Synthesis of acetylenic cyclophanes via intramolecular self-assembly: Evidence of perfluorophenyl-phenyl quadrupole interactions in the solution state

Article abstract of DOI:10.1021/ol015511k

matrix presented Reported herein is an example of a solution-state cross-coupling cyclization with an outcome mediated by perfluorophenyl-phenyl electrostatic interactions.

Full text of DOI:10.1021/ol015511k

ORGANIC
LETTERS
2001
Vol. 3, No. 6
885-887
Synthesis of Acetylenic Cyclophanes via
Intramolecular Self-Assembly: Evidence
of Perfluorophenyl−Phenyl Quadrupole
Interactions in the Solution State
Michael J. Marsella,* Zhi-Qiang Wang, Rodney J. Reid, and Kunsang Yoon
Department of Chemistry, UniVersity of California at RiVerside,
RiVerside, California 92521-0403
michael.marsella@ucr.edu
Received January 3, 2001
ABSTRACT
Reported herein is an example of a solution-state cross-coupling cyclization with an outcome mediated by perfluorophenyl−phenyl electrostatic
interactions.
The alternate coplanar stacking of benzene and hexafluo-
robenzene in the solid state is a well-known phenomenon
attributed to the nearly equal yet opposite quadrupole
moments of the two species.1 Indeed, the prevalence of the
aryl-perfluoroaryl (ArH-ArF) solid-state packing motif has
established this couple as a reliable supramolecular synthon
for use in crystal engineering, as exemplified by the elegant
studies of Coates and co-workers.2,3 Despite proven utility
in the solid state, such electrostatic interactions have not
established themselves as viable components of template-
directed synthesis in the solution state. The paucity of
examples illustrating solution-state self-assembly of confor-
mationally flexible molecules via ArH-ArF stacking interac-
tions is not surprising considering that quadrupole-
quadrupole attractive forces are weak and diminish at a rate
of r-5 (where r is the distance between the two quadrupoles).
Indeed, ArH-ArF interactions in the solution state are
typically observed in organic solvents only when ArH and
ArF species are present in high concentrations or held in close
proximity by an appropriate scaffold.4-6 Despite this fact,
electrostatic interactions remain a critical component in
(4) Laatikainen, R.; Ratilainen, J.; Sebastian, R.; Santa, H. J. Am. Chem.
Soc. 1995, 117, 11006-11010.
(5) Williams, V. E.; Lemieux, R. P.; Thatcher, G. R. J. J. Org. Chem.
1996, 61, 1927-1933.
(6) Cozzi, F.; Ponzini, F.; Annunziata, R.; Cinquini, M.; Siegel, J. S.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1019-1020.
(7) Ballardini, R.; Balzani, V.; Credi, A.; Brown, C. L.; Gillard, R. E.;
Montalti, M.; Philp, D.; Stoddart, J. F.; Venturi, M.; White, A. J. P.;
Williams, B. J.; Williams, D. J. J. Am. Chem. Soc. 1997, 119, 12503-
12513.
(1) Williams, J. H.; Cockcroft, J. K.; Fitch, A. N. Angew. Chem., Int.
Ed. Engl. 1992, 31, 1655-1657.
(2) Coates, G. W.; Dunn, A. R.; Henling, L. M.; Ziller, J. W.; Lobkovsky,
E. B.; Grubbs, R. H. J. Am. Chem. Soc. 1998, 120, 3641-3649.
(3) Coates, G. W.; Dunn, A. R.; Henling, L. M.; Dougherty, D. A.;
Grubbs, R. H. Angew. Chem., Int. Ed. Engl.1997, 36, 248-251.
10.1021/ol015511k CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/17/2001

Scheme 1a
a (a) PdCl2(PPh3)2; CuI; NH(i-Pr)2; THF; 80 °C.
supramolecular chemistry,2,3,7-9 as re-emphasized by recent
studies involving catenane formation.10 Herein we report an
example of a solution-state reaction cyclization with an
outcome influenced by ArH-ArF electrostatic interactions.
During the course of unrelated studies directed at designing
helical conjugated molecular architectures,11 we serendipi-
tously discovered a model system exhibiting evidence of
quadrupole-enhanced self-assembly in the solution state.
Specifically, this reaction involved the Sonogashira cross-
coupling of 1 and 2 to yield compound 4, an acetylenic
cyclophane analogous to the type recently reported by Fallis
and co-workers.12 Presuming that the formation of cyclo-
phane 4 proceeds via a stepwise cross-coupling, the favored
conformation of linear intermediate 3 plays a decisive role
in the production of cyclophane 4 or the corresponding poly-
(4) (Scheme 1). As such, favorable interactions between the
aryl diad in the folded conformer of intermediate 3 should
promote the formation of cyclophane 4. In this case,
intermediate 3 would serve as both substrate and template.
In theory, the attractive (or repulsive) interactions between
the phenyl moieties of intermediates 3a-c can be qualita-
tively assessed by comparing the yields of cyclophanes 4a-c
versus their corresponding polymers. The syntheses of
compounds 1 and 2 are shown in Scheme 2.
For our purposes, the synthesis of macrocycle 4 required
subtle modifications to typical Sonogashira coupling condi-
tions.13 First, to minimize intermolecular ArH-ArF interac-
tions with solvent, THF was used in place of toluene (a
potential ArH source) for the Sonogashira coupling.14 Second,
the reaction was performed under pseudo-high-dilution
Scheme 2a
(8) Gillard, R. E.; Stoddart, J. F.; White, A. J. P.; Williams, B. J.;
Williams, D. J. J. Org. Chem. 1996, 61, 4504-4505.
(9) Nagase, S.; Kobayashi, K.; Akasaka, T. Bull. Chem. Soc. Jpn. 1996,
69, 2131-2142.
(10) Raymo, F. M.; Houk, K. N.; Stoddart, J. F. J. Org. Chem. 1998,
63, 6523-6528.
a (a) n-BuLi; I2, diethyl ether, -78 °C. (b) 1,4-diethynylbenzene,
PdCl2(PPh3)2, CuI, NH(i-Pr)2, toluene, 80 °C. (c) TMSA, PdCl2-
(PPh3)2, CuI, NH(i-Pr)2, toluene, 80 °C. (d) K2CO3, MeOH/CH2Cl2.
(e) 1,4-diethynyl-2,3,5,6-tetrafluorobenzene, PdCl2(PPh3)2, CuI,
NH(i-Pr)2, toluene, 80 °C.
(11) Marsella, M. J.; Kim, I. T. J. Am. Chem. Soc. 2000, 122, 974-975.
(12) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett. 2000, 2, 3189-
3192.
(13) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 3.
(14) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553.
886
Org. Lett., Vol. 3, No. 6, 2001

conditions to minimize polymer formation.15 The yields of
the three cross-coupling reactions (1a + 2a f 4a; 1a + 2b
f 4b; 1b + 2b f 4c) are given in Scheme 1.
cyclization was similar to that observed for 4. Specifically,
the yield of 6a (ArH-ArF; 26%) exceeded that of 6b (ArH-
ArH; 10%).
On the basis of the aforementioned results, we propose
that the folded (productive) conformer of 3b is stabilized
relative to that of 3a and 3c as a result of attractive ArH-
ArF electrostatic interactions (Scheme 1). An analogous
argument holds true for differences observed in compounds
6a versus 6b. Calculations16 on the diethynylbenzene moiety
diads of compounds 4a and 4b at the PM3 level of theory
estimate an energy difference of 0.35 kcal/mol in favor of
compound 4b, thus qualitatively supporting our aforemen-
tioned presupposition. These effects may further be amplified
if reversible intramolecular coordination to the Pd catalyst
in folded intermediate 3 requires an even more intimate
contact between the aryl diad. Although entropic effects
would typically overwhelm such a small energy difference
in solution, the conformationally restricted and rigid nature
of intermediate 3 allows this weak interaction to have
relatively profound consequences on the outcome of the
reaction.
As would be predicted from electrostatic arguments,
cyclophane 4b (X ) H; Y ) F) is obtained in highest yield
(30% versus 12% and 10% for 4b, 4a, and 4c, respectively).
These results were completely reproducible over several
attempts despite minor changes to reaction conditions. As a
result of the fact that no starting materials were recovered,
we have tentatively ruled out inherent reactivity differences
among substrates as the source of our observations. These
results implicate ArH-ArF quadrupole interactions as a
decisive force in determining the outcome of the reaction.
In an effort to test the generality of this observation,
Sonogashira cross-coupling of components 2 and 5 to yield
macrocycle 6, a regioisomer of compound 4, was also
performed (Scheme 3). As anticipated, the outcome of this
Scheme 3a
By extension of the results presented herein, electrostatic
tuning of cofacial aryl moieties (via perfluorination or its
equivalent) should provide a valid mechanism to alter both
yield and effective ring strain in conformationally restricted
macrocycles such as cyclophanes.
Acknowledgment. This work was generously supported
by DuPont (Young Professor Grant to M.J.M.) Research
Corporation (Research Innovation Award to M.J.M.), donors
of the Petroleum Research Fund (administered by the
American Chemical Society), the University of California
Cancer Coordinating Committee, and the University of
California at Riverside.
Supporting Information Available: Experimental pro-
cedures and characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL015511K
a (a) n-BuLi, I2, diethyl ether, -78 °C. (b) 1,4-diethynylbenzene,
PdCl2(PPh3)2, CuI, NH(i-Pr)2, toluene, 80 °C. (c) K2CO3, MeOH/
CH2Cl2. (d) PdCl2(PPh3)2, CuI, NH(i-Pr)2, THF, 80 °C.
(15) Zhang, J. S.; Pesak, D. J.; Ludwick, J. L.; Moore, J. S. J. Am. Chem.
Soc. 1994, 116, 4227-4239.
(16) Calculations were performed using Titan software. Schro¨dinger, Inc.,
1500 SW First Avenue, Suite 1180, Portland, OR 97201.
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