1
,1′-Bipyrroles: Synthesis and Stereochemistry
In contrast to the well-studied atropisomeric stereochemistry
of biaryls, there are only two known optically active bipyr-
1
3
roles: a 1,1′-bipyrrole (2,2′,5,5′-tetramethyl-1,1′-bipyrrole-3,3′-
Sanjeev K. Dey and David A. Lightner*
14a
dicarboxylic acid) and a 2,2′-bipyrrole (1,1′,2,2′,5,5′-hexam-
14b
Department of Chemistry, UniVersity of NeVada, Reno,
NeVada 89557
ethyl-2,2′-bipyrrole-3,3′-dicar-boxylic acid). Molecular orbital
calculations and photoelectron spectroscopy have indicated a
preference for orthogonal rings in 1,1′-bipyrrole.10 Ab initio
calculations on 2,2′-bipyrrole show it adopting preferentially
an anti-clinal (ac) conformation at the global minimum with
an N-2-2′-N′ torsion angle ∼148° and a 3-4 kcal/mol greater
stability than the sc local minimum conformation, where the
1
1,12b
N-2-2′-N′ torsion angle is ∼46°.
Theory also predicts the
ac conformations of 3,3′- and 2,3′-bipyrrole to be the most
1
1a,c
stable.
Such theoretical predictions do not necessarily relate to the
solid phase: an X-ray structure of 2,2′-bipyrrole shows it to
1
2
adopt an ap planar conformation in the crystal. There are no
crystal structures available of any of the other parent constitu-
tional isomers of bipyrrole. And although crystallographic
structures of octa-substituted 1,1′-bipyrroles may not reflect that
1
,1′-Bipyrrole is synthesized in four steps from hydrazine.
A colorless solid, mp 52 °C, it sublimes readily at room
temperature and forms X-ray quality crystals in which the
rings are not coplanar but are nearly orthogonal.
(4) (a) Vetter, W.; Gaul, S.; Olbrich, D.; Gaus, C. Chemosphere 2007,
6
6, 2011-2018. (b) Blank, D. H.; Gribble, G. W.; Schneekloth, J. S., Jr.;
Jasinski, J. P. J. Chem. Crystallogr. 2002, 32, 541-546. (c) Vetter, W.
ReV. EnViron. Contamin. Toxicol. 2006, 188, 1-57.
1
Bipyrroles are N-heterocyclic analogs of biphenyl, although
(5) (a) Bricker, C.; Devillers, C. H.; Moutet, J-C.; Percaut, J.; Sessler, J.
far less well studied. Bipyrrole articles entered the literature
only about a dozen times during the first half of the last century;
yet, in the past 25 years, there has been a relative explosion of
interest in bipyrroles and bipyrrole-based more complex struc-
tures with more than 400 citations. Bipyrroles are found in nature
as components of clinically interesting and important natural
products for the treatment of cancer and viral and bacterial
L. J. Chem. Soc. Chem. Comm. 2006, 3981-3983. (b) Sessler, J. L.; An,
D.; Cho, W-S.; Lynch, V.; Yoon, D-W.; Hong, S-J.; Lee, C-H. J. Org.
Chem. 2005, 61, 321-347. (c) Sessler, J. L.; An, D.; Cho, W-S.; Lynch,
V. Angew. Chem., Int. Ed. 2003, 42, 2278-2281.
(6) (a) Naumovski, L.; Sirisawad, M.; Lecane, P.; Chen, J.; Ramos, J.;
Wang, Z.; Cortez, C.; Magda, D.; Thiemann, P.; Boswell, G.; Miles, D.;
Cho, D. G.; Sessler, J. L.; Miller, R. Mol. Cancer Ther. 2006, 5, 2798-
2
6
805. (b) Tanada, M.; Shibata, Y.; Maeda, M.; Saski, S. Heterocycles 2004,
3, 29-39.
2
3
infection; (in reduced form) in vitamin-B12; in marine natural
(7) (a) Wenbo, E.; Ohkubo, K.; Sanchez-Garcia, D.; Zhang, M.; Sessler,
4
5
L. J.; Fukuzumi, S.; Kadish, K. M. J. Phys. Chem. 2007, 590, 49-54. (b)
Erben, C.; Will, S.; Kadish, K. M. In The Porphyrin Handbook; Vol. 2,
Heteroporphyrins, Expanded Porphyrins and Related Macrocyles; Kadish,
K. M., Smith, K. M., Guilard, R., Eds; Academic Press, Inc.: New York,
products; in macrocyclic oligopyrroles for use as ionophores
6
and in medicine; and in synthetic linear oligopyrrole conductive
polymers.7
1
999. (c) Benicori, T.; Brenna, E.; Sannicolo, F.; Zotti, G.; Zechin, S.;
Schiavon, G.; Gatti, C.; Frigerio, G. Chem. Mater. 2000, 12, 1480-1489.
d) Street, G. B.; Lindsey, S. E.; Nazzal, A. I.; Wynne, K. J. Mol. Cryst.
There are six different bond connections that can be drawn
between two pyrrole molecules, leading to six constitutionally
isomeric bipyrroles: 3 symmetric (1,1′; 2,2′; and 3,3′) and 3
nonsymmetric (1,2′; 1,3′; and 2,3′). All but one, 1,1′-bipyrrole,
have C-C or N-C bonds linking the two pyrrole rings. Four
of the six parent, unsubstituted bipyrroles (1,1′, 2,2′, 3,3′, and
(
Liq. Cryst. 1985, 118, 137-148. (e) Ford, W. K.; Duke, C. B.; Salaneck,
W. R. J. Chem. Phys. 1982, 77, 5030-5039.
(
8) Farnier, M.; Soth, S.; Fournari, P. Can. J. Chem. 1976, 54, 1083-
1
086.
(
9) Flitsch, W.; Schulten W. Synthesis 1977, 414-415.
8
9
2
,3′) have been synthesized in 1976 and 1977, and subsequent
(10) (a) Flitsch, W.; Peeters, H.; Schulten, W.; Radmacher, P. Tetrahe-
10
11,12
dron 1978, 34, 2301-2304. (b) Andr e´ , J. M.; Vercauteren, D. P.; Street,
G. B.; Br e´ das, J. L. J. Chem. Phys. 1984, 80, 5643-5648. (c) Nazzal, I.
A.; Street, G. B.; Wynne, K. J. Mol. Cryst. Liq. Cryst. 1985, 125, 303-
307.
spectroscopic and theoretical analyses
were reported in
only a few publications. Unlike biphenyls and other biaryls,
rotational stereochemistry (atropisomerism) about the intercon-
necting bond of the six possible bipyrrole isomers is not well
(11) (a) Sancho-Garcia, J. C.; Karpfen, A. Chem. Phys. Lett. 2005, 411,
1
,12
3421-326. (b) Orti, E.; S a´ nchez-Marin, J.; Viruela-Martin, P. M.; Tom a´ s,
F. Chem. Phys. Lett. 1986, 130, 285-290. (c) Rabias, I.; Howlin, B. J.;
Provata, A.; Theodore, D. Mol. Simul. 2000, 24, 95-109. (c) Orti, E.;
S a´ nchez-Marin, J.; Tom a´ s, F. Theor. Chim. Acta 1986, 69, 41-49. (d) Falk,
H.; Stressler, G.; M u¨ ller, N. Monatsh. Chem. 1988, 119, 505-508. (d)
Millefiori, S.; Alparone, A. J. Chem. Soc. Faraday Trans. 1988, 94, 25-
32.
understood.
(
1) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pigments;
Springer-Verlag: New York, 1989, and references therein.
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(
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, 195-218. (b) Murthy, M. S. R.; Steenart, N. A. E.; Johnson, R. A.;
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compositions, and methods for treating cancer or viral diseases. Patent No.
WO2001055131, U.S. Patent 6,407,244, 2002; Chem. Abstr. 2001, 135,
(12) Skowronek, P.; Lightner, D. A. Monatsh. Chem. 2003, 134, 889-
899.
(13) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons, Inc.: New York, 1994; pp 1142-1150. See also: Eliel,
E. L. Stereochemistry of Carbon Compounds; McGraw-Hill, Inc.: New
York, 1962; pp 156-179 and Shriner, R. L.; Adams, R.; Marvel, C. S. In
Organic Chemistry. An AdVanced Treatise; Gilman, H., Ed.; John Wiley
& Sons: New York, 1943; Vol. I, pp 343-377.
1
5
52662. (c) Bhovi, M. G.; Gadaginamath, G. S. Asian J. Chem. 2005, 17,
11-517.
(
3) (a) Smith, K. M. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds; Pergamon Press: Oxford, 1984; Vol. 4. (b)
Kr a¨ utler, B.; Ostermann, S. In The Porphyrin Handbook; Vol. 11,
Bioinorganic and Bioorganic Chemistry; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds; Academic Press, Inc.: New York, 2003.
(14) (a) Chang, C.; Adams, R. J. Am. Chem. Soc. 1931, 53, 2353-2357.
(b) Webb, J. L. A. J. Org. Chem. 1953, 18, 1423-1427.
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0.1021/jo7016789 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/25/2007
J. Org. Chem. 2007, 72, 9395-9397
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