C O M M U N I C A T I O N S
nonpolar solvents. (2) The programmable specificity of our H-
bonded duplexes allows the generation of a large number of
duplexes that are cross-linked sequence-specifically by disulfide
bonds, which greatly expands the diversity of this important, but
symmetrical, dynamic covalent interaction. Using these supra-
molecular-dynamic covalent linking units, the directed, specific
formation of covalently linked structures and materials based on a
self-assembling fashion under mild, biocompatible conditions can
be envisioned. (3) Fundamentally, this system offers a platform
for studying the role of H-bonding interaction in water and other
competitive media. Obviously, H-bonding interactions play a critical
role in this case. Such a role can be either kinetic, based on the
sequence-specific association of the complementary stands, which
increases the effective molarity of the disulfide formation reaction,
or thermodynamic, based on the stabilization of the cross-linked
products through fully matched H-bonding sequences. Elucidating
the corresponding mechanism should lead to a deeper understanding
and better control of H-bonding in aqueous media, a challenge
worthy of addressing.
Figure 1. MALDI-TOF MS spectra of (a) the 1:1 mixture of 1 and 2 and
(b) the 1:1:1 mixture of 1, 2, and 3, in H2O/THF (9/1, v/v) in the presence
of iodine (6 mM).
Figure 2. HPLC traces of aliquots of the solutions of (a) the 1:1 mixture
of 1 and 2 and (b) the 1:1:1 mixture of 1, 2, and 3, in H2O/THF (9/1, v/v)
in the presence of iodine (6 mM). Retention time: 1-2 (21 min); 3-3 (35
min); 3′ (42 min).
Acknowledgment. This work was supported by the Petroleum
Research Fund, administered by the ACS (37200-AC4). ONR, NSF,
and NIH are acknowledged for partial funding.
using MALDI-TOF. It was found that, although having four and
three matched sites with 1 and 2, respectively, strand 3 did not
interfere with the formation of 1-2. The cross-linked 1-2 was
detected as the major product (Figure 1b). Compared to 1-2, other
possible products, such as the cross-linked 3-1 or 3-2, did not
appear in significant portion. In contrast, when mixed in water in
the presence of iodine, amide 3 did pair with 4 and form the cross-
linked 3-4 as the dominant product,14 suggesting that the observed
specific pairing and cross-linking were not a special case associated
with 1 and 2 only.
While MALDI-TOF experiments provide clear, yet qualitative,
evidence for the sequence-specific formation of the cross-linked
duplexes in aqueous solution, the cross-linking of 1 and 2 in water
was also examined by reverse phase HPLC. As shown in Figure
2a, the 1:1 mixture of 1 and 2, after being treated with iodine in
water, formed the cross-linked 1-2 exclusively. In contrast, strands
1 or 2 alone formed mostly the disulfide cyclized monomeric 1′
and 2′.14 The presence of strand 3 did not interfere with the
exclusive formation of 1-2 (Figure 2b). The identity of each HPLC
fraction was confirmed by comparing with standards or by ESI
and MALDI. These results are fully consistent with those from the
MALDI experiments, which provide conclusive evidence for the
sequence-dependent nature of the formation of the disulfide cross-
linked duplexes in aqueous media.
The efficiency of the sequence-dependent disulfide cross-linking
was also demonstrated by isolating 1-2 from a reaction on a larger
scale.14 The cross-linked crude product 1-2 formed nearly quan-
titatively and was still obtained in 80% yield even after exhaustive
purification using flash column chromatography followed by reverse
phase HPLC.
The above results clearly indicate that, in highly competitive
media, such as methanol and water, by introducing reversible
covalent forces into a H-bonded system, the high sequence
specificity offered by the H-bond arrays can be completely
preserved. This discovery is significant in several aspects: (1) The
combination of the sequence specificity of H-bond arrays and the
strength of disulfide bonds offers a novel class of molecular
associating and ligating units that are applicable in both polar and
Supporting Information Available: Experimental details, NMR
data, MS spectra, HPLC traces, and structures of cross-linked products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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