Chiral discrimination in hydrogen-bonded [7]helicenes

Article abstract of DOI:10.1021/ol006366y

(matrix presented) A series of racemic [7]helicenes have been prepared and characterized both in solution and in the solid state. Despite the helicenes having the ability to self-assemble in a variety of stereochemical and topological relationships, they

Full text of DOI:10.1021/ol006366y

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3169-3172
Chiral Discrimination in
Hydrogen-Bonded [7]Helicenes
Elisa Murguly, Robert McDonald, and Neil R. Branda*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
neil.branda@ualberta.ca
Received July 21, 2000
ABSTRACT
A series of racemic [7]helicenes have been prepared and characterized both in solution and in the solid state. Despite the helicenes having
the ability to self-assemble in a variety of stereochemical and topological relationships, they formed only enantiomerically pure dimers held
together by two pairs of cooperative hydrogen bonds. The self-assembly process was enantiospecific in solution and diastereoselective in the
crystal.
The design and synthesis of molecules that distinguish
between stereoisomers can provide models to rationalize
substrate-receptor selectivity, create chiral environments for
asymmetric synthesis and separation, and supply building
blocks for constructing supramolecular complexes having
novel chemical and topological properties.1 This last goal
requires a great degree of stereocontrol and can be achieved
by taking advantage of the appealing concept of autoreso-
lution where, through the interaction of molecular recognition
elements, molecules sort themselves out into stereochemi-
cally pure assemblies based on their handedness.
must be eliminated through the rational choice of a scaffold
onto which the molecular recognition sites are fused. The
twisted backbone in helicenes results in stereodiscrimination
because they possess a high degree of structural integrity
which minimizes conformational scrambling that would
otherwise result in the possible recognition of more than one
substrate stereoisomer. The high optical stability (often
greater than 35 kcal mol-1) of hexahelicene and larger
[n]helicenes2 and their use as metal ligands for enantio-
selective catalysis3 and as optically active crown ethers for
chiral recognition4 is testament to this stability.
Programming molecules to spontaneously and selectively
assemble into stereochemically predictable architectures
requires the consideration of two critical factors. First, the
most appropriate functionality must be chosen to act as
constructive recognition elements (hydrogen bonds, van der
Waal’s interactions, dative metal bonds, for example) and
guide the self-assembly reaction along the desirable pathway.
In this regard, the strength and directionality of hydrogen
bonds are particularly useful. Second, undesirable assemblies
The above considerations make the combination of
hydrogen bonding and helicenes ideally suited for supra-
molecular projects where stereocontrol is paramount.5,6
In this Letter, we describe the synthesis and characteriza-
tion of three novel racemic [7]helicenes 1a-c bearing
pyridinone hydrogen bond sites on the ends of the twisted
(2) Janke, R. H.; Haufe, G.; Wu¨rthwein, E.-U.; Borkent, J. H. J. Am.
Chem. Soc. 1996, 118, 6031.
(3) (a) Reetz, M. T.; Beuttenmu¨ller, E. W.; Goddard, R. Tetrahedron
Lett. 1997, 83, 3211. (b) Terfort, A.; Go¨rls, H.; Brunner, H. Synthesis 1997,
79. (c) Dreher, S. D.; Katz, T. J.; Lam, K. C.; Rheingold, A. L. J. Org.
Chem. 2000, 65, 815.
(4) Yamamoto, K.; Ikeda, T.; Kitsubki, T.; Okamoto, Y.; Chikamatsu,
H.; Nakazaki, M. J. Chem. Soc., Perkin Trans. 1 1990, 271.
(5) For a review on self-assembling helices, see: Rowan, A. E.; Nolte,
R. J. M. Angew. Chem., Int. Ed. 1998, 37, 63.
(1) (a) Katz, T. J. Angew. Chem., Int. Ed. 2000, 39, 1921 and references
therein. (b) Cuccia, L. A.; Lehn, J.-M.; Homo, J.-C.; Schmutz, M. Angew.
Chem., Int. Ed. 2000, 39, 233. (c) Deshayes, K.; Broene, R. D.; Chao, I.;
Knobler, C. B.; Diederich, F. J. Org. Chem. 1991, 56, 6787. (d) Mazik,
M.; Bla¨ser, D.; Boese, R. Tetrahedron Lett. 1999, 40, 4783. (e) Gin, M. S.;
Moore, J. S. Org. Lett. 2000, 2, 135.
10.1021/ol006366y CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

backbone. The self-complementary nature of these molecular
recognition elements and their position on the helical scaffold
allows for several possible stereochemical products of the
self-assembly reaction. This reaction can follow two general
pathways and generate two topologically distinct supra-
molecular architectures as illustrated in Figure 1. One
solution, helicenes 1b and 1c undergo a discrimination
process that selects for only the dimeric topology. In the
crystal, a second level of geometric discrimination occurs,
resulting in only two of the four possible dimers illustrated
in Figure 1.
All [7]helicenes were prepared as outlined in Scheme 1.
The synthesis of parent helicene 1a began with the conden-
Scheme 1
Figure 1. Schematic representations of all possible hydrogen-
bonded assemblies of [7]helicenes 1b and 1c. Enantiomeric (e) and
diasteriomeric (d) relationships between the dimers are highlighted
in the top set of architectures. For clarity, the positions of the side
groups (R) in the stereochemically heterogeneous fiber are not
shown (bottom architecture).
pathway leads to a fiber composed of alternating M and P
stereoisomers as shown in the bottom of the figure.7
Alternatively, cooperative hydrogen bonding drives the
building blocks into four stereochemically unique dimers
with respect to the R-group as shown in the top of the figure.
In this report we show that the self-assembly reaction takes
the latter pathway both in solution and in the solid state. In
sation of 2-benzoxy-6-quinolinecarboxaldehyde (2b)8 with
p-xylenenebis(triphenylphosphonium bromide) (3a) to afford
a mixture of cis,cis-, cis,trans-, and trans,trans-4a.9 Irradia-
tion of this isomeric mixture in the presence of iodine as an
oxidizing agent and propylene oxide as an HI scavenger
generated the desired [7]helicene 5a but in only minor
amounts. Instead, the major product was the extended
aromatic 6a.10 Removal of the benzyl groups from 5a with
trifluoroacetic acid cleanly afforded pyridinone 1a as a
yellow solid. However, the insolubility of 1a in all common
solvents, as well as the large amounts of the undesirable
S-isomer 6a, forced us to pursue alternative functional
[7]helicenes.
The incorporation of a bromine atom onto the central
benzene ring of the [7]helicene as reported by Katz11
conveniently addressed these critical issues. Here, the
bromine plays two roles: (1) it minimizes the photoinduced
cyclization to form structure 6 and (2) it provides a site to
introduce solubilizing functional groups. Brominated
(6) For other studies that use rigid polyazaclefts, helicopodands, or
bifunctional helicenes for hydrogen-bonding recognition, see: (a) Perreault,
D. M.; Chen, X.; Anslyn, E. V. Tetrahedron 1995, 51, 353. (b) Huang,
C.-Y.; Lynch, V.; Anslyn, E. V. Angew. Chem., Int. Ed. Engl. 1992, 31,
1244. (c) Owens, L.; Thilgen, C.; Diederich, F.; Knobler, C. B. HelV. Chim.
Acta 1993, 76, 2757. (d) Tanaka, K.; Kitahara, Y. J. Chem. Soc., Chem.
Commun. 1998, 1141. (e) Tanaka, K.; Shogase, Y.; Osuga, H.; Suzuke, H.;
Nakanishi, W.; Nakamura, K.; Kawai, Y. J. Chem. Soc., Chem. Commun.
1995, 1873. (f) Tanaka, K.; Kitahara, Y.; Suzuki, H.; Osuga, H.; Kawai,
Y. Tetrahedron Lett. 1996, 37, 5925.
(7) For a description of M and P nomenclature and how it is used to
describe the stereochemistry of helicenes, see: Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley: New York, 1994; Chapter
14, pp 1121, 1163-1166.
(8) The precursor to 2b was prepared as described for the methyl ether:
Osborne, A. G.; Miller, L. A. D. J. Chem. Soc., Perkin Trans. 1 1993, 181.
(9) The structures of all new compounds were verified by 1H and 13C
NMR spectroscopy, infrared spectroscopy, and mass spectrometry.
(10) 1H NMR of 4a (R ) H) shows a resonance peak at 9.22 ppm,
characteristic of the S-isomer. Katz, T. J.; Sudhakar, A.; Teasley, M. F.;
Gilbert, A. M.; Geiger, W. E.; Robben, M. P.; Wuensch, M.; Ward, M. D.
J. Am. Chem. Soc. 1993, 115, 3182.
(11) Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem.
1991, 56, 3769.
3170
Org. Lett., Vol. 2, No. 20, 2000

[7]helicene 1b was synthesized starting from bis(phos-
phonium salt) 3b in a manner analogous to that of 1a
(Scheme 1). It was immediately found that the bromine atom
greatly improved the solubility of the helicene in typical
organic solvents such as chloroform, DMSO, and THF,
allowing the stereodiscrimination process to be assessed in
solution.
All of the signals in the 1H NMR spectrum of 1b in CDCl3
were assigned on the basis of chemical shifts, coupling
constants, and G-COSY experiments. These experiments
allowed the broad singlet at 13.70 ppm to be unambiguously
identified as that corresponding to the N-H protons. It is
significant that this signal resides downfield (∆δ ) 1.5 ppm)
from where it appears in the 1H NMR spectrum in the more
competitive solvent DMSO-d6. This downfield shift can only
be a result of the presence of strong noncovalent interactions
between [7]helicenes and suggests the presence of coopera-
tive hydrogen bonding. The significant upfield shift (∆δ )
-0.97 ppm, 6 × 10-3 M) of the signal corresponding to the
N-H proton of 2-quinolinone 7, which can be considered
to represent one of the hydrogen bond surfaces in 1b, when
the solvent is changed from DMSO-d6 to CDCl3 supports
the involvement of cooperative hydrogen bonds in the
association of 1b.
1H NMR studies of 1b in CDCl3 and THF-d8 show the
N-H resonance to be concentration independent (∆δ is
unchanging over a 10-4-10-1 M range). Changing to a
solvent such as pyridine-d5 that competes more effectively
for hydrogen bonds shows the N-H resonance to be
concentration dependent. The data from the dilution experi-
ment correlate well with calculated curves using a dimer
binding model (although, as expected, it fits equally well to
a polymer binding model), giving an association constant
(Ka) of 207 M-1 (Figure 2). This value of Ka is much higher
than would be expected if the two recognition surfaces are
acting independently. More importantly, the association
constant is also significantly higher than that calculated for
the analogous dilution titration of 2-quinolinone 7 (Ka < 1).
The position of the N-H resonance in the 1H NMR spectrum
(δ ) 12.91 ppm) for 7 is unchanging over a 10-4-10-2
M
range and close to the chemical shift recorded for the most
dilute solution of helicene 1b (δ ) 13.09 ppm at <10-5 M).
The large discrepancy between the chemical shifts and the
values of Ka for 1b compared to 7 clearly indicates that
cooperativity is the driving force for self-assembly.
These experimental observations would only result if 1b
exists as a dimer sewn together by four noncovalent bonding
interactions. Molecular modeling shows that in order for 1b
to exist in this form, the building blocks within each dimer
must be of the same helicity (M with M and/or P with P).
This implies that there is enantiospecificity with respect to
the building blocks and the possibility that the racemic fiber
exists in solution can be eliminated. These observations,
however, do not imply stereoselectivity, and any of the
proposed dimers in Figure 1 are reasonable under these
conditions.
X-ray crystallographic structure determination could not
be accomplished as crystals of 1b showed twinning, render-
ing this particular helicene inappropriate for investigating
the stereodiscrimination in the solid state. We, therefore,
focused our attention on replacing the bromine in helicene
1b with a more utilitarian side group. Palladium- and CuI-
cocatalyzed coupling of TMS-acetylene with 5b yielded the
ethynyl helicene 5c (Scheme 1). Treatment of 5c with
trifluoroacetic acid cleanly liberated the pyridinone hydrogen
bond sites and simultaneously deprotected the TMS-acetylene
moiety, generating methyl ketone derivative 1c in nearly
quantitative yield.
X-ray quality single crystals of 1c were isolated by slowly
diffusing pentane into a chloroform solution of the [7]heli-
cene. The crystal structure reveals what was already observed
in the solution experiments of 1b, analogue 1c exists solely
as a dimer (Figure 3). What is more significant is that a
diastereoselective recognition process has taken place and
only homochiral dimers where the R-groups exist exclusively
Figure 2. Concentration dependency of the chemical shift for the
N-H proton in the 1H NMR spectrum of [7]helicene 1b and
quinolinone 7 in pyridine-d5.
Figure 3. Two views of the X-ray diagram of one of the
enantiomerically pure hydrogen-bonded dimers.
Org. Lett., Vol. 2, No. 20, 2000
3171

in a cis-relationship appear in the crystal. These enantio-
merically pure dimers are held together by four strong
intermolecular hydrogen bonds (N‚‚‚O distance of 2.740 and
2.829 Å) between the two pyridinone residues. The dimers
are similar in nature to one previously observed by Tanaka
and coauthors.6d-f These authors describe a bifunctional
[7]helicene that contains a terminus hydroxythiophene ring
and a terminus pyridine ring. The crystal structure reveals a
pair of intermolecular hydrogen bonds between the hydroxy
group of one helicene to the pyridine nitrogen atom of an
adjacent molecule. Here, the crystals were enantiomerically
pure because the starting solution was also enantiomerically
pure.
benzene rings of the P and M diastereomers are orientated
in a face-to-face type orientation with an average distance
of 3.64 Å between aromatic rings (Figure 4). The fact that
The bond lengths, bond torsional angles, and inter-
molecular distances of 1c closely resemble those found in
crystal structures of other [7]helicenes.6c,12 Significant C,C-
bond alternation is observed in the helicene. The outer bonds
(C(9)-C(10), C(6)-C(7), C(15)-C(16), and C(18)-C(19))
are shortened to 1.340-1.352 Å while the inner bonds
(C(24)-C(28) and C(28)-C(1)) are lengthened to 1.427-
1.458 Å. These variations from standard aromatic bond
lengths (1.39 Å for benzene) indicate that strain is localized
in the inner aromatic rings. The torsional angles along the
inner helical rim, which vary from 20.8(16)° for C(2)-C(1)-
C(28)-C(27) to 27.9(16)° for C(25)-C(26)-C(27)-C(28),
are in accordance with that observed in other heptahelicenes.
The overlapping terminal rings in 1c are separated by greater
than van der Waal’s half-radii of an aromatic ring on the
outside of the helicene (C(22)-C(5) ) 3.807(15) Å; C(20)-
C(3) ) 3.859(15) Å) but come into close contact on the
interior of the helicene (C(23)-C(1) ) 3.149(15) Å; C(24)-
C(2) ) 3.185(15) Å).
Figure 4. Packing diagram of [7]helicene 1c.
the crystal is composed of racemic dimers reveals that the
stereodiscrimination occurs at the molecular and not at the
macroscopic level.
We have shown that although [7]helicene 1b may associate
into a variety of hydrogen-bonded assemblies, they initially
self-assemble into dimers composed of the same helicity.
These optically pure dimers then pack to form racemic
columns, maximizing π-stacking interactions. Optimization,
resolution, and applications in the areas of substrate selectiv-
ity and catalysis are in progress.
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada and by the University of Alberta.
Supporting Information Available: Experimental pro-
cedures for preparation of compounds 1-6 and X-ray
crystallographic data for 1c. This material is available free
of charge via the Internet at http://pubs.acs.org.
The packing diagram of 1c shows that the homochiral
dimers arrange into offset racemic columns where the
(12) Navaza, J.; Toucaris, G.; Le Bas, G.; Navaza, A.; de Rango, C.
Bull. Soc. Chim. Belg. 1979, 88, 863.
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