A new quadruple hydrogen-bonding module based on five-membered heterocyclic urea structure

Article abstract of DOI:10.1021/ol100385b

N,N-Di-4-triazolylurea (DTU) has developed as a new ADDA module and DTU forms a stable ADDA·DAAD heterocomplex with 2,7-diamido-1,8-naphthyridine (DAN) (K_s = 2.6 - 10⁵ M^-1 in CHCl ₃). The K_s value of the complex between DTU and DAN is 100-fold greater than that of the complex between N,N-di-2-pyridylurea and DAN due to replacement of a pyridine ring with a 1,2,3-triazole ring.

Full text of DOI:10.1021/ol100385b

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1776-1779
A New Quadruple Hydrogen-Bonding
Module Based on Five-Membered
Heterocyclic Urea Structure
Yosuke Hisamatsu,*,†,‡ Naohiro Shirai,† Shin-ichi Ikeda,† and Kazunori Odashima†
Graduate School of Pharmaceutical Sciences, Nagoya City UniVersity, Tanabe-dori,
Mizuho-ku, Nagoya 467-8603, Japan
y_hisamatsu@sagami.or.jp
Received February 16, 2010
ABSTRACT
N,N′-Di-4-triazolylurea (DTU) has developed as a new ADDA module and DTU forms a stable ADDA•DAAD heterocomplex with 2,7-diamido-
1,8-naphthyridine (DAN) (Ks ) 2.6 × 105 M-1 in CHCl3). The Ks value of the complex between DTU and DAN is 100-fold greater than that of
the complex between N,N′-di-2-pyridylurea and DAN due to replacement of a pyridine ring with a 1,2,3-triazole ring.
Supramolecular architectures obtained by quadruple hydrogen-
bonding modules with linear arrays have become an impor-
tant research topic in supramolecular chemistry such as
supramolecular polymers, nanofibers, and stimuli-responsive
assembles.1 Among these quadruple hydrogen-bonded sys-
tems,1 highly stable heterocomplexes with high selectivity
can offer diversity and great potential in this field.2,3
Zimmerman reported ADDA (A ) hydrogen-bond accep-
tor, D ) hydrogen-bond donor) modules inspired by a
nucleobase. Ureidoguanine (UG)2a,b and 7-deazaguanine urea
(DeUG)2c,d form highly stable ADDA•DAAD heterocom-
plexes with 2,7-diamido-1,8-naphthyridine (DAN)4 as the
complementary DAAD module (Ks > 107 M-1 in CDCl3),
and exhibit weak self-association (Kdim for UG ≈ 2.3 × 102
M-1 and Kdim for DeUG ) 8.8 × 102 M-1 in CDCl3).5 Their
conformers with ADDA arrays can be well-preorganized with
the use of an intramolecular hydrogen bond,6 and other
unfavorable conformers and tautomers are disfavored. The
† Nagoya City University.
‡ Current address: Sagami Chemical Research Center, Hayakawa, Ayase,
252-1193, Japan.
(1) For reviews, see: (a) Zimmerman, S. C.; Corbin, P. S. Struct. Bonding
(Berlin) 2000, 96, 63. (b) Sijbesma, R. P.; Meijer, E. W. Chem. Commun.
2003, 5. (c) Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P.
Chem. ReV. 2001, 101, 4071. (d) Wilson, A. J. Soft Matter 2007, 3, 409.
(e) Dankers, P. Y. W.; Meijer, E. W. Bull. Chem. Soc. Jpn. 2007, 80, 2047.
(f) de Greef, T. F. A.; Meijer, E. W. Nature 2008, 453, 171. (g) de Greef,
T. F. A.; Smulders, M. M. J.; Wolffs, M.; Schenning, A. P. H. J.; Sijbesma,
R. P.; Meijer, E. W. Chem. ReV. 2009, 109, 5687. (h) Lee, C. C.; Grenier,
C.; Meijer, E. W.; Schenning, A. P. H. J. Chem. Soc. ReV. 2009, 38, 671.
(2) (a) Park, T.; Zimmerman, S. C.; Nakashima, S. J. Am. Chem. Soc.
2005, 127, 6520. (b) Park, T.; Todd, E. M.; Nakashima, S.; Zimmerman,
S. C. J. Am. Chem. Soc. 2005, 127, 18133. (c) Ong, H. C.; Zimmerman,
S. C. Org. Lett. 2006, 8, 1589. (d) Kuykendall, D. W.; Anderson, C. A.;
(4) (a) Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W.
J. Org. Chem. 2006, 71, 375. (b) Todd, E. M.; Quinn, J. R.; Park, T.;
Zimmerman, S. C. Isr. J. Chem. 2005, 45, 381.
(5) While ureidopyrimidinone (UPy) and deazapterin (DeAP) can
provide ADDA arrays and form highly stable heterocomplexes with DAN
(Ks > 107 M-1), these systems compete with highly stable self-associated
dimers with DDAA arrays (Kdim > 107 M-1), see: (a) Ligthart, G. B. W. L.;
Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. J. Am. Chem. Soc. 2005, 127,
810. (b) de Greef, T. F. A.; Ercolani, G.; Ligthart, G. B. W. L.; Meijer,
E. W.; Sijbesma, R. P. J. Am. Chem. Soc. 2008, 130, 13755. (c) de Greef,
T. F. A.; Ligthart, G. B. W. L.; Lutz, M.; Spek, A. L.; Meijer, E. W.;
Sijbesma, R. P. J. Am. Chem. Soc. 2008, 130, 5479. (d) Wang, X.-Z.; Li,
X.-Q.; Shao, X.-Q.; Zhao, X.; Deng, P.; Jiang, X.-K.; Li, Z.-T.; Chen, Y.-
Q. Chem.sEur. J. 2003, 9, 2904. (e) Corbin, P. S.; Zimmerman, S. C. J. Am.
Chem. Soc. 1998, 120, 9710.
Zimmerman, S. C. Org. Lett. 2009, 11, 61
.
(3) With regard to application to a supramolecular polymer, it has been
suggested that the ideal association constant for useful degrees of polym-
g
erization is comparable to or greater than ∼105 M-1 in CHCl3.1d-
10.1021/ol100385b  2010 American Chemical Society
Published on Web 03/16/2010

utility of the UG•DAN complex has been demonstrated in
supramolecular block copolymers and supramolecular poly-
mer blends.7
Scheme 2
Scheme 1
such as 4-oxazolylurea derivatives, were capable of forming
unfolded conformers, since the unfavorable interactions in
six-membered heterocyclic ureas are reduced in five-
membered heterocyclic ureas.10 Recently, we applied our
concept to development of a new DDAA module, ureidoimi-
dazo[1,2-a]pyrimidine (UImp).11 This module forms a highly
stable homodimer (Kdim > 1.1 × 105 M-1 in CDCl3) without
competition from undesired hydrogen-bonded dimers.
In this paper, we report N,N′-di-4-triazolylurea (DTU) as
a new ADDA module based on a five-membered heterocyclic
urea structure (Scheme 2). The 1,2,3-triazole ring system in
DTU is easily synthesized via the Huisgen 1,3-dipolar
cycloaddition, which is known as the click reaction.12 To
the best of our knowledge, DTU is the first example of an
ADDA module that forms a highly stable heterocomplex with
DAN (Ks ) 2.6 × 105 M-1 in CHCl3) without preorgani-
zation of its conformation by intramolecular hydrogen-
bonding. The Ks value of DTU•DAN complex is 100-fold
greater than that of DPU•DAN complex due to replacement
of the pyridine ring with the 1,2,3-triazole ring.
As another type of ADDA module, N,N′-di-2-pyridylurea
(DPU) has been studied in detail (Scheme 1).8 Unfortunately,
the Ks value of DPU with DAN (Ks ) 1.2 × 103 M-1 in
CDCl3) is much lower than the predicted value since DPU
prefers to form a folded conformer, which is stabilized by
intramolecular hydrogen-bonding.8,9 Therefore, the intramo-
lecular hydrogen-bonding of DPU in the folded conformer
must be broken prior to the complexation with DAN.
We have been interested in development of quadruple
hydrogen-bonding modules based on five-membered hetero-
cyclic urea structures because these have a clear advantage
over 2-pyridylurea structures in regard to providing linear
multiple hydrogen-bonding arrays.10 We considered that six-
membered heterocyclic ureas such as 2-pyridylurea structures
would be destabilized as a result of steric repulsion due to
the shorter distance between 3-H in the pyridine ring and
the oxygen on the urea carbonyl substitute. Thus, their
conformational equilibrium was biased toward the folded
conformer that was stabilized by the intramolecular hydrogen-
bonding. In contrast, some five-membered heterocyclic ureas,
DTU was easily synthesized in four steps from com-
mercially available reagents (Scheme 3). Triazole 1 was
prepared in a one-pot synthesis via the Huisgen 1,3-dipolar
cycloaddition from 1-hexylbromide in 92% yield,13 and
hydrolysis to give acid 2 in 89% yield. DTU was then
prepared from 2 via the Curtius rearrangement with diphe-
nylphosphoryl azide (DPPA) in 60% yield.14
(6) A hydrazide-based ADDA module reported by Li is also well-
preorganized with the use of intramolecular hydrogen-bonding and exhibits
highly stable ADDA•DAAD heterocomplexes with DAN (Ks ) 6.0 × 105
M-1 in CDCl3) and weak self-association (Kdim ) 5.5 × 101 M-1 in CDCl3),
see: Zhao, X.; Wang, X.-Z.; Jiang, X.-K.; Chen, Y.-Q.; Li, Z.-T.; Chen,
G.-J. J. Am. Chem. Soc. 2003, 125, 15128.
(7) (a) Park, T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 13986.
(b) Park, T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 14236. (c)
Park, T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 11582.
(8) (a) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk,
N. A.; Murray, T. J. J. Am. Chem. Soc. 2001, 123, 10475. (b) Singha, N. C.;
Sathyanarayana, D. N. J. Chem. Soc., Perkin Trans. 2 1997, 157. (c) Lu¨ning,
U.; Ku¨hl, C.; Uphoff, A. Eur. J. Org. Chem. 2002, 4063. (d) Sudha, L. V.;
Sathyanarayana, D. N. J. Chem. Soc., Perkin Trans. 2 1986, 1647.
(11) Hisamatsu, Y.; Shirai, N.; Ikeda, S.; Odashima, K. Org. Lett. 2009,
11, 4342.
(12) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Moses, J. E.; Moorhouse, A. D.
Chem. Soc. ReV. 2007, 36, 1249.
(9) Sartorius, J.; Schneider, H.-J. Chem.sEur. J. 1996, 2, 1446
.
(13) Kacprzak, K. Synlett 2005, 6, 943.
(10) Hisamatsu, Y.; Fukumi, Y.; Shirai, N.; Ikeda, S.; Odashima, K.
(14) Vereshchagin, L. I.; Kirillova, L. P.; Shafeev, M. A. Russ. J. Org.
Chem. 1998, 34, 258.
Tetrahedron Lett. 2008, 49, 2005.
Org. Lett., Vol. 12, No. 8, 2010
1777

Scheme 3. Synthesis of DTU
First, the self-association of DTU was investigated by 1H
NMR. In a dilution study of DTU in CDCl3 from 45 mM to
0.40 mM, NHa and CHb proton signals were shifted upfield,
respectively. This indicated the self-association of DTU in
CDCl3 by intermolecular hydrogen bonds involving NHa
protons. The change in the chemical shift (∆δ) of NHa
between 45 mM and 1.0 mM was 0.72 ppm, and the
NHa broadened below 1.0 mM. The change in the chemical
shift (∆δ) of CHb from 45 mM to 0.40 mM was 0.13 ppm
and the Kdim value was determined to be (7.1 ( 0.6) × 102
M-1 by the nonlinear least-squares curve-fitting method.15,16
When the CDCl3 solution of DTU (10 mM) was cooled from
25 to -50 °C, both NHa (∆δ ) 0.76 ppm) and CHb (∆δ )
0.10 ppm) proton signals showed downfield shifts that were
consistent with self-association. Furthermore, the splitting
of NHa and CHb proton signals, which indicated the folded
conformer,8a,10 was not observed. Similar variable-temper-
1
Figure 1. Partial H NMR spectra (500 MHz) of (A) DTU (10
mM), (B) DTU (10 mM) + DAN (10 mM), and (C) DAN (10
mM) at 25 °C in CDCl3.
changes in the chemical shift support the formation of a
DTU•DAN complex via multiple hydrogen bonds involving
NHa and NHc protons. The stoichiometry of the complex
between DTU and DAN was confirmed to be 1:1 by a Job
plot.18 NOE contact was observed between the NHa of DTU
and NHc of DAN. In addition, the ESI mass spectrum shows
molecular ion peaks of DTU•DAN (m/z: 887.6 [DTU +
DAN + H]+). These results strongly indicate that DTU forms
a quadruple hydrogen-bonded heterocomplex with DAN by
ADDA•DAAD arrays, as shown in Scheme 2. The formation
of a DTU•DAN complex was also supported by the
DFT calculation at the B3LYP method with a 6-31+G**
basis set. The distance of hydrogen-bonding NHa · · ·N and
NHc · · ·N was estimated to be 2.1 Å and 2.0 Å, respectively.
When DAN (1.0 mM) was titrated with DTU (0 - 3.0 equiv)
by 1H NMR, significant downfield shifts were observed for
both the NHc (∆δ ) 3.9 ppm) and CHd (∆δ ) 0.26 ppm)
proton signals and these were almost saturated upon the
addition of 1.0 equiv of DTU. In a dilution study of a 1:1
mixture of DTU and DAN from 20 mM to 0.4 mM,2 no
clear changes were observed in the chemical shift values of
NHa and NHc proton signals.19 This shows that the
DTU•DAN complex persists at a low concentration.
We investigated the binding property in the DTU•DAN
complex by UV/vis spectroscopy in CHCl3 at 25 °C (Figure
2). Upon the addition of DTU (0 - 3.0 equiv) to DAN (20
µM), the absorption intensity of DAN at 353 and 370 nm
increased with an isosbestic point at 349 nm. Based on the
change in the absorption intensity at 353 nm, the stability
constant of a 1:1 complex between DTU and DAN was
determined to be (2.6 ( 0.2) × 105 M-1 by the nonlinear
least-squares curve-fitting method.15,20 The Ks value of DTU
with DAN is 100-fold greater than that of DPU (Ks ) 1.2
1
ature H NMR spectra were obtained in a dilute concentra-
tion of DTU (0.80 mM). On the other hand, the major
conformer of DPU is the folded one.8 Indeed, in the 1H NMR
spectra of DPU in CDCl3, proton signals of urea NH and
aromatic 3-H in the pyridine ring disappear due to broadening
at 25 °C, and two pairs of split proton signals of the urea
NH and 3-H were observed at -40 °C, since these protons
are not equivalent in the folded conformer.8a These results
suggested the minimal contribution of the formation of folded
DTU dimer17 and the proposed major dimeric structure of
DTU should be unfolded one (see Supporting Information).
Next, the formation of a heterocomplex between DTU and
the complementary DAAD module DAN was monitored by
1H NMR spectroscopy in CDCl3 (Figure 1). At a 1:1 ratio
of DTU (10 mM) and DAN (10 mM), a significant downfield
shift was observed for the urea NHa of DTU (∆δ ) 1.88
ppm) and the amide NHc of DAN (∆δ ) 3.82 ppm). These
(15) Connors, K. A. Binding Constants; Wiley: New York, 1987
.
(16) When we tried to determine the Kdim value of DTU based on
chemical shift changes of urea NHa proton signals at the concentration from
1.0 mM to 45 mM, the Kdim value gave large error due to insufficiency of
the chemical shift data at lower concentration range (<1 mM).
(17) The Kdimer value of DTU was higher than those for general folded
dimers with DA•AD arrays (Kdim < 3 × 102 M-1 in CDCl3)6,8a see: (a)
EArcher, A.; Gong, H.; Krische, M. J. Tetrahedron 2001, 57, 1139. (b)
McGhee, A. M.; Kilner, C.; Wilson, A. J. Chem. Commun. 2008, 344. (c)
Lafitte, V. G. H.; Aliev, A. E.; Horton, P. N.; Hursthouse, M. B.; Bala, K.;
Golding, P.; Hailes, H. C. J. Am. Chem. Soc. 2006, 128, 6544.
(18) Job, P. Ann. Chim. Appl. 1928, 9, 113.
(19) For a 1:1 mixture of DTU and DAN at a concentration of less
than 0.4 mM, the NHa proton signal of DTU disappeared due to broadening.
Assuming that there is less than 10% dissociation at 0.4 mM, the Ks value
2
of DTU•DAN was estimated to be a lower limit of 1.1 × 105 M-1
.
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Org. Lett., Vol. 12, No. 8, 2010

This calculated ∆G298 value was similar to the experimental
value (∆G298 ) -7.4 kcal mol-1). This supports the notion
that DTU is suitable for use as an ADDA module and
preorganization is not needed to give a linear ADDA array.
In conclusion, we have developed a new ADDA module
based on the five-membered heterocyclic urea structure.
N,N’-Di-4-triazolylurea(DTU)formsahighlystableADDA•DAAD
complex with DAN (Ks ) 2.6 × 105 in CHCl3) without
preorganization. Due to replacement of the pyridine ring with
a 1,2,3-triazole ring, the Ks value of DTU•DAN complex is
100-fold greater than that of DPU•DAN complex. This result
shows that the 1,2,3-triazole system via the click reaction is
useful for obtaining components of multiple hydrogen-
bonding modules. Our concept would contribute to develop-
ment of promising quadruple hydrogen-bonding modules
without the competition of undesired folded conformers and
tautomers. Since limited examples of DADD modules have
been reported,8c,22 we are currently studying the development
of novel DADD module based on the five-membered
heterocyclic urea structure.
Figure 2. Changes in the absorption spectra of DAN (20 µM) in
CHCl3 at 25 °C upon addition of DTU (0-3.0 equiv).
× 103 M-1 in CDCl3) by replacement of the pyridine ring
with the 1,2,3-triazole ring.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan. We
thank Professor Bert Meijer and Dr. Tom de Greef (Uni-
versity of Eindhoven) for the supply of 2,7-diamido-1,8-
naphthyridine (DAN). The calculation was carried out with
the GAUSSIAN-98 program on the IBM 7038-6M2
pSeries650 computer system of the Library and Information
Processing Center of Nagoya City University.
To predict the ∆G values of linear multiple hydrogen-
bonded complexes, Zimmerman developed a formula based
on an empirical method.21 This formula takes into account
several variables including intramolecular hydrogen bonds
that are broken before complexation (e.g., 2-pyridylureas).8
The ∆G298 value calculated for DTU•DAN complex from
the formula was estimated to be -7.0 kcal mol-1, when the
variable for the intramolecular hydrogen bond was not used.
(20) Due to small absorption intensity changes (370 nm) of DAN at the
lower concentration range of DTU (<1.0 equiv), it was difficut to determine
the Ks value.
Supporting Information Available: Details of the syn-
thesis and characterization for all new compounds, the
complexation studies by NMR measurements, ESI-MS
measurement and DFT calculation. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Quinn, J. R.; Zimmerman, S. C.; Del Bene, J. E.; Shavitt, I. J. Am.
Chem. Soc. 2007, 129, 934.
(22) DADD•ADAA arrays exhibit low affinity (Ks < 103 M-1 in CHCl3)
since DADD modules contain 2-pyridylurea structurs, see: (a) Taubitz, J.;
Lu¨ning, U. Eur. J. Org. Chem. 2008, 5922. (b) Quin, J. R.; Zimmerman,
S. C. Org. Lett. 2004, 6, 1649.
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