Interplay of olefin metathesis and multiple hydrogen bonding interactions: Covalently cross-linked zippers

Article abstract of DOI:10.1021/ol201282d

Hydrogen-bonded zippers bearing terminal alkene groups were treated with Grubbs' catalyst, leading to covalently cross-linked zippers without violating H-bonding sequence specificity. The yield of a cross-linked zipper depended on the stability of its H-b

Full text of DOI:10.1021/ol201282d

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3798–3801
Interplay of Olefin Metathesis and Multiple
Hydrogen Bonding Interactions:
Covalently Cross-linked Zippers
Jisen Zeng,† Wei Wang,† Pengchi Deng,† Wen Feng,† Jingjing Zhou,† Yuanyou Yang,†
Lihua Yuan,*,† Kazuhiro Yamato,‡ 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; bgong@buffalo.edu
Received May 12, 2011
ABSTRACT
Hydrogen-bonded zippers bearing terminal alkene groups were treated with Grubbs’ catalyst, leading to covalently cross-linked zippers without
violating H-bonding sequence specificity. The yield of a cross-linked zipper depended on the stability of its H-bonded precursor, with a weakly
associating pair giving reasonable yields only at high concentrations while strongly associating pairs showed nearly quantitative yields. The
integration of thermodynamic (H-bonding) and kinetic (irreversible CdC bond formation) processes suggests the possibility of developing many
different covalent association units for constructing molecular structures based on a self-assembling way.
One major objective of modern chemistry involves the
development of strategies for controlling both the specifi-
city and strength of the association of various structural
components into higher-order assemblies or structures.1 In
nature, the assembly of molecular components mediated
by highly specific, multiple noncovalent interactions leads
to well-defined, thermodynamically stable aggregates. In-
spired by natural examples, many artificial self-assembling
structures have been successfully constructed.2 For exam-
ple, the pioneering studies by Jorgenson and Zimmerman
on the association of nucleobases resulted in H-bonded
pairs that mediate specific intermolecular interactions.3
Subsequently, the groups of Zimmerman4 and Meijer5
reported highly stable H-bonded complexes based on
† Sichuan University.
‡ The State University of New York.
(1) (a) Lehn, J. M. Supramolecular Chemistry: Concepts and Perspec-
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1997, 97, 1647. (c) Moore, J. S. Curr. Opin. Colloid Interface Sci. 1999, 4,
108. (d) Leininger, S.; Olenyuk, B.; Stang, P. J. Chem. Rev. 2000, 100,
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Zimmerman, S. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5099. (b) Park,
T.; Todd, E. M.; Nakashima, S.; Zimmerman, S. C. J. Am. Chem. Soc.
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(5) (a) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.;
Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761. (b) Folmer, B. J. B.;
Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W. J. Am. Chem.
Soc. 1999, 121, 9001. (c) Brunsveld, L.; Zhang, H.; Glasbeek, M.;
Vekemans, J. A. J. M.; Meijer, E. W. J. Am. Chem. Soc. 2000, 122, 6175.
r
10.1021/ol201282d
Published on Web 06/24/2011
2011 American Chemical Society

aromatic heterocycles. These H-bonded complexes served as
association units for forming various supramolecular
structures.6 Enlightened by duplex DNA, a series of infor-
mation-storing molecular duplexes or zippers, consisting
of oligoamide strands carrying complementary arrays
(sequences) of H-bond donors and acceptors, were devel-
oped by us.7 These H-bonded zippers are featured by tunable
affinity, programmable sequence specificity, and ready syn-
thetic availability and represent an alternative class of readily
adjustable association units for the instructed assembly of
molecular components. For example, our H-bonded zippers
assisted the formation of β-sheets by bringing natural pep-
tide strands into close proximity,8 “glued” different polymer
chains into supramolecular block copolymers,9 andservedas
templates for directing reactions.10
Despite their advantages, H-bonded complexes are limited
by their thermal instability and dissociation in polar media.
These drawbacks impede the application of H-bonded units
in competitive media or at elevated temperatures. It was
reasoned that introducing additional stabilizing forces, such
as dynamic covalent interactions,11 may address the inherent
instabilty of H-bonded systems while maintaining the high
specificity typical of multiple noncovalent forces. We have
demonstrated that equipping our H-bonded zippers with
disulfide bonds led to association units that are stable in
aqueous media.12 By combining both the sequence specifi-
city of multiple H-bonds and the stability of covalent bonds,
such units provided a new strategy for the construction of
covalent structures in a self-assembling way. Olefin metath-
esis, as the other major type of dynamic covalent interac-
tions, allows the formation of CdC bonds that are much
more stable than disulfide bonds. As an attempt to establish
the generality of integrating multiple H-bonding with dy-
namic covalent bonding interactions, we set to explore
H-bonded zippers cross-linked via olefin metathesis.9,13,14
We describe herein H-bond-mediated covalent cross-
linking of oligoamides 1, 2, and 3 that dimerize into two-,
four-, and six-H-bonded zippers, as defined by their self-
complementary H-bonding sequences.15 With terminal
alkene moieties attached to their ends, the H-bonded
duplexes of these oligoamides are expected to undergo
metathesis reactions in the presence of Grubbs’ catalyst,
leading to products 1-1, 2-2, and 3-3 cross-linked by CdC
bonds (Scheme 1).
Oligoamide strands 1ꢀ3 were synthesized16 and sub-
jected to metathesis in CH2Cl2. As established by our
previous studies, in solution, compounds like 1a, 2a, and
3 exist as H-bonded dimers with stabilities proportional to
the numbers of their interstrand H-bonds.15,16
Thus, compounds 1aꢀ1d (2 mM) were first treated with
Grubbs’ catalyst in CH2Cl2 under reflux for 4 h, results
from which should reveal the effect of the aliphatic
[ꢀ(CH2)mꢀ and ꢀ(CH2)nꢀ] spacers on the efficiencies of
the corresponding reactions. The conversion of 1c or 1d
was very inefficient (<11%). In each case, a mixture
containing the cross-linked 1c-1c or 1d-1d, the unreacted
starting material, and another product from the metathesis
of only one of the two terminal alkene groups was
obtained. In contrast, compound 1b exhibited a much
higher conversion (40%), with 1b-1b as the major product
(36%). A drastic improvement of conversion (90%) was
observed for 1a, with 1a-1a being formed in 41.5% yield
(Table 1). However, the reaction of 1a also led to a self-
cyclized product 4 (49%).16 Similar intramolecular cycli-
zation was not observed for 1b, 1c, and 1d. The shortened
aliphatic spacers of these three compounds seemed to have
compromised the yields of the cross-linked zippers. Thus
the samealiphatic spacers of 1a(m = 3, n = 8) were chosen
to design 2a and 3. Compound 2b, with shortened spacers,
was also prepared for comparison.
Scheme 1. Metathesis of Oligoamide Strands 1ꢀ3
(6) For selected examples, see: (a) Brunsveld, L.; Folmer, B. J. B.;
Meijer, E. W.; Sijbesma, R. P. Chem. Rev. 2001, 101, 4071. (b) Todd,
E. M.; Zimmerman, S. C. J. Am. Chem. Soc. 2007, 129, 14534. (c) 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.
(7) (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.; Brown, A. L.; Martinovic, S.;
Smith, R. D.; Gong, B. Chem. Commun. 2003, 1556.
(8) (a) Zeng, H. Q.; Yang, X. W.; Flowers, R. A., II; Gong, B. J. Am.
Chem. Soc. 2002, 124, 2903. (b) Yang, X. W.; Martinovic, S.; Smith,
R. D.; Gong, B. J. Am. Chem. Soc. 2003, 125, 9932.
(9) Yang, X. W.; Hua, F. J.; Yamato, K.; Ruckenstein, E.; Gong, B.;
Kim, W.; Ryu, C. Y. Angew. Chem., Int. Ed. 2004, 43, 6471.
(10) Yang, X. W.; Gong, B. Angew. Chem., Int. Ed. 2005, 44, 1352.
(11) (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders,
J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898. (b) Furlan,
R. L. E.; Otto, S.; Sanders, J. K. M. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 4801.
(12) Li, M. F.; Yamato, K.; Ferguson, J. S.; Singarapu, K. K.;
Szyperski, T.; Gong, B. J. Am. Chem. Soc. 2008, 130, 491.
(13) 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.
(14) Gong, B. Synlett 2001, 582.
Under the same conditions, compound 2a (2 mM),
which dimerizes via four H-bonds, was converted nearly
(15) Gong, B. Polym. Int. 2007, 56, 436.
(16) See Supporting Information for details.
Org. Lett., Vol. 13, No. 15, 2011
3799

quantitatively into 2aꢀ2a, with only a trace of the self-
cyclized product being detected. In contrast, the metathesis
of 2b (2 mM) showed a significantly lowered conversion of
65%, resulting in a mixture consisting of the cross-linked
product 2bꢀ2b and another open-chain product16 derived
from two molecules of 2b that are cross-linked at one of
their ends.16 Results based on 2a and 2b again confirmed
that the aliphatic spacers revealed by 1a were appropriate
for efficient cross-linking. High cross-linking efficiency
was also observed for 3. At 2 mM, cross-linked 3-3 formed
as the only product (Table 1).
Thus, at the same concentration (2 mM), the efficiency
for an oligoamide to form its cross-linked dimer is corre-
lated to the stability of its H-bonded dimer. Compound 1a
formed the least stable H-bonded dimer and gave the
lowest yield of the cross-linked 1a-1a, while 3 formed the
most stable H-bonded dimer and resulted in the highest
yield of the cross-linked 3-3. This suggests that the forma-
tion of a cross-linked zipper is determined by the abun-
dance of its H-bonded precursor. A H-bonded zipper such
as that of 3 represents the dominant species in solution,
which forms 3-3 nearly quantitatively.
CHCl3)15 in a much broader concentrations range, gave
2a-2aasthe dominant product withonly a small amount of
the self-cyclized product appearing when the concentra-
tion was lowered to 0.05 mM. The H-bonded zipper
formed by 3, with its extremely high stability (Kdimer
g
109 Mꢀ1 in CHCl3),7b exists as the dominant form down to
extremely low concentrations, which translates into the
exclusive formation of 3-3 at all the concentrations tested.
These results suggest that the presence of the H-bonded
dimer of 1a, 2a, or 3 precedes the formation of the cross-
linked 1a-1a, 2a-2a, or 3-3. The abundance of a H-bonded
dimer relies on both the concentration of the oligoamide
component and the stability of such a dimer. At low
concentrations, the weakly H-bonding 1a exists mostly as
free molecules whose only option was to self-cyclize.
Increasing the concentration of 1a drives the equilibrium
toward the H-bonded dimer, which led to 1a-1a in increas-
ing yields. The strongly dimerizing 2a and 3, on the other
hand, exist mostly as their H-bonded dimers in a wide
range of concentrations, which led to 2a-2a and 3-3 in a
seemingly concentration-independent fashion.
Thus, the above results indicate that the formation of the
cross-linked 1a-1a, 2a-2a, and 3-3 relies on the presence of
their H-bonded zipper precursors in solution. Such an
observation may be rationalized by a mechanism consist-
ing of two synergistically interacting steps: (1) the rever-
sible, sequence-specific pairing of the oligoamide
components, which leads to the correponding H-bonded
dimers that then undergo (2) irreversible cross-linking due
to the metathesis of the terminal olefin units that is brought
intoclose proximity. The rate of the second step is expected
to be very rapid, i.e., similar to that of a intramolecular
Table 1. Duplex-Assisted Olefin Cross Metathesis of Com-
pounds 1ꢀ3a
self-
cyclized
concn
(mM)
conv (%)
product
compd
(total yield %)
yield (%)
yield (%)
1a
2.0
0.5
0.05
2.0
2.0
2.0
2.0
0.5
0.05
2.0
2.0
0.5
0.05
2.0
0.5
95 ( 1 (90 ( 1)
94 ( 1 (90 ( 1)
98 ( 1 (96 ( 1)
40 ( 1 (36 ( 1)
10 ( 1
41 ( 2
14 ( 1
traceb
mixb
49 ( 1
76 ( 2
96 ( 1
trace
ndc
1b
1c
1d
2a
mixb
< 5
mixb
ndc
100 (94 ( 1)
100 (95 ( 1)
100 (95 ( 1)
65 ( 2 (61 ( 2)
100 (97 ( 1)
100 (98 ( 1)
100 (97 ( 1)
100 (97 ( 1)
100 (95 ( 1)
94 ( 1b
91 ( 1b
83 ( 1b
mixb
trace
4 ( 1
12 ( 1
ndc
2b
3
97 ( 1
98 ( 1
97 ( 1
97 ( 1
95 ( 1
ndc
ndc
ndc
5 þ 6
trace
trace
a Grubbs’ catalyst 10 mmol %; solvent: CH2Cl2; temperature: reflux.
Conversions and yields of the cross-linked products were based on
isolated products by chromatography or by PTLC or on the reaction
mixture determined by 1H NMR (400 MHz) analyses using DMF as an
internal quantification standard. b Containing the cross-linked zipper,
the product cross-linked at one of their ends and/or unreacted starting
material. c Not detectable on TLC and by MALDI-TOF.
The metathesis of 1a, 2a, and 3 was further explored at
different concentrations (Table 1). Upon diluting from 2.0
to 0.05 mM, the yield of 1a-1a decreased from ∼42% to
nearly 0, with the self-cyclized 4 becoming increasingly
predominant as the concentration decreased. On the other
hand, boosting the concentration of 1a to 40 mM led to 1a-
1a in 60% yield. Compared to 1a, compound 2a, which
exists mainly as its H-bonded dimer (Kdimer > 104 Mꢀ1 in
Figure 1. MALDI-TOF spectra of (a) the 1:1 mixture of 1a and
2a; (b) the 1:1 mixture of 1a and 3; (c) the 1:1 mixture of 2a and 3;
(d) the 1:1 mixture of 1a, 2a, and 3 at 2.0 mM in CH2Cl2 (m/z
values: 1079.7 [1a-1a þ Naþ], 551.4 [4 þ Naþ]; 1704.5 [2a-2a þ
Kþ], 1688.1 [2a-2a þ Naþ], 1666.5 [2a-2a þ Hþ], 2364.4 [3-3 þ
Naþ]) (2.0 mM).
3800
Org. Lett., Vol. 13, No. 15, 2011

reaction, because of the greatly enhanced molarity of the
terminal olefins attached to a H-bonded zipper. The rapid,
irreversible metathesis reaction serves to covalently cap-
ture the various molecular and H-bonded species that exist
in equilibrium in solution.
Scheme 2. Cross Metathesis of Strands 5 (2.0 mM) in AADA
and 6 (2.0 mM) in DDAD Sequence for Forming H-Bonded
Heteroduplex in CH2Cl2
The irreversible, i.e., kinetically controlled, nature of the
cross-linking step is reasonable given that the metathesis
reaction of terminal olefin units generates ethylene as the
other product that is highly volatile and thus is easily lost
from the reaction system.17 Despite the irreversibility of the
cross-linking step, the above results demonstrate that
H-bonded zippers with a large dimerization constant, when
equipped with terminal alkene groups, could serve as
specific covalent association units at very low concentra-
tions. In contrast, the low stability of the H-bonded pair of
1a means that acceptable yields of the cross-linked product
could only be achieved at elevated concentrations.16
Despite their overlapping H-bonding sequences, com-
pounds 1a, 2a, and 3 (2.0 mM in CH2Cl2) demonstrated an
interesting self-sorting behavior in the formation of their
cross-linked dimers (Figure 1). When subjecting these
compounds to Grubbs’ catalyst, only homodimers and
the self-cyclized product of 1a were detected. For example,
a mixture of 1a and 2a led to products 1a-1a and 2a-2a and
the self-cyclized 4. The presence of 1a, 2a, and 3 in solution
did not lead to any cross-coupled products. Such high
selectivity was further evidenced by NMR experiments.16
The high efficiency observed for the metathesis of 2a and
3 is not a phenomenon limited to those having self-com-
plementary H-bonding sequences only. Oligoamides 5 and
6 pair sequence-specifically based on their complementary
H-bonding sequences.16 Upon treating with Grubbs’ cata-
lyst, 5 and 6 (2.0 mM in CH2Cl2) led to the cross-linked 5ꢀ6
almost exclusively, which demonstrates the strict sequence
specificity of these covalent association units (Scheme 2).
In summary, the cross-linking of H-bonded pairs with
four and six interstrand H-bonds demonstrated high effi-
ciency and selectivity. The formation of a cross-linked
zipper involves a mechanism consisting of a reversible
association step followed by an irreversible covalent
cross-linking step. In comparison to the formation of
disulfide-linked zippers,12 which is based on fully reversible
noncovalent and covalent interactions and shows no con-
centration or stability dependence, forming the cross-linked
zippers based on olefin metathesis depends on stability (i.e.,
1avs 2avs 3) and/or concentration (i.e., 1a). Besides leading
to covalent linkages of greatly enhanced strength, the
mechanism revealed for the current system could add
additional options for tuning covalent linking units. The
self-sorting behavior shown by the self-complementary
pairs and the similarly high efficiency in the cross-linking
of the heterozipper consisting of 5 and 6 greatly enhancethe
diversity and specificity allowed by this class of H-bond-
mediated covalent association units, which may be used in
the construction of various covalent assemblies, robust
materials, and supramolecular polymers.
Acknowledgment. The authors acknowledge the Na-
tional Natural Science Foundation of China (20874062),
the National Science Foundation of the USA (CBET-
1036171 and CBET-1066947). This work is also part of a
Project sponsored by SRF for ROCS, SEM (20071108-18-
16). We also thank the Analytical Center of Sichuan
University for NMR analyses.
Supporting Information Available. Synthesis, analytical
data, 2D NMR, HPLC, and MALDI-TOF spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Conrad, J. C.; Eelman, M. D.; Silva, J. A. D.; Monfette, S.;
Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007, 129,
1024. (b) Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2006, 10, 185.
Org. Lett., Vol. 13, No. 15, 2011
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