SCHEME 1. (a) Graham’s Hypohalite Oxidation of
Amidines (X ) Cl or Br); (b) Diazirine Halogen-Exchange
Reaction
Reactivity of 1-Chloro-3-phenyldiazirines
Tomas Martinu and William P. Dailey*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
ReceiVed February 17, 2006
the intermediacy of 2-X in this process.5 However, the relative
rates of halogen-exchange reactions of other 3-halodiazirines
are not always in keeping with the general trend for cation-
stabilizing substituents and could suggest intermediates other
than 2-X.6 Additional observations, such as the reported failures
in obtaining chemical or spectroscopic evidence for the ioniza-
tion of 1 to 2-X under a variety of conditions7,8 or the facile
halogen exchange occurring on the diazirine ring substituted
with strongly cation-destabilizing trifluoromethyl group,9 raised
further questions about the accessibility of 2-X in solution.
Dailey and Bainbridge10 and Creary and Sky11 presented
experimental evidence that 3-bromo-3-phenyldiazirine (4c)
reacts with terminally 15N-labeled azide ion at the ring nitrogen,
in accordance with the SN2′ mechanism. Indeed, additions of
other nucleophiles (e.g., organometals12 or phosphines13) to the
ring nitrogen of diazirines are known. In light of these facts,
the experimental data supporting the intermediacy of 2-X were
reinterpreted in the framework of SN2′ chemistry.
The mechanistic origins of the chemistry of 1 became still
more complex after diazirine halogen-exchange reactions,
proceeding via diazirinyl radicals (SRN1)2c,14 or, conceivably,
via the formally antiaromatic diazirinyl anions,15 had been
reported.
If the majority of experimental observations, originally
attributed to the intermediacy of 2-X, can be explained in terms
of SN2′ or SRN1 chemistry, where do 2-X fit in the overall
p-Substituted 1-chloro-3-phenyldiazirines (5), the putative
intermediates of the reaction of N,N,N’-trichlorobenzamidines
(10) with excess of bromide ions, react further to afford
mixtures of 3-bromo- (4) and 3-chloro-3-phenyldiazirines (6).
The 6:4 ratios inversely correlate with the Hammett σp and
+
σp constants of the p-substituents. The formation of 4,
proposed to proceed by anti-SN2′ mechanism, is predominant
with electron-withdrawing p-substituents. Compounds 6, the
major products with electron-donating p-substituents, may
arise from 5 by a [1,3]-sigmatropic shift of chlorine proceed-
ing via polar transition structures 12. The results of a gas-
phase DFT (B3LYP/6-31+G*) study on the two mechanisms
are consistent with experiment.
Two important reactions of 3-halodiazirines (1), that is, the
formation of 1 by Graham’s hypohalite oxidation of amidines1
and the halogen-exchange reaction of 1,2 have been subject to
scrutiny over the past two decades (Scheme 1).
The Graham reaction was proposed to proceed through
1-halodiazirines 3,1 which may be transformed to 1 via
diazirinium-halide ion pairs 2-X or by an SN2′ displacement.
The former alternative was supported by the stability of
diazirinium ions (2) deriving from their formal aromatic
character; fragments with m/z corresponding to 2 were observed
in the mass spectra of 1. Calculated geometry and π-bond orders
indicate that 3-unsubstituted diazirinium ion (2a) is aromatic.3
However, the negative delocalization energy of 2a, likely caused
by significant positive charge located on each nitrogen atom,
points at the nonaromaticity of 2a.4
(5) Moss, R. A.; Terpinski, J.; Cox, D. P.; Denney, D. Z.; Krogh-
Jespersen, K. J. Am. Chem. Soc. 1985, 107, 2743.
(6) Moss, R. A.; Fedorynski, M.; Kmiecik-Lawrynowicz, G.; Terpinski,
J. Tetrahedron Lett. 1986, 27, 2707.
(7) Moss, R. A.; Wlostowska, J.; Guo, W.; Fedorynski, M.; Springer, J.
P.; Hirshfield, J. M. J. Org. Chem. 1981, 46, 5048.
(8) (a) Creary, X.; Sky, A. F. J. Org. Chem. 1988, 53, 4637. (b) Moss,
R. A.; Fede, J. M.; Yan, S. J. Am. Chem. Soc. 2000, 122, 9878.
(9) Dailey, W. P. Tetrahedron Lett. 1987, 28, 5801.
(10) Bainbridge, K. E.; Dailey, W. P. Tetrahedron Lett. 1989, 30, 4901.
(11) Creary, X.; Sky, A. F. J. Am. Chem. Soc. 1990, 112, 368.
(12) (a) Padwa, A.; Eastman, D. J. Org. Chem. 1969, 34, 2728. (b) Moss,
R. A.; Cox, D. P.; Tomioka, H. Tetrahedron Lett. 1984, 25, 1023.
(13) Alcaraz, G.; Baceiredo, A.; Nieger, M.; Bertrand, G. J. Am. Chem.
Soc. 1994, 116, 2159.
(14) (a) Creary, X.; Sky, A. F.; Phillips, G. J. Org. Chem. 1990, 55,
2005. (b) Creary, X. J. Org. Chem. 1993, 58, 7700.
(15) (a) Creary, X.; Sky, A. F.; Phillips, G.; Alonso, D. E. J. Am. Chem.
Soc. 1993, 115, 7584. (b) Moss, R. A.; Xue, S.; Liu, W. J. Am. Chem. Soc.
1994, 116, 10821.
Ion pairs 2-X were also commonly invoked in the diazirine
halogen-exchange reactions. The kinetics and the leaving-group
and salt effects of azide ion exchange with a series of
p-substituted 3-bromo-3-phenyldiazirines (4) are consistent with
(1) Graham, W. H. J. Am. Chem. Soc. 1965, 87, 4396.
(2) (a) Wlostowska, J.; Moss, R. A.; Guo, W.; Chang, M. J. J. Chem.
Soc., Chem. Commun. 1982, 432. (b) Cox, D. P.; Moss, R. A.; Terpinski,
J. J. Am. Chem. Soc. 1983, 105, 6513. (c) Creary, X. Acc. Chem. Res. 1992,
25, 31. (d) Moss, R. A. Acc. Chem. Res. 2006, 39, 267.
(3) (a) Pittman, C. U., Jr.; Kress, A.; Patterson, T. B.; Walton, P.; Kispert,
L. D. J. Org. Chem. 1974, 39, 373. (b) Byun, Y.-G.; Saebo, S.; Pittman, C.
U. J. Am. Chem. Soc. 1991, 113, 3689.
(4) Krogh-Jespersen, K. Tetrahedron Lett. 1980, 21, 4553.
10.1021/jo060341g CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/26/2006
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J. Org. Chem. 2006, 71, 5012-5015