Molecular folding of C60 acetylenic cyclophanes: π-stacking of superimposed aromatic rings

Article abstract of DOI:10.1021/ol0345576

(Matrix presented) The syntheses of two distinct families of phenylyne helical cyclophanes with potential for organic materials are described. The meta-bonded atropisomers afford interesting bowtie-like and butterfly-like conformers from a palladium(0), c

Full text of DOI:10.1021/ol0345576

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1911-1914
Molecular Folding of C60 Acetylenic
Cyclophanes: π-Stacking of
Superimposed Aromatic Rings
Matthew A. Heuft, Shawn K. Collins,† and Alex G. Fallis*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
afallis@science.uottawa.ca
Received March 31, 2003
ABSTRACT
The syntheses of two distinct families of phenylyne helical cyclophanes with potential for organic materials are described. The meta-bonded
atropisomers afford interesting bowtie-like and butterfly-like conformers from a palladium(0), copper-mediated coupling sequence. Molecular
modeling revealed the contrasting stereochemistry in these systems from differential molecular folding pathways during cyclization. The
interplanar separation of the superimposed aromatic rings is ∼3.5 Å.
Carbon-rich molecules with 60 or more carbon atoms are
currently of widespread interest, particularly if they have
potential to eventually generate new fullerenes and related
structures.1
Experience has demonstrated that despite careful design
of suitable building blocks, the experimental realization of
these goals is frequently thwarted by nature.2 This is reflected
in recent reports describing the synthesis and design of new
cyclophanes3 and assorted cage compounds4 with novel
shapes and supramolecular geometries.5 These investigations
have encompassed the incorporation of molecular architec-
tures with shape-persistent characteristics6 for liquid crystals7
and nonlinear optics applications, as well as π-stacking
between aromatic systems.8
We have established previously that para-cyclophanes with
eneyne bridges composed of double bonds and/or benzene
rings may be prepared by sequential palladium(0) and
copper(II)-mediated coupling reactions.7b,9 The combination
(3) (a) Vo¨gtle, F. Cyclophane Chemistry; Wiley: New York, 1999. (b)
Bodwell, G. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2085. (c) de Meijere,
A.; Ko¨nig, B.; Synlett 1997, 1221. (d) Hopf, H. Classics in Hydrocarbon
Chemistry; Wiley-VCH: Weinheim, Germany, 2000. (e) Bodwell, G. J.;
Saton, T. Angew. Chem., Int. Ed. 2002, 41, 4003.
(4) (a) Ko¨nig, B. Top. Curr. Chem. 1998, 196, 91. (b) Tsuji, T. In
AdVances in Strained Interesting Organic Molecules; Halton, B. Ed.; JAI
Press: Greenwich, CT, 1999; pp 103-152.
(5) Diederich, F.; Gobbi, L. Top. Curr. Chem. 1999, 201, 43.
(6) (a) Haley, M. M.; Pak, J. J.; Brand, S. C. Top. Curr. Chem. 1999,
201, 81. (b) Grave, C.; Schlu¨ter, A. D. Eur. J. Org. Chem. 2002, 3075. (c)
Ho¨ger, S.; Rosselli, S.; Ramminger, A.-D.; Enkelmann, V. Org. Lett. 2002,
4, 4269.
(7) (a) Schmidt-Mende, L.; Fechtenkotter, A.; Mullen, K.; Moons, E.;
Friend, R. H.; MacKenize, J. D. Science 2001, 293, 1119. (b) Collins, S.
K.; Yap, G. P. A.; Fallis, A. G. Org. Lett. 2000, 2, 3189.
(8) (a) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Chem. 1996,
118, 1019. (b) Tobe, Y.; Utsumi, N.; Kawabata, K.; Nagano, A.; Adachi,
K.; Araki, S.; Sonoda, M.; Hirose, K.; Naemura, K. J. Am. Chem. Chem.
2002, 140, 4544. (c) Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini,
M.; Raimondi, L.; Baldridge, K. K.; Siegel, J. S. Org. Biomol. Chem. 2003,
1, 157.
† Present Address: Department of Chemistry, University of California-
Irvine, Irvine, CA.
(1) (a) Hirsh, A. Fullerenes and Related Structures; Springer-Verlag:
Berlin, 1999. (b) Scott, L. T.; Boorum, M. M.; McMahon, B. J.; Hagen, S.;
Mack, J.; Blank, J.; Wegner, H.; de Meijere, A. Science 2002, 295, 1500.
(2) (a) Rubin, Y.; Parker, T. C.; Timothy, C.; Khan, S. I.; Holliman, C.
L.; McElvany, S. W. J. Am. Chem. Soc. 1996, 118, 5308. (b) Rubin, Y.;
Parker, T. C.; Pastor, S. J.; Jalisatgi, S.; Boulle, C.; Wilkins, C. L. Angew.
Chem., Int. Ed. 1998, 37, 1353. (c) Tobe, Y.; Nakagawa, N.; Naemura, K.;
Wakabayashi, T.; Shida, T.; Achiba, Y. J. Am. Chem. Chem. 1998, 120,
4544. (d) Fallis, A. G. Can. J. Chem. 1999, 77, 159. (e) Collins, S. K.;
Yap, G. P. A.; Fallis, A. G. Org. Lett. 2002, 4, 11. (f) Manini, P.; Amrein,
W.; Gramlich, V.; Diederich, F. Angew. Chem., Int. Ed. 2002, 41, 4339.
10.1021/ol0345576 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/08/2003

of the number and type of unsaturated linkages in these
compounds creates a twisted conformation that imparts
helical chirality to the assembled molecule.10 Consequently,
the preparation of C60 acetylenic cyclophanes that possess
different molecular conformations and variable through-space
interactions are also of interest.
Compounds 1 and 3 each possess 60 carbons but differ in
the acetylene bridges employed and the point of attachment
to the benzene cap. Cyclophane 1 possesses a para-(1,4)-
bridged phenyl skeleton, while cyclophane 3 is composed
of meta-(1,3)-bridged benzene caps. Due to the frequent
insolublity of these unsaturated hydrocarbons, we and others,
have circumvented this difficulty by alkylamine substitu-
tion.10d,11 Consequently, we decided to synthesize and
investigate the properties of the more soluble amine-
substituted cyclophanes 2 and 4 in order to gain further
understanding of various features, including their helical
geometry, through-space interactions, and preferred confor-
mations from various molecular folding pathways.
Symmetrical double dissection between the tetrayne
bridges of cyclophane 2 suggested that dimerization of a
suitable C30 precursor would be an attractive building block.
However, when this C30 precursor was subjected to our one-
pot desilylation/coupling procedure, only the intramolecular
product was formed.12
Figure 1. Aceylenic, 60-carbon atom macrocyclic cyclophanes
with (para- and meta-substituted capping groups).
n-BuLi (2 equiv) and quenching with ZnBr2 to give 7.
Subsequent one-pot desilylation/coupling with K2CO3 and
Cu(OAc)2‚H2O in pyridine/methanol (1:1)14 led to tetrayne
8 in 92% yield. Exposure to tetrabutylammonium fluoride
afforded chromatographically (SiO2) unstable acetylene 9 that
was reacted directly with 1-bromo-4-iodobenzene (2 equiv,
Pd(PPh3)2Cl2, CuI, Et3N) to give the desired dibromide 10.
This compound also decomposed during chromatography.
Therefore, the coupling with 1-bromo-4-iodobenzene was
repeated and its disappearance was monitored. Once all of
the iodobenzene was consumed, Pd(PhCN)2Cl2 and P(t-Bu)315
were added and the reaction was heated to reflux. Dropwise
addition of a second equivalent of 9 led to cyclophane 2 as
desired. The use of this improved ligand for Pd(0) coupling
reactions greatly facilitated the stepwise construction of this
cyclophane macrocycle. This protocol is also useful for the
synthesis of unsymmetrical cyclophanes with nonlinear
optical potential.
Consequently, a stepwise approach to the C60 cyclophane
core with early assembly of the tetraoctyne moiety was
investigated (Scheme 1). Iodide 5 underwent a Negishi
coupling with the organozincate derived from cis-4-chloro-
1-trimethylsilyl-but-3-en-1-yne (6)13 upon treatment with
Scheme 1. Synthesis of Cyclophane 2a
Proton and carbon NMR spectra revealed that 2 adopted
a highly symmetrical conformation in solution (Figure 2).
Figure 2. Proposed conformation of cyclophane 2.
In contrast to our experience with related cyclophanes,9,10e
cyclophane 2 was conformationally stable at room temper-
(9) (a) Romero, M. A.; Fallis, A. G. Tetrahedron Lett. 1994, 35, 4711.
(b) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Angew. Chem., Int. Ed.
2000, 39, 385.
(10) For examples of helical chirality in cyclophanes, see: (a) Boese,
R.; Matzger, A. J.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1997, 119, 2052.
(b) Marsella, M. J.; Kim, I. T.; Tham, F. J. Am. Chem. Soc. 2000, 122,
974. (c) Baxter, P. N. W. J. Org. Chem. 2001, 66, 4170. (d) Heuft, M. A.;
Fallis, A. G. Angew. Chem., Int. Ed. 2002, 41, 4520.
a Conditions: (a) (1) 6, n-BuLi (2 equiv), THF, -78 °C, 2 min;
(2) ZnBr2, 0 °C, 15 min; (3) 5, [Pd(PPh3)4], ∆, 48 h, 80%. (b)
K2CO3, Cu(OAc)2 (6 equiv), MeOH/py (1:1), 6 h, 92%. (c) TBAF,
THF, 18 h, 97%. (d) 1-Bromo-4-iodobenzene, Pd(PPh3)2Cl2, CuI,
Et3N, THF, ∆, 13 h. (e) 9, Pd(PhCN)2Cl2, P(t-Bu)3, 17 h, 4%.
1912
Org. Lett., Vol. 5, No. 11, 2003

ature. This is expected since isomerization requires the
adoption of a strained, planar, rectangular-like intermediate.
Molecular modeling (Figure 3) and NMR data were con-
sistent with a C2-symmetric conformation of 2.
dimethylformamide (DMF). Aldehyde 11 was then treated
with Ohira’s reagent (12),17 followed by K2CO3 in MeOH
to yield acetylene 13. A Cadiot-Chodkiewicz alkyne cross-
coupling reaction of 13 with dibromide 14 gave the amino-
substituted C30 precursor 15 required for the dimerization
experiment. This hexyne was then transformed by our in situ
12
disilylation/coupling protocol with TBAF and Cu(OAc)2
to afford two new molecules (15% yield) that were consistent
with the generic cyclophane structure 4. However, this flat
cyclic representation of 4 does not accurately reflect the
actual conformation of these molecules.
The two isomers of cyclophane 4 were separated via size-
exclusion semiprep HPLC. The major isomer 4a displayed
higher symmetry than the minor isomer 4b (4a/4b 3:1) on
the basis of their proton and carbon NMR spectra. Unfor-
tunately, crystalline samples suitable for X-ray analysis could
not be obtained. However, computer-based molecular model-
ing revealed that two different isomeric conformers were
possible.18 These symmetrical isomeric “bowtie-like” and
“butterfly-like” structures, 4a and 4b, respectively, are
illustrated in Figures 4-6.
Figure 3. Molecular modeling representations of the C2-symmetric,
helical conformation of cyclophane 2.
Our previous observations regarding the competition
between acetylenic intramolecular and dimerization reactions
revealed that the favored reaction was dictated by the termini
separation.16 The intramolecular alternative was inhibited
when the reactive acetylenic termini were separated by more
than 7.5 Å. Consequently, the dimerization strategy toward
cyclophane 4 was particularly attractive, as the termini
separation was approximately 10.7 Å. Cyclophane 4 was
synthesized by our established dimerization protocol. Un-
fortunately, iodide 5 failed to undergo a direct Sonogashira
coupling reaction with trimethylsilylacetylene under a variety
of reaction conditions (Scheme 2). To overcome this chal-
Scheme 2. Synthesis of Cyclophane 4a
Figure 4. Figure 4. Proposed conformations of cyclophanes 4a
and 4b.
Cyclophane conformer 4a possesses C2h symmetry, while
cyclophane 4b belongs to the lower symmetry C2 point
group. This creates an environment in which the aromatic
a (a) (1) t-BuLi (2 equiv), THF, -78 °C, 5 min; (2) DMF, ∆, 12
h, 97%. (b) 12, K2CO3, MeOH, 48 h, 61% conversion. (c) 14,
Pd2(dba)3, CuI, 1,2,2,6,6-pentamethylpiperidine, THF, 16 h, 30%.
(d) TBAF, Cu(OAc)2 (6 equiv), Et2O/py (1:3), 18 h, 15%.
(13) (a) Lu, Y.-F.; Harwig, C. W.; Fallis, A. G. J. Org. Chem. 1993, 58,
4202. (b) Lu, Y.-F.; Harwig, C. W.; Fallis, A. G. Can. J. Chem. 1995, 73,
2253.
(14) Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.;
Wan, W. B. Tetrahedron Lett. 1997, 38, 7483.
(15) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
Lett. 2000, 2, 1729.
(16) Collins, S. K. Ph.D. Thesis, University of Ottawa, Ottawa, Ontario,
Canada, December 2001.
lenge, iodide 5 was converted to aldehyde 11 by halogen-
metal exchange with t-BuLi (2 equiv) and quenching with
(17) Ohira, S. Synth. Commun. 1989, 19, 561.
(11) Pak, J. J.; Weakley, T. J. R.; Haley, M. M. J. Am. Chem. Soc. 1999,
121, 8182.
(12) Heuft, M. A.; Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett.
2001, 3, 2883.
(18) Universal force field (UFF) calculations were obtained using the
Cerius2-Dmol3 molecular modeling suite from Molecular Simulations, Inc.
(San Diego, 1999). We thank S. Drouin and Prof. D. Fogg (University of
Ottawa) for assistance.
Org. Lett., Vol. 5, No. 11, 2003
1913

Figure 6. Figure 6. Molecular modeling representation of the
butterfly-like, C2-symmetric conformation of cyclophane 4b.
π-stack. The meta isomer follows different molecular folding
pathways during the macrocyclization reaction to generate
two atropisomers, 4a and 4b, as depicted in Figures 4-6.
These acetylenic, shape-persistent, π-stacked C60 cyclo-
phanes with modified functional groups possess interesting
potential. New families can be designed with different
molecular conformations, variable through-space interactions,
and modified levels of unsaturation. These features hold
promise, with appropriate substitutents, for the preparation
of different types of discotic,21 nematic, and ferroelectric
liquid crystals,22 metallomesogens,23 and electronic devices.24
Figure 5. Figure 5. Molecular modeling representation of the
bowtie-like, C2h-symmetric conformation of cyclophane 4a.
π-π stacking interactions between the capping phenyl rings
in each structure are quire similar despite their pictorial
appearance.19 The interplanar separations for the super-
imposed aromatic rings in 4a and 4b are 3.55 and 3.52 Å,
respectively. These “sandwich-like” arrangements are clearly
evident, and these values are similar to theoretical numbers
calculated for the parallel dimer of benzene itself.20
Cyclophanes 4a and 4b constitute a pair of atropisomers
due to their restricted rotation. They are both conformation-
ally and configurationally stable even upon heating to 100
°C. Interconversion of 4a to 4b involves a significant energy
barrier, which requires one of the capping benzene rings to
undergo a “skipping rope” type rotation through the other
cyclophane macrocycle ring en route to the second isomer.
In conclusion, we have synthesized two novel C60
cyclophanes. The stereochemistry of these compounds is
governed by the para-(1,4) or meta-(1,3) substitution of the
capping phenyl ring. Both series are geometrically distinct
but adopt helical conformations in which the benzenoid caps
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
for financial support of this research. S. K. Collins and M.
A. Heuft thank NSERC and the University of Ottawa for
Graduate Scholarships.
Supporting Information Available: Experimental details
and characterization for cyclophanes 2, 4a, and 4b and
characterization for intermediates 9, 10, and 15. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0345576
(19) For recent benzenoid examples, see: Tobe, Y.; Utsumi, N.;
Kawabata, K.; Nagano, A.; Adachi, K.; Araki, S.; Sonoda, M.; Hirose, K.;
Naemura, K. J. Am. Chem. Chem. 2002, 140, 4544. For a thiophene
example, see: Marsella, M. J.; Wang, Z.-Q.; Reid, R. J.; Yoon. K. Org.
Lett. 2001, 3, 885.
(20) (a) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanaba, K.
J. Am. Chem. Soc. 2000, 124, 104. (b) Hobza, P.; Selzle, H. L.; Schlag, E.
W. J. Phys. Chem. 1996, 100, 18790.
(21) Bushby, R. L.; Lozman, O. R. Curr. Opin. Colloid Interface Sci.
2002, 7, 343.
(22) Hird, M.; Goodby, J. W.; Hindmarsh, P.; Lewis, R. A.; Toyne, K.
J. Ferroelectronics 2002, 276, 219.
(23) Costisor, O.; Schweifer, J.; Grunert, M.; Linert, W. Recent Res. DeV.
Mater. Sci. 2001, 2, 1.
(24) Ito, K.; Suzuki, T.; Sakamoto, Y.; Kubota, D.; Inoue, Y.; Sato, F.;
Tokito, S. Angew. Chem., Int. Ed. 2003, 42, 1159.
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Org. Lett., Vol. 5, No. 11, 2003