hydrogen bond between the OH and the NO radical groups
in solution as well as in the crystalline state.2,7
Additional multistep equilibrations involving (e) formation
of the other phenoxy radical (cis-9), (f) formation of the
quinoid intermediate (10), (g) intermolecular recombination
to give trans-9, and (h) intermolecular hydrogen abstraction
to give trans-(2R,5R)-1 can effectively explain the mecha-
nism of this eventual racemization of trans-(2S,5S)-1.
To gain more insight into the mechanism of the racemi-
zation and epimerization, we have synthesized phenolic
nitroxides (S)-4 (89% ee) and (S)-5 (87% ee), which are the
m-hydroxy analogue and the biphenyl homologue of (S)-2,
respectively. These optically active nitroxides as well as
trans-(2S,5S)-6 did not undergo spontaneous racemization
at all in solution. Furthermore, bis(p-alkoxy) analogues of
trans-(2S,5S)-1 showed neither epimerization nor racemiza-
tion in solution.1 These results strongly suggest the participa-
tion of a planar quinoid intermediate, which is known as
the cause of racemization for a few chiral closed-shell
molecules,8 in both racemization and epimerization processes.
Namely, the mechanism of epimerization of trans-(2S,5S)-1
can be accounted for in terms of the multistep equilibrations
involving (a) intermolecular abstraction of a phenolic
hydrogen atom by the neighboring NO radical to generate
the phenoxy radical trans-7 and the corresponding hydrox-
ylamine, (b) formation of the planar quinoid intermediate 8,
(c) free rotation of the quinoid moiety in 8 and the subsequent
intramolecular regeneration of the C-N bond to give cis-7,
and (d) intermolecular hydrogen abstraction by the phenoxy
radical of cis-7 from the resulting hydroxylamine or another
hydroxy group to give meso cis-(2R,5S)-1 (Scheme 1).
The kinetics of racemization of (S)-rich 2 of 85% ee in
CHCl3 (20.0 mM) at 20 °C was solved numerically by using
a laboratory-made program that implemented a fourth-order
Runge-Kutta algorithm.9 Because, as mentioned above, the
observed spontaneous racemization is initiated by intermo-
lecular association of nitroxides, five generic species that
can interconvert would be involved in the present racemi-
zation, as shown in Scheme 2. R and S represent the
Scheme 2. Racemization Pathway of 2a
Scheme 1. Mechanism of Epimerization and Racemization of
trans-(2S,5S)-1a
a Values in parentheses represent the rate constants (10-3 mol
L-1 sec-1).
monomeric (R)- and (S)-enantiomers, respectively. R2 and
S2 indicate the homodimers of (R)- and (S)-enantiomers,
respectively, and RS designates their heterodimer. Use of
the program allows systems of linked differential equations,
which are formulated by a combination of the five concen-
tration terms and the six rate constants, to be solved
simultaneously to analyze the concentrations of the five
species as a function of time (Figure 3). The program
(7) (a) Reznikov, V. A.; Volodarskii, L. B. Russ. Chem. Bull. 1996, 45,
384-392. (b) Reznikov, V. A.; Burchak, O. N.; Vishnivetskaya, L. A.;
Volodarsky, L. B.; Rybalova, T. V.; Gatilov, Yu. V. Russ. J. Org. Chem.
1997, 33, 1302-1310. (c) Kotake, Y.; Kuwata, K.; Janzen, E. G. J. Phys.
Chem. 1979, 83, 3024-3029. (d) Chiarelli, R.; Rassat, A.; Rey, P. Chem.
Commun. 1992, 1081-1082. (e) Ahrens, B.; Davidson, M. G.; Forsyth, V.
T.; Mahon, M. F.; Johnson, A. L.; Mason, S. A.; Price, R. D.; Raithby, P.
R. J. Am. Chem. Soc. 2001, 123, 9164-9165.
(8) (a) Matsuo, K.; Yamamoto, Y.; Kado, N.; Yamazaki, M.; Nagata,
O.; Kata, H.; Tsuji, A. Chem. Pharm. Bull. 2001, 49, 101-104. (b) Venter,
D. P. Tetrahedron 1991, 47, 5019-5024.
(9) Jurs, P. C. Computer Software Applications in Chemistry, 2nd ed.;
Wiley & Sons: New York, 1996; pp 78-103.
a See the text for the details of processes a-h.
Org. Lett., Vol. 7, No. 9, 2005
1799