A self-associating ADADA hydrogen-bonded double helix

Article abstract of DOI:10.1021/ol071171c

We report the design, synthesis, and characterization of an oligomer which incorporates a non-coplanar ADADA (hydrogen bond donor/acceptor) array within its structure. The molecule associates through self-complementary hydrogen bonding to form a dimeric double-helical complex.

Full text of DOI:10.1021/ol071171c

ORGANIC
LETTERS
2
007
Vol. 9, No. 17
267-3269
A Self-Associating ADADA
Hydrogen-Bonded Double Helix
3
Jiaxin Li, James A. Wisner,* and Michael C. Jennings
The UniVersity of Western Ontario, Department of Chemistry,
London, Ontario, N6A 5B7 Canada
wisner@uwo.ca
Received May 22, 2007
ABSTRACT
We report the design, synthesis, and characterization of an oligomer which incorporates a non-coplanar ADADA (hydrogen bond donor/
acceptor) array within its structure. The molecule associates through self-complementary hydrogen bonding to form a dimeric double-helical
complex.
The design of wholly synthetic molecules which self-
assemble into double helical structures from single molecular
strands has been a goal of chemists since the inspirational
discovery of the DNA double helix by Watson and Crick.
A large number of such systems have been realized using
program to design information-containing molecules, we
report here the synthesis and characterization of an oligomer
which incorporates a non-coplanar ADADA (hydrogen bond
donor/acceptor) array within its structure and its self-
complementary dimerization to form a double helix.
1
metal-ligand coordination as the driving force for their
formation. Much less common are schemes which utilize
The design of a double-helical complex was approached
by basing the intermolecular recognition motif on the
hydrogen-bonding interaction between planar six-membered
heterocycles which contain nitrogen-based donor or acceptor
groups and are connected sequentially in a 1,3-manner. The
obvious choice for the acceptor is pyridine owing to the
expansive synthetic repertoire developed over the last
century. Less obvious is the selection of the heterocycle
containing a donor group. 4-Pyridone itself is unsuitable, as
it exists primarily as the hydroxypyridine tautomer. However,
simple isosteric replacement of the pyridone carbonyl group
2
solely noncovalent interactions to stabilize a discrete double
helical complex in solution and solid states. These approaches
have previously been based on the hybridization of oligo-
3
4
resorcinols, oligopyridinedicarboxamides, complementary
association of amidinium/carboxylate functionalized oligo-
5
6
mers, or anion-templated self-assembly. As part of a wider
(
1) Watson, J. D.; Crick, F. C. H. Nature 1953, 171, 737.
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Tsukube, H. Supramol. Chem. 2005, 17, 53. (c) Hannon, M. J.; Childs, L.
J. Supramol. Chem. 2004, 16, 7.
7
for sulfone results in 1,4-thiazine-1,1-dioxide. As a further
design element, the thiazine dioxide heterocycles of the final
(
3) (a) Goto, H.; Furusho, Y.; Yashima, E. J. Am. Chem. Soc. 2007,
29, 109. (b) Goto, H.; Katagiri, H.; Furusho, Y.; Yashima, E. J. Am. Chem.
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1
(
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4
Ed. 2006, 45, 5483. (c) Dolain, C.; Zhan, C.; L e´ ger, J.-M.; Daniels, L.;
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Lehn, J.-M. Chem.sEur. J. 2001, 7, 2810. (f) Berl, V.; Huc, I.; Khoury, R.
G.; Krische, M. J.; Lehn, J.-M. Nature 2000, 407, 721.
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1
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Published on Web 07/18/2007

product are substituted with methyl groups at the 2,6-posi-
tions to bias adjacent rings in the system out of coplanarity,
a requirement for double helix formation in this context. To
test the efficacy of this strategy, a simple ADADA pentamer
1
was chosen as an initial target and synthesized (Scheme
1). The synthesis employs readily available starting materials
Scheme 1. Synthesis of ADADA Pentamer
1
Figure 1. 400 MHz H NMR spectra of aromatic region of 1 in
CDCl at three different concentrations and temperatures. NH
3
protons corresponding to 1 (O) and 1
2
(b) at 213 K undergoing
slow exchange are indicated.
-
1
-1
be 4.5 M , which corresponds to a ∆G of -3.7 kJ mol
(estimated error e20%). The weak nature of the dimerization
equilibrium at room-temperature could be expected owing
to the entirely negative secondary hydrogen-bonding interac-
9
tions present in the alternating sequence of donors/acceptors
and is similar to an analogous ladderlike system previously
1
0
reported.
and proceeds in reasonable overall yield (40% from 2-pro-
pionylpyridine).
Assuming the equilibrium observed at room temperature
was a result of double-helix formation, a series of H NMR
1
A dilution study of 1 monitored by 1H NMR was
undertaken to evaluate whether any dimerization is occurring
3
spectra of 1 in CDCl were recorded at lower temperatures
(
298-213 K) in an effort to observe the complexation/
3
in CDCl solution. Spectra were recorded at 298 K and a
decomplexation process under slow exchange conditions. The
resonances corresponding to 1 broaden as the temperature
decreases and coalesce at 248 K. At lower temperatures the
spectrum resolves into two separate sets of resonances
series of concentrations ranging from 224 to 4.2 mM. A
comparison of the proton chemical shifts of 1 in concentrated
and dilute solutions displays changes which are consistent
with formation of the anticipated double helix under fast
exchange conditions (Figure 1). The N-H protons of the
thiazine dioxide rings shift downfield at higher concentrations
which may be attributed to the hydrogen-bonding interactions
predicted in the double-helical geometry. Conversely, all of
the pyridyl protons shift upfield to varying degrees likely as
a consequence of π-π interactions between opposing strands
of the double helix. UV-vis spectra of the solutions used
to acquire the NMR spectra (Supporting Information) support
this conclusion. As the concentration of 1 increases, a charge-
transfer band appears at approximately 490 nm turning the
solution a burnt orange color which is reversible upon
(
Figure 1 and Supporting Information) which may be
attributed to monomeric 1 (symmetry related protons are
isochronous) and double-helical dimer 1 (all protons of a
2
given strand have a unique environment). COSY and ROESY
spectra performed at 213 K supported the assignment of each
set of protons. Notably, the relative integrals of 1 and 1
change as a function of decreasing temperature, with those
corresponding to 1 becoming more intense as the temper-
ature lowers. Knowledge of the starting concentration of 1
and the integrals of each species yields K values for dimer
2
2
d
formation in the range of temperatures where slow exchange
conditions prevail (213-243 K). Given this information, a
1
dilution. H NMR shift data obtained from the N-H protons
of the thiazine dioxide rings were fit to a simple dimerization
(9) (a) Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114,
4010. (b) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem.
Soc. 1991, 113, 2810. (c) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc.
8
d
model, and a dimerization constant (K ) was calculated to
1
990, 112, 2008.
(8) Bisson, A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger, R. C.;
(10) Leung, M.-K.; Mandal, A. B.; Wang, C.-C.; Lee, G.-H.; Peng,
Hunter, C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger, C.; Rowan, A.
E. J. Am. Chem. Soc. 2000, 122, 8856.
S.-M.; Cheng, H.-L.; Her, G.-R.; Chao, I.; Lu, H.-F.; Sun, Y.-C.; Shiao,
M.-Y.; Chou, P.-T. J. Am. Chem. Soc. 2002, 124, 4287.
3268
Org. Lett., Vol. 9, No. 17, 2007

Figure 2. van’t Hoff plot of the dimerization equilibrium between
and 1 in CDCl from 213 to 243 K including the line of best fit
R ) 0.9942).
1
(
2
3
2
Figure 3. Stick representation of the solid-state structure of 1 .
All C-H hydrogen atoms have been removed for clarity. NH‚‚‚N
hydrogen bonds are indicated by dashed orange lines.
van’t Hoff plot was constructed (Figure 2) which yielded
-1
thermodynamic parameters of -16 kJ mol for ∆H and -42
in register ((N‚‚‚N)inner ) 3.11 Å, (N‚‚‚N)outer ) 2.98 Å,
(N-H‚‚‚N)inner ) 175°, and (N-H‚‚‚N)outer ) 166°). None
of the adjacent heterocyclic rings in each molecule are
coplanar with dihedral angles between those rings participat-
ing in the hydrogen-bond array varying from 36 to 53°.
In conclusion, we have demonstrated the design, synthesis,
and self-assembly of a molecular strand which forms a
dimeric double-helical complex using a self-complementary
ADADA array of hydrogen bonds. We are currently inves-
tigating the synthesis of analogous molecules which have
different lengths and hydrogen-bond sequences to fully
delineate the parameters of this system.
-1
-1
J mol
K
for ∆S, indicating complex formation is a result
of molecular recognition rather than solvophobic in nature.
Extrapolation of ∆G to 298 K using these parameters results
-
1
in a free energy at that temperature of -3.5 kJ mol which
-
1
d
corresponds to a K of 4.3 M . The result is within error of
the equilibrium measured by dilution at room temperature
and engenders the conclusion that the two processes are one
and the same.
Confirmation of the complex geometry in the solid state
was obtained by single-crystal X-ray diffraction. Slow
diffusion of isopropyl ether into a concentrated solution of
1
in dichloroethane yielded pale yellow crystals which were
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for funding this
research.
suitable for crystallographic analysis. Pentamer 1 crystallizes
in orthorhombic space group Fdd2 and contains eight
symmetry-related dimers per unit cell. The structures of these
discrete complexes manifest the double-helical geometry of
the intended design (Figure 3). The two molecules of 1 which
Supporting Information Available: Syntheses, charac-
terization, and experimental details. This material is available
free of charge via the Internet at http://pubs.acs.org.
compose each dimer are related by a C
each other such that four contiguous donors/acceptors
ADAD) on either strand are hydrogen-bonded to the other
2
axis and wrap around
(
OL071171C
Org. Lett., Vol. 9, No. 17, 2007
3269