Alternative strategy for adjusting the association specificity of hydrogen-bonded duplexes

Article abstract of DOI:10.1021/ol102522m

A strategy for creating new association specificity of hydrogen-bonded duplexes by varying the spacings between neighboring hydrogen bonds is described. Incorporation of naphthalene-based residues has provided oligoamide strands that pair into duplexes sharing the same H-bonding sequences (e.g., DDAA) but differing in the spacings between their intermolecular hydrogen bonds, leading to homo- or heteroduplexes. The ability to manipulate association-specificity as demonstrated by this work may be extended to other multiple hydrogen bonded systems, thereby further enhancing the diversity of multiple hydrogen-bonded association units for constructing supramolecular structures.

Full text of DOI:10.1021/ol102522m

ORGANIC
LETTERS
2011
Vol. 13, No. 1
54-57
Alternative Strategy for Adjusting the
Association Specificity of
Hydrogen-Bonded Duplexes
Penghui Zhang,† Hongzhu Chu,† Xianghui Li,† Wen Feng,† Pengchi Deng,†
Lihua Yuan,*,† and Bing Gong‡
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,
and Department of Chemistry, The State UniVersity of New York, Buffalo,
New York 14260, United States
lhyuan@scu.edu.cn
Received October 18, 2010
ABSTRACT
A strategy for creating new association specificity of hydrogen-bonded duplexes by varying the spacings between neighboring hydrogen
bonds is described. Incorporation of naphthalene-based residues has provided oligoamide strands that pair into duplexes sharing the same
H-bonding sequences (e.g., DDAA) but differing in the spacings between their intermolecular hydrogen bonds, leading to homo- or heteroduplexes.
The ability to manipulate association-specificity as demonstrated by this work may be extended to other multiple hydrogen bonded systems,
thereby further enhancing the diversity of multiple hydrogen-bonded association units for constructing supramolecular structures.
Artificial duplexes with arrays of hydrogen bond donors (D)
and acceptors (A) are of great importance for the design of
various host-guest and self-assembling systems.1 Many
hydrogen-bonded complexes of different size, shape, and
number of hydrogen bonds have been utilized as association
modules.2,3 Among known examples, the ureido-pyrimidi-
none derivatives (UPy)4 and deazapterin (DeAP)5 carrying
the DDAA hydrogen-bonding sequence have been success-
fully applied for developing supramolecular polymers,2a,d,6
and for constructing other molecular architectures7 because
of their high dimerization constant (Kdimer ≈ 107 M-1 in
† Sichuan University.
‡ The State University of New York.
(1) (a) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford
University Press: Oxford, 1997. (b) Conn, M. M.; Rebek, J., Jr. Chem. ReV.
1997, 97, 1647. (c) Zimmerman, S. C.; Corbin, P. S. Struct. Bonding (Berlin,
Ger.) 2000, 96, 63. (d) Archer, E. A.; Gong, H.; Krische, M. J. Tetrahedron
2001, 57, 1139. (e) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew.
Chem., Int. Ed. 2001, 40, 2382. (f) Cooke, G.; Rotello, V. M. Chem. Soc.
ReV. 2002, 31, 275. (g) Sivakova, S.; Rowan, S. J. Chem. Soc. ReV. 2005,
34, 9. (h) Sivakova, S.; Rowan, S. J. Chem. Soc. ReV. 2005, 34, 9. (i) Sessler,
J. L.; Lawrence, C. M.; Jayawickra- marajah, J. Chem. Soc. ReV. 2007, 36,
314.
(2) For selected reviews, see: (a) Brunsveld, L.; Folmer, B. J. B.; Meijer,
E. W.; Sijbesma, R. P. Chem. ReV. 2001, 101, 4071. (b) Schmuck, C.;
Wienand, W. Angew. Chem., Int. Ed. 2001, 40, 4363. (c) Sijbesma, R. P.;
Meijer, E. W. Chem. Commun. 2003, 5. (d) Wilson, A. J. Soft Matter 2007,
3, 409. (e) Yashima, E.; Maeda, K.; Iida, H.; Furusho, Y.; Nagai, K. Chem.
ReV. 2009, 109, 6102
.
10.1021/ol102522m  2011 American Chemical Society
Published on Web 12/06/2010

CDCl3) and synthetic accessibility. Efforts on addressing the
limit often associated with the simultaneous presence of
interconverting tautomers in heterocycle-based systems led
to the design of various multiply (number of hydrogen bonds
>3) hydrogen-bonded homo- and heterodimers with enhanced
strength, directionality, and specificity.8 Recently, a self-
complementary amidourea motif stabilized by four intermo-
lecular hydrogen bonds was found to be highly stable in polar
solvents of low polarity.9
Besides stability, specificity is the other major parameter
that determines the success and usefulness of designed
association modules.10 Among known systems, few allow
the adjustment (or programming) of association specificity.
We have constructed oligoamide strands carrying multiple
amide H and O atoms. These oligoamide strands associate
into duplexes via multiple hydrogen-bonding interactions
involving their amide H and O atoms. Our hydrogen-bonded
duplexes11 were found to be free of the tautomerism that
typically accompanies heterocycle-based complexes. In ad-
dition, secondary electrostatic interaction,12 a phenomenon
associated with most hydrogen-bonded heterocycles, is absent
in our oligoamide duplexes. As a result, the stability of a
hydrogen-bonded duplex is readily predictable, being directly
proportional to its number of interstrand hydrogen bonds.
The tuning of hydrogen-bonding sequence-specificity has so
far relied on varying the arrangement of hydrogen bond
donors and acceptors. Herein we describe a new approach
that adds to the diversity of association specificity while
maintaining the same sequence of hydrogen donors and
acceptors.
Instead of varying the arrangement of hydrogen bond
donors and acceptors, it was reasoned that changing the
spacings between interstrand hydrogen bonds in a duplex
should lead to altered association specificity. Such a pos-
sibility was first explored by the design of two oligoamide
strands 1 and 2 that contain napthalene residues with the
spacing of 7.2 Å between two close H-bonds. The benzene
residies, however, could only afford H-bonding sites with a
distance of 4.9 Å between two neighboring H-bonds, which
is obviously shorter than naphthalene units (Figure 1A).13
Sharing the same (DDAA) hydrogen-bonding sequence that
leads to the self-dimerization of the originally designed
oligoamide (e.g., 6 in Figure 2) with the spacing of ca. 4.8
Å, neither 1 nor 2 could undergo self-dimerization because
of the expanded spacing between the amide NH or carbonyl
groups attached to the napthalene residue. Instead, strands 1
and 2 carry complementary hydrogen-bonding sequences,
pairing of which leads to a heteroduplex 1·2.
(3) For recent examples, see: (a) Park, T.; Zimmerman, S. C.; Na-
kashima, S. J. Am. Chem. Soc. 2005, 127, 6520. (b) 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. (c) Park, T.; Zimmerman, S. C.
J. Am. Chem. Soc. 2006, 128, 11582. (d) Mather, B. D.; Baker, M. B.;
Beyer, F. L.; Green, M. D.; Berg, M. A. G.; Long, T. E. Macromolecules
2007, 40, 4396. (e) 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. (f) Kuykendall, D. W.; Anderson,
A. C.; Zimmerman, S. C. Org. Lett. 2009, 11, 61. (g) Hisamatsu, Y.; Shirai,
N.; Ikeda, S.; Odashima, K. Org. Lett. 2010, 12, 1776.
(4) (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. (b) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.;
Spek, A. L.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761. (c) So¨ntjens,
S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. J. Am.
Chem. Soc. 2000, 122, 7487.
(5) (a) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120,
9710. (b) Corbin, P. S.; Lawless, L. J.; Li, Z.-T.; Ma, Y.; Witmer, M. J.;
Zimmerman, S. C. Proc. Nat. Acad. Sci. U.S.A. 2002, 99, 5099.
(6) Greef, T. F. A. De; Smulders, M. M. J.; Wolffs, M.; Schenning,
A. P. H. J.; Sijbesma, R. P.; Meijer, E. W. Chem. ReV. 2009, 109, 5687.
(7) For selected examples, see: (a) Lange, R. F. M.; van Gurp, M.;
Meijer, E. W. J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 3657. (b)
Folmer, B. J. B.; Sijbesma, R. P.; Versteegen, R. M.; van der Rijt, J. A. J.;
Meijer, E. W. AdV. Mater. 2000, 12, 874. (c) Sanchez, L.; Rispens, M. T.;
Hummelen, J. C. Angew. Chem., Int. Ed. 2002, 41, 838. (d) Moriuchi, T.;
Tamura, T.; Hirao, T. J. Am. Chem. Soc. 2002, 124, 9356. (e) Bosman,
A. W.; Brunsveld, L.; Folmer, B. J. B.; Sijbesma, R. P.; Meijer, E. W.
Macromol. Symp. 2003, 201, 143. (f) Wang, X.-Z.; Li, X.-Q.; Shao, X.-B.;
Zhao, X.; Deng, P.; Jiang, X.-K.; Li, Z.-T.; Chen, Y.-Q. Chem.sEur. J.
2003, 9, 2904. (g) Albrecht, M. Angew. Chem., Int. Ed. 2005, 44, 6448. (h)
Shi, L.; Wang, X.-W.; Sandoval, C. A.; Li, M.-X.; Qi, Q.-Y.; Li, Z.-T.;
Ding, K.-L. Angew. Chem., Int. Ed. 2006, 45, 4108. (i) Huerta, E.; Cequier,
E.; de Mendoza, J. Chem. Commun. 2007, 5016. (j) Huerta, E.; Metselaar,
G. A.; Fragoso, A.; Santos, E.; Bo, C.; de Mendoza, J. Angew. Chem., Int.
Ed. 2007, 46, 202. (k) Mahesh, S.; Thirumalai, R.; Yagai, S.; Kitamurab,
A.; Ajayaghosh, A. Chem. Commun. 2009, 5984. (l) Kushner, A. M.;
Vossler, J. D.; Williams, G. A; Guan, Z. J. Am. Chem. Soc. 2009, 131,
8766. (m) Yang, S. K.; Ambade, A. V.; Weck, M. J. Am. Chem. Soc. 2010,
132, 1637.
Oligoamide strands 1-5 and 7 were synthesized in the
presence of EDCI and HOBt by standard amide coupling
chemistry.13,14 These strands could either self-dimerize (i.e.,
3 and 7) into a homoduplex or pair (i.e., 1 and 2, or 4 and
5) into a heteroduplex.
Oligoamide strand 6, with its DDAA array, was found to
dimerize in chloroform with a binding constant of 6.5 × 104
M-1.11a In contrast, 1H NMR dilution experiments revealed
a dimerization constant of ∼33 M-1 for 1 in chloroform,
confirming the weak self-association expected of this strand.
1
However, a H NMR titration experiment using 1 upon
(8) (a) Bisson, A. P.; Hunter, C. A. Chem. Commun. 1996, 1723. (b)
Deans, R.; Cooke, G.; Rotello, V. M. J. Org. Chem. 1997, 62, 836. (c)
Folmer, B. J. B.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W.
J. Am. Chem. Soc. 1999, 121, 9001. (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) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 2000, 122,
3779. (f) Rieth, L. R.; Eaton, R. F.; Coates, G. W. Angew. Chem., Int. Ed.
2001, 40, 2153. (g) Gonza´lez, J. J.; Gonza´lez, S.; Priego, E. M.; Luo, C.;
Guldi, D. M.; de Mendoza, J.; Mart´ın, N. Chem. Commun. 2001, 163. (h)
Zhao, X.; Wang, X.-Z.; Jiang, X.-K.; Chen, Y.-Q.; Li, Z.-T.; Chen, G.-J.
J. Am. Chem. Soc. 2003, 125, 15128. (i) Baruah, P. K.; Gonnade, R.;
Phalgune, U. D.; Sanjayan, G. J. J. Org. Chem. 2005, 70, 6461. (j) Nowick,
J. S. Acc. Chem. Res. 2008, 41, 1319. (k) Hisamatsu, Y.; Shirai, N.; Ikeda,
S.; Odashima, K. Org. Lett. 2009, 11, 4342.
addition of 2 from 1:0 to 1:1.8 at 1.8 mM revealed a
(11) (a) Gong, B.; Yan, Y.; Zeng, H.; Skrzypczak-Jankunn, E.; Kim,
Y. W.; Zhu, J.; Ickes, H. J. Am. Chem. Soc. 1999, 121, 5607. (b) Zeng,
H. Q.; Miller, R. S.; Flowers, R. A.; Gong, B. J. Am. Chem. Soc. 2000,
122, 2635. (c) Zeng, H. Q.; Yang, X. W.; Flowers, R. A.; Gong, B. J. Am.
Chem. Soc. 2002, 124, 2903. (d) Zeng, H. Q.; Yang, X. W.; Brown, A. L.;
Martinovic, S.; Smith, R. D.; Gong, B. Chem. Commun. 2003, 1556. (e)
Yang, X. W.; Martinovic, S.; Smith, R. D.; Gong, B. J. Am. Chem. Soc.
2003, 125, 9932. (f) Bialecki, J. B.; Yuan, L. H.; Gong, B. Tetrahedron
2007, 63, 5460. (g) Cao, R. K.; Zhou, J. J.; Wang, W.; Feng, W.; Li, X. L.;
Zhang, P. H.; Deng, P. C.; Yuan, L. H.; Gong, B. Org. Lett. 2010, 12,
2958.
(9) Chu, W.-J.; Yang, Y.; Chen, C.-F. Org. Lett. 2010, 12, 3156.
(10) (a) Sessler, J. L.; Wang, R. Z. J. Org. Chem. 1998, 63, 4079. (b)
Sijbesma, R. P.; Meijer, E. W. Curr. Opin. Colloid Interface Sci. 1999, 4,
24. (c) Sherrington, D. C.; Taskinen, K. A. Chem. Soc. ReV. 2001, 30, 83.
(d) Keizer, H. M.; Sijbesma, R. P. Chem. Soc. ReV. 2005, 34, 226.
(12) (a) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112,
2008. (b) Pranata, J.; Wierschkem, S. G.; Jorgensen, W. L. J. Am. Chem.
Soc. 1991, 113, 2810.
(13) See the Supporting Information.
(14) Valeur, E.; Bradley, M. Chem. Soc. ReV. 2009, 38, 606
.
Org. Lett., Vol. 13, No. 1, 2011
55

1
Table 1. Binding Constants (M-1) from H NMR Dilution and
Titration Experimentsa
compound
Kdim (M-1
)
compound
Ka (M-1
)
1·1
2·2
3·3
4·4
5·5
(3.3 ( 0.3) × 10
(1.7 ( 0.2) × 10
(1.6 ( 0.3) × 103
(4.2 ( 0.3) × 10
(5.2 ( 0.4) × 10
1·2
1·7
2·7
4·5b
(1.9 ( 0.6) × 104
(9.6 ( 0.8) × 102
(6.8 ( 0.7) × 102
(2.4 ( 0.7) × 105
a Measured by a dilution and titration experiment in CDCl3. Errors
represent the standard error of the data fit to the calculated isotherm.
b Measured by a titration experiment in CDCl3-5% DMSO-d6.
substantial downfield change for 1-Ha (∆δ ) 1.10 ppm) and
1-Hb (∆δ ) 2.15 ppm), indicating that protons Ha and Hb of
1 are involved in intermolecular hydrogen bonding, whereas
protons 1-Hc (∆δ ) 0.58 ppm) and 1-Hd (∆δ ) 0.23 ppm),
which are intramolecularly hydrogen-bonded, experienced
only a minor change. By fitting the concentration-dependent
change of the chemical shifts of proton Ha of 1 to a 1:1
binding motif,15 an association constant of 1.9 × 104 M-1
was obtained (Table 1).13 Two-dimensional NOE spectros-
copy (2D-NOESY) in CDCl3 provided the evidence for
formation of heteroduplex 1·2.13 Cross-strand NOEs between
1-Ha and 2-Hf, 1-Hb and 2-He, 1-Hl and 2-Ha, 1-Hl and 2-Hj,
and 1-Hf and 2-Hf in a 1:1 mixture of 1 and 2 (10 mM each)
were observed. Another piece of evidence confirming the
formation of hydrogen-bonded 1·2 came from mass spec-
trometry (ESI), which showed a peak (m/z 1789.23) of high
intensity that points to the presence of the species [1·2 +
H]+.13 Furthermore, ESI result clearly shows the absence of
both 1·1 dimer and 2·2 homodimers, demonstrating the
fidelity of heterodimer formation.
Figure 1. Oligoamide strands containing naphthalene residues and
sharing the same (DDAA) sequences but assemble into heterodu-
plexes 1·2 and 4·5 or homoduplex 3·3.
The DDAA sequences of 1 and 2, although they bear
nominal similarity in sequence order to benzene-based
oligoamide strands such as 6 and 7,11a only led to the
formation of a heteroduplex. Such an altered association
specificity is further demonstrated by a competition experi-
ment that involved adding stand 7 from 0 to 2 equiv to a
mixture of 1 and 2 (2.0 mM each) in 1:1 molar ratio. The
chemical shifts of both protons Ha and Hb of 1 and 2 showed
insignificant changes (∆δ ) 0-0.09 ppm) in the presence
of 7 (Figure 3a)13 as compared to a change of 0.24 or 0.19
ppm in the control experiments by adding 7 to 1 or to 2.
This observation clearly indicates that duplex 1·2 experiences
only a very small change despite the presence of an
oligoamide strand having also borne a DDAA sequence.
Besides expanding diversity of association specificity, the
availability of naphthalene-derived building blocks allows
many new duplexes to be constructed. For example, with
two naphthalene residues in its structure, strand 3 is self-
complementary and was found to dimerize into hydrogen-
bonded duplex 3·3 with a Kdimer of 1.6 × 103 M-1 obtained
by standard nonlinear least-squares regression analysis of the
concentration-depdendent chemical shift changes of proton
3-Hb.13 2D-NOESY experiment (10 mM in CDCl3) and ESI-
Figure 2. Self-complementary oligoamide dimer structures of 6·611a
and 7·7 with the DDAA arrays.
(15) Conners, K. A. Binding Constants: The Measurement of Molecular
Complex Stability; Wiley-Interscience: New York, 1987.
56
Org. Lett., Vol. 13, No. 1, 2011

experiment of 5 with 4 from 0 to 2.0 equiv in CDCl3-5%
DMSO-d6 revealed the downfield shift for amide protons
5-Ha and an upfield shift for protons 4-Ha and 4-Hb,
indicating the specific pairing of the two strands via hydrogen
bonding. Since the six-hydrogen-bond benzene-based het-
eroduplex demonstrated an extremely high binding affinity
with Kdimer of ∼109 M-1 in chloroform, the association
constant of 4·5 having the same number of H-bonding sites
was expected to be beyond the limit of detection by 1H NMR
technique. Thus, using 1H NMR titration in a solvent
containing CDCl3-5% DMSO-d6, the Ka of 4·5 was deter-
mined to be 2.4 × 105 M-1, which is about 10-fold lower
than that of six-hydrogen-bond benzene-derived duplexes
(∼106 M-1),11b strongly suggestive of the spacing effect of
H-bonding sites in tuning both binding affinity as well as
specificity by incorporating naphthalene residues.
When two different molecular components such as 1 and
2 associate via multiple hydrogen bonding interactions, the
self-association of each individual component is usually
inevitable, which compromises the stability of the target
complex. Examining the self-dimerization of naphthalene-
1
Figure 3.
1H NMR titration of strand 7 from 0 to 2 equiv into (a)
based oligoamide strands 1, 2, 4, and 5 using H NMR
dilution experiments indicates that the self-association of
these strands was very weak, with Kdimer values of 33, 17,
42, and 52 M-1, respectively.13 Therefore, as compared to
our previously developed oligoamide strands, many of which
undergo appreciable extent of self-association,11b the self-
association of oligoamide strands containing naphthalene
residues was significantly reduced.
In conclusion, by incorporating naphthalene-based resi-
dues, we have demonstrated an approach for creating new
association specificity for hydrogen-bonded duplexes. De-
pending on their specific benzene or naphthalene residues,
the designed duplexes may share the same hydrogen-bonding
sequences but may form either homo- or heteroduplexes.
Manipulating association specificity by varying the spacings
between interstrand hydrogen bonds, as demonstrated by this
work, may be extended to other multiple hydrogen bonded
systems. Detailed studies on these aspects are currently being
investigated and will be reported in due course.
duplex 1·2 (2.0 mM) and (b) duplex 3·3 (2.0 mM) in CDCl3 at 298
K.
HRMS ([3·3 + H]+, m/z: 1647.75) provided the evidence
for formation of homoduplex 3·3.13 When strand 3 (2.0 mM)
was titrated with 7 from 0 to 2 equiv., the chemical shifts
for the amide protons 3-Ha and 3-Hb were found to undergo
negligible change (∆δ ≈ 0.03 ppm), which exhibits that the
presence of strand 7 inflicted insignificant impact on the
binding affinity of 3·3 (Figure 3b) and thus led to the high
association specificity of duplex 3·3. It is noteworthy that
enlarged distance between the near two H-bonding sites
caused a decrease in binding ability (1.6 × 103 M-1)
compared to normal benzene-based oligoamide duplexes such
as 6 (∼104 M-1).
While shorter naphthalene-derived duplexes with matched
sequence demonstrated appreciable affinity, does extension
to the longer ones lead to the increased binding capability?
Thus, strands 4 and 5 were prepared and examined for their
hydrogen bond-mediated association. With heterocomple-
mentary H-bonding sequences DDAADD and AADDAA,
strands 4 and 5 are supposed to pair via six interstrand
hydrogen bonds. 2D-NOESY experiment (10 mM in CDCl3)
provided the evidence for the formation of heteroduplex
4·5.13 Cross-strand NOEs between 4-Hd and 5-Ha, 4-Hi and
5-Ha, 4-Ha and 5-Hi, and 4-Ha and 5-Hg were observed in a
1:1 mixture of 4 and 5 (5.0 mM each). In the ESI-HRMS
spectra, an ion peak corresponding to duplex of 4·5 (m/z:
Acknowledgment. The authors acknowledge the National
Natural Science Foundation of China (20874062) and SRF
for ROCS for funding this work and Analytical & Testing
Center of Sichuan University for NMR analysis.
Supporting Information Available: Synthesis, analytical
data, 2D NMR and ESI mass spectra, and the assemblies of
the duplexes. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
2640.62 for [4·5 + H]+) was observed. H NMR titration
OL102522M
Org. Lett., Vol. 13, No. 1, 2011
57