With the aim of increasing both the binding affinity and
the selectivity we now designed pyridine-based receptors
with enhanced basicity of the heterocyclic recognition units,
incorporating multiple, adjacent hydrogen bonding sites and
π-bonds for facilitating CH-π interactions. In this paper we
report the complexation properties of three representatives
(1-3) of this novel series of hydrogen-bonding receptors
for monosaccharides, which show a high binding affinity and
diastereoselectivity. Compounds 1-3 were synthesized from
1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene5 and 2-amino-
6-methylpyridine, 2-amino-4,6-dimethylpyridine, or 2,6-
diaminopyridine, respectively (THF or CH3CN, K2CO3, room
temperature).
The aminomethyl groups attached to the pyridine units as
well as a second methyl group at the 4-position of the
pyridine ring in host 2 or an additional R-amino group in 3
favorably increased the basicity of the pyridine moieties.6
The increase in the electron density on the pyridine nitrogen
should cause an enhancement of the receptor affinity mainly
due to enthalpic factors.7 In addition, the incorporation of a
second amino group in 3 provides an additional binding site
for carbohydrates. The substituted central phenyl ring in 1-3
should be able to participate in effective CH-π interactions
with CH’s of sugar molecules. Moreover, the methyl groups
increase the solubility of the hosts in chloroform. As shown
by Davis et al., receptors which are designed for solubility
in nonpolar media can be studied in a two-phase system,
demonstrating the ability to extract or transport some
carbohydrates.2a
constants were determined in chloroform at 25 °C by titration
experiments and the titration data were analyzed by nonlinear
regression analysis.8 The stoichiometry of receptor-sugar
complexes was determined by the curve-fitting analysis of
the titration data and by mole ratio plots.9 Self-aggregation
of the receptors in the applied concentration range was
excluded on the basis of dilution experiments.
The complexation between the receptors 1-310 and
glucopyranosides 4r and 4â was evidenced by a significant
downfield shift of the receptor amine protons and moderate
upfield shift of the CH2 resonances. The curve fitting of the
titration data for receptor 1 and octyl-â-D-glucopyranoside
(4â) suggested the existence of both 1:1 and 1:2 receptor-
sugar complexes in the chloroform solution, with a strong
1:1 association constant (Ka1 ) 10 500 M-1) and a rather
weak association constant for a 1:2 receptor-sugar complex
1
(Ka2 ) 250 M-1). A H NMR titration of 2 with glucopy-
ranoside 4â produced similar spectral changes. In particular,
the signal due to the amine NH moved downfield by about
1.3 ppm (∆δmax) and the methylene CH2 moved upfield by
0.15 ppm (Figure 1).
The motions of the NH of 2 were consistent with 1:1 and
1:2 binding (Figure 2a), providing association constants of
20 950 M-1 (Ka1) and 790 M-1 (Ka2), respectively, indicating
stronger binding than with 1.
These data reveal that the effect of the increased basicity
of the pyridine moieties causes a marked increase in the value
of association constants in comparison with previously
studied receptors.2i,j Possible structures for the complexes
As a starting point, we examined the adaptability of
receptors 1-3 for the recognition of glucopyranosides. The
octyl derivatives 4r and 4â were selected to evaluate the
recognition capabilities of the receptors for glucopyranoside
in aprotic solvents such as chloroform and compare their
binding properties with the properties of previously studied
receptors. In addition, the affinity of the receptors for methyl
glucopyranosides 5r and 5â was tested. Since the methyl
glucopyranosides are insoluble in CDCl3, the binding proper-
ties were determinated by the extraction method.
(6) The increase in pKa of substituted pyridines is generally greater for
R- and γ- than for â-amino or -methyl groups: Katritzky, A. R.; Pozharski,
A. F. Handbook of Heterocyclic Chemistry; Pergamon: Amsterdam, The
Netherlands, 2000; p 178.
(7) For examples on the use of the effect of increased basicity of pyridine
moieties in other hydrogen-bonded systems, see: (a) Inouye, M.; Miyake,
T.; Furusyo, M.; Nakazumi, H. J. Org. Chem. 1999, 64, 8170-8176. (b)
Tecilla, P.; Dixon, R. P.; Slobodkin, G.; Alavi, D. S.; Waldeck, D. H.;
Hamilton, A. D. J. Am. Chem. Soc. 1990, 112, 9408-9410.
(8) Wilcox, C. S.; Glagovich, N. M. Program HOSTEST 5.6, University
of Pittsburgh. This program is designed to fit data to different binding
models, which include both “pure” binding models, taking into consideration
the formation of only one type of complex in solution, and “mixed” binding
models containing more than one type of complex in solution.
(9) For examples on the use of the mole ratio method, see: (a) Tsukube,
H.; Furuta, H.; Odani, A.; Takeda, Y.; Kudo, Y.; Inoue, Y.; Liu, Y.;
Sakamoto, H.; Kimura, K. In ComprehensiVe Supramolecular Chemistry;
Atwood, J. L., Davis, J. E. D., MacNicol, D. D, Vo¨gtle, F., Eds.;
Pergamon: Oxford, UK, 1996; Vol. 8, pp 425-482. (b) Liu, M. T. H.;
Bonneau, R. J. Am. Chem. Soc. 1990, 112, 3915-3919.
(10) Selected physical and spectroscopic data for compounds 1-3. 1,3,5-
Tris[(6-methylpyridin-2-yl)aminomethyl]-2,4,6-trimethylbenzene (1): Yield
1
53%. Mp 160-162 °C. H NMR (CDCl3) δ 2.36 (s, 9H, 3 × CH3), 2.39
(s, 9H, 3 × CH3), 4.17 (t, 3H, 3 × NH, J ) 4.3 Hz), 4.39 (d, 6H, 3 × CH2,
J ) 4.3 Hz), 6.25 (d, 3Hpyr, J ) 8.2 Hz), 6.46 (d, 3Hpyr, J ) 7.3 Hz), 7.34
(t, 3Hpyr, J ) 7.3 Hz). 13C NMR (CDCl3) δ 15.89, 24.40, 41.77, 103.08,
112.33, 133.75, 136.82, 137.80, 157.11, 158.12. HR-MS calcd for
C30H36N6: 480.3001. Found: 480.2999. 1,3,5-Tris[(4,6-dimethylpyridin-
2-yl)aminomethyl]-2,4,6-trimethylbenzene (2): Yield 60%. Mp. 195 °C.
1H NMR (CDCl3) δ 2.21 (s, 9H, 3 × CH3), 2.33 (s, 9H, 3 × CH3), 2.38 (s,
9H, 3 × CH3), 4.11 (t, 3H, 3 × NH, J ) 4.2 Hz), 4.37 (d, 6H, 3 × CH2,
J ) 4.2 Hz), 6.08 (s, 3Hpyr), 6.32 (s, 3Hpyr). 13C NMR (CDCl3) δ 15.85,
21.09, 24.18, 41.85, 103.42, 113.94, 133.74, 136.77, 148.76, 156.74, 158.41.
HR-MS calcd for C33H42N6: 522.3471. Found: 522.3477. 1,3,5-Tris[(6-
aminopyridin-2-yl)aminomethyl]-2,4,6-trimethylbenzene (3): Yield 30%.
Mp 130-132 °C. 1H NMR (CDCl3) δ 2.38 (s, 9H, 3 × CH3), 4.01 (t, 3H,
3 × NH, J ) 4.4 Hz), 4.15 (s, 6H, 3 × NH2), 4.35 (d, 6H, 3 × CH2, J )
4.4 Hz), 5.81-5.84 (m, 6Hpyr), 7.24 (d, 3Hpyr). 13C NMR (CDCl3) δ 15.83,
41.65, 95.70, 96.81, 133.78, 136.84, 139.25, 157.68, 157.99. HR-MS calcd
for C27H33N9: 483.2859. Found: 483.2867.
The interactions of hosts 1-3 and glucopyranosides 4r-
4â were investigated by 1H NMR spectroscopy. The binding
(5) van der Made, A. W.; van der Made, R. H. J. Org. Chem. 1993, 58,
1262-1263.
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