Self-complementary quadruply hydrogen-bonded duplexes based on imide and urea units

Article abstract of DOI:10.1021/ol2018455

The quadruply hydrogen-bonded duplexes based on an imide-urea structure preorganized by three-center hydrogen bonds were found to associate via bifurcated hydrogen bonds. ¹H NMR dilution experiments revealed the high stability of the homodimer in apolar solvent (K_dim > 10 ⁵ M^-1 in CDCl₃) and enhancement of association ability due to electron-withdrawing substituent effects. The ready synthetic availability and adjustable association affinity via electronic effects may render these association units potentially applicable in constructing supramolecular architectures.

Full text of DOI:10.1021/ol2018455

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4628–4631
Self-Complementary Quadruply
Hydrogen-Bonded Duplexes Based on
Imide and Urea Units
Xianghui Li, Yuyu Fang, Pengchi Deng, Jinchuan Hu, Tian Li, Wen Feng, and
Lihua Yuan*
College of Chemistry, Key Laboratory for Radiation Physics and Technology of
Ministry of Education, Institute of Nuclear Science and Technology, Analytical &
Testing Center of Sichuan University, Sichuan University, Chengdu 610064, China
lhyuan@scu.edu.cn
Received July 9, 2011
ABSTRACT
The quadruply hydrogen-bonded duplexes based on an imide-urea structure preorganized by three-center hydrogen bonds were found to
associate via bifurcated hydrogen bonds. 1H NMR dilution experiments revealed the high stability of the homodimer in apolar solvent (Kdim > 105 Mꢀ1 in
CDCl3) and enhancement of association ability due to electron-withdrawing substituent effects. The ready synthetic availability and adjustable
association affinity via electronic effects may render these association units potentially applicable in constructing supramolecular architectures.
With their high strength, specificity, directionality and
reversibility, multiple hydrogen-bonding modules with
arrays of hydrogen-bond donors (D) and acceptors (A),1
especially quadruple hydrogen-bonding ones, have trig-
gered wide research interest in stimuli-responsive materi-
als, photoelectric materials, surface materials, and molec-
ular recognition.2 For these applications many artificial
hydrogen-bonding modules were designed and tailored to
suit a different purpose. Among them, the quadruple
ureidopyrimidone derivatives (UPy) by Meijer et al.3 and
deazapterin (DeAP) by Zimmerman et al.4 are excellent
association units to form the stable homodimers in CDCl3
(Kdim > 107 Mꢀ1). These binding units have been success-
fully applied to construct various supramolecular materi-
als with extraordinary features that fail to display for
covalent polymers.5 An exceptionally stable quadruply
hydrogen-bonded heterodimer lately reported by Leigh
(1) (a) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem.,
Int. Ed. 2001, 40, 2382–2426. (b) Zimmerman, S. C.; Corbin, P. S. Struct.
Bonding (Berlin) 2000, 96, 63–94. (c) Brunsveld, L.; Folmer, B. J. B.;
Meijer, E. W.; Sijbesma, R. P. Chem. Rev. 2001, 101, 4071–4097. (d)
Wilson, A. J. Soft Matter 2007, 3, 409–425.
(2) For selected examples, see: (a) de Greef, T. F. A. D.; Smulders,
M. M. J.; Wolffs, M.; Schenning, A. P. H. J.; Sijbesma, R. P.; Meijer,
E. W. Chem. Rev. 2009, 109, 5687–5754. (b) Wojtecki, R. J.; Meador,
M. A.; Rowan, S. J. Nat. Mater. 2011, 10, 14–27. (c) Binder, W. H.;
Zirbs, R. Adv. Polym. Sci. 2007, 207, 1–78. (d) South, C. R.; Burd, C.;
Weck, M. Acc. Chem. Res. 2007, 40, 63–74. (e) Yang, S. K.; Ambade,
A. V.; Weck, M. Chem. Sov. Rev. 2011, 40, 129–137. (f) Yagai, S. J.
ꢀ
Photochem. Photobiol., C 2006, 7, 164–182. (g) Sanchez, L.; Martın, N.;
´
Guldi, D. M. Angew. Chem., Int. Ed. 2005, 44, 5374–5382. (h) Sanchez,
L.; Rispens, M. T.; Hummelen, J. C. Angew. Chem., Int. Ed. 2002, 41,
838–840. (i) Tancini, F.; Genovese, D.; Montalti, M.; Cristofolini, L.;
Nasi, L.; Prodi, L.; Dalcanale, E. J. Am. Chem. Soc. 2010, 132, 4781–
4789. (j) Sessler, J. L.; Lawrence, C. M.; Jayawickramarajah, J. Chem.
Soc. Rev. 2007, 36, 314–325. (k) Cooke, G.; Rotello, V. M. Chem. Sov.
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Santos, E.; Bo, C.; de Mendoza, J. Angew. Chem., Int. Ed. 2007, 46, 202–
205.
(3) (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) Beijer, F. H.; Sijbesma, R. P.; Kooij-
man, H.; Spek, A. L.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761–
6769.
(4) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120,
9710–9711.
r
10.1021/ol2018455
Published on Web 08/05/2011
2011 American Chemical Society

and co-workers is another successful example.6 Many
other heterocycle-based modules were also described.7
To address the tautomeric problem often associated with
the heterocycle modules, different types of the hydrogen-
bonding motifs were designed.8 For example, the aromatic
oligoamideduplexesweredevelopedbyGong etal.,9 which
are free of the complication from unfavorable tautomer-
ism. Other duplexes based on amide units were described
by Nowick10 and Hunter.11 In addition, molecular du-
plexes based on hydrazide and amidourea motifs were
reported by Li et al.12 and Chen et al.13 Recently, we
reported with collaborators oligoamide hydrogen-bonding
duplexes as organogelators and an alternative strategy for
tuning the association specificity by varying the spacings
between neighboring hydrogens based on incorporation of
naphthalene-based residues.14
So far the hydrogen-bonded association modules with
respect to nonheterocycles include those based on amide,
urea, hydrazide, and amidourea moieties. Use of the
combination of imide and urea units as building blocks
for constructing duplexes has still been unexplored. With
increasing interest in supramolecular materials fabricated
with multiple hydrogen-bonding modules, the design of
molecular hydrogen-bonded duplexes that are structurally
simple, synthetically readily accessible, and of high and
tunable association ability still represents an urgent need.
hydrogen bonding interactions (Figure 1). The high stabi-
lity is attributed to the preorganization of intramolecular
three-center hydrogen bonds and the substituent effect.
Compounds 4 and 5 are designed for comparison. This
work shown here demonstrated a new type of molecular
duplexes based on the combination of imide and urea units
that are readily accessible via a simple synthetic strategy.
Since the imide units in our designed molecules serve as
hydrogen-bond acceptors it is important to orient its
carbonyl oxygens to the same side. Among the three
possible conformational isomers, the transꢀtrans form is
preferred to align the acceptor atoms for hydrogen bond-
ing interactions (Figure 2a). Thus, compound 6 was de-
signed and synthesized first to examine the possibility of
preorganizing the imide structure along one edge of the
molecule. The presence of an intramolecular three-center
hydrogen bond in 6 ensures the rigidification of the back-
bone and helps circumvent the possible intermolecular
hydrogen bonding interactions from the upper edge.
Figure 2. (a) Conformational isomerization and the transꢀtrans
conformer of imide 6 fixed with a three-center H-bond; (b)
X-ray structure of 6 with hydrogen-bond geometry and torsion
angles denoted. For clarity, only hydrogen atoms involved in
H-bonds are shown.
(7) For selected examples, see: (a) 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, 6544–6545. (b) Schmuck, C.; Wienand, W. J.
Am. Chem. Soc. 2003, 125, 452–459. (c) Blight, B. A.; Camara-Campos,
A.; Djurdjevic, S.; Kaller, M.; Leigh, D. A.; McMillan, F. M.; McNab,
H.; Slawin, A. M. Z. J. Am. Chem. Soc. 2009, 131, 14116–14122. (d)
Baruah, P. K.; Gonnade, R.; Phalgune, U. D.; Sanjayan, G. J. J. Org.
Chem. 2005, 70, 6461–6467. (e) Hisamatsu, Y.; Shirai, N.; Ikeda, S.;
Odashima, K. Org. Lett. 2009, 11, 4342–4345.
Figure 1. Imide-urea strands 1ꢀ3 that pair into self-complemen-
tary duplexes A A via bifurcated hydrogen bonds. Compounds
3
4 and 5 are designed for comparison.
(8) For selected examples, see: (a) Corbin, P. S.; Zimmerman, S. C. J.
Am. Chem. Soc. 2000, 122, 3779–3780. (b) Corbin, P. S.; Zimmerman,
S. C.; Thiessen, P. A.; Hawryluk, N. A.; Murray, T. J. J. Am. Chem. Soc.
2001, 123, 10475–10488. (c) Moriuchi, T.; Tamura, T.; Hirao, T. J. Am.
Chem. Soc. 2002, 124, 9356–9357.
(9) (a) Gong, B.; Yan, Y. F.; Zeng, H. Q.; Skrzypczak-Jankunn, E.;
Kim, Y. W.; Zhu, J.; Ickes, H. J. Am. Chem. Soc. 1999, 121, 5607–5068.
(b) Zeng, H. Q.; Miller, R. S.; Flowers, R. A.; Gong, B. J. Am. Chem.
Soc. 2000, 122, 2635–2644.
Herein we report on a new class of DDAA self-comple-
mentary imide-urea modules 1ꢀ3 that have a high dimer-
ization constant (Kdim > 105 Mꢀ1 in CDCl3) via bifurcated
hydrogen bonds involving both conventional and weak
(10) Nowick, J. S. Acc. Chem. Res. 2008, 41, 1319–1330.
(5) (a) Folmer, B. J. B.; Sijbesma, R. P.; Versteegen, R. M.; vander
Rijt, J. A. J.; Meijer, E. W. Adv. Mater. 2000, 12, 874–878. (b) Abbel, R.;
Grenier, C.; Pouderoijen, M. J.; Stouwdam, J. W.; Leclere, P. E. L. G.;
Sijbesma, R. P.; Meijer, E. W.; Schenning, A. P. H. J. J. Am. Chem. Soc.
2009, 131, 833–843. (c) Kushner, A. M.; Vossler, J. D.; Williams, G. A;
Guan, Z. J. Am. Chem. Soc. 2009, 131, 8766–8768.
(6) Blight, B. A.; Hunter, C. A.; Leigh, D. A.; McNab, H.; Thomson,
P. I. T. Nat. Chem. 2011, 3, 244–248.
(11) 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, 8856–8868.
(12) (a) 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. (b) Zhu, J.; Lin,
J.-B.; Xu, Y.-X.; Shao, X.-B.; Jiang, X.-K.; Li, Z.-T. J. Am. Chem. Soc.
2006, 128, 12307–12313.
ꢁ
Org. Lett., Vol. 13, No. 17, 2011
4629

A single crystal of 6 was obtained for X-ray analysis via
slow evaporation from CH2Cl2/ethyl acetate (Figure 2b).
As expected, the imide moiety in the molecule is preorga-
nized in a transꢀtrans conformation by virtue of three-
center hydrogen bonds consisting of two S(6)-type intra-
molecular hydrogen bonds. The backbone is a little twisted
with the torsion angles of 24.99° and 13.97°, suggesting the
nonplanarity of the backbone containing the three-center
hydrogen bond that may result from the repulsion of two
adjacent carbonyl oxygens.
NOEs between protons Hd and Hm were observed.
Also, contacts were observed between Hh and Hi, Hj
and Hi for 1a, indicating the presence of the intramo-
lecular three-center hydrogen bond.16 More direct evi-
dence for the dimerization came from ESI-MS studies.
The ESI mass spectrum showed highly intense peaks
(m/z: 1171.49 [1a 1a þ H]þ, calcd 1171.50; 1193.46
3
[1a 1a þ Na]þ, calcd 1193.48; 1209.42 [1a 1a þ K]þ,
3
3
calcd 1209.45) corresponding to the presence of the
dimeric species.16
Scheme 1. Synthesis of Compounds 1a and 1b
Figure 3. Stacked plots of variable-concentration 1H NMR
spectra of compound 1a in 5% DMSO-d6/CDCl3 (v/v) at 298 K.
This preorganized imide structure is more rigid as
compared to the one-hydrogen bonded imide15 and thus
should lead to added stability upon incorporating the urea
moiety for forming an intermolecular hydrogen bonded
dimer. Therefore, following the successful rigidification of
the imide backbone in the desired conformation, com-
pounds 1ꢀ4 were designed by incorporating urea units as
hydrogen bonding donors to furnish the complementarity
of duplexes in DDAA arrays (Figure 1).
The synthesis of these imide-urea duplexes is simple and
straightforward (Scheme 1). For example, compound 1a
(or 1b) was readily prepared by the reaction of acyl choride
of 8a (or 8b) and 2-methoxybenzamide (7) in the presence
of NaH to afford 9a (or 9b) in 98% yield, followed by
reduction and condensation with commercially available
isocyanate in a yield of ca. 80%. Following similar proce-
dures, compounds 2ꢀ5 were synthesized in 74ꢀ83% over-
all yields.16
The binding affinity of 1a was examined by the 1H NMR
dilution experiment. When a CDCl3 solution of 1a was
diluted from 10.0 to 0.40 mM, no change was found in the
chemical shift of urea protons. The Kdim of duplex 1a 1a
,
3
was estimated to be a lower limit of 1.1 ꢁ 105 Mꢀ1 16
almost 1 order of magnitude larger than that of oligoamide
duplexesinthesameDDAAsequence(∼104 Mꢀ1).9a More
accurate Kdim data for dimerization were obtained by
increasing the polarity of the solvent. As shown in the 1H
NMR spectra of 1a in 5% DMSO-d6/CDCl3 (Figure 3),
the protons Ha, Hb of NH both shifted downfield with
increasing concentration, indicating these protons were
involved in intermolecular hydrogen bonds. Unexpect-
edly, a pronounced downfield shift of Hc of CH (0.35 ppm)
demonstrated the presence of the CH
O interaction
3 3 3
as intermolecular hydrogen bonds.17 Nonlinear regres-
sion analysis of the chemical shift data gave the dimer-
ization constant Kdim value of 2.8 ꢁ 102 Mꢀ1 in 5%
DMSO-d6/CDCl3 and 1.9 ꢁ 103 Mꢀ1 in 2% DMSO-d6/
CDCl3 (Table 1).
The formation of the dimer 1a 1a was evidenced
by two-dimensional NOESY in CDCl3. Cross-strand
3
(13) (a) Yang, Y.; Yang, Z.-Y; Yi, Y.-P.; Xiang, J.-F.; Chen, C.-F.;
Wan, L.-J.; Shuai, Z.-G. J. Org. Chem. 2007, 72, 4936–4946. (b) Chu,
W.-J.; Yang, Y.; Chen, C.-F. Org. Lett. 2010, 12, 3156–3159.
(14) (a) Cao, R.-K.; Zhou, J.-J.; Wang, W.; Feng, W.; Li, X.-H.;
Zhang, P.-H.; Deng, P.-C.; Yuan, L.-H.; Gong, B. Org. Lett. 2010, 12,
2958–2961. (b) Zhang, P.-H.; Chu, H.-Z.; Li, X.-H.; Feng, W.; Deng, P. -
C.; Yuan, L.-H.; Gong, B. Org. Lett. 2011, 13, 54–57.
More convincing evidence for the dimerization is from
X-ray crystallography. A single crystal of 1b,16 differing
only in the side chains from 1a, was obtained for X-ray
(15) Sijbesma, R. P.; Ligthart, G. B. W. L.; Versteegen, R. M.;
Koevoets, R.; Meijer, E. W. Polym. Prepr. (Am. Chem. Soc., Div.
Polym. Chem.) 2003, 44, 457–458.
(17) (a) Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 5063–
5070. (b) Etter, M. C.; Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.;
~
(16) See the Supporting Information for details.
Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415–8426.
4630
Org. Lett., Vol. 13, No. 17, 2011

observed in the molecule. Furthermore, in another com-
pound 3b with two trifluoromethyl groups the crystal struc-
ture also revealed the dimeric complex in the solid state.16
To evaluate the influence of the intramolecular three-
center H-bond in 1a on a Kdim value, compound 5 with
only one S(6)-type intramolecular H-bond was prepared.
Table 1. Dimerization Constants (Kdim) of Compounds 1ꢀ5 in
ꢀ1 Based on Ha Proton
M
compound
solventa
Kdim (Ha)
1a
2%
5%
2%
2%
2%
2%
2%
(1.9 ( 0.4) ꢁ 103
(2.8 ( 0.2) ꢁ 102
(1.8 ( 0.2) ꢁ 103
(2.6 ( 0.2) ꢁ 103
(1.2 ( 0.3) ꢁ 104
(5.6 ( 0.5) ꢁ 102
(7.9 ( 0.5) ꢁ 102
A lower Kdim value of 7.9 ꢁ 102 Mꢀ1 for 5 5 was obtained
3
1b
2
in 2% DMSO-d6/CDCl3 as compared to that of 1.9 ꢁ
103 Mꢀ1 of 1a 1a, indicating that the three-center
3
3a
4
hydrogen bonding favors the formation of a stable
dimeric complex.
5
In addition, electron-withdrawing groups also exerted a
marked influence upon the stability of the dimer due to the
enhanced acidity of hydrogen-bond donors.18 As demon-
strated in compounds 1a and 2 with only one electron-
withdrawing substituent in the urea moiety, the dimer-
ization constant was determined to be around 2 ꢁ 103
Mꢀ1 in 2% DMSO-d6/CDCl3; however, introducing
two trifluoromethyl groups into the urea unit led to an
increase in Kdim value to 1.2 ꢁ 104 Mꢀ1 for compound
3a in the same mixed solvent. In contrast, replacing the
nitro group of 2 with an electron-donating methyl
group provided compound 4 with a lower Kdim of 5.6
ꢁ 102 Mꢀ1 (Table 1). This suggests that the association
ability could be tuned by electronic properties of sub-
stituents for these imide-urea duplexes.
a Percentage of DMSO-d6 in the mixed solvent of DMSO-d6/CDCl3.
In conclusion, we have demonstrated a new class of
association units based on imide and urea structures that
are able to self-associate into stable dimers (>105 Mꢀ1 in
CDCl3) via bifurcated hydrogen bonds in the solid state
and in solution. The enhanced association capability of
these designed duplexes stems mainly from preorganiza-
tionvia intramolecular three-centerhydrogen bonding and
electron-withdrawing effects. These imide-urea duplexes,
which are of high stability and of easy synthetic accessi-
bility, may be used for assembly of supramolecular poly-
mers and other well-defined supramolecular architectures.
Detailed studies on the potential application of these
association units are currently being investigated in our
laboratory.
Figure 4. X-ray structure of compound 1b showing the involve-
ment of CH O hydrogen bonds in the dimer. For clarity, only
hydrogen atoms involved in H-bonds are shown.
3 3 3
analysis via slow evaporation from the mixed solvent of
CH2Cl2/ethyl acetate (Figure 4).
As expected, in the homodimer arrayed in an AADD
sequence, both of the urea hydrogens are involved in
hydrogen bond formation with two imide oxygens of
another strand. The distance of NHa O1 (H O 1.91
3 3 3
3 3 3
A, 172.6°) is much shorter than that of NHb O2 (H
O
3 3 3
3 3 3
2.41 A, 154.3°), indicative of the stronger hydrogen bond-
ing for the former. Interestingly, the distance of CHc O2
Acknowledgment. The authors acknowledge the Na-
tional Natural Science Foundation of China (20874062)
and the Doctoral Program of the Ministry of Education of
China (20090181110047) for funding this work, and the
Analytical & Testing Center of Sichuan University for
NMR analysis.
3 3 3
(H O 2.33 A, 153.1°) accompanied by a larger angle is
3 3 3
even a little shorter than that of both NHb O1 (H
O
3 3 3
3 3 3
2.72 A, 140.2°) and NHb O2. This suggests the presence
3 3 3
of a bifurcated H-bond consisting of conventional and
weak CꢀH H-bonds. The intramolecular three-center
hydrogen bonds consisting of NHi O3 (H O 2.39 A,
3 3 3
3 3 3
Supporting Information Available. Synthesis, analytical
data, 2D NMR, the assemblies of the duplexes and X-ray
crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
102.2°) and NHi O4 (H O 1.86 A, 140.4°) were
3 3 3
3 3 3
(18) Gooch, A.; McGhee, A. M.; Pellizzaro, M. L.; Lindsay, C. I.;
Wilson, A. J. Org. Lett. 2011, 13, 240–243.
Org. Lett., Vol. 13, No. 17, 2011
4631