × 1010
2.59 × 1010
-40.57
-47.97
-48.48
-49.39
-54.67
-59.34
-60.44
0.005
0.006
0.004
0.0016
0.0006
0.0005
a Receptor (0.6 mM) in CHCl3 was equilibrated with aqueous substrate at 30 °C. After separation and evaporation, extracts were analyzed by
NMR integration (CH3CH2N+ vs receptor protons). For further details see Supporting Information. b [complex]/[receptor] in organic phase. Aqueous
substrate concentrations were chosen such that this figure lay between 0.4 and 0.7. c Calculated according to the method of Cram et al.10 Experimental
errors estimated as e15%.
yielded a further enhancement. All receptors were moderately
selective for chloride over bromide (although bromide gave the
higher extraction constants, due to its greater lipophilicity).
Especially notable are the very high affinities recorded for 9
and 10, rising to 1011 M-1 for 10 + Cl-. It is clearly important
to consider sources of error, especially in these cases. The analysis
of the extraction data assumes 1:1 substrate:receptor stoichiometry,
membranes or the polymer materials used in ion-selective
with no complicating phenomena such as self-association. To
electrodes. We therefore decided to retain CHCl3 as solvent,
check for interference from higher stoichiometries (and for
resorting to the classical extraction method of Cram10 to measure
incomplete separation of aqueous from organic phases), we
the association constants. Briefly, an organic phase containing a
performed an extraction with 10 and [Et4N+Cl-]aq ) 0.1 M
lipophilic receptor (H) is stirred or shaken with an aqueous phase
(a 100-fold increase compared to the conditions in Table 1). Even
containing substrate (A+X-). The extraction constant Ke
)
at this high substrate concentration, only 1.09 equiv of Et4N+Cl-
was detected in the organic phase. The NMR data did suggest
that some of the receptors may self-associate in CHCl3; however,
this is likely to lead to an underestimate of Ka. Indeed, for most
of these receptors the (apparent) Ka values increased slightly with
receptor dilution. For example, when the concentrations of 9 and
10 were reduced by a factor of 6 to 0.1 mM, extractions of
Et4N+Cl- implied Ka ) 1.02 × 1011 and 1.22 × 1011 M-1
respectively.
[HAX]org/[H]org[A+]aq[X-]aq is determined from the quantity of
substrate extracted into the organic phase at equilibrium. The
association constant can then be calculated from the equation
Ka ) Ke/Kd, where Kd ) [AX]org/[A+]aq[X-]aq, that is, the
distribution constant of the substrate between the two phases in
the absence of the receptor. The method is especially useful for
the determination of high binding constants because the degree
of complexation in the organic phase can be controlled by varying
substrate concentration in the aqueous phase. Receptor saturation
can therefore be avoided. We have found that Et4N+Cl- and
Et4N+Br- are convenient substrates for such experiments, with
Kd (CHCl3/H2O) ) 1.27 × 10-5 and 2.18 × 10-4 M-1 respec-
tively.11
In conclusion, by combining Cram’s extraction methodology
with the cholapod architecture, we have been able to demonstrate
electroneutral anionophores which are exceptionally potent while
retaining compatibility with nonpolar media. Such molecules may
find use in “phase transfer” applications such as sensing and
catalysis, and may also show biological activity. In future work
we plan to investigate these possibilities, and to improve
selectivities by further elaborating the “legs” to create more
enclosed and preorganized binding sites.
Application of Cram’s method to receptors 4-10 gave the
results shown in Table 1. Note that the binding constants refer to
water-saturated CHCl3 and are presumably slightly smaller than
the corresponding values in dry solvent. As expected, the receptors
were found to be substantially more powerful than 1 and 2.
Affinities increased through the series 4-7, reflecting the electron-
withdrawing character of the R groups and the transition from
urea to thiourea.12 The additional nitrosulfonamide group in 8-10
Acknowledgment. We thank the European Commission (Marie Curie
Fellowship to M.N.P.), the University of Bristol, and the EPSRC (GR/
R04584/01) for financial support of this work.
(10) Kyba, E. P.; Helgeson, R. C.; Madan, K.; Gokel, G. W.; Tarnowski,
T. L.; Moore, S. S.; Cram, D. J. J. Am. Chem. Soc. 1977, 99, 2564.
(11) Ayling, A. J.; Broderick, S.; Clare, J. P.; Davis, A. P.; Pe´rez-Paya´n,
M. N.; Lahtinen, M.; Nissinen, M. J.; Rissanen, K. Full paper in preparation.
(12) Thioureas are more acidic than ureas and have often found use in
anion receptors. See: Fan, E.; Arman, S. A. V.; Kincaid, S.; Hamilton, A. D.
J. Am. Chem. Soc. 1993, 115, 369; also refs 4a, 4c and 4g.
Supporting Information Available: Synthetic schemes and details
for 4-10, experimental procedure, and data analysis for extraction
experiments (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org/.
JA016796Z