Heteromeric double helix formation by cross-hybridization of chloro-and fluoro-substituted quinoline oligoamides

Article abstract of DOI:10.1039/b910435f

Oligoamides of 8-chloroquinoline have been synthesized and shown to assemble into double helical dimers both in solution and in the solid state, and to undergo cross-hybridization with 8-fluoroquinoline oligoamide analogues; the handedness of these double

Full text of DOI:10.1039/b910435f

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Heteromeric double helix formation by cross-hybridization of chloro-and
fluoro-substituted quinoline oligoamidesw
Quan Gan,a Fei Li,a Guoping Li,a Brice Kauffmann,b Junfeng Xiang,a Ivan Huc*b and
Hua Jiang*a
Received (in Cambridge, UK) 28th May 2009, Accepted 12th November 2009
First published as an Advance Article on the web 25th November 2009
DOI: 10.1039/b910435f
Oligoamides of 8-chloroquinoline have been synthesized and
shown to assemble into double helical dimers both in solution
and in the solid state, and to undergo cross-hybridization with
8-fluoroquinoline oligoamide analogues; the handedness of these
double helices can be controlled via chiral residues.
halogen atoms may act as hydrogen-bond acceptors has
remained unclear.9 Li et al. reported that chlorine atoms
participate in the formation of five-membered N–Hꢂ ꢂ ꢂCl
hydrogen-bonded rings in aromatic mono-amides.10 Intrigued
by the possibility to direct folding of an entire aromatic amide
oligomer using N–Hꢂ ꢂ ꢂCl hydrogen bonds, we envisaged to
replace fluorine atoms by chlorine atoms in position 8 of each
Considerable progress has been achieved in the design and
characterization of synthetic oligomers that hybridize into
multiple helices based on non-natural hybridization motifs.1
Prominent examples include metal coordination-based helicates,2
aromatic oligoamides,3 oligoresorcinols,4 ethynylhelicene
oligomers,5 m-terphenyl backbone oligomers exploiting
amidinium–carboxylate salt bridges,6 alternate sequences of
aromatic hydrogen-bond donors and acceptors.7 Most of
these systems however, consist of homodimeric double helices.
Heteromeric double helices are less common,2a,e,3e,4c,5b,6
despite the fact that they constitute more attractive targets
since they might provide artificial molecular platforms to
achieve information storage and duplication as in DNA. This
scarcity reflects the difficulty to achieve reliable heterologous
pairing modes between artificial molecular strands. In this
respect, the aminidium–carboxylate pairing described by
Yashima and Furusho represents a significant advance.6
As a part of our program aiming at investigating double
helices of aromatic oligomers, we recently reported the
synthesis, folding and hybridization of 8-fluoroquinoline
oligoamides.3g Solid-state and solution studies demonstrated
that octamer QF8 adopts helical conformations and assembles
into an antiparallel double-helical homoduplex, with a dimeri-
zation constant Kdim = 8.5 ꢀ 105 L molꢁ1 in CDCl3 at 298 K.
ring of QF oligomers. We now report the synthesis, folding
n
and aggregation properties of QCl and QCl8. We find that
4
QCl hybridizes into double helical homodimers similar to
8
(QF8)2, that QCl8 and QF8 undergo cross-hybridization to form
a heterodimer, and that helical handedness of these duplexes
can be induced by means of a terminal chiral residue.
8-Chloroquinoline oligoamides were synthesized according
to procedures similar to those used for their fluoro-
counterparts and have been fully characterized (see ESIw).
NMR studies of QCl4 solutions compare well with those of QF
4
and can be summarized as follows. 1H NMR spectra are sharp
and show strong downfield shifts of NH (amide) resonances of
QCl (d 4 11.5 ppm, which is higher than in QF4) as well as
4
spreading over a wide range (Dd up to 0.5 ppm), consistent
with their involvement in intramolecular hydrogen bonds
(Fig. S1–S3w) and with a helically folded conformation.
Concentration-dependent and variable-temperature NMR
spectra suggest that QCl4, like QF4, forms weak and labile
aggregates in rapid exchange with the monomer on the NMR
time scale (Fig. S2–S4w). No evidence was sought for
regarding the exact nature of these aggregates.
Tetrameric QF also assembles into double helices, albeit
4
much less stable than (QF8)2, which further aggregate into a
quadruply stranded structure.3g
Among other factors, these helical conformations are
stabilized by intramolecular N–Hꢂ ꢂ ꢂF hydrogen bonds and
CQOꢂ ꢂ ꢂF repulsions between consecutive quinoline units of
the sequence.8 On the other hand, the extent to which other
The folding and aggregation behaviour of QCl was able to
8
be examined in more detail thanks to a solid-state structure
a Beijing National Laboratory for Molecular Sciences,
CAS Key Laboratory of Photochemistry, Institute of Chemistry,
Chinese Academy of Sciences, Beijing, 100190, China.
E-mail: hjiang@iccas.ac.cn
(Fig. 1)z showing its hybridization into an antiparallel double
helical dimer almost superimposable to the structure of (QF
)
8 2
(Fig. S16w).3g The structure of (QCl8)2 confirms the formation
of N–Hꢂ ꢂ ꢂCl hydrogen bonds between adjacent quinolines of
each strand. The average N–Hꢂ ꢂ ꢂCl distance in five-membered
hydrogen bonded rings is 2.5 A compared to 2.2 A for
N–Hꢂ ꢂ ꢂF hydrogen bonds in (QF8)2. This difference appears
to simply reflect the larger van der Waals radii of chlorine
atoms and not a change in the curvature of the strand.
b Universite´ de Bordeaux – CNRS UMR5248 and UMS3003,
´
Institut Europeen de Chimie et Biologie, 2 rue Robert Escarpit,
F-33607 Pessac, France. E-mail: i.huc@iecb.u-bordeaux.fr
w Electronic supplementary information (ESI) available: Synthetic
procedures, experimental details and additional spectroscopic data.
CCDC 745835. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b910435f
ꢃc
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Chem. Commun., 2010, 46, 297–299 | 297

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Fig. 1 Structure of (QCl
) in the crystal. Isobutyl side chains and
8 2
Fig.
2
Part of the temperature-dependent 1H NMR spectra
included solvent molecules have been omitted for clarity.
(300 MHz) of QCl (1 mM) in pyridine-d5 showing amide and methyl
8
Another consequence of the larger size of chlorine is that in the
inner hollow of the duplex is too small to accommodate any
solvent or guest molecules.
ester resonances.
new signals appeared suggesting the formation of a hetero-
dimer QCl8ꢂQF8. This assignment was confirmed by TLC, ESI
and CD studies (vide infra). Signal multiplicity (two methyl
ester peaks of equal intensities) indicates that this hybrid exists
in only one form, like (QF8)2 and unlike (QCl8)2, presumably
an antiparallel double helix. In support to the fact that all
species present are double helices is the observation that their
proportions at equilibrium are concentration independent.
Yet, the time needed to reach equilibrium does depend on
concentration: ca. 300 h at 2 mM; 250 h at 4 mM, 150 h at
8 mM and 50 h at 50 mM (Fig. S11w). Most notably, the
Double helix formation in solution was supported by mass
spectrometry (Fig. S13w) and by strong similarities with 1H
NMR spectra of (QF
) such as slightly broadened lines at
8 2
room temperature and downfield shifted signals indicative of
strong ring currents effects as can be expected for the duplex
structure observed in the solid state. However, some differences
were noted too. In particular, the 1H spectra of QCl8 in CDCl3
and pyridine-d5 show two sets of signals (Fig. 2, S6, S7w). This
might have been interpreted as signals belonging to single and
double helices in slow exchange as for (QF8)2 and QF
3g
,
8
but
proportion of QCl8ꢂQF at equilibrium represents 70%, above
8
several facts disprove this interpretation: (i) except for the
terminal methyl ester, the two sets of signals largely overlap
whereas signals of single helices normally appear at lower field;
(ii) proportions between the two sets of signals do not vary
with concentration from 0.5 to 40 mM (Fig. S5w); (iii) upon
heating to 52 1C in CDCl3 and 47 1C in pyridine-d5, the two
sets of signals coalesce and rapidly split again upon cooling
(Fig. 2, S6, S7w). The latter is incompatible with a single
helix–double helix equilibrium of an octamer, for which
equilibrium remains slow on the NMR time scale and even
sometimes on the chromatographic timescale (see below). The
two sets of signals cannot either be assigned to parallel and
antiparallel double helices as this would require strand
dissociation and would not give rise to rapid equilibration.
The most plausible explanation appears to be the existence of
isomeric forms of (QCl8)2 that equilibrate through the sliding
of one strand with respect to the other through a screw-like
motion, as has been observed in pyridinecarboxamide oligo-
mers.3a Remarkably, diluting or heating did not give rise to
the 50% expected for a statistical distribution of QF8 and QCl
8
among the various duplexes (Fig. 3(f)). A possible reason for
this preference might be steric complementarity between F and
Cl atoms in the double helix hollow, as occurs between side
chains in leucine zippers.
An equilibrated mixture of (QF8)2 and (QCl8)2 was subjected
to thin layer chromatography (TLC). As shown in Fig. 4, a
new spot was observed between those of (QF8)2 (Rf 0.1) and
(QCl8)2 (Rf 0.9) assignable to QF8ꢂQCl (Rf 0.45). The separa-
8
tion of these three species by TLC is illustrative of their kinetic
stability: exchange with single helices is minor at the TLC time
scale.3j The formation of QF8ꢂQCl8 was also evidenced by high-
resolution electrospray ionization mass spectrometry (ESI MS).
Indeed, spectra of an equilibrated mixture of (QF8)2 and (QF
)
8 2
show peaks that could be assigned to the three double helices,
all as doubly charged species, according to their m/z values and
their isotopic distribution (Fig. 4 and S12w).
any signal that could be assigned to single helical QCl
8
(Fig. S6, S7w). The Kdim value of QCl appears to be too high
8
to measure using NMR even at high temperatures in solvents
less favourable to hybridization such as pyridine-d5. Chlorine
substituents thus make (QCl8)2 at least 10 to 100 times more
stable than (QF8)2. Such stable aromatic duplexes have been
encountered in one other series.3i
Since QF8 and QCl8 both form stable and structurally similar
double helices, we decided to investigate possible hetero-
hybridization between them. When these compounds were
mixed 1H NMR spectra initially showed signals corresponding
1
Fig. 3 Part of 400 MHz H NMR spectra at 296 K showing methyl
to (QF
) ) (Fig. 3(a)). Thus, cross-hybridization
8 2 8 2
and (QF
ester resonances at different time intervals after mixing QCl and QF
8
8
does not occur immediately, in contrast with other hetero-
meric double helices.3e,6 Instead, the intensities of (QCl8)2 and
(QF8)2 signals slowly decreased and, concomitantly, one set of
(8 mM each): (a) 0 h, (b) 12 h, (c) 28 h, (d) 70 h, (e) 118 h, (f) 155 h.
Solid, empty and half filled circles show signals assigned to (QCl8)2,
(QF
)
8 2
and QCl8ꢂQF8, respectively.
ꢃc
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298 | Chem. Commun., 2010, 46, 297–299

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stoichiometry of this aggregate, consistent with a S-QF8ꢂQCl
8
heteroduplex.
In summary, we have shown that folding of aromatic
oligoamides may be directed by N–Hꢂ ꢂ ꢂCl hydrogen bonds,
that 8-chloroquinoline oligoamides hybridize into double
helices and that these have a preference for cross-hybridization
with their fluoro-quinoline counterparts. This preference may
constitute the basis for a more refined heteromeric association
based on steric complementarity.
We thank the CAS ‘Hundred talents program’ and NSFC
(20772127) and 973 program of China (2009CB930802) for
financial support.
Fig. 4 Left: TLC on SiO2 eluting with chloroform–ethyl acetate
Notes and references
(95 : 5 v/v) showing the hetero-hybridization of QCl and QF
.
8
8
z Crystal data: (C118H114Cl8N16O19)2, M = 4687.72, T = 173(2) K,
A: QCl8; B: QCl + QF8; C: QF8. Right: experimental (top) ESI MS
8
monoclinic, space group C2/c,
a = 31.428(6), b = 36.642(7),
c = 24.101(5) A, b = 114.01(3)1, V = 25353(9) A3, Dc
=
and theoretical (bottom) isotopic distribution of hetero-double helix
[QCl8ꢂQF8 + 2H]2+
1.228 g cmꢁ3, Z = 8, 56 066 reflections collected, 9628 independent
reflections (Rint = 0.063), final R indices [I 4 2s(I)]: R1 = 0.1389,
wR2 = 0.3449, R indices (all data) R1 = 0.2104, wR2 = 0.3872.
.
Finally, the formation of hetero-double helices was further
explored by circular dichroism (CD). Chiral octamer S-QF
1 Foldamers: Structure, Properties, and Applications, ed. S. Hecht
and I. Huc, Wiley-VCH, Weinheim, 2007.
8
was synthesized for this purpose (Scheme S3w). Variable-
2 Selected examples: (a) B. Hasenknopf, J.-M. Lehn, G. Baum and
D. Fenske, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 1397;
(b) C. R. Woods, M. Benaglia, F. Cozzi and J. S. Siegel, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1830; (c) A. Orita, T. Nakano,
D. L. An, K. Tanikawa, K. Wakamatsu and J. Otera, J. Am.
Chem. Soc., 2004, 126, 10389; (d) H. Katagiri, T. Miyagawa,
Y. Furusho and E. Yashima, Angew. Chem., Int. Ed., 2006, 45,
1741; (e) A. Marquis, V. Smith, J. Harrowfield, J.-M. Lehn,
H. Herschbach, R. Sanvito, E. Leise-Wagner and
A. V. Dorsselaer, Chem.–Eur. J., 2006, 12, 5632.
temperature 1H NMR and high resolution ESI MS studies
revealed that S-QF8 forms double helices similar to that of QF
8
(see ESIw). Additionally, CD spectroscopy shows that the
chiral phenethylamine residue of S-QF results in intense CD
8
bands, suggesting (S-QF
)
8 2
has a preferred handedness
which can tentatively be assigned to P helicity as in other
S-phenethylamine-bearing oligoamides (Fig. 5 and S17w).11
CD spectra of mixtures of S-QF8 and QCl8 were then measured
while keeping the total concentration equal to 1 ꢀ 10ꢁ5 M. As
shown in Fig. 5, CD intensities at 331 nm decreased when the
3 (a) V. Berl, I. Huc, R. Khoury, M. J. Krische and J.-M. Lehn, Nature,
2000, 407, 720; (b) V. Berl, I. Huc, R. Khoury and J.-M. Lehn,
Chem.–Eur. J., 2001, 7, 2810; (c) H. Jiang, V. Maurizot and I. Huc,
proportion of non-chiral QCl increased, but this decreases
Tetrahedron, 2004, 60, 10029; (d) C. Dolain, C. Zhan, J.-M. Le
I. Huc, J. Am. Chem. Soc., 2005, 127, 2400; (e) C. Zhan, J.-M. Le
and I. Huc, Angew. Chem., Int. Ed., 2006, 45, 4625; (f) D. Haldar,
H. Jiang, J.-M. Leger and I. Huc, Angew. Chem., Int. Ed., 2006, 45,
5483; (g) Q. Gan, C. Bao, B. Kauffmann, A. Grelard, J. Xiang, S. Liu,
´
ger and
8
´
ger
deviates positively from linearity. As expected, a linear
relationship was found in the case of S-QF and QF
,
´
8
8
(data not shown). On the other hand, a solution of S-QF
´
8
I. Huc and H. Jiang, Angew. Chem., Int. Ed., 2008, 47, 1715;
(h) E. Berni, B. Kauffmann, C. Bao, J. Lefeuvre, D. Bassani and
I. Huc, Chem.–Eur. J., 2007, 13, 8463; (i) E. Berni, J. Garric,
C. Lamit, B. Kauffmann, J.-M. Le
2008, 1968.
4 (a) H. Goto, H. Katagiri, Y. Furusho and E. Yashima, J. Am.
Chem. Soc., 2006, 128, 7176; (b) H. Goto, Y. Furusho and
E. Yashima, J. Am. Chem. Soc., 2007, 129, 109; (c) H. Goto,
Y. Furusho and E. Yashima, J. Am. Chem. Soc., 2007, 129, 9168.
5 (a) H. Sugiura, Y. Nigorikawa, Y. Saiki, K. Nakamura and
M. Yamaguchi, J. Am. Chem. Soc., 2004, 126, 14858;
(b) R. Amemiya, N. Saito and M. Yamaguchi, J. Org. Chem.,
2008, 73, 7137.
was titrated with QF and QCl8, respectively. The data show
8
(Fig. S17 and S18w) that the CD intensity S-QF at 331 nm
8
follows a sigmoid increase upon adding QCl8, however,
it increases linearly upon adding QF8. These results are
consistent with the preferred formation of heteromeric aggre-
gates between S-QF and QCl possessing a preferred helix
´
ger and I. Huc, Chem. Commun.,
8
8
sense bias. The isosbestic point with De = 0 at 305 nm and a
Job plot derived from CD data (Fig. S15w) both support a 1 : 1
6 (a) Y. Tanaka, H. Katagiri, Y. Furusho and E. Yashima, Angew.
Chem., Int. Ed., 2005, 44, 3867; (b) H. Ito, Y. Furusho, T. Hasegawa
and E. Yashima, J. Am. Chem. Soc., 2008, 130, 14008.
7 J. Li, J. A. Wisner and M. C. Jennings, Org. Lett., 2007, 9, 3267.
8 C. Li, S.-F. Ren, J.-L. Hou, H.-P. Yi, S.-Z. Zhu, X. K. Jiang and
Z.-T. Li, Angew. Chem., Int. Ed., 2005, 44, 5725.
9 (a) H. A. K. Howard, V. J. Hoy, D. O’Hagan and G. T. Smith,
Tetrahedron, 1996, 52, 12613; (b) J. D. Dunitz and R. Taylor,
Chem.–Eur. J., 1997, 3, 89; (c) J. D. Dunitz, ChemBioChem, 2004,
5, 614.
10 Y.-Y. Zhu, H.-P. Yi, C. Li, X.-K. Jiang and Z.-T. Li, Cryst.
Growth Des., 2008, 8, 1294.
Fig. 5 CD spectra of mixtures of S-QF8 and QCl8 in CHCl3 at a fixed
total concentration of 10ꢁ5 M. Solutions were equilibrated at 23 1C for
5 days before measurements. Right: plot of De values at 331 nm as a
11 H. Jiang, C. Dolain, J.-M. Le
Chem. Soc., 2004, 126, 1034; V. Maurizot, C. Dolain and I. Huc,
Eur. J. Org. Chem., 2005, 1293; C. Dolain, J.-M. Leger, N. Delsuc,
´
ger, H. Gornitzka and I. Huc, J. Am.
´
function of the proportion of S-QF
.
8
P. Guionneau and I. Huc, J. Am. Chem. Soc., 2005, 127, 12943.
ꢃc
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Chem. Commun., 2010, 46, 297–299 | 299