Minimal complementary hydrogen-bonded double helices

Article abstract of DOI:10.1039/c0cc02475a

Molecular strands incorporating three hydrogen bond donor (D) or acceptor (A) heterocycles form highly stable double helical complexes through a complementary AAA-DDD array structure.

Full text of DOI:10.1039/c0cc02475a

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Minimal complementary hydrogen-bonded double helicesw
Hong-Bo Wang, Bhanu P. Mudraboyina, Jiaxin Li and James A. Wisner*
Received 9th July 2010, Accepted 7th August 2010
DOI: 10.1039/c0cc02475a
Molecular strands incorporating three hydrogen bond donor (D) or
acceptor (A) heterocycles form highly stable double helical com-
plexes through a complementary AAA–DDD array structure.
The design and characterization of linear oligomers that self-
assemble into double helical structures has been a subject of
interest to chemists since the elucidation of the double helix
structure of DNA in 1953.1 Transition metal templates have
been widely used in the construction of artificial double helical
complexes (helicates) from linear multidentate ligands.2 The
use of other non-covalent interactions as the driving force in
the self-assembly of these types of complexes is less common.
Aromatic stacking interactions,3–5 anion templates,6 and
salt-bridges7 have all been applied in this context. The great
majority of these investigations have been concerned with
the dimerization of identical linear oligomers to form homo-
duplex products. There are very few examples of artificial
double helices that form from complementary strands to give
heteroduplexes.3e,j,4c,5c,7 Notably, Yashima, Furusho and
Scheme
1 Syntheses of 7 and 8. Reagents and conditions:
coworkers have demonstrated that two complementary
molecules may interact via amidinium–carboxylate salt bridges
in a sequence dependent manner resembling the hybridization
of ss-DNA.7
(a) HC(OMe)3, conc. H2SO4; (b) 2-mercapto-propiophenone,
K2CO3, CH3CN; (c) m-CPBA, CH2Cl2, ꢀ78 1C to rt; (d) NH4OAc/
AcOH, reflux; (e) formic acid, reflux; (f) NaSH, H2O, CH2Cl2;
(g) (i) UHP/TFAA, CH3CN, (ii) NH4OAc/AcOH, reflux; (h) Pd(PPh3)4,
toluene, reflux.
We have reported the formation of a double helical com-
plex based on self-associating molecular strands containing
alternating hydrogen bond donors (D) and acceptors (A) but
its dimerization constant was very low (Kdimer = 5 Mꢀ1 at
298 K).8 Herein, we report the formation of minimal com-
plementary AAA–DDD hydrogen bonded double helices
stabilized by three hydrogen bonds that exhibit much larger
binding constants.
8 to a heterogeneous mixture of 7 and chloroform yields
the soluble hydrogen bonded complex 7ꢁ8. The 1H NMR
spectrum of the complex in CDCl3 displays extreme downfield
shifts for the thiazine dioxide NH protons of 7 at 12.88 (Ha)
and 12.00 (Hb) ppm as would be expected from a strong
hydrogen bond interaction with 8 (Fig. 1). Using the chemical
shift of the thiazine NH proton of 14b (see below) in CDCl3 as
a reasonable approximation of free 7 in this solvent, we
calculate complexation induced shifts Dd = 5.60 (Ha) and
4.73 (Hb) ppm. In addition, significant upfield shifts of
the phenyl proton resonances of 7 are the result of either
p-stacking with the pyridyl rings of 8, or induction due to
hydrogen bonding, or a combination of the two effects.
Dilution of an equimolar solution of 7ꢁ8 to 1 ꢂ 10ꢀ4 M results
in no change of the chemical shifts of the resonances observed
Molecular strand 7 was designed to include three thiazine-
1,1-dioxide heterocycles that would present a DDD hydrogen
bond sequence complementary to terpyridyl derivative 8 that
presents an AAA pattern (Scheme 1). The synthesis of DDD
component 7 is straightforward and can be executed in seven
steps from commercially available 1,4-dibromobutane-2,3-
dione. The AAA component 8 was synthesized in a single
step from 2-tributyltinpyridine and 2,6-diiodo-3,5-lutidine via
Stille coupling.
Unfortunately, 7 is completely insoluble in nonpolar solvents
such as chloroform that are commonly used to mediate
the self-assembly of systems based on hydrogen bonding.
However, the addition of a molar equivalent of complementary
Department of Chemistry, The University of Western Ontario,
Chemistry Building, 1151 Richmond Street, London, ON,
Canada N6A 5B7. E-mail: jwisner@uwo.ca
w Electronic supplementary information (ESI) available: Synthetic
protocols, characterization, Ka data for 14bꢁ8. CCDC 783459 and
783460. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c0cc02475a
Fig. 1 Downfield region of the 1H NMR spectrum of 7ꢁ8 in CDCl3
at 298 K.
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Scheme 2 Syntheses of 14. Reagents and conditions: (a) (i) NaOH,
EtOH/H2O, (ii) PhN2Cl, 0 1C, (iii) formic acid, reflux; (b) PhNMe3Br3,
THF, reflux; (c) for 12a: Na2S, acetone/water, 0 1C to rt; (d) for 11:
(i) KSAc, DMF, (ii) cysteamine hydrochloride, NaHCO3, MeOH;
(e) for 12b: Et3N, CH3CN; (f) m-CPBA, DMF, ꢀ25 1C to rt;
(g) NH4OAc/AcOH, reflux.
Fig. 2 Stick representation of the solid state structure of 7ꢁ8. All C–H
hydrogen atoms have been removed for clarity. NHꢁ ꢁ ꢁN hydrogen
bonds are indicated by dashed orange lines.
for the complex, allowing an estimation of the lower limit for
the association constant (Ka) of 1 ꢂ 105 Mꢀ1 9
.
The solid state structure of complex 7ꢁ8 further supports the
hydrogen bonded nature of the complex in solution. Single
crystals were grown by slow diffusion of isopropyl ether into a
chloroform solution of 7ꢁ8 and analyzed by X-ray diffraction.z
The complex crystallizes with the two molecular strands
intertwined in a double helical coconformation (Fig. 2). The
three NH groups of the thiazine-1,1-dioxide heterocycles form
short primary hydrogen bonds with the three nitrogen atoms
of the pyridyl rings (N6Hꢁ ꢁ ꢁN1 = 2.85, N5Hꢁ ꢁ ꢁN2 = 2.88,
N4Hꢁ ꢁ ꢁN3 = 3.06 A and N6Hꢁ ꢁ ꢁN1 = 162, N5Hꢁ ꢁ ꢁN2 =
177, N4Hꢁ ꢁ ꢁN3 = 1691, respectively). Three carbon atoms
(ipso, ortho, and meta) of a terminal phenyl ring of 7 are
positioned over and engaged in p-stacking with the central
pyridyl ring of 8 (Cꢁ ꢁ ꢁp(pyridyl least squares plane) = 3.59,
3.37, and 3.42 A) providing further rationalization of the upfield
shifts observed for the attached phenyl proton resonances in the
1H NMR spectrum.
Fig. 3 Stick representations of the solid state structure of 14a. View
along b direction (top). View perpendicular to b direction (bottom).
All C–H hydrogen atoms have been removed for clarity. NHꢁ ꢁ ꢁN
hydrogen bonds are indicated by dashed orange lines.
The insolubility of 7 in chloroform prompted us to incorporate
different donor groups into this scheme in an effort to
modify the solubility of the DDD component. Incorporation
of 3-methylindole (skatole) heterocycles as terminal donor
groups was a straightforward and potentially versatile alteration.
A Japp–Klingemann/Fischer indole synthesis was employed as
a route to 2-acylskatole intermediates 9a/b (Scheme 2).10
These were carried forward to elaborate the central thiazine
dioxide ring, in a similar manner to the methods used to
synthesize 7, producing 14a and 14b.
molecule of 14a and the sulfone oxygen atoms of the next in
the chain. The individual molecules reside in a helical con-
formation such that each indole NH donor forms a hydrogen
bond with one or the other of the two sulfone oxygen atoms in
the adjacent molecule (NHꢁ ꢁ ꢁO = 3.04 A and NHꢁ ꢁ ꢁO =
1391). The thiazine NH donor participates in a bifurcated
hydrogen bonding arrangement with both oxygen atoms of the
same sulfone (NHꢁ ꢁ ꢁO = 3.10 A and NHꢁ ꢁ ꢁO = 1491). In
non-polar solvents this intermolecular attraction is likely
strong enough to generate the observed insolubility of 14a
(and by analogy 7).
14a also displayed very poor solubility in non-polar
solvents. However, in this case we were able to crystallize
14a by slow diffusion of isopropyl ether into an acetone
solution and gained some insight into the likely reason for
the insolubility of both 7 and 14a. The single crystal X-ray
analysisz revealed a structure composed of antiparallel C2
symmetric 1-D chains (Fig. 3) that lie along the b direction
of the lattice. The chains are held together by four intermolecular
hydrogen bonds between the donor NH groups of one
We surmised that steric crowding of the sulfone in 14a
would reduce or prevent the aggregation observed in the
solid state by hindering the close intermolecular approach of
the NH donors. Hence, the addition of a methyl group to the
2-position of the thiazine dioxide ring in 14b was anticipated
to improve its solubility in nonpolar solvents. To our
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(Rint = 0.0637), R(F2 4 2s) = 0.0482, Rw(F2, all data) = 0.1289.
CCDC 783460.
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Fig. 4 Complexation induced chemical shift changes of NH protons
of 14b (Ha (K), Hb (’), Hc (m)) upon titration with 8 in CDCl3 at
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a 1 : 1 host : guest binding model11 using non-linear regression
software to yield a Ka value of 3700 Mꢀ1 (DG = ꢀ20.4 kJ molꢀ1).
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mates a sulfonamide).
We have outlined the synthesis and characterization of a
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analogues with significantly greater hydrogen bond donor
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higher Ka values, can be accomplished by the addition of
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simple modification of the syntheses outlined in Scheme 2. We
are currently pursuing these alterations and investigating the
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polymer applications.
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We thank the University of Western Ontario and NSERC
for their generous support of this research.
Notes and references
z Crystal data for 7ꢁ8: C43H38N6O6S3ꢁHCCl3, M = 950.34 g molꢀ1
,
triclinic, a = 12.1851(4), b = 12.7756(4), c = 15.7666(5) A, a =
82.465(1)1, b = 77.978(1)1, g = 70.320(1)1, U = 2255.40(12) A3, T =
150 K, space group C2/c, Z = 2, 143 783 reflections measured, 14 429
unique reflections (Rint = 0.0804), R(F2 4 2s) = 0.0456, Rw(F2,
all data) = 0.1181. CCDC 783459. For 14a: C22H19N3O2S, M =
389.46 g molꢀ1, monoclinic, a = 27.937(6), b = 6.7394(13), c =
9.871(2) A, b = 92.11(3)1, U = 1857.24(60) A3, T = 150 K, space
group C2/c, Z = 2, 6382 reflections measured, 1657 unique reflections
11 A. P. Bisson, C. A. Hunter, J. C. Morales and K. Young,
Chem.–Eur. J., 1998, 4, 845.
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Chem. Commun., 2010, 46, 7343–7345 7345