Self-assembly with degenerate prototropy

Article abstract of DOI:10.1021/jo0508705

This work describes a rational approach for addressing the prototropy-related problems in heterocycle-based self-assembling systems by the use of degenerate prototropy, As a proof of principle, the utility of degenerate prototropy is demonstrated herein b

Full text of DOI:10.1021/jo0508705

Self-Assembly with Degenerate Prototropy
Pranjal K. Baruah,† Rajesh Gonnade,‡ Usha D. Phalgune,§ and Gangadhar J. Sanjayan*,†
Division of Organic Synthesis, Central Material Characterization Division, and Central NMR Facility,
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
sanjayan@ems.ncl.res.in
Received April 29, 2005
This work describes a rational approach for addressing the prototropy-related problems in
heterocycle-based self-assembling systems by the use of degenerate prototropy. As a proof of principle,
the utility of degenerate prototropy is demonstrated herein by developing heterocycle-based AADD-
type self-assembling modules that exist as “single set of protameric pair (duplex)” in both solution
and solid states. These self-assembling modules are quickly accessible in good yield by reacting
2-amino-5,5-disubstituted-1H-pyrimidine-4,6-diones, available in one step by the condensation of
R,R-dialkyl malonates and free guanidine, with isocyanates. Evidence from NMR spectroscopy, ESI
mass spectrometry, and single-crystal X-ray diffraction studies confirmed the formation of molecular
duplexes. The effect of electronic repulsion in duplex formation is also investigated. Their ready
synthetic accessibility, remarkably high propensity to crystal formation, and the novel property of
degenerate prototropy would make these novel self-assembling molecules promising candidates for
many proposed applications.
Introduction
smaller molecular components to generate supramolecu-
lar ensembles with predefined structural features. To
further enhance the strength, directionality, and specific-
ity of hydrogen bonding interactions, there is currently
intense research interest in designing self-assembling
molecules having arrays of hydrogen bond donor (D) and
acceptor (A) sites.4,5 Among various such self-assembling
modules reported thus far, heterocycle-based AADD-type
self-complementary systems have ushered into promi-
Self-assembly, a process that creates structures through
a statistical exploration of many possibilities, has emerged
as a powerful tool for the construction of novel supramo-
lecular architectures and nanomaterials with remarkable
structural diversity and applications.1-3 Owing to the
directionality and specificity, hydrogen bonds are par-
ticularly useful for the programmed self-assembly of
† Division of Organic Synthesis.
(2) (a) Zhang, W.; Liao, S. S.; Cui, F. Z. Chem. Mater. 2003, 15,
3221-3226. (b) Erma, S.; Hauck, T.; El-Khouly, M. E.; Padmawar, P.
A.; Canteenwala, T.; Pritzker, K.; Ito, O.; Chiang, L. Y. Langmuir 2005,
21, 3267-3272. (c) Hu, W.; Nakashima, H.; Furukawa, K.; Kashimura,
Y.; Ajito, K.; Liu, Y.; Zhu, D.; Torimitsu, K. J. Am. Chem. Soc. 2005,
127, 2804-2805. (d) Tsonchev, S.; Schatz, G. C.; Ratner, M. A. J. Phys.
Chem. B 2004, 108, 8817-8822.
(3) (a) Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991,
254, 1312-1319. (b) Hummer, G.; Garde, S.; Garcia, A. E.; Paulaitis,
M. E.; Pratt, L. R. J. Phys. Chem. B 1998, 102, 10469-10482. (c)
Bowden, N.; Choi, I. S.; Grzybowski, B. A.; Whitesides, G. M. J. Am.
Chem. Soc. 1999, 121, 5373-5391. (d) Bowden, N.; Terfort, A.; Carbeck,
J.; Whitesides, G. M. Science 1997, 276, 233-235. (e) Wu, H.; Bowden,
N.; Whitesides, G. M. Appl. Phys. Lett. 1999, 75, 3222-3224. (f) Choi,
I. S.; Bowden, N.; Whitesides, G. M. Angew. Chem., Int. Ed. 1999, 38,
3078-3081.
‡ Central Material Characterization Division.
§ Central NMR Facility.
(1) (a) Lehn, J.-M. Supramolecular Chemistry: Concepts and Per-
spectives; VCH: Weinheim, Germany, 1995. (b) Steed, J. W.; Atwood,
J. L. Supramolecular Chemistry; Wiley: New York, 2000. (c) White-
sides, G. M.; Grzybowski, B. Science 2002, 295, 2418-2421. (d) Bushey,
M. L.; Nguyen, T.-Q.; Zhang, W.; Horoszewski, D.; Nuckolls, C. Angew.
Chem., Int. Ed. 2004, 43, 5446-5453. (e) Conn, M. M.; Rebek, J., Jr.
Chem. Rev. 1997, 97, 1647-1668. (f) Lindsey, J. S. New J. Chem. 1991,
15, 153-180. (g) Fredericks, J. R.; Hamilton, A. D. In Comprehensive
Supramolecular Chemistry; Sauvage, J.-P., Hosseini, M. W., Eds.;
Pergamon Press: Oxford, 1996; Vol. IX, Chapter 16. (h) Hill, D. J.;
Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001,
101, 3893-4011. (i) Sessler, J. L.; Jayawickramarajah, J. Chem.
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10.1021/jo0508705 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/09/2005
J. Org. Chem. 2005, 70, 6461-6467
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Baruah et al.
nence primarily due to their relatively high dimerization
constants coupled with ready synthetic accessibility. Of
particular interest are the dimers of AADD-type self-
complementary arrays, developed independently by
Meijer’s6 and Zimmerman’s7 groups, that are stable in
nonpolar solvents in a wide concentration range, making
them excellent building blocks for supramolecular archi-
tectures and polymers.8 However, the generality of self-
assembling systems based on rigid heterocycles is some-
times complicated by prototropy9 that is often associated
with heterocycles. Furthermore, the supramolecular
polymers derived from such prototropy-prone heterocycle-
based self-assembling modules can exist in multiple
prototropic forms, rendering their structural studies
tricky.10
FIGURE 1. Degenerate prototropy in imidazole.
Here we introduce for the first time the use of degener-
ate prototropy as a means to develop heterocycle-based
self-assembling systems free of prototropy-related prob-
lems. As a proof of principle, the utility of degenerate
prototropy is demonstrated herein by developing hetero-
cycle-based AADD-type self-assembling modules that
exist as a single set of protameric pair (duplex) in both
solution and solid states. The strategy disclosed herein
has the potential for significantly augmenting the “tool
box” of the modern day supramolecular chemist, as well
as providing a novel approach to the field of rational
design using the concept of degenerate prototropy.
(4) For excellent reviews, see: (a) Brunsveld, L.; Folmer, B. J. B.;
Meijer, E. W.; Sijbesma, R. P. Chem. Rev. 2001, 101, 4071-4097. (b)
Sijbesma, R. P.; Meijer, E. W. Chem. Commun. 2003, 5-16. (c)
Zimmerman, S. C.; Corbin, P. S. Struct. Bonding (Berlin) 2000, 96,
63-94. (d) Schmuck, C.; Wienand, W. Angew. Chem., Int. Ed. 2001,
40, 4363-4369.
(5) (a) Yang, X.; Gong, B. Angew. Chem., Int. Ed. 2005, 44, 1352-
1356. (b) Yang, X.; Hua, F.; Yamato, K.; Ruckenstein, E.; Gong, B.;
Kim, W.; Ryu, C. Y. Angew. Chem., Int. Ed. 2004, 43, 6471-6474. (c)
Schmuck, C.; Wienand, W. J. Am. Chem. Soc. 2003, 125, 452-459. (d)
Schmuck, C. Chem.-Eur. J. 2000, 6, 709-718. (e) Schmuck, C.; Geiger,
L. J. Am. Chem. Soc. 2004, 126, 8898-8899. (f) Zeng, H.; Yang, X.;
Brown, A. L.; Martinovic, S.; Smith, R. D.; Gong, B. Chem. Commun.
2003, 1556-1557. (g) Zhao, X.; Wang, X.-Z.; Jiang, X.-K.; Chen, Y.-Q.;
Li, Z. -T.; Chen, G.-J. J. Am. Chem. Soc. 2003, 125, 15128-15139. (h)
Davis, A. P.; Draper, S. M.; Dunnea, G.; Ashtonb, P. Chem. Commun.
1999, 2265-2266. (i) Lu¨ning, U.; Ku¨hl, C.; Uphoff, A. Eur. J. Org.
Chem. 2002, 4063-4070.
(6) (a) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.;
Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761-6769. (b) Cate, A.
T.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. J. Am.
Chem. Soc. 2004, 126, 3801-3808. (c) Ligthart, G. B. W. L.; Ohkawa,
H.; Sijbesma, R. P.; Meijer, E. W. J. Am. Chem. Soc. 2005, 127, 810-
811 and references therein.
(7) (a) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998,
120, 9710-9711. (b) Corbin, P. S.; Lawless, L. J.; Li, Z.; Ma, Y.; Witmer,
M. J.; Zimmerman, S. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5099-
5104.
(8) Meijer’s ureidopyrimidinone self-assembling modules have been
extensively used for supramolecular polymer synthesis. See: (a)
Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.;
Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W.
Science 1997, 278, 1601-1604. (b) Hirschberg, J. H. K. K.; Beijer, F.
H.; van Aert, H. A.; Magusin, P. C. M. M.; Sijbesma, R. P.; Meijer, E.
W. Macromolecules 1999, 32, 2696-2705. (c) Folmer, B. J. B.; Sijbesma,
R. P.; Versteegen, R. M.; van der Rijt, J. A. J.; Meijer, E. W. Adv. Mater.
2000, 12, 874-878.
(9) Due to prototropy, Zimmerman’s pyrido-pyrimidinone-based self-
assembling system exists in as many as four protamers (see ref 7a),
and Meijer’s ureidopyrimidinone has been shown to display mainly
two types of protamer formation, depending upon the substitution
pattern on the heterocyclic ring (see ref 6a).
FIGURE 2. Degenerate prototropy in 1. Block arrows indicate
rotation (180°) of urea moiety about the bond connecting the
heterocycle.
Design Principles. Degenerate prototropy, also known
as degenerate tautomerism, is a phenomenon by which
annular prototropic shift regenerates the same structure
due to the chemical equivalence of the protamers.11 One
of the simplest systems that exhibit degenerate proto-
tropy is imidazole wherein both the protamers, formed
by 1,3-annular prototropic shift, are rendered equivalent
by prototropic degeneracy (Figure 1).
Though a number of systems have been shown to
exhibit this fascinating phenomenon,12 its utility as a
nifty concept in the rational design of novel systems
largely remains unexplored. To tackle the multiple prota-
mer formations in heterocycle-based AADD-type self-
assembling systems, we designed the urea construct 1
(Figure 2).
The design principles were based on the observation
that 1,3 annular prototropic shift in heterocycles such
as imidazole results in prototropic degeneracy due to the
chemical equivalence of the protamers. It was anticipated
that acylation of the amidino urea moiety with a sym-
metrical bis-acyl unit, as in 1, should provide the mole-
cule sufficient room for degenerate prototropy. In the
urea construct 1, the amidino urea moiety is tethered to
an R,R-disubstituted malonyl unit such that annular 1,3
(11) Elguero, J.; Marzin, C.; Katritzky, A. R.; Linda, P. The Tau-
tomerism of Heterocycles: Advances in Heterocyclic Chemistry; Aca-
demic Press: New York, 1976.
(10) The tautomeric rearrangement of supramolecular polymers
having ureidopyrimidinone self-assembling modules had been inves-
tigated by 1H DQ NMR spectroscopy under fast MAS conditions. See:
Schnell, I.; Langer, B.; Sontjens, S. H. M.; Sijbesma, R. P.; van
Genderen, M. H. P.; Spiess, H. W. Phys. Chem. Chem. Phys. 2002, 4,
3750-3758.
(12) (a) Komber, H.; Limbach, H. H.; Boehme, F.; Kunert, C. J. Am.
Chem. Soc. 2002, 124, 11955-11963. (b) Maki, J.; Klika, K. D.; Sjoholm,
R.; Kronberg, L. J. Chem. Soc., Perkin Trans. 1 2001, 1216-1219. (c)
Thoburn, J. D.; Luettke, W.; Benedict, C.; Limbach, H. H. J. Am. Chem.
Soc. 1996, 118, 12459-12460. (d) Helaja, J.; Montforts, F. P.; Kil-
pelaeinen, I.; Hynninen, P. H. J. Org. Chem. 1999, 64, 432-437.
6462 J. Org. Chem., Vol. 70, No. 16, 2005

Self-Assembly with Degenerate Prototropy
SCHEME 1. Synthesis of 1a-ea
a Reagents and conditions: (i) NaOEt, EtOH, guanidine HCl, reflux, 4h. (ii) R2NCO, pyridine, 90-100 °C, 2h. (iii) H2/Pd-C (10%).
FIGURE 3. 1H [top (500 MHz)] and 13C [bottom (125 MHz)] NMR spectra of 1a in CDCl3 showing single set of well-resolved
signals.
prototropic shift, accompanied by the 180° rotation of the
urea moiety13 about the bond connecting the heterocyclic
ring, would result in prototropic degeneracy, since the
protamers would be, in all respects, equivalent. Thus, the
dimerization of 1 can be expected to lead to only a single
set of hydrogen-bonded duplex. Structural studies, vide
infra, indeed showed that 1 forms only a single set of
molecular duplex 1.1 in both solution and solid states.
gates.15 1H and 13C NMR (500 and 125 MHz, respectively)
spectra of 1a in CDCl3 show a single set of well-resolved
signals16 (Figure 3).
The significant downfield NH chemical shifts were
indicative of strong hydrogen-bonding interactions in
solution. Both urea NH signals of 1a, appearing at 9.24
and 11.38 ppm, showed concentration-dependent changes
in their chemical shifts, supporting their role in forming
intermolecular hydrogen bonding. The NH group (12.74
ppm) involved in the formation of the intramolecular S(6)
ring17 that pre-fixes the linear AADD hydrogen-bonding
array showed an insignificant concentration-dependent
shift. 1H NMR binding studies,18 in the concentration
range of 100-0.5 mM range, gave the dimerization
constant (Kdim) 1.2 × 104 M-1 for 1a in CDCl3.19
Results and Discussion
Urea construct 1 is quickly accessible in good yield by
reacting 2-amino-5,5-disubstituted-1H-pyrimidine-4,6-di-
ones, available in one step by the condensation of R,R-
dialkyl malonates and free guanidine,14 with isocyanates
in pyridine (Scheme 1).
Contrary to its precursors, 1 was highly soluble in
nonpolar organic solvents including petroleum ether
(.100 mM in petroleum ether) at ambient temperature.
This observation suggested that the polar hydrogen-
bonding groups of 1 were strongly protected by dimer-
ization, preventing the formation of polymeric aggre-
(15) (a) Similar observation has been reported by Whitesides’s group
for the solubility of hydrogen-bonded aggregates: Mathias, J. P.;
Simanek, E. E.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116, 4326-
4340. (b) For the use of hydrogen bonds to control molecular aggrega-
tion, see also: Simard, M.; Su, D.; Wuest, J. D. J. Am. Chem. Soc.
1991, 113, 4696-4698.
(16) Separate sets of NMR signals become evident if more than one
protamer exists in solution; see refs 6a and 7a.
(13) The amide bond prefers trans geometry. See: Katrizky, A. R.;
Ghiviriga, I. J. Chem. Soc., Perkin Trans. 2 1995, 1651-1653.
(14) Lehn, J.-M.; Mascal, M.; DeCian, A.; Fischer, J. J. Chem. Soc.,
Perkin Trans. 2 1992, 461-467.
(17) Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126.
(18) Wilcox, C. S. In Frontiers in Supramolecular Chemistry and
Photochemistry; Schneider, H. J., Durr, H., Eds.; VCH: Weinheim,
Germany, 1990; pp 123-144.
J. Org. Chem, Vol. 70, No. 16, 2005 6463

Baruah et al.
solid state, maintaining similar hydrogen-bonding codes.25
The dimers are held together by four C(4)-type17 inter-
molecular hydrogen bonds between self-complementary
AADD-type linear hydrogen-bonding arrays.
The urea functionality is in a trans-trans geometry,
as expected, and an intramolecular S(6)-type17 hydrogen
bond bridges the pyrimidine N-H to the urea carbonyl
group that preorganizes the AADD array of hydrogen
bonding sites. In all the cases, the AADD array deviates
slightly from linearity, the outer N-H‚‚‚O hydrogen
bonds being somewhat shorter than the inner N-H‚‚‚N
hydrogen bonds.
Interestingly, the dimer 1.1a forms self-assembled
infinite chains of helical nature (Figure 6) through a
relatively weaker bifurcated intermolecular hydrogen
bonding involving the pyrimidine ring N-H and the
remaining carbonyl group of another molecule forming
an eight-membered ring hydrogen-bonded network, al-
though similar arrangement is not observed in 1.1b and
1.1c. The eight-membered ring hydrogen-bonded net-
work, formed by the self-assembly of the duplexes, is
FIGURE 4. ESI mass spectrum of 1a.
ESI mass spectrometry is an effective tool in investi-
gating the formation of hydrogen-bonded molecular self-
assemblies. The formation of discrete dimers 1.1 was
further confirmed by ESI mass spectrometry. In addition
to the molecular ion peaks (MH+) ascribable due to the
monomers 1, the ESI spectrum (Figure 4) showed sizable
peaks corresponding to the dimers 1.1 (M2H+).
characterized by the graph set R2 (8).17 The bifurcated
2
hydrogen bonds in the extended self-assembled network
of 1.1a are relatively weaker because the D-H‚‚‚A
distances are longer [d(H‚‚‚O) ) 2.464 and 2.526 Å].
Although a highly symmetrical pattern of hydrogen
bonding is maintained in 1b, a similar trend is absent
in 1a and 1c. Notably, in 1.1c, the hydrogen-bonding
arrays are considerably forced out of plane presumably
due to the steric clash between benzyl and isobutyl
substituents, though such an interaction does not prevent
dimer formation.
Effect of Electronic Hindrance in Duplex Forma-
tion. Substituents are known to play a crucial role in
dictating the mode of association of self-assembling
systems, either through steric hindrance27 or through
hyperconjugation effects.6a Whitesides et al. have cleverly
made use of steric hindrance as a major driving force in
specifically obtaining cyclic rosette, tape, or crinkled tape
self-assembled structures using the melamine-cyanuric
acid self-assembling motifs.27 In an effort to evaluate the
influence of electronic hindrance in duplex formation, we
designed and synthesized the self-complementary motif
1e, having an o-carboxymethyl phenyl substituent teth-
ered to the urea moiety. 1e was highly soluble in nonpolar
organic solvents, suggesting that the protons were solvent-
shielded. Observation of 2M+ peak in the ESI mass
spectrum also strongly suggested the dimer formation
(see Supporting Information).
An interesting property associated with the self-
assembling systems reported herein is their remarkably
high propensity to easily crystallize into large crystals
under ambient conditions, presumably as a consequence
of the intrinsic nature of rigid R,R-dialkylated systems
to efficiently pack into crystalline lattices.20 It is note-
worthy that hydrogen-bonded self-assembling systems
usually show a poor tendency to crystallize under ordi-
nary conditions, presumably due to their inefficient
packing in crystalline lattices.21 This has prompted
researchers to utilize drastic conditions to crystallize self-
assembling organic systems, using high pressure and
temperature,22 a condition routinely used for crystallizing
quartz, zeolites, and inorganic open-frame structures.23
The solid-state structures of 1a-c were determined by
single-crystal X-ray diffraction24 (Figure 5). Comparison
of the X-ray structures of 1a-c reveals the following
facts. All three compounds, irrespective of the nature of
substituents, form centrosymmetric dimers 1.1 in the
(19) This value is relatively low when compared to the dimerization
constant (Kdim) of Meijer’s AADD-type ureidopyrimidinones containing
a heterocyclic aromatic unit that is in keto-enol tautomeric equilibrium
(see ref 6a). The relatively low Kdim of the present system is presumably
due to the absence of π-electron density in the heterocyclic ring that
could have positively contributed to the duplex stability as in ureido-
pyrimidinones. For a related example, see: Lafitte, V. G. H.; Aliev, A.
E.; Hailes, H. C.; Bala, K.; Golding, P. J. Org. Chem. 2005, 70, 2701-
2707.
(20) Karle, I. L. Acta Crystallogr., Sect. B 1992, 48, 341-356.
(21) Comprehensive Supramolecular Chemistry; Atwood, J. L.,
Davies, J. E. D., MacNicol, D. D., Vogtle, F., Eds.; Pergamon Press:
Oxford, 1996; Vol. 9, pp 671-700.
In stark contrast to such findings, surprisingly, the
duplex formation through quadruple intermolecular hy-
drogen bonding could not be observed in the solid state
as unambiguously confirmed by single-crystal X-ray
studies. Instead of dimerization, 1e formed an extended
sheetlike structure through intermolecular hydrogen
bonding (Figure 7). Analysis of the single-crystal struc-
ture of 1e revealed the presence of two intramolecular
(22) Ranganathan, A.; Pedireddi, V. R.; Rao, C. N. R. J. Am. Chem.
Soc. 1999, 121, 1752-1753.
(23) Rao, C. N. R. Chemical Approaches to the Synthesis of Inorganic
Materials; Wiley: New York, 1993.
(24) The crystal structures of 1a-c,e were solved by direct method
using SHELXS-97, and the refinement was performed by full matrix
least squares of F2 using SHELXL-97 (Sheldrick, G. M. SHELX-97,
program for crystal structure solution and refinement; University of
Go¨ttingen: Go¨ttingen, Germany, 1997). Hydrogen atoms were included
in the refinement as per the riding model. CIF files are available in
Supporting Information.
(25) Substituents can influence the mode of hydrogen bonding
(hydrogen-bonding codes) in dimer formation; see ref 6a.
(26) Delano, W. L. The PyMOL Molecular Graphics System;
http://www.pymol.org, 2004.
(27) 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,
37-44.
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Self-Assembly with Degenerate Prototropy
FIGURE 5. Single-crystal X-ray structures of dimers 1.1a (left), 1.1b (middle), and 1.1c (right). Hydrogen bonding is highlighted
in dashes (salmon colored), above which hydrogen bond distances (NH‚‚‚N and NH‚‚‚O) are displayed in Å. All hydrogens, other
than those at the hydrogen-bonding sites, have been deleted for clarity. This figure was made using PyMOL.26
FIGURE 6. Further self-assembly of 1.1a, both capped stick
(left) and sphere (right) representations, showing infinite
chains of helical nature. All hydrogens have been deleted for
clarity in the sphere representation. This figure was made
using PyMOL.26
hydrogen bonding within the molecule, as expected.
Interestingly, unlike in 1a-c, the AADD-type hydrogen-
FIGURE 7. Single-crystal X-ray structure of 1e showing self-
bonding linear array is nonexistent in 1e. The nonfor-
assembly, through intermolecular hydrogen bonding, forming
mation of duplex 1.1e is presumably due to the unfavor-
one-dimensional sheetlike network. This figure was made
using PyMOL.26
able electronic repulsion that would have resulted by the
close proximity of the anthranilic acid carbonyls and the
heterocyclic carbonyls in the duplex 1.1e.
constructs free of multiple protamers. Our unique design
strategy has allowed for an added dimension in the self-
assembled H-bonded molecular duplexes reported herein,
drawing a stark distinction between itself and previously
known systems having similar hydrogen bonding codes.6,7
Their ready synthetic accessibility coupled with the novel
property of degenerate prototropy and the great ease of
crystal formation would make these novel self-assembling
molecules promising candidates for many proposed ap-
Summary
In summary, this article describes a rational approach
for addressing the prototropy-related problems in het-
erocycle-based self-assembling systems by the use of
degenerate prototropy. As a proof of principle, we dem-
onstrated herein the utility of degenerate prototropy in
designing heterocycle-based AADD-type self-assembling
J. Org. Chem, Vol. 70, No. 16, 2005 6465

Baruah et al.
1695, 1649, 1485, 1390; 1H NMR (Na salt) (300 MHz, D2O): δ
5.49-5.35 (m, 2H), 4.91 (t, 4H, J ) 8.7 Hz), 2.43 (d, 4H, J )
6.4 Hz); 13C NMR (Na salt) (75 MHz, D2O): δ 200.8, 182.9,
145.8, 131.3, 68.1, 55.3; ESI Mass: 208.05 (M + 1); Anal. Calcd
for C10H13N3O2: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.67;
H, 6.53; N, 20.11.
plications. We are currently probing their utility for the
construction of supramolecular polymers and will report
the results in due course.
Experimental Section
2-Amino-5,5-dibenzyl-1H-pyrimidine-4,6-dione 2b. Fol-
lowing the similar procedure for the synthesis of 2a and using
R,R-dibenzyl-malonic acid diethyl ester (15.02 g, 44.1 mmol),
2b was synthesized which was purified by crystallization from
aqueous DMSO (8.7 g, 64%). mp > 260 °C; IR (Nujol) ν (cm-1):
3240, 3197, 2923, 2854, 1689, 1454, 1384; 1H NMR (500 MHz,
DMSO-d6): δ 10.44 (s, 1H), 7.21-7.02 (m, 12H), 3.18 (s, 4H);
13C NMR (125 MHz, DMSO-d6): δ 177.1, 157.2, 136.4, 129.5,
128.2, 126.9, 59.0, 44.5; ESI Mass: 308.04 (M + 1); Anal. Calcd
for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67. Found: C, 69.97;
H, 5.74; N, 13.69.
Single-Crystal X-ray Crystallographic Studies. The
X-ray data of 1a-c,e were collected on a SMART APEX CCD
diffractometer with ω and æ scan mode, λ MoKR ) 0.71073 Å at
T ) 133(2) K. All the data were corrected for Lorentzian,
polarization, and absorption effects using the SAINT and
SADABS programs. The crystal structures of 1a-c,e were
solved by direct method using SHELXS-97, and the refinement
was performed by full matrix least squares of F2 using
SHELXL-9724. Hydrogen atoms were included in the refine-
ment as per the riding model.
Crystal data for 1a (C15H22N4O3): M ) 306.37, crystal
dimensions 0.75 × 0.65 × 0.25 mm3, triclinic, space group P1h,
a ) 13.5798(18), b ) 14.1602(19), c ) 17.503(2) Å, R )
91.381(2)°, â ) 94.924(2)°, γ ) 98.849(2)°, V ) 3311.0(8) Å3,
Z ) 8; Fcalcd ) 1.229 gcm-3, µ(Mo KR) ) 0.087 mm-1, F(000) )
1312, 2θmax ) 50.00°, 31 720 reflections collected, 11 607
unique, 9602 observed (I > 2σ(I)) reflections, 827 refined
parameters, R value 0.0440, wR2 ) 0.1146 (all data R )
0.0537, wR2 ) 0.1216), S ) 1.051, minimum and maximum
transmission 0.9373 and 0.9785, respectively, maximum and
1-(5,5-Diallyl-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-
yl)-3-isobutyl-urea 1a. To a stirred solution of dry dichloro-
methane (10 mL) at 0 °C containing triphosgene (2.71 g, 9.1
mmol, 0.63 equiv) was added a mixture of isobutylamine (2.61
mL, 26.1 mmol, 1.8 equiv) and N-ethyldiisopropylamine (9.81
mL, 57.3 mmol, 3.96 equiv) dissolved in dry DCM (5 mL)
dropwise. After being stirred for 10 min at 0 °C, dry pyridine
(40 mL) was added to the above reaction mixture, followed by
the addition of 5,5-diallyl-2-amino-1H-pyrimidine-4,6-dione
(3.0 g, 14.5 mmol, 1 equiv). The reaction mixture was heated
on an oil bath held at 90-100 °C for 2 h. After cooling, the
reaction mixture was filtered off, and the solvents were
removed under vacuum. The residue was dissolved in ethyl
acetate and was washed with water and brine. The organic
layer was dried with anhydrous sodium sulfate and concen-
trated under reduced pressure. The crude product was purified
by column chromatography (5% ethyl acetate/petroleum ether)
on silica gel to give 3.52 g (79%) of 1a as colorless crystalline
solid which could be further easily crystallized from petroleum
ether (60-80 °C) to give large crystals. mp 121 °C; IR (CHCl3)
ν (cm-1): 3232, 3076, 3026, 2964, 1706, 1614, 1571, 1529, 1245;
1H NMR (500 MHz, CDCl3): δ 12.74 (s, 1H), 11.38 (s, 1H),
9.24 (s, 1H), 5.66-5.58 (m, 2H), 5.11 (t, 4H, J ) 13.6 Hz), 3.11
(t, 2H, J ) 6.2 Hz), 2.70 (d, 4H, J ) 7.4 Hz), 1.8 (sept, 1H,
J ) 6.7 Hz), 0.95 (d, 6H, J ) 6.6 Hz); 13C NMR (125 MHz,
CDCl3): δ 182.7, 171.8, 158.3, 155.5, 131.0, 120.4, 58.5, 47.8,
42.8, 28.3, 20.1; ESI Mass: 307.05 (M + 1), 614.03 (2M + 1);
Anal. Calcd for C15H22N4O3: C, 58.81; H, 7.24; N, 18.29.
Found: C, 58.53; H, 7.45; N, 18.18.
1-(5,5-Dibenzyl-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-
2-yl)-3-dodecyl-urea 1b. Following the similar procedure for
the synthesis of 1a and using 2-amino-5,5-dibenzyl 1H-
pyrimidine-4,6-dione (1.1 g, 3.6 mmol), 1b was synthesized
(1.19 g, 62%), which was easily crystallized from petroleum
ether into large crystals. mp 72-73 °C; IR (CHCl3) ν (cm-1):
3230, 3020, 2927, 2854, 1703, 1612, 1569, 1529, 1245, 1215;
1H NMR (500 MHz, CDCl3): δ 12.28 (s, 1H), 10.52 (s, 1H),
8.94 (s, 1H), 7.23-7.08 (m, 10H), 3.36 (q, 4H, J ) 13, 11.5
Hz), 3.23 (q, 2H, J ) 6.9, 5.4 Hz), 1.61 (q, 2H, J ) 6.9 Hz),
1.38-1.25 (b, 18H), 0.88 (t, 3H, J ) 6.9 Hz); 13C NMR (125
MHz, CDCl3): δ 182.0, 171.8, 157.2, 155.2, 135.1, 129.6, 128.4,
127.4, 62.1, 45.1, 40.3, 31.9, 29.6, 29.4, 29.3, 29.2, 27.0, 22.6,
14.0; ESI Mass: 520.03 (M + 1), 1038.02 (2M + 1); Anal. Calcd
for C31H42N4O3: C, 71.78; H, 8.16; N, 10.80. Found: C, 71.88;
H, 8.35; N, 10.83.
minimum residual electron densities +0.427 and -0.306 e Å-3
.
Crystal data for 1b (C31H42N4O3): M ) 518.69, crystal
dimensions 0.94 × 0.09 × 0.03 mm3, triclinic, space group P1h,
a ) 6.467(4), b ) 13.910(8), c ) 16.488(10) Å, R ) 90.717(11)°,
â ) 91.918(11)°, γ ) 95.011(11)°, V ) 1476.6(15) Å3, Z ) 2;
Fcalcd ) 1.167 gcm-3, µ(Mo KR) ) 0.076 mm-1, F(000) ) 560,
2θmax ) 50.00°, 10 631 reflections collected, 5176 unique, 2703
observed (I > 2σ(I)) reflections, 344 refined parameters, R
value 0.0553, wR2 ) 0.0992 (all data R ) 0.1255, wR2 )
0.1202), S ) 0.939, minimum and maximum transmission
0.9323 and 0.9977, respectively, maximum and minimum
residual electron densities +0.152 and -0.154 e Å-3
.
Crystal data for 1c (C23H26N4O3): M ) 406.48, crystal
dimensions 0.70 × 0.68 × 0.13 mm3, monoclinic, space group
P21/n, a ) 23.675(3), b ) 18.479(3), c ) 30.427(4) Å, â )
100.690(3)°; V ) 13 081(3) Å3; Z ) 24; Fcalcd ) 1.238 gcm-3
,
µ(Mo KR) ) 0.084 mm-1, F(000) ) 5184, 2θmax ) 50.00°, 64 574
reflections collected, 22 995 unique, 14 350 observed (I > 2σ(I))
reflections, 1685 refined parameters, R value 0.0647, wR2 )
0.1495 (all data R ) 0.1109, wR2 ) 0.1693), S ) 1.014,
minimum and maximum transmission 0.9437 and 0.9892,
respectively, maximum and minimum residual electron densi-
ties +0.725 and -0.420 e Å-3
.
Crystal data for 1e (C21H24N4O5): M ) 412.44, crystal
dimensions 0.67 × 0.41 × 0.29 mm3, triclinic, space group P1h,
a ) 12.065(9), b ) 13.786(10), c ) 14.428(10) Å, R ) 98.58(3)°,
â ) 108.43(2)°, γ ) 100.28(2)°, V ) 2185(3) Å3, Z ) 4; Fcalcd
)
)
1.254 gcm-3, µ(Mo KR) ) 0.091 mm-1, F(000) ) 872, 2θmax
50.00°, 10 384 reflections collected, 6921 unique, 4800 observed
(I > 2σ(I)) reflections, 569 refined parameters, R value 0.0762,
wR2 ) 0.2161 (all data R ) 0.1031, wR2 ) 0.2461), S ) 1.044,
minimum and maximum transmission 0.9416 and 0.9741,
respectively, maximum and minimum residual electron densi-
ties +0.553 and -0.298 e Å-3
.
Experimental Procedures. 5,5-Diallyl-2-amino-1H-py-
rimidine-4,6-dione14 2a. Sodium metal (4.66 g, 202.6 mmol,
3.04 equiv) was dissolved carefully in absolute ethanol (56 mL).
To the above solution was added R,R-diallyl-malonic acid
diethyl ester (16 g, 66.6 mmol, 1 equiv) followed by the addition
of guanidine hydrochloride (10.83 g, 113.3 mmol, 1.7 equiv).
The reaction mixture was refluxed for 4 h, cooled, and filtered
through Celite. The filtrate was acidified with aqueous acetic
acid, and the precipitated amino pyrimidine was filtered,
washed with water, and dried. The product was purified by
crystallization from aqueous DMSO (10.5 g, 76%). mp > 260
°C; IR (Nujol) ν (cm-1): 3238, 3193, 2947, 2923, 2854, 1730,
1-(5,5-Dibenzyl-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-
2-yl)-3-isobutyl-urea 1c. Following the similar procedure for
the synthesis of 1a and using 2-amino-5,5-dibenzyl-1H-pyrim-
idine-4,6-dione (2.0 g, 6.5 mmol), 1c was synthesized (1.9 g,
72%), which could be further easily crystallized from DCM/
petroleum ether to give large crystals. mp 157-158 °C; IR
(CHCl3) ν (cm-1): 3230, 3062, 3031, 2962, 1706, 1612, 1571,
1529, 1244; 1H NMR (500 MHz, CDCl3): δ 12.32 (s, 1H), 10.50
(s, 1H), 9.02 (s, 1H), 7.23-7.08 (m, 10H), 3.36 (q, 4H, J ) 13.0,
14.5 Hz), 3.07 (t, 2H, J ) 6.1 Hz), 1.91 (sept., 1H, J ) 6.5 Hz),
6466 J. Org. Chem., Vol. 70, No. 16, 2005

Self-Assembly with Degenerate Prototropy
1.00 (d, 6H, J ) 6.9 Hz); 13C NMR (125 MHz, CDCl3): δ 181.9,
171.7, 157.2, 155.4, 135.1, 129.6, 128.4, 127.3, 62.1, 47.7, 45.0,
28.4, 20.1; ESI Mass: 407.05 (M + 1), 814.05 (2M + 1); Anal.
Calcd for C23H26N4O3: C, 67.96; H, 6.45; N, 13.78. Found: C,
67.85; H, 6.57; N, 13.61.
mp 140-141 °C (DCM/petroleum ether); IR (CHCl3) ν (cm-1):
3265, 3083, 3020, 2981, 1730, 1689, 1652, 1585, 1512, 1442,
1377, 1255; 1H NMR (500 MHz, CDCl3): δ 12.06 (s, 1H), 11.09
(s, 1H), 8.18 (b, 1H), 8.56 (d, 1H, J ) 8.45 Hz), 8.03 (d, 1H,
J ) 7.65 Hz), 7.54 (t, 1H, J ) 8.03 Hz), 7.08 (t, 1H, J ) 7.65
Hz), 5.70-5.63 (m, 2H), 5.28-5.14 (m, 5H), 2.75 (d, 2H, J )
7.65 Hz), 1.39 (d, 6H, J ) 6.12 Hz); 13C NMR (75 MHz,
CDCl3): δ 171.6, 169.7, 167.1, 160.3, 149.7, 141.0, 133.9, 130.7,
130.4, 122.1, 120.9, 119.4, 115.7, 68.8, 57.8, 42.1, 21.7; ESI
Mass: 413.3 (M + 1), 825.6 (2M + 1); Anal. Calcd. for
C21H24N4O5: C, 61.16; H, 5.87; N, 13.58. Found: C, 61.22; H,
5.84; N, 13.55.
1-(4,6-Dioxo-5,5-di-n-propyl-1,4,5,6-tetrahydro-pyrimi-
din-2-yl)-3-isobutyl-urea 1d. 1-(5,5-Diallyl-4,6-dioxo-1,4,5,6-
tetrahydro-pyrimidin-2-yl)-3-isobutyl-urea 1a (300 mg, 1.0
mmol) was subjected to hydrogenation with 10% Pd/C (60 mg)
under balloon atmosphere for 12 h. Purification by recrystal-
lization from petroleum ether afforded needle-shaped crystals
of 1d (203 mg, 67%). mp 161 °C; IR (CHCl3) ν (cm-1): 3232,
3062, 3026, 2964, 1706, 1614, 1571, 1529, 1463, 1245; 1H NMR
(500 MHz, CDCl3): δ 12.71 (s, 1H), 11.51 (s, 1H), 9.17 (s, 1H),
3.11 (t, 2H, J ) 6.2 Hz), 1.97-1.83 (m, 5H), 1.28-1.15 (m, 4H),
0.93 (d, 6H, J ) 6.6 Hz), 0.86 (t, 6H, J ) 7.3 Hz); 13C NMR
(125 MHz, CDCl3): δ 183.8, 173.1, 158.0, 155.8, 58.4, 47.6,
41.8, 28.2, 20.0, 18.6, 14.0; ESI Mass: 311.05 (M + 1), 622.03
(2M + 1); Anal. Calcd for C15H26N4O3: C, 58.04; H, 8.44; N,
18.05. Found: C, 58.37; H, 8.16; N, 17.82.
2-[3-(5,5-Diallyl-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-
2-yl)-ureido]-benzoic Acid Isopropyl Ester 1e. Following
the similar procedure for the synthesis of 1a and using
2-amino-5,5-diallyl-1H-pyrimidine-4,6-dione (0.5 g, 2.4 mmol),
1e was synthesized (0.8 g, 80%), which could be further easily
crystallized from DCM/petroleum ether to give large crystals.
Acknowledgment. P.K.B. is thankful to CSIR, New
Delhi, for a Junior Research fellowship. We gratefully
acknowledge the constant encouragement of Dr. S.
Sivaram, Director, NCL and Dr. K. N. Ganesh, Head of
the Division, NCL.
Supporting Information Available: General experimen-
tal procedures, 1H and 13C NMR spectra and ESI mass spectra
of 1a-e (PDF), and crystallographic data of 1a-c,e (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0508705
J. Org. Chem, Vol. 70, No. 16, 2005 6467