Hydrazide-Based Quadruply Hydrogen-Bonded Heterodimers. Structure, Assembling Selectivity, and Supramolecular Substitution

Article abstract of DOI:10.1021/ja037312x

This paper describes the synthesis, self-assembly, and characterization of a new class of highly stable hydrazide-based quadruply hydrogen-bonded heterodimers. All of the hydrazide-derived heterodimers possess the complementary ADDA-DAAD hydrogen-bonding sequences. Hydrazide derivatives 1, which has two intramolecular S(6) RO...H-N hydrogen bonds, and 2 complex to afford two fastly exchanging isomeric heterodimers 1·2 and 1·2′ in chloroform, as a result of two different conformational arrangements of 2. An average binding constant K_assoc of 4.7 × 10⁴ M^-1 was determined for heterodimer 1·2 and 1·2′ by ¹H NMR titration of 1 with changing 2 in chloroform-d. In contrast, 1 binds 11 and 12, both of which are introduced with two intramolecular S(6) hydrogen bonds, to exclusively afford heterodimers 1·11 and 1·12, with K_assoc values of 1.8 × 10⁴ and 5.0 × 10² M^-1, respectively. Fluorine-containing 19, which has a hydrazide skeleton identical to that of 1 but two intramolecular S(6) F...H-N hydrogen bonds, can also complex with 2, 11, and 12, to afford heterodimers 19·2, 19·2′, 19·11, and 19·12, with K_assoc values of of 1.2 × 10⁴ (average value for 19·2 and 19·2′), 5.4 × 10³, and 1.9 × 10² M^-1, respectively. The structures of the new heterodimers have been proven with NOESY, IR, and VPO (for some of the heterodimers) experiments. Moreover, 1 and 19 can also strongly bind 2,7-dilauroylamido-1,8-naphthyridine 23 to afford dimers 1·23 and 19·23 with K_assoc values of 6.0 × 10⁵ and 1.4 × 10⁵ M^-1, respectively. Adding 1 to the 1:1 solution of 23 and 1-octyl-3-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)urea 24 or 1-octyl-3-(4-oxo-1,4-dihydropyrimidin-2-yl)urea 25, which had been developed initially by Zimmerman and Meijer, respectively, induces dimers 23·24 and 23·25 to dissociate, leading to the formation of dimers 1·23 and 24·24 or 25·25, respectively. The new hydrazide-based hydrogen-bonding modules described are useful building blocks for self-assembly and open a new avenue to recognition between discrete supramolecular species.

Full text of DOI:10.1021/ja037312x

Published on Web 11/12/2003
Hydrazide-Based Quadruply Hydrogen-Bonded Heterodimers.
Structure, Assembling Selectivity, and Supramolecular
Substitution
Xin Zhao,† Xiao-Zhong Wang,†,‡ Xi-Kui Jiang,† Ying-Qi Chen,‡ Zhan-Ting Li,*,† and
Guang-Ju Chen*,§
Contribution from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China, Department of Chemical Engineering,
Zhejiang UniVersity, Hangzhou, Zhejiang 310027, China, and Department of Chemistry,
Beijing Normal UniVersity, Beijing 100875, China
Received July 16, 2003; E-mail: ztli@mail.sioc.ac.cn
Abstract: This paper describes the synthesis, self-assembly, and characterization of a new class of highly
stable hydrazide-based quadruply hydrogen-bonded heterodimers. All of the hydrazide-derived heterodimers
possess the complementary ADDA-DAAD hydrogen-bonding sequences. Hydrazide derivatives 1, which
has two intramolecular S(6) RO‚‚‚H-N hydrogen bonds, and 2 complex to afford two fastly exchanging
isomeric heterodimers 1‚2 and 1‚2′ in chloroform, as a result of two different conformational arrangements
of 2. An average binding constant Kassoc of 4.7 × 104 M-1 was determined for heterodimer 1‚2 and 1‚2′ by
1H NMR titration of 1 with changing 2 in chloroform-d. In contrast, 1 binds 11 and 12, both of which are
introduced with two intramolecular S(6) hydrogen bonds, to exclusively afford heterodimers 1‚11 and 1‚12,
with Kassoc values of 1.8 × 104 and 5.0 × 102 M-1, respectively. Fluorine-containing 19, which has a hydrazide
skeleton identical to that of 1 but two intramolecular S(6) F‚‚‚H-N hydrogen bonds, can also complex with
2, 11, and 12, to afford heterodimers 19‚2, 19‚2′, 19‚11, and 19‚12, with Kassoc values of of 1.2 × 104
(average value for 19‚2 and 19‚2′), 5.4 × 103, and 1.9 × 102 M-1, respectively. The structures of the new
heterodimers have been proven with NOESY, IR, and VPO (for some of the heterodimers) experiments.
Moreover, 1 and 19 can also strongly bind 2,7-dilauroylamido-1,8-naphthyridine 23 to afford dimers 1‚23
and 19‚23 with Kassoc values of 6.0 × 105 and 1.4 × 105 M-1, respectively. Adding 1 to the 1:1 solution of
23 and 1-octyl-3-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)urea 24 or 1-octyl-3-(4-oxo-1,4-dihydro-
pyrimidin-2-yl)urea 25, which had been developed initially by Zimmerman and Meijer, respectively, induces
dimers 23‚24 and 23‚25 to dissociate, leading to the formation of dimers 1‚23 and 24‚24 or 25‚25,
respectively. The new hydrazide-based hydrogen-bonding modules described are useful building blocks
for self-assembly and open a new avenue to recognition between discrete supramolecular species.
simple doubly hydrogen-bonded systems, such as amide,2
sulfamide,3 carboxylic acid,4 pyridone derivatives, and 2-ami-
Introduction
The construction of new supramolecular architectures with
well-established structures and functions would be greatly
facilitated if a diverse set of structural motifs with strong and
specific intermolecular interactions becomes available. Because
of their directionality and strength, hydrogen bonds are one of
the most important interactions in the self-assembly of supra-
molecular structures.1 Although early study had established that
nopyridine-carboxylic acid complexes,5 and triply hydrogen-
bonded systems, such as cyanuric acid-melamine and cytosine-
guanine motifs,1a,6 could be used to construct various molecular
aggregators, recent investigations have demonstrated that mul-
tiply (>3) hydrogen-bonded modules are even more powerful
assembling tools due to their increased binding strength,
specificity, and directionality.1j-l,7 Particularly, the self-
complementary quadruply hydrogen-bonded homodimers based
on rigid heterocyclic derivatives had found extensive applica-
tions in the construction of well-defined supramolecular oligo-
mers and polymers.8,9 Nevertheless, the self-complementary
† Chinese Academy of Sciences.
‡ Zhejiang University.
§ Beijing Normal University.
(1) (a) Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin,
D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37. (b)
Lawrence, D. S.; Jiang, T.; Levitt, M. Chem. ReV. 1995, 95, 2229. (c) Conn,
M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647. (d) Zimmerman, S. C.;
Corbin, P. S. Struct. Bonding 2000, 96, 63. (e) Bong, D. T.; Clark, T. D.;
Granja, J. R.; Ghadiri, M. R. Angew. Chem., Int. Ed. 2001, 40, 988. (f)
Archer, E. A.; Gong, H.; Krische, M. J. Tetrahedron 2001, 57, 1139. (g)
Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem., Int. Ed. 2001,
40, 2383. (h) Gong, B. Chem.-Eur. J. 2001, 7, 4337. (i) Sherrington, D.
C.; Buggy, M. Chem Soc. ReV. 2001, 30, 83. (j) Brunsveld, L.; Folmer, B.
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Schmuck, C.; Wienand, W. Angew. Chem., Int. Ed. 2001, 40, 4363. (l)
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2768.
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1996, 271, 1095.
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9
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J. AM. CHEM. SOC. 2003, 125, 15128-15139
10.1021/ja037312x CCC: $25.00 © 2003 American Chemical Society

Hydrazide-Based Hydrogen-Bonded Heterodimers
A R T I C L E S
feature of homodimers also makes it difficult to use this kind
of binding motif to selectively assemble specific heterodimeric
supramolecular structures from distinct monomers, because a
mixture of possible dimers consisting of different monomers
would always be generated statistically on account of their
comparable binding stability.8f,10 In principle, non-self-comple-
mentary binding arrays are ideal tools to selectively assemble
heterodimeric systems. However, the number of this kind of
quadruply hydrogen-bonding modules available for use in
supramolecular assembly is notably limited.11 Therefore, there
is a strong need to develop new types of non-self-complementary
quadruply hydrogen-bonding units of high stability and specific-
ity.
We were interested in developing new unnatural molecular
recognition units with programmable strength and specificity.
Moreover, we also hoped to use new binding modules as model
systems to explore, if any, new recognition or interaction
between discrete supramolecular species with distinct structural
skeletons and binding motifs. We envisioned that investigations
along this line would lead to a new possibility for creating
recognition diversity and, more importantly, for developing new
principles to construct new supramolecular architectures. Herein,
we describe (1) the design, self-assembly, and characterization
of a new class of quadruply hydrogen-bonded heterodimers from
readily available hydrazide derivatives and (2) the competitive
associating behaviors of the new supramolecular species with
two rigid heterocyclic homodimers, which were initially reported
by Zimmerman and Meijer.7d,e To our knowledge, the construc-
tion of the new class of highly stable hydrazide-based ADDA-
DAAD (A ) hydrogen-bond acceptor, D ) hydrogen-bond
donor) heterodimers also represents the first successful applica-
tion of hydrazide derivatives in the self-assembly of hydrogen-
bond-mediated supramolecular systems with well-established
structures.12,13
Figure 1. The designed binding motif of the new generation of hydrazide-
based quadruply hydrogen-bonded heterodimers.
Results and Discussion
The underlying assembling strategy for the new type of
quadruply hydrogen-bonded heterodimers involves the combina-
tion of two series of readily available hydrazide derivatives I
and II, as shown in Figure 1. In principle, monomers I and II
are expected to give rise to the complementary DAAD and
ADDA hydrogen-bonding sequences, leading to the formation
of a new generation of hydrogen-bonded supramolecular species.
The hydrogen-bonding components, that is, CdO and NH units
in both series, are designed to be arranged as closely as possible
to reduce the influence of structural flexibility. Also, additional
intramolecular RO‚‚‚H-N and F‚‚‚H-N hydrogen bonds are
introduced to increase the binding stability and selectivity of
the new class of heterodimers.
Compounds 1 and 2, which possess the complementary
ADDA and DAAD hydrogen-bonding sequence, respectively,
were first designed and synthesized. The octyloxy groups were
incorporated into 1 for the formation of two highly favorable
intramolecular S(6)-type hydrogen bonds,14 which should
facilitate its complexation with complementary counterpart
molecules. The introduction of the dodecyloxy and cyclohexyl
groups in 2 provided good solubility in organic solvents, and
the latter group was also expected to facilitate the complexation
of 2 with 1 as a result of steric hindrance between it and the
adjacent hadrazide groups. The syntheses of both 1 and 2 are
outlined in Scheme 1. Treatment of 3 with commercially
available carbohydrazide 4 in the presence of EDCI afforded 1
in 60% yield. For preparation of 2, malonic acid diethyl ester
5 was first treated with dibromide 6 in the presence of sodium
ethoxide to yield 7, which was hydrolyzed and then converted
to diacyl chloride 8 with thionyl chloride. Subsequent reaction
of 8 with 10 in chloroform with triethylamine as base yielded
compound 2 in 67% yield. Compound 10 could be conveniently
prepared from the reaction of 9 with hydrazine.
(6) For representative examples, see: (a) Hamilton, A. D.; Van Engen, D. J.
Am. Chem. Soc. 1987, 109, 5035. (b) Schneider, H.-J.; Juneva, R. K.;
Simova, S. Chem. Ber. 1989, 122, 1211. (c) Kelly, T. R.; Bridger, G. J.;
Zhao, C. J. Am. Chem. Soc. 1990, 112, 8024. (d) Adrian, J. C., Jr.; Wilcox,
C. S. J. Am. Chem. Soc. 1991, 113, 678. (e) Murray, T. J.; Zimmerman, S.
C.; Kolotuchin, S. C. Tetrahedron 1994, 50, 635. (f) Schall, O. F.; Gokel,
G. W. J. Am. Chem. Soc. 1994, 116, 6089. (g) Kotera, M.; Lehn, J.-M.;
Vigneron, J. P. Tetrahedron 1995, 51, 1953. (h) Bell, D. A.; Anslyn, E. V.
Tetrahedron 1995, 51, 7161. (i) Vreekamp, R. H.; van Duynhoven, J. P.
M.; Hubert, M.; Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1215. (j) Mascal, M.; Hext, N. M.; Warmuth, R.; Moore,
M. H.; Turkenburg, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 2204. (k)
Chen, L.; Sakai, N.; Moshiri, S. T.; Matile, S. Tetrahedron Lett. 1998, 39,
3627.
(7) (a) Lu¨ning, U.; Ku¨hl, C. Tetrahedron Lett. 1998, 39, 5735. (b) Beijer, F.
H.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. Angew.
Chem., Int. Ed. 1998, 37, 75. (c) Sessler, J. L.; Wang, R. Angew. Chem.,
Int. Ed. 1998, 37, 1726. (d) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.;
Spek. A. L.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761. (e) Corbin,
P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120, 9710. (f) Gong, B.;
Yan, Y.; Zeng, H.; Skrzypczak-Jankunn, E.; Kim, Y. W.; Zhu, J.; Ickes,
H. J. Am. Chem. Soc. 1999, 121, 5607.
(8) (a) Folmer, B. J. B.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer,
E. W. J. Am. Chem. Soc. 1999, 121, 9001. (b) Rieth, L. R.; Eaton, R. F.;
Coates, G. W. Angew. Chem., Int. Ed. 2001, 40, 2153. (c) Gonza´lez, J. J.;
de Mendoza, J.; Gonza´lez, S.; Priego, E. M.; Martin, N.; Luo, C.; Guldi,
D. M. Chem. Commun. 2001, 163. (d) Sa´nchez, L.; Rispens, M. T.;
Hummelen, J. C. Angew. Chem., Int. Ed. 2002, 40, 4363. (e) ten Cate, A.
T.; Dankers, P. Y. W.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer,
E. W. J. Am. Chem. Soc. 2003, 125, 6860. (f) Wang, X.-Z.; Li, X.-Q.;
Zhao, C.-X.; Shao, X.-B.; Zhao, X.; Deng, P.; Jiang, X.-K.; Li, Z.-T.; Chen,
Y.-Q. Chem.-Eur. J. 2003, 9, 2904.
A crystal of compound 1 suitable for X-ray analysis was
grown from chloroform by slow evaporation. Figure 2 shows
the X-ray structure of the centrosymmetric homodimer 1‚1. The
two molecules are held together by four intermolecular tricenter
hydrogen bonds (O‚‚‚H distances ) 2.230 and 2.383 Å,
respectively) between the two hydrazide skeletons which are
arranged within a slightly twisted plane. A similar type of
tricenter hydrogen bonds had been observed for simple sym-
(12) Ureas derivatives have been investigated extensively for hydrogen-bond-
mediated self-assembly and molecular recognition. However, to our
knowledge, no examples of hydrogen-bond-driven supramolecular systems
from hydrazine derivatives with well-established structures have ever been
reported.
(9) Corbin, P. S.; Lawless, L. J.; Li, Z.-T.; Ma, Y.; Witmer, M. J.; Zimmerman,
S. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5099.
(10) Rispens, M. T.; Sa´nchez, L.; Knol, J.; Hummelen, J. C. Chem. Commun.
2001, 161.
(11) (a) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk, N. A.;
Murray, T. J. J. Am. Chem. Soc. 2001, 123, 10475. (b) Brammer, S.; Lu¨ning,
U.; Ku¨hl, C. Eur. J. Org. Chem. 2002, 4054. (c) Zeng, H.; Yang, X.;
Flowers, R. A.; Gong, B. J. Am. Chem. Soc. 2002, 124, 2903.
(13) Hydrazide units have been successfully used by Nowick et al. to control
the folding structures of artificial peptides, see: (a) Nowick, J. S.; Smith,
E. M.; Pairish, M. Chem. Soc. ReV. 1996, 25, 401. (b) Soth, M. J.; Nowick,
J. S. Curr. Opin. Chem. Biol. 1997, 1, 120. (c) Nowick, J. S. Acc. Chem.
Res. 1999, 32, 287.
(14) Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
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A R T I C L E S
Zhao et al.
Scheme 1
Figure 2. X-ray structure of 1, showing the intermolecular tricenter
hydrogen-bonded dimerization and the intramolecular S(6)-type hydrogen
bonds.
Mixing 1 equiv of 1 (5 mM) and 1 equiv of 2 (5 mM) in
CDCl3 led to a substantial downfield change of the chemical
shifts for the NH-1 signal (∆δ ) 0.81 ppm) of 1 and for both
the NH-1 (∆δ ) 0.71 ppm) and the NH-2 (∆δ ) 0.57 ppm)
signals of 2 as compared to those of the pure samples of 1 and
2 at the same concentration, initially suggesting that there might
be two isomeric dimers 1‚2 and 1‚2′ generated as a result of
the distinct arrangements of 2 (Chart 2). No important shift (∆δ
< 0.02 ppm) was observed for the NH-2 signal of 1, which
was involved in the formation of the strong intramolecular
hydrogen bond. The 1H NMR dilution study in CDCl3 at room
temperature also supported the formation of two isomeric
dimers. Reducing the concentration of the 1:1 solution from 80
mM to 80 µM led to the signals of the NH-1 (∆δ ) 0.94 ppm)
of 1 and the NH-1 (∆δ ) 0.82 ppm) and NH-2 (∆δ ) 0.72
ppm) of 2 to shift upfield remarkably. In contrast, the NH-2
signal of 1 showed no significant concentration dependence (∆δ
1
< 0.04 ppm). Variable-temperature H NMR experiments in
metric aryl urea derivatives.15 As expected, there are two
intramolecular S(6)-type hydrogen bonds (O‚‚‚H distance )
1.983 Å) for every molecule, that rigidify the backbone of the
molecule.
CDCl3 from 10 to 55 °C revealed that the signals of the NH-1
of 1 and the NH-1 and NH-2 of 2 exhibited much greater
temperature dependence than that of the NH-2 of 1.18 All of
these observations are consistent with the formation of two
dimeric isomers 1‚2 and 1‚2′.
1
The NH signals of compounds 1 and 2 in H NMR spectra
were assigned by the NOE and gradient experiments (Chart 1).
The peak of NH-2 protons was substantially shifted downfield
(9.99 ppm) relative to that of the NH-1 protons (8.48 ppm) in
1, suggesting that the NH-2 protons were involved in strong
intramolecular hydrogen bonds.16 Dilution studies (50 mM to
100 µM) in CDCl3 revealed weak self-binding for both
compounds at room temperature. A fit of the chemical shift
data for both NH-1 of 1 and 2 to a 1:1 isotherm afforded binding
constant Kassoc values of 55 M-1 for dimer 1‚1 and 112 M-1
for dimer 2‚2 (Chart 1), respectively.17 No obvious chemical
shift changes (∆δ < 0.03 ppm) were observed for the NH-2
signals of both 1 and 2, indicating that these protons did not
involve important intermolecular hydrogen bonds.
Additional compelling evidence for the formation of both 1‚
2 and 1‚2′ came from 2D-NOESY experiments (see the
Supporting Information). Important NOE connections were
observed between all of the NH signals of both 1 and 2, all
with comparable intensities (Chart 2). Considering that, in dimer
1‚2, the distances between the NH-1 or NH-2 of 1 and the NH-2
of 2 are remarkably longer than those between the NH-1 or
NH-2 of 1 and the NH-1 of 2, respectively, the comparably
strong NOE correlation between the NH-2 of 2 and the NH’s
of 1 should more reasonably correspond to the structure of dimer
1‚2′. Reducing the temperature to -20 °C led to broadening
but not splitting of the NH signals of both 1 and 2 in a 1:1
solution (5 mL) in CDCl3, indicating that the exchange between
the two conformationally isomeric heterodimers was still rapid
1
(15) (a) Etter, M. C.; Frankenbach, G. M. J. Am. Chem. Soc. 1988, 110, 5896.
(b) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem., Int.
Ed. 2002, 41, 1488. (c) Lortie, F.; Boileau, S.; Bouteiller, L. Chem.-Eur.
J. 2003, 9, 3008.
(16) Similar intramolecular hydrogen bonds have been established in several
folded artificial peptides, see: (a) Smith, E. M.; Holmes, D. L.; Shaka, A.
J.; Nowick, J. S. J. Org. Chem. 1997, 62, 7906. (b) Nowick, J. S.; Pairish,
M.; Lee, I. Q.; Holmes, D. L.; Ziller, J. W. J. Am. Chem. Soc. 1997, 119,
5413. (c) Holmes, D. L.; Smith, E. M.; Nowick, J. S. J. Am. Chem. Soc.
1997, 119, 7665.
on the H NMR time scale at this temperature.
(17) (a) Conners, K. A. Binding Constants: The Measurement of Molecular
Complex Stability; Wiley: New York, 1987. (b) Wilcox, C. S. In Frontiers
in Supramolecular Organic Chemistry and Photochemistry; Schneider, H.
J., Du¨rr, H., Eds.; VCH: New York, 1991; p 123.
(18) (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118,
7529. (b) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc.
1997, 119, 10587.
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Hydrazide-Based Hydrogen-Bonded Heterodimers
A R T I C L E S
Chart 1
Chart 2
An average molecular mass of 1300 ( 100 u was determined
with vapor pressure osmometry (VPO) in toluene at 30 °C,
which agrees well with that calculated for the dimeric structure
(1330 u). FT-IR data were also consistent with dimerization.
The pure samples displayed one hydrogen-bonded NH-stretch
at 3150 cm-1 for 1 and 3155 cm-1 for 2, respectively, and one
hydrogen-bond-free NH-stretch at 3430 cm-1 for 1 and 3433
cm-1 for 2, respectively, in CHCl3 solution (30 mM), while a
mixture of 1 and 2 (20 mM) in CHCl3 exhibited a substantially
increased hydrogen-bonded NH-stretch at 3157 cm-1 and a
decreased NH-stretch at ca. 3430 cm-1 as compared to the pure
samples, showing that the previously hydrogen-bond-free
N-H’s had been involved in intermolecular hydrogen bonding
in the mixture.
1H NMR titration was carried out for the solution of 1 in
CDCl3 with 2, and the representative results are presented in
Figure 3. Fitting the chemical shift data for the NH-1 signals
of 1 to a 1:1 binding isotherm afforded an average Kassoc value
of approximately 4.7 × 104 M-1 for the complex of 1 and 2.19
In contrast, only small chemical shift changes (∆δ e 0.04 ppm)
were observed for the NH-2 of 1, which implies that this proton
was not importantly involved in intermolecular hydrogen
bonding. Heterodimer 1‚2 represents one of the most stable
examples of quadruply hydrogen-bonded heterodimers that are
assembled from nonheterocyclic monomers.11,20
bonded modules would be important for future application in
the self-assembly of new supramolecular systems. Therefore,
two new hydrazide derivatives 11 and 12, both with the ADDA
hydrogen-bonding sequence, were designed and synthesized
(Scheme 2). It was conceived that, for 11, two stable intra-
molecular S(6)-type hydrogen bonds would be generated from
the central NH protons and, as a result, only the peripheral NH
protons were free for any intermolecular complexation.1h In
contrast to 11, compound 12 would possess two intramolecular
S(6)-type hydrogen bonds formed from the peripheral NH
protons, as has been observed for 1. As a result, the selective
formation of a dimeric structure similar to that of 1‚2′ would
be greatly facilitated. The syntheses of compounds 11 and 12
are straightforward, as shown in Scheme 2. Thus, treatment of
pyridine-2-carboxylic acid hydrazide 14, which was prepared
in high yield from compound 13 and hydrazine, with diacyl
Because what is formed from 1 and 2 in chloroform is a
mixture of two isomeric dimers, which exchange fastly to each
other at room temperature, further improvement of the as-
sembling selectivity of this new class of quadruply hydrogen-
(19) Titration of 2 (1.33 mM) with 1 in CDCl3 revealed important chemical
shift changes for both NH-1 (∆δ 0.90 ppm) and NH-2 (∆δ 0.85 ppm)
signals of 2, indicating that both protons were involved in important
intermolecular hydrogen bonding. Because both dimers 1‚2 and 1‚2′ exist
and exchange fastly to each other in the solution, no binding constants of
separate isomeric dimers could be obtained by titration of 2 with 1. We
thank one of the reviewers for critical comments concerning this issue.
Figure 3. Chemical shift summaries of the NH-1 (b) and NH-2 (9) signals
of 1 (1.0 mM) titrated with 2 in CDCl3 at 25 °C.
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A R T I C L E S
Zhao et al.
Scheme 2
Chart 3
NH-2 data of 11, we derived a Kassoc value of approximately
1.8 × 104 M-1 for heterodimer 1‚11 (Chart 3). Only small
chemical shift changes (e0.08 ppm) were observed for the NH-1
signal of 11, which suggested an obviously smaller binding
stability for 1‚11′. The 2D-NOESY experiment also supported
the binding selectivity of 1 and 11. Different from the case of
1 and 2 in which both the NH-1 and the NH-2 of 2 exhibited
important intermolecular NOEs, NOE was observed only
between the NH-2 signal of 11 and the NH signals of 1, while
the NH-1 signal in 11 did not display any intermolecular
connection. The lower Kassoc value of dimer 1‚11 relative to
dimer 1‚2 can be rationalized by considering that steric
hindrance should exist between the pyridine group and the
cyclohexyl group of 11 in dimer 1‚11.
chloride 8 in dichloromethane in the presence of triethylamine
afforded 11 in 72% yield. For preparation of 12, hydrazide 16
was first generated in quantitative yield from the reaction of
2-octyloxybenzoic acid methyl ester 15 and hydrazine. Subse-
quent reaction of 16 with 8 afforded 12 in 55% yield under the
reaction conditions described for preparing 11.
1H NMR spectra in CDCl3 (5 mM) supported the existence
of intramolecular S(6)-type hydrogen bonds in both 11 and 12.
All of the NH protons in both compounds were assigned with
the NOESY techniques (numbered in Scheme 2). For 11, the
NH-1 peak (9.89 ppm) was remarkably downfield shifted as
compared to its NH-2 peak (9.37 ppm). In contrast, the NH-2
peak (10.66 ppm) in 12 was substantially more downfield than
its NH-1 peak (9.58 ppm). These observations clearly showed
that the former two NH protons were involved in intramolecular
hydrogen bonds. Variable-temperature 1H NMR investigations
from 10 to 55 °C revealed an obviously lower temperature
dependence of the former two signals in both compounds, which
was also consistent with their involvements with intramolecular
hydrogen bonds. The self-association of 11 and 12 in CDCl3
was then investigated by 1H NMR spectroscopy. A pronounced
upfield shift was observed only for the NH-2 signal (ca. 0.15
ppm) in 11 upon dilution of the solution from 50 to 0.5 mM,
which afforded a Kdim value of 25 M-1 for homodimer 11‚11
(Chart 3). No important shifts (∆δ < 0.04 ppm) were observed
for the NH-1 signal in 11 and for both NH signals in 12,
implying that these protons did not involve important inter-
molecular hydrogen bonding.
1
The H NMR titration study of 12 with 1 in CDCl3 (Figure
4) revealed that these two compounds exhibited a binding
affinity that is opposite to that between compounds 1 and 11:
No important change of chemical shift (e0.04 ppm) was found
The binding ability of 11 toward 1 was then investigated with
1
the H NMR titration method. The representative results are
presented in Figure 4. By fitting a 1:1 binding motif for the
(20) Gong et al. have recently reported a nonheterocyclic DADD-ADAA
binding motif with a Kassoc of approximately 1250 M-1 in 5% DMSO-d6/
CDCl3. No binding constant of the dimer in pure chloroform was provided,
see ref 11c.
Figure 4. Chemical shift summaries of the NH-1 (9) and NH-2 (b) protons
of 11 (1.0 mM) and the NH-1 (1) and NH-2 (2) of 12 (10 mM), both
titrated with 1 in CDCl3 at 25 °C.
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Hydrazide-Based Hydrogen-Bonded Heterodimers
A R T I C L E S
Scheme 3
Figure 5. Partial 1H NMR spectrum (400 MHz, 10 mM) of (a) 1, (b) 1 +
23 (1:1), (c) 23, (d) 19 + 23, and (e) 19 in CDCl3 at room temperature,
highlighting the formation of heterodimer 1‚23 and 19‚23.
which, in turn, was obtained from the oxidation of commercially
available 2-fluoro-m-xylene 20 with potassium permanganate.
The initial attempt to prepare 22 from the selective hydrolysis
of 2-fluoro-iso-phthalic acid dioctyl ester was not successful,
which always afforded 21 as the sole product. As expected, the
incorporation of two octoxycarbonyl groups into 19 provided
good solubility in common solvents such as chloroform and
benzene.
Prior to binding studies with compounds 2, 11, and 12, the
1
self-association of 19 in CDCl3 was investigated by H NMR
for its NH-2 signal, which was proven to be involved in strong
intramolecular S(6)-type hydrogen bonds. From nonlinear
regression of the titration data of the NH-1 signal of 12 with a
1:1 binding motif, a Kassoc value of approximately 500 M-1 was
obtained for dimer 1‚12 (Chart 3). The binding constant is
remarkably lower than that of dimer 1‚11, which might be
attributed to the substantially increased spatial hindrance
between the cyclohexyl group and the intramolecularly hydrogen-
bonded moiety of 12.
spectroscopy. Different from 1 where only the chemical shift
of the H-1 peak exhibited important concentration dependence,
both NH signals (numbered in Chart 4) of 19 moved upfield
upon dilution of its solution in CDCl3 from 100 mM to 80 µM,
which gave Kassoc values of 75 and 20 M-1 for homodimers
19‚19 and 19′‚19′, respectively, after fitting to a dimeric binding
motif. Moreover, it can be found that the NH-1 signal (ca. 9.12
ppm) of 19 is less downfield shifted than the NH-1 signal (ca.
10.00 ppm) of 1 at the same concentration (20 mM). The results
appear to indicate that the intramolecular S(6) F‚‚‚H-N
hydrogen bond in 19 is notably weaker than the intramolecular
S(6) RO‚‚‚H-N hydrogen bond in 1.22
1H NMR titration studies were then carried out in CDCl3 for
compound 19 with 2, and for compounds 11 and 12 with 19,
respectively. Fitting the chemical shift data for the NH-1 of
19, 11, and 12 to a 1:1 binding model gave association constants
of approximately 1.2 × 104, 5.4 × 103, and 1.9 × 102 M-1 for
dimers 19‚2 (a mixture with 19‚2′, the existence of which was
The formation of intramolecular S(6)-type hydrogen bonds
in compound 1 is obviously crucial for efficient self-assembly
of the new class of heterodimeric structures. Considering that
fluorine has the highest electronegativity and its van der Waals
radius (1.35 Å) is very close to that of oxygen (1.40 Å), it was
envisioned that the octyloxy group might be replaced with
fluorine to form similar intramolecular S(6) F‚‚‚H-N hydrogen
bonds.21 To test this hypothesis, compound 17 was first prepared
from the coupling reaction of commercially available 18 and 4
in the presence of EDCI (Scheme 3). Unfortunately, compound
17 was found to be insoluble in nonpolar solvents such as
chloroform or dichloromethane. Therefore, another fluorine-
containing compound 19 was synthesized, as outlined in Scheme
3. In brief, the immediate precursor to 19, fluorine-containing
acid 22, was prepared from the monoesterification of diacid 21,
1
proven with H NMR dilution and NOESY experiments), 19‚
11, and 19‚12 (Chart 5), respectively. The signals of the NH-2
protons of 19 (<0.07 ppm), 11, and 12 (<0.04 ppm) did not
shift obviously within the concentration range studied, indicating
that these protons, which were involved in strong intramolecular
hydrogen bonds, were not engaged in important intermolecular
hydrogen bonding. NOESY experiments revealed important
intermolecular NOE connections between the NH signals of the
(21) It has been reported that fluorine can act as a weak hydrogen-bond acceptor.
Nevertheless, to the best of our knowledge, no examples of F‚‚‚H-N
hydrogen-bond-promoted self-assembly of supramolecular systems with
defined structures have been available, see: (a) Vinogradov, S. N.; Linnell,
R. H. Hydrogen Bonding; Van Nostrand Reinhold: New York, 1971; pp
124-135. (b) Jones, D. A. K.; Watkinson, J. G. J. Chem. Soc. 1964, 2366.
(c) Kool, E. T. Acc. Chem. Res. 2002, 35, 936.
(22) Intramolecular S(7) F‚‚‚H-N hydrogen bonds might also be formed from
the H-2 protons of 19, which compete with the S(6) hydrogen bonds and
reduce the latter’s strength.
9
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A R T I C L E S
Zhao et al.
Chart 4
Chart 5
former three complexes (Chart 5), which were consistent with
the formation of the heterodimers.
evidenced by the observation of strong NOE connections
between the NH signals of the two compounds, as shown in
Chart 6. The VPO experiment afforded an average mass of 1050
( 100 u in chloroform (calculated value for dimer 1‚23: 1078
u), which is also consistent with the formation of the dimer. 1H
NMR titration studies of 23 (0.7 mM) with 1 were then
performed in CDCl3, which gave a Kassoc value of approximately
6.0 × 105 M-1 for heterodimer 1‚23.
The fact that two conformationally isomeric heterodimers
were generated, respectively, between 1 or 19 and 2 revealed
that these flexible nonheteroaromatic hydrazide derivatives could
readily adjust their conformations to facilitate the self-assembly
of new kinds of heterodimers. Previous studies by Meijer and
Zimmerman et al. have revealed that quadruply hydrogen-
bonded dimers from rigid heterocyclic monomers usually
exhibited very strong binding affinity.7d,e Therefore, it was
conceived that more stable binding modules might be con-
structed from hydrazide monomers and complementary rigid
heteroaromatic monomers. To investigate this potential, the
binding behaviors of 1 and 19 with 23 in CDCl3 were
investigated. Mixing 1 equiv of 1 with 1 equiv of 23 in CDCl3
(10 mM) caused substantial downfield shifting for the NH-1
signal (∆δ ) 2.03 ppm) of 1 and the N-H signal (∆δ ) 1.54
ppm) of 23, while the chemical shift of the NH-2 of 1 did not
change downfield greatly (∆δ ) ca. 0.10 ppm), as shown in
Figure 5. These observations clearly indicated that a new
heterodimer 1‚23 was formed (Chart 6), which was further
A remarkable downfield shift (∆δ ) 1.17 ppm) was also
observed for the NH-1 signal of 19 upon mixing it with 23 in
a 1:1 ratio (Figure 5d), as a result of the formation of
heterodimer 19‚23, which was further evidenced by inter-
molecular NOE connections (Chart 6). A 1H NMR titration study
in CDCl3 afforded this heterodimer a Kassoc value of ap-
proximately 1.4 × 105 M-1
.
Development of new approaches to efficiently regulate the
assembling processes of supramolecular recognition modules
is potentially useful for the design of novel molecular device
and functional materials.23 The facts that the hydrazide-based
hydrogen-bonded heterodimers display varying stability and
affinity and that the monomers display good conformational
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Hydrazide-Based Hydrogen-Bonded Heterodimers
A R T I C L E S
Chart 6
Chart 7
adjustability make them ideal recognition modules for reversible
regulation of hydrogen-bonded assemblies with discrete binding
motifs. To test this potential, the competitive binding behavior
of 1, 23, and 24 in CDCl3 was investigated by 1H NMR
spectroscopy. Previously, Zimmerman and Corbin had reported
that a heterocyclic compound similar to 23 could cause a dimer
similar to 24‚24 to dissociate to generate a new more stable
heterodimer such as 23‚24 (Chart 7).7e Adding 1 equiv of 1 to
the 1:1 solution of 23 and 24 in CDCl3 did induce dimer 23‚24
to partially dissociate, leading to the release of 24, which self-
associated to form the stable dimer 24‚24, as indicated by the
1H NMR spectra (Figure 6). The peaks of the NH protons of 1
and 23 in the mixture solution had been assigned by changing
the ratio of 1 with 23 and 24 (Figure 6c). However, we could
not quantitatively assess the dissociation process of 23‚24 by
1H NMR spectroscopy due to the fast exchange between the
different dimers and the complicated tautomerization of dimer
24‚24.24
The competitive binding properties of 1 and 25 with 23 were
then investigated by 1H NMR spectroscopy. Previously, we had
found that compound 23 could induce dimer 25‚25, the binding
module of which had been initially reported by Meijer at al.,7d
to dissociate to generate heterodimer 23‚25 and the exchange
process could be regulated with additional donor-acceptor
interaction between p-dialkoxybenzene and naphthalene-1,4,5,8-
tetracarboxylic diimide.8f The 1H NMR results are presented in
Figure 7. It can be found that approximately 70% (based on
the relative integrative intensity of the H-4 signal of 25 in dimers
23‚25 and 25‚25 at 5.99 and 5.72 ppm, respectively) of dimer
23‚25 was dissociated upon addition of 1 equiv of 1 to the 1:1
1
Figure 6. Partial 400 MHz H NMR spectrum (10 mM) of (a) 23 + 24 (1:1), (b) 1 + 23 + 24 (1:1:1), (c) 1 + 23 + 24 (2:1:1), and (d) 1 + 23 (1:1) in
CDCl3 at 25 °C, highlighting the competitive complexing behavior of 1 and 24 to 23.
9
J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003 15135

A R T I C L E S
Zhao et al.
Figure 7. Partial 1H NMR spectra (400 MHz, CDCl3, 25 °C, [23] ) 10 mM), highlighting the substitution process between 1 and 25 of 23‚25: (a) 1 + 23
(1:1), (b) 23 + 25 (1:1), (c) 1 + 23 + 25 (1:1:1), (d) 1 + 23 + 25 (3:1:1), (e) 1 + 23 + 25 (6:1:1), (f) 25 (10 mM), and (g) 1 + 2 + 23 + 25 (1:1:1:1).
Scheme 4
solution of 23‚25 in CDCl3 (Figure 7c), as a result of the
formation of heterodimer 1‚23. The dissociation was complete
(with a lower limit of 95%, considering the sensitivity of the
1H NMR measurement) after about 6 equiv of 1 was added
(Figure 7e). Assuming that any other new complexes that might
be formed in the mixture solution were negligible, we deter-
mined an equilibrium constant to be approximately 12 M-1 for
the substitution process shown in Scheme 4, based on the
integrating intensity of the sharp H-4 signal of 25 in the homo-
and heterodimers. It is reasonable to assume that the binding
constant of dimer 25‚25 is the reported value of 5.7 × 107 M-1
(23) (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem.,
Int. Ed. 2000, 39, 3348. (b) Ballardini, R.; Balzani, V.; Credi, A.; Gandolfi,
M. T.; Venturi, M. Acc. Chem. Res. 2001, 34, 445.
(24) This kind of dimers had been reported to have four tautomeric isomers,
see ref 7e.
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15136 J. AM. CHEM. SOC. VOL. 125, NO. 49, 2003

Hydrazide-Based Hydrogen-Bonded Heterodimers
A R T I C L E S
Figure 8. Energy-minimized structures of dimers 1‚2, 1‚2′, and 1‚23. All 504of the side chains of monomers 1, 2, and 23 are replaced with methyl groups
for clarity.
Table 1. A Summary of Association Constants of the New
for this type of homodimers;25 a lower limit Kassoc value of
Generation of Hydrazide-Based Dimersa
approximately 1.5 × 109 M-1 was estimated for dimer 23‚25
K
∆G
(kcal/mol)
K
∆G
(kcal/mol)
assoc
assoc
from a simple thermodynamic circle. Direct measurement of
dimer
(M-1
)
dimer
2‚2
12‚12
19′‚19′
1‚11
19‚2
19‚12
19‚23
(M-1
)
1
the binding constants with the H NMR method is obviously
1‚1
55
2.4
1.9
2.6
6.3
3.7
5.1
7.9
1.1 × 102
2.8
0.9
1.8
5.8
5.7
3.1
6.7
impossible for robust dimers such as 23‚25. This kind of
competitive experiment represents an alternate approach for
measuring the binding constants of highly stable hydrogen-
bonded dimers.26
11‚11 25
19‚19 75
<5
20
1‚2
4.7 × 104
5.0 × 102
5.4 × 103
6.0 × 105
1.8 × 104
1‚12
19‚11
1‚23
1.2 × 104
1.9 × 102
1.4 × 105
Addition of 1 equiv of 2 to the mixture solution could notably
promote the reassociation of 23 and 25 to 23‚25 (with an
increase of ca. 10%) (Figure 7g), as a result of the competitive
association of 2 with 1. However, new low-resolved signals were
also produced (Figure 7g), which indicated that new complexes
might be formed between 2 and 23 or 25 in the mixture.
Because ADDA-sequenced hydrazide monomers 1 and 19
can efficiently associate with different kinds of DAAD-
sequenced compounds 2, 11, 12, and 23, respectively, to form
discrete heterodimers, these hydrazide monomers are obviously
able to adopt quite varying conformations to achieve an optimal
binding module. The density function method B3LYP at the
level 3-21g basis was carried out to investigate the structures
of three heterodimers, that is, 1‚2, 1‚2′, and 1‚23.27 The energy-
minimized conformations of these dimers are presented in Figure
8. It was revealed that both compounds 1 and 2 existed in a
twisted conformation in all of the dimers, whereas the rigid 23
adopted a planar arrangement. The average hydrogen-bond
lengths and angles between two molecules for 1‚2, 1‚2′, and
1‚23 are 2.70 Å and 171.7°, 2.74 Å and 170.3°, 2.84 Å and
165.6°, respectively. As expectedly, monomer 2 displayed the
most twisted conformation in dimer 1‚2′. The interaction energy
of 1‚2 is 49.3 kJ/mol larger than that of 1‚2′. The stronger
interaction of 1‚2 relative to its isomer 1‚2′ is consistent with
a The association constants are typically averages of two experiments at
25 °C, with an error of less than 15%.
building blocks.28,29 A new kind of unique conformational
isomerization of dimeric systems, generated as a result of distinct
arrangement of the binding sites of the monomers, has been
revealed. Selective self-assembly of single heterodimers can be
achieved by simple introduction of additional intramolecular
S(6) hydrogen bonds into the monomers. The association
constants of the new heterodimers and the self-binding constants
of the monomers are summarized in Table 1. Because the new
class of heterodimers do not adopt an identical binding motif,
the binding stability of these heterodimers does not fit a general
incremental energy model,30 but mainly depends on the ar-
rangement of the binding sites and steric effect.
For the first time, the intramolecular S(6)-type F‚‚‚H-N
hydrogen bond has been utilized to stabilize the binding
conformation of monomers for self-assembly. Although this kind
of hydrogen bond does not appear to be as strong as the classic
S(6) O‚‚‚H-N hydrogen bond, the considerably smaller size
of fluorine, relative to the RO (even R ) MeO) group, bodes
well for the future application of the F‚‚‚H-N hydrogen bond
in self-assembly. Moreover, the unique substitution behavior
displayed between 1 and dimers 23‚24 and 23‚25 to generate
1
the H NMR binding investigation mentioned above.
Conclusions
(28) For examples of other hydrogen-bonded artificial duplexes, see: (a)
Hamilton, A. D.; Little, D. J. Chem. Soc., Chem. Commun. 1990, 297. (b)
Sessler, J. L.; Wang, R. J. Org. Chem. 1998, 63, 4079. (c) Zeng, H.; Miller,
R. S.; Flowers, R. A., II; Gong, B. J. Am. Chem. Soc. 2000, 122, 2635. (d)
Bisson, A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger, R. C.; Hunter,
C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger, C.; Rowan, A. E. J. Am.
Chem. Soc. 2000, 122, 8856. (e) Zeng, H.; Yang, X.; Brown, A. L.;
Martinovic, S.; Smith, R. D.; Gong, B. Chem. Commun. 2003, 1556.
(29) For recent examples of other kinds of sunthetic duplexes, see: (a) Taylor,
P. N.; Anderson, H. L. J. Am. Chem. Soc. 1999, 121, 11538. (b) Anderson,
H. L. Chem. Commun. 1999, 2323. (c) Fatin-Rouge, N.; Blanc, S.; Pfeil,
A.; Rigault, A.; Albrecht-Gary, A.-M.; Lehn, J.-M. HelV. Chim. Acta 2001,
84, 1694. (d) Berl, V.; Huc, I.; Khoury, R. G.; Lehn, J.-M. Chem.-Eur. J.
2001, 7, 2810. (e) Gregory, J.; Gabriel, B.; Iverson, L. J. Am. Chem. Soc.
2002, 124, 15174. (f) Zhou, Q.-Z.; Jiang, X.-K.; Shao, X.-B.; Chen, G.-J.;
Jia, M.-X.; Li, Z.-T. Org. Lett. 2003, 5, 1955.
A new series of quadruply hydrogen-bonded ADDA-DAAD-
sequenced heterodimers have been assembled in chloroform
from readily available hydrazide derivatives, and their structures
and binding stability have been investigated. Dimers 1‚2 and
19‚2 represent one of the most stable quadruply hydrogen-
bonded modules that are constructed from nonheterocyclic
(25) So¨ntjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E.
W. J. Am. Chem. Soc. 2000, 122, 7487.
(26) Heath, R. E.; Dykes, G. M.; Fish, H.; Smith, D. K. Chem.-Eur. J. 2003, 9,
850.
(27) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(30) Sartorius, J.; Schneider, H.-J. Chem.-Eur. J. 1996, 2, 1446.
9
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A R T I C L E S
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Cyclohexane-1,1-dicarbonyl Chloride (8). Compound 7 was first
hydrolyzed with sodium hydroxide in hot water to cyclohexane-1,1-
dicarboxylic acid as described in the literature.33 The diacid was then
treated with excessive thionyl chloride under reflux for 6 h. After the
solvent was removed under reduced pressure, compound 8 was obtained
as an oil, which was used for the next step without further purification.
4-Dodecyloxybenzoic Acid Hydrazide (10). A suspension of
4-dodecyloxybenzoic acid methyl ester 934 (3.00 g, 9.40 mmol) and
hydrazine monohydrate (5.00 g) in methanol (50 mL) was heated under
reflux for 10 h and then cooled to room temperature. The precipitate
formed was filtered, washed with water thoroughly, and then recrystal-
lized from ethyl acetate to afford compound 10 as colorless solid (2.80
relatively weaker dimers 1‚23 and 24‚24 or 25‚25 from stronger
dimers demonstrates that inherent connections may exist
between seemingly unrelated hydrogen-bonded assembling
systems. Detailed investigations of these connections should
point to new chemistry beyond supramolecules.
Experimental Section
General Methods. All reactions were carried out under a dry
nitrogen atmosphere. Melting points are uncorrected. The 1H NMR
spectra were recorded on 600, 400, or 300 MHz spectrometers in the
indicated solvents. Chemical shifts are expressed in parts per million
(δ) using residual solvent protons as internal standards (chloroform, δ
7.27 ppm; DMSO, δ 2.49 ppm). Mass spectra (EI, ESI) were obtained
on a Varian SATURN 2000 spectrometer. Vapor pressure osmometry
(VPO) experiments were performed with a Knauer K-700 osmometer.
IR spectra were recorded with a FT-185 infrared absorption spectrom-
eter. X-ray analysis data were collected on an SMART APEX
diffractometer. Elemental analysis was carried out at the SIOC analytical
center. All solvents were dried before use following standard proce-
dures. Unless otherwise indicated, all starting materials were obtained
from commercial suppliers and were used without further purification.
Analytical thin-layer chromatography (TLC) was performed on 0.2 mm
silica 60 coated on glass plates with F254 indicator. Compounds 23 was
prepared according to the reported method.8f Theoretical calculation
was performed with Gaussian 98 software on a Pentium III 866
computer.31
1
g, 93%). Mp 94-96 °C. H NMR (CDCl3): δ 7.70 (d, J ) 8.6 Hz,
2H), 7.27 (br, 1H), 6.93 (d, J ) 8.6 Hz, 2H), 4.00 (t, J ) 6.5 Hz, 2H),
3.05 (br, 2H), 1.80 (q, J ) 7.2 Hz, 2H), 1.46-1.27 (m, 18H), 0.89 (t,
J ) 6.4 Hz, 3H). EI-MS: m/z 320 [M+]. Anal. Calcd for C19H32O2N2:
C, 71.19; H, 10.08; N, 8.84. Found: C, 71.19; H, 9.88; N, 8.63.
Cyclohexane-1,1-dicarboxylic Acid N′,N′-Di(2-octyloxybenzoyl)-
hydrazide (2). To a stirred solution of compound 10 (1.76 g, 5.50
mmol) and triethylamine (1.00 mL, 10.0 mmol) in chloroform (50 mL)
was added dropwise a solution of compound 8 (0.57 g, 2.74 mmol) in
chloroform (10 mL) over 30 min at room temperature. Stirring was
continued for 24 h at room temperature. The solution was then washed
with dilute hydrochloric acid (2 N), water, and was dried over sodium
sulfate. After removal of the solvent, the resulting residue was purified
by column chromatography (CH2Cl2/EtOH 60:1) to afford compound
2 as a colorless solid (1.42 g, 67%). Mp 186-188 °C. 1H NMR
(CDCl3): δ 9.53 (s, 2H), 9.17 (s, 2H), 7.79 (d, 4H), 6.72 (d, 4H), 3.88
(t, 4H), 2.06 (s, 4H), 1.77-1.70 (m, 4H), 1.51 (s, 4H), 1.44-1.27 (m,
38H), 0.88 (t, 6H). ESI-MS: m/z 777 [M + H]+. IR (KBr): 3269,
N′,N′-(2-Octyloxybenzoyl) Carbonic Dihydrazide (1). To a solu-
tion of 2-octyloxybenzoic acid 316b (0.52 g, 2.10 mmol), carbohydrazide
4 (0.09 g, 1.00 mmol), and 1-hydroxybenzotriazole hydrate (HOBT)
(0.32 g, 2.30 mmol) in dichloromethane-water (30 mL, 2:1) cooled
in an ice-bath was added 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide hydrochloride (EDCI) (0.35 g, 2.30 mmol) with stirring. The
mixture was stirred for 1 h at 0 °C and then for 12 h at room
temperature. Dichloromethane (20 mL) was added, and the organic
phase was washed with aqueous hydrochloric acid (2 N, 20 mL),
saturated sodium bicarbonate solution (20 mL), water (20 mL), and
brine (20 mL), and was dried over sodium sulfate. Upon removal of
the solvent, the resulting residue was purified by column chromatog-
raphy (CH2Cl2/EtOH 60:1) to afford compound 1 (0.32 g, 60%) as a
colorless crystal. Mp 108-109 °C. 1H NMR (CDCl3): δ 9.99 (d, 2H),
8.48 (br, 2H), 8.16 (d, d, 2H), 7.45-7.40 (m, 2H), 7.03 (t, 2H), 6.94
(d, 2H), 4.11 (t, 4H), 1.95-1.88 (m, 4H), 1.47-1.25 (m, 20H), 0.85
2924, 1669, 1608, 1499, 1256, 844 cm-1
. Anal. Calcd for
C46H72O6N4: C, 71.08; H, 9.36; N, 7.21. Found: C, 71.03; H, 9.04; N,
6.96.
Pyridine-2-carboxylic Acid Hydrazide (14). This compound was
prepared as a white solid (95%) from pyridine-2-carboxylic acid methyl
ester 13 and hydrazine according to the procedure described for 10.
Mp 102-103 °C [lit.35 101 °C]. 1H NMR (CDCl3): 9.03 (br, 1H), 8.56-
8.53 (m, 1H), 8.17-8.14 (m, 1H), 7.87-7.82 (m, 1H), 7.45-7.41 (m,
1H), 4.09 (br, 2H). EI-MS: m/z 138 [M + H]+.
Cyclohexane-1,1-dicarboxylic Acid N′,N′-Di(pyridine-2-carbon-
yl)dihydrazide (11). This compound was prepared as a white solid
(72%) from the reaction of diacyl chloride 8 and hydrazide 14 according
to the procedure described for compound 2. Mp 210-212 °C. 1H NMR
(CDCl3): δ 9.89 (d, J ) 3.0 Hz, 2H), 9.37 (d, J ) 3.0 Hz, 2H), 8.55-
8.59 (m, 2H), 8.14-8.10 (m, 2H), 7.87-7.81 (m, 2H), 7.48-7.44 (m,
2H), 2.20-2.16 (m, 4H), 1.64-1.62 (m, 4H), 1.48-1.40 (m, 2H). EI-
MS: m/z 411 [M+ + H]. IR (KBr): 3332, 3162, 2945, 1701, 1652,
1507, 749 cm-1. Anal. Calcd for C20H22N6O4: C, 58.52; H, 5.41; N,
20.48. Found: C, 58.43; H, 5.40; N, 20.26.
(t, 6H). IR (KBr): 3333, 3180, 2926, 1629, 1479, 1233, 753 cm-1
.
ESI-MS: m/z 355 [M+ + H]. Anal. Calcd for C31H46O5N4: C, 67.11;
H, 8.37; N, 10.09. Found: C, 67.40; H, 7.99; N, 10.27.
Cyclohexane-1,1-dicarboxylic Acid Diethyl Ester (7). Diethyl
malonate 5 (24.0 g, 0.15 mol), 1,5-dibromoalkane 6 (34.5 g, 0.15 mol),
and sodium ethanolate (20.0 g, 0.33 mol) were reacted in dry ethanol
(150 mL) and worked up as described in the literature.32 After workup
and column chromatography (petroleum ether (60-90 °C)/AcOEt 10:
1), the title compound was obtained as a colorless oil (18.0 g, 53%).
1H NMR (CDCl3): δ 9.53 (s, 2H), 9.17 (s, 2H), 7.79 (d, J ) 6.4 Hz,
4H), 6.72 (d, J ) 6.4 Hz, 4H), 3.88 (t, J ) 5.9 Hz, 4H), 2.06 (s, 4H),
1.77-1.70 (m, 4H), 1.51 (s, 4H), 1.44-1.27 (m, 38H), 0.88 (t, J ) 5.
9 Hz, 6H). EI-MS: m/z 228 [M+].
2-Octyloxybenzoic Acid Hydrazide (16). This compound was
prepared as a white solid (98%) from the reaction of 2-octyloxybenzoic
acid methyl ester 1528c with hydrazine according to the procedure
1
described for 10. Mp 76 °C. H NMR (CDCl3): δ 9.06 (s, 1H), 8.21
(d, d, J ) 7.8 Hz, 2.1 Hz, 1H), 7.43 (t, d, J ) 7.7 Hz, 1.8 Hz, 1H),
7.07 (t, d, J ) 8.7 Hz, 0.9 Hz, 1H), 6.96 (d, J ) 7.8 Hz, 1H), 4.12 (t,
J ) 6.6 Hz, 2H), 3.90 (br, 2H), 1.91-1.84 (m, 2H), 1.50-1.26 (m,
10H), 0.87 (t, J ) 6.9 Hz, 3H). EI-MS: m/z 265 [M+ + H].
Cyclohexane-1,1-dicarboxylic Acid N′,N′-Di(2-octyloxycarbon-
ylbenzoyl)dihydrazide (12). This compound was prepared as a white
solid in 55% yield from 8 and 16 according to the procedure described
for compound 1. Mp 136-137 °C. 1H NMR (CDCl3): δ 10.66 (d, J )
(31) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98; Gaussian, Inc.: Pittsburgh,
PA, 1998.
(33) Dmowski, W.; Wolniewicz, A. J. Fluorine Chem. 2000, 102, 141.
(34) Lesac, A.; Moslavac-Forjan, D.; Bruce, D. W.; Sunjic, V. HelV. Chim. Acta
1999, 82, 1707.
(35) Teotia, M. P.; Gurtu, J. N.; Rana, V. B. Indian J. Chem., Sect. A 1981, 20,
(32) Bergson, L. G.; Biezais, A. Ark. Kemi 1964, 22, 475.
520.
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Hydrazide-Based Hydrogen-Bonded Heterodimers
A R T I C L E S
6.6 Hz, 2H), 9.57 (d, J ) 6.0 Hz, 2H), 8.19 (d,d, J ) 8.1 Hz, 1.5 Hz,
2H), 7.44 (t, J ) 7.2 Hz, 2H), 7.06 (t, J ) 8.1 Hz, 2H), 6.98 (d, J )
8.1 Hz, 2H), 4.17 (t, J ) 6.6 Hz, 4 Hz), 2.18 (t, J ) 5.4 Hz, 4H),
2.03-1.98 (m, 4H), 1.66 (s, 4H), 1.54-1.27 (m, 22H), 0.86 (t, J )
6.9 Hz, 6H). IR (KBr): 3368, 2926, 1701, 1658, 1625, 1469, 1232,
755 cm-1. ESI-MS: m/z 665 [M+ + H]. Anal. Calcd for C28H56N4O6:
C, 68.63; H, 8.51; N, 8.43. Found: C, 68.75; H, 8.56; N, 8.46.
N′,N′-(2-Fluorobenzoyl) Carbonic Dihydrazide (17). This com-
pound was prepared as a white solid (75%) from the reaction of 4 and
18 according to the procedure described for compound 1. Mp 190-
191 °C. 1H NMR (CDCl3): δ 8.82 (d, J ) 11.4 Hz, 2H), 8.36 (s, 2H),
8.00 (t, J ) 7.8 Hz, 2H), 7.50-7.43 (m, 2H), 7.20 (t, J ) 7.5 Hz, 2H),
7.11-7.04 (m, 2H). EI-MS: m/z 334 [M+]. IR (KBr): 3321, 1661,
1479, 1274, 758 cm-1. Anal. Calcd for C15H12F2N4O3: C, 53.89; H,
3.63; N, 16.76. Found: C, 53.80; H, 3.67; N, 17.13.
2-Fluoroisophthalic Acid (21). A suspension of 2-fluoro-m-xylene
20 (0.50 g, 4.00 mmol), cetyltrimethylammonium bromide (0.10 g),
and potassium permanganate (2.50 g, 16.0 mmol) in water (25 mL)
was heated under reflux for 3 h. The mixture was cooled to room
temperature, and the solid was filtered off and washed with water (10
mL). The filtrate was acidified with concentrated hydrochloric acid to
pH ) 5. The resulting precipitate was filtered, washed with water (3
× 10 mL), and dried to give the title compound as a white solid (0.30
g, 41%). Mp > 250 °C. 1H NMR (DMSO-d6): δ 13.49 (br, 2H), 8.04
(t, J ) 6.9 Hz, 2H), 7.38 (t, J ) 8.4 Hz, 1H). EI-MS: m/z 184 [M+].
Anal. Calcd for C8H5FO4: C, 52.18; H, 2.74. Found: C, 52.26; H,
3.08.
2-Fluoroisophthalic Acid Monooctyl Ester (22). To a solution of
compound 21 (0.73 g, 3.80 mmol) and n-octanol (5 mL) in THF (20
mL) was added dropwise concentrated H2SO4 (0.3 mL) under stirring
at room temperature. The solution was heated under reflux for 24 h
and then cooled to room temperature. Dichloromethane (50 mL) was
added, and the organic phase was washed with water (3 × 30 mL),
brine (30 mL), and was then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure to give an oily residue,
which was purified by column chromatography (CH2Cl2/EtOH 20:1).
The title compound was obtained as a white solid (0.57 g, 49%). Mp
92-93 °C. 1H NMR (CDCl3): δ 8.20-8.15 (m, 2H), 7.32 (t, J ) 7.8
Hz, 1H), 4.36 (t, J ) 6.9 Hz, 2H), 1.80-1.75 (m, 2H), 1.44-1.28 (m,
10H), 0.87 (t, J ) 6.3 Hz, 3H). EI-MS: m/z 296 [M+]. Anal. Calcd
for C16H21FO4: C, 64.84; H, 7.16. Found: C, 64.80; H, 7.29.
N′,N′-(3-Octyloxycarbonyl-2-fluorobenzoyl) Carbonic Dihy-
drazide (19). This compound was prepared as a white solid (78%)
from the reaction of compounds 8 and 22 following the procedure
described above for preparing 1. Mp 122-123 °C. 1H NMR (CDCl3):
δ 9.11 (d, J ) 9.6 Hz, 2H), 8.69 (s, 2H), 8.10-8.04 (m, 2H), 7.96-
7.91 (m, 2H), 7.18 (t, J ) 7.5 Hz, 2H), 4.25 (t, J ) 6.9 Hz, 4H), 1.73-
1.64 (m, 4H), 1.40-1.26 (m, 20H), 0.86 (t, J ) 6.6 Hz, 6H). ESI-MS:
m/z 669.3 [M+ + Na]. Anal. Calcd for C33H44F2N4O7: C, 61.27; H,
6.87; N, 8.66. Found: C, 61.35; H, 6.92; N, 8.71.
column chromatography (MeOH/CH2Cl2 1:25) to afford 19 as a white
solid (0.50 g, 14%). Mp 173-175 °C. 1H NMR (DMSO-d6): δ 11.20
(s, 1H), 9.76 (s, 1H), 8.78 (s, 1H), 8.33 (s, 1H), 7.69 (s, 1H), 7.22-
7.24 (m, 1H), 3.17-3.20 (m, 2H), 1.42-1.44 (m, 2H), 1.22-1.27 (m,
10H), 0.82 (t, J ) 5.5 Hz, 3H). FAB-MS: m/z 318 [M+ + H]. Anal.
Calcd for C16H23N5O2: C, 60.55; H, 7.30; N, 22.07. Found: C, 60.35;
H, 7.21; N, 21.88.
1-(6-Methyl-4-oxo-1,4-dihydropyrimidin-2-yl)-3-octylurea (25). A
suspension of 2-amino-4-hydroxy-6-methylpyrimidine (0.50 g, 0.40
mmol) and n-octyl isocyanate (0.62 g, 0.40 mmol) in THF (120 mL)
was heated at 90 °C for 48 h. The solvent was then removed, and the
resulting residue was washed thoroughly with cooled ether to give a
solid, which was subjected to flash chromatography (CH2Cl2/MeOH
10:1) to afford compound 25 (1.08 g, 97%) as a white solid. Mp 171-
173 °C. 1H NMR: δ 13.14 (s, 1H), 11.85 (s, 1H), 10.13 (s, 1H), 5.81
(s, 1H), 3.20-3.26 (m, 2H), 2.22 (s, 3H), 1.54-1.61 (m, 2H), 1.25-
1.30 (m, 10H), 0.86 (t, J ) 6.6 Hz, 3H). EI-MS: m/z 280 [M+]. Anal.
Calcd for C14H24N4O2: C, 59.98; H, 8.63; N, 19.98. Found: C, 59.84;
H, 8.60; N, 19.97.
1H NMR Binding Studies. All 1H NMR binding studies were carried
out at 25 °C. CDCl3 used in binding studies was passed though a short
column of dry, activated basic alumina prior to use. Volumetric flasks
and syringes used in preparing solutions were washed with dried
dichloromethane and dried in a vacuum before use. Samples (usually
0.6 mL) were prepared from stock solutions, transferred to the NMR
tubes, and diluted accordingly with syringes. For one series, usually
13-20 samples were prepared, and binding constants reported typically
are averages of two experiments, which were obtained by fitting
chemical shift change data to 1:1 binding isotherms with standard
nonlinear curve-fitting procedures.17 The nonlinear equations were
derived from mass-balance equations and the relationship between the
concentrations of free and complexed samples and the weighted
chemical shifts under the condition of rapid exchange.17 The data were
obtained with 400 or 600 MHz (for samples of dilute concentration)
spectrometers.
X-ray Data. Compound 1 was crystallized from chloroform by slow
evaporation of solvent at room temperature. Crystal size, 0.423 × 0.347
× 0.128 mm; space group, P-1 (triclinic); unit cell dimensions, a )
9.3928(13) Å, b ) 9.5527(14) Å, c ) 18.941(3) Å, R ) 76.966(3)°, â
) 78.834(3)°, γ ) 74.785(3)°; volume, 1581.3(4) (Å)3.
Acknowledgment. We thank the Ministry of Science and
Technology (G2000078100), the Natural Science Foundation
of China (90206005, 20172069), State Laboratory of Bio-
Organic Chemistry and Natural Products, and the Chinese
Academy of Sciences for support of this work. We also thank
Professors Ji-Liang Shi and Min Shi for beneficial discussions.
Supporting Information Available: (Partial) 2D-NOESY
spectra (400 MHz) of heterodimers 1‚2, 1‚11, 1‚12, 19‚2, 19‚
11, 19‚12, 1‚23, and 19‚23 in CDCl3, scheme of the thermo-
dynamic cycle for the calculation of the binding constant of
complex 23‚25, and X-ray crystallographic data for 1 (PDF and
CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
1-Octyl-3-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)urea (24).
A suspension of 2-amino-3H-pyrido[2,3-d]pyrimidin-4-one36 (2.00 g,
12.4 mmol) and n-octyl isocyanate (2.0 mL, 12.4 mmol) in THF (200
mL) was stirred under reflux for 6 days, and the solvent was then
removed under reduced pressure. The resulting residue was washed
thoroughly with petroleum ether (30-60 °C) and then purified by
(36) Ivery, M. T. G.; Gready, J. E. J. Heterocycl. Chem. 1994, 31, 1385.
JA037312X
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