Synthesis of a redox-responsive quadruple hydrogen-bonding unit for applications in supramolecular chemistry

Article abstract of DOI:10.1021/ja2069278

A redox-responsive quadruple hydrogen-bonding module (eDAN) has been developed. The strong binding between the reduced form and its partner (DeUG) can be significantly decreased upon oxidation but restored upon subsequent reduction. This on-off switch was successfully applied to provide reversible control of macroscopic supramolecular polymer networks.

Full text of DOI:10.1021/ja2069278

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pubs.acs.org/JACS
Synthesis of a Redox-Responsive Quadruple Hydrogen-Bonding Unit
for Applications in Supramolecular Chemistry
Ying Li, Taiho Park,† J. Kwansima Quansah, and Steven C. Zimmerman*
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
S Supporting Information
b
Scheme 1. Interconversion of 1red and 1ox and the Structure
of 2
ABSTRACT: A redox-responsive quadruple hydrogen-
bonding module (eDAN) has been developed. The strong
binding between the reduced form and its partner (DeUG)
can be significantly decreased upon oxidation but restored
upon subsequent reduction. This onꢀoff switch was suc-
cessfully applied to provide reversible control of macro-
scopic supramolecular polymer networks.
Scheme 2. Synthesis of 1red
upramolecular building blocks featuring arrays of hydrogen-
S
bond donor and acceptor groups have played a key role in
self-assembled systems, nanofabrication, and supramolecular
polymer chemistry.1 One advantage of the supramolecular ap-
proach is that it allows for the development of stimuli-responsive
or smart systems and devices. For example, the hydrogen-bond
complexation strength is quite sensitive to pH, temperature, and
solvent polarity.2 Indeed, Leigh and co-workers showed that
protonation of 2,6-diaminopyridine, a unit with a DAD hydro-
gen-bonding array (D = donor, A = acceptor) converts it into a
DDD unit, thereby increasing its affinity for an AAA unit by >109-
fold.3 Smith recently defined a good switch as one in which the
external signal changes the association constant (Kassoc) by at
least 10-fold.4 By this measure, the Leigh system is remarkable,
equivalent to an onꢀoff switch. Furthermore, it points to the
general utility of altering the hydrogen-bonding motif in devel-
oping effective stimuli-responsive units. However, external stimuli
such as pH, temperature, and solvent polarity changes often lack
the necessary selectivity when more than one hydrogen-bonded
complex is involved, and switching can prove difficult to achieve
in a practical setting.
Compound 1 (1red or 1ox), designated as eDAN, is based on our
previously reported 2,7-diamido-1,8-naphthyridine (DAN) unit
that forms a very stable8 and high-fidelity9 quadruply hydrogen-
bonded complex with the ureas of guanosine (UG)10 and deaza-
guanosine 2 (DeUG).11 The DeUG unit is a more stable and
preparatively scalable analogue of UG. We further report that the
eDAN redox switch can be applied to supramolecular hydrogen-
bonded polymer blends.12
The three-step synthesis of 1red from commercially available 3
is outlined in Scheme 2. Compound 4 was recently reported as
a substrate for copper-catalyzed amination.13 However, neither
Cu2O nor various palladium catalysts effected the CꢀN bond
formation between 4 and 4-aminophenol. Ultimately it was
found that this amination reaction takes place directly using
pyridine in dioxane at high temperature.14
Photo- and electrochemical approaches have some distinct
advantages because often they are reversible and efficient, avoid-
ing the addition of chemical reagents. Apart from Hecht’s photo-
switchable triple hydrogen-bonding motif,5 considerable effort
has focused on electroactive units.4,6 Rotello7 has pioneered a
particularly useful redox approach involving the reduction of
recognition units with imide-like groups. The reduction does not
alter the hydrogen-bonding motif but rather converts the ADA
array of hydrogen-bond donor and acceptor groups into the
corresponding radical anion (ADA•ꢀ), which pairs more strongly
with its complementary (DAD) partner.
The interconversion of 1red and 1ox was examined both
chemically and electrochemically. Cyclic voltammetry indicated
that the oxidation of 1 was not fully reversible [see the Support-
ing Information (SI)]. The redox half-reactions could be accom-
plished chemically and on a preparative scale by treatment of 1red
with activated MnO2.15 The reduction back to 1red occurred with
zinc/acetic acid (Zn/H+).16 With an eye toward applications and
specifically an interest in materials that might respond to oxygen,
a broader set of redox reagents were examined. As shown in
Table 1, copper(II) acetate and N,N0-bis(salicylidene)ethylene-
diaminocobalt(II) (salcomine)17 serve as catalysts for the O2
Herein we report an approach that uses a redox reaction
to transform the DAAD hydrogen-bonding array in 1red to a
DAA (or DAAA) array in 1ox, which leads to a surprisingly large
change in hydrogen-bonding complexation strength (Scheme 1).
Received: July 24, 2011
Published: October 04, 2011
r
2011 American Chemical Society
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Table 1. Redox Chemistry of 1a
entry
redox agent
equiv temp. (°C) time (min) yield (%)b
Ox-1
Ox-2
Ox-3
activated MnO2
Cu(OAc)2/O2
salcomine/O2
5
25
50
25
25
25
30
720
30
89
82
92
80
96
0.2
0.05
2/20
1
Red-1 Zn/H+
30
Red-2 hydroquinone
a Reactions were performed in chloroform. b Isolated yields.
30
oxidation of 1red. However, in the presence of 2, only salcomine
effected the conversion of 1 red to 1ox, with 0.1 equiv required to
reach ca. 80% conversion. The resistance to oxidation in the
presence of 2 can be attributed to the high stability of the 1red
2
3
complex and the low solubility of Cu(OAc)2 in chloroform. The
reduction of 1ox was effected by hydroquinone in 96% yield.
The abilities of 1red and 1ox to complex 2 were examined
qualitatively by 1H NMR spectroscopy (Figure 1). For the sake
of clarity, CD2Cl2 was chosen as the NMR solvent. Worthy of
note are the significant downshifts of the NHA and NHB pro-
tons of 2 upon addition of 1red. In contrast, the same protons
shift minimally upon addition of 1ox. Quantitative complexation
studies were performed with 1 and 2 in chloroform using iso-
thermal titration calorimetry (ITC) (Figure 2). The 1red
2
3
complex exhibited an apparent association constant (Kassoc) of
1.1 ꢁ 106 Mꢀ1. After correction for the weak dimerization of 2,
which causes the endothermal dip leading up to 1 equiv in the
ITC curve, the actual value of Kassoc was found to be 1.4 ꢁ 106
Mꢀ1 11,14
Although the ITC data for 1ox 2 did not allow the
1
.
3
binding to be quantified, a H NMR titration study afforded a
corrected Kassoc of 6.7 ꢁ 102 Mꢀ1 for 1ox 2. The large value of
3
Kassoc for 1red 2 is similar to that reported for the DAN UG and
3
3
DAN DeUG complexes.
3
The more than 2 ꢁ 103-fold decrease in Kassoc represents one
of the largest attenuations of binding strength for a redox switch.
Indeed, the nearly 5 kcal molꢀ1 loss of binding affinity is too large
to be attributed to the loss of a single hydrogen bond. Similar
DAA ADD complexes show Kassoc values of ca. 104 Mꢀ1.8 Two
1
3
Figure 1. (a) H NMR spectra (500 MHz, CD2Cl2, 295 K) of (top)
red, (middle) 1red 2, and (bottom) 2 showing the changes to 1red and 2
factors may readily account for the weaker binding by 1ox. First,
simple modeling indicates that 1ox prefers the conformer shown
in Figure 2b, in which the azaquinone unit sterically blocks the
DAA hydrogen-bonding edge. The complexation may occur as
1
3
1
upon association to form 1red 2. (b) H NMR spectra (500 MHz,
CD2Cl2, 295 K) of (top) 1ox, (middle) 1ox 2, and (bottom) 2. The
assignments in (a) and (b) are tentative. The 1red 2 complex may form
two ways, both likely in fast exchange. Some peaks are cut off.
3
3
3
shown in the 1ox 2 complex in Figure 1b (DAAA array), but it
3
contains two flanking nonbonded electron pairs (a destabilizing
interaction) and uses a less stable conformer.
yield, of each step in Scheme 3 perhaps because of its increased
resistance to cleavage and improved solubility.18
We previously reported that polystyrene (PS) and poly(butyl
methacrylate) (PBMA), two ordinarily immiscible polymers,
form miscible blends/gels when the PS and PBMA contain
DAN and UG units, respectively, at compositions of a few
mole percent.12 The ability of free DAN to inhibit this supra-
molecular polymer blend suggested the use of eDAN 1 to create
stimuli-responsive systems. PS-DAN (5) was synthesized in
three steps, including a free radical polymerization as described
previously, except with the small but significant change that
the synthesis began with 2-ethylhexylamido-containing DAN 4
(Scheme 3a). In comparison with the previous approach,12 the
incorporation of the branched alkyl chain greatly improved the
PBMA-DeUG (6) was synthesized analogously to the pre-
viously described12 UG-containing PBMA (Scheme 3b). Shorter
linkages between the DeUG unit and the polymer backbone were
examined but led to opaque, viscous polymer solutions upon
mixing with PS-DAN 5 in chloroform, indicating phase separa-
tion. Both of the polymers were characterized by size-exclusion
1
chromatography (SEC) and H NMR spectroscopy, the latter
indicating that the degrees of recognition-unit incorporation
were 6 and 4 mol % for 5 and 6, respectively. The SEC instrument
was equipped with a UV detector, which confirmed the attach-
ment of DAN and DeUG and gave the following polymer
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with respect to 1red) and bubbling of O2 through the solution for
5 min, the gel was restored (Figure 3c). Finally, the reformed gel
was treated with hydroquinone (1 equiv per eDAN 1), leading to
1
a solution (Figure 3d). Each step was followed by H NMR
spectroscopy, and control experiments were performed to confirm
that the redox reagents were responsible for the 1red to 1ox inter-
conversion and that this in turn controlled the formation of the
supramolecular polymer blend.14 Multiple cycles were not exam-
1
ined, but in H NMR experiments with 1 alone, several redox
cycles were possible, although obvious byproducts were formed.14
In conclusion, the redox-responsive eDAN module 1 was
designed and shown to pair with high affinity to DeUG in its
reduced form (ꢀΔG° = 8.3 kcal molꢀ1 for 1red 2) but to bind
3
weakly when oxidized (ꢀΔG° = 3.8 kcal molꢀ1 for 1ox 2). The
3
very large decrease in binding points to the utility of coupling
the stimulus and the hydrogen-bonding motif displayed by the
recognition unit. A simple application to stimuli-responsive
supramolecular polymer networks that did not require incor-
poration of the responsive unit into the polymers was demon-
strated. Future improvements will involve altering the naphthy-
ridine unit in a way that allows reversible electrochemical
switching.
Figure 2. ITC data for (a) 1red 2 and (b) 1ox 2. A detailed discussion
3
3
of the ITC data can be found in the SI.
Scheme 3. Synthesis of Reactive Monomers and Copolym-
erization To Give (a) PS-DAN (5) and (b) PBMA-DeUG (6)a
’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic procedures and
b
1
characterization data, H NMR and UVꢀvis titration studies,
and ITC data. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
sczimmer@illinois.edu
Present Addresses
†Department of Chemical Engineering, POSTECH, Pohang
790-784, Korea.
a Abbreviations: AIBN, azobis(isobutyronitrile); DMAP, 2,6-dimethyla-
minopyridine; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
’ ACKNOWLEDGMENT
Funding for this work provided by the National Science
Foundation (CHE-1012212) is gratefully acknowledged.
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