Spontaneous racemization and epimerization behavior in solution of chiral nitroxides

Article abstract of DOI:10.1021/ol050401p

(Chemical Equation Presented) Enantiomerically enriched samples of chiral cyclic nitroxides with a 4-hydroxyphenyl group on the stereogenic center bearing the NO radical group undergo unprecedented spontaneous racemization and/or epimerization in aprotic solvents, which can be well accounted for by the multistep equilibrations involving planar quinoid intermediates.

Full text of DOI:10.1021/ol050401p

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1797-1800
Spontaneous Racemization and
Epimerization Behavior in Solution of
Chiral Nitroxides
Naohiko Ikuma,†,‡ Hirohito Tsue,†,‡ Naoko Tsue,‡ Satoshi Shimono,‡
Yoshiaki Uchida,‡ Kazuyoshi Masaki,‡ Nagahisa Matsuoka,‡ and Rui Tamura*,†,‡
Graduate School of Global EnVironmental Studies and Graduate School of Human and
EnVironmental Studies, Kyoto UniVersity, Kyoto 606-8501, Japan
tamura-r@mbox.kudpc.kyoto-u.ac.jp
Received February 24, 2005
ABSTRACT
Enantiomerically enriched samples of chiral cyclic nitroxides with a 4-hydroxyphenyl group on the stereogenic center bearing the NO radical
group undergo unprecedented spontaneous racemization and/or epimerization in aprotic solvents, which can be well accounted for by the
multistep equilibrations involving planar quinoid intermediates.
Recently, we have successfully prepared all-organic para-
magnetic liquid crystals that contain a chiral five-membered
cyclic nitroxide unit (trans-1) within the rigid core and show
nematic and chiral-nematic (cholesteric) phases.1 During this
synthetic study,2,3 we have noticed that the optical rotations
of the enantiomerically enriched trans-1, 2, and trans-3
gradually decrease in aprotic solvents. Furthermore, HPLC
analytical studies using a chiral stationary phase column4 to
determine their ee and/or de values have indicated the
occurrence of spontaneous racemization for 2, epimerization
for trans-3, and both racemization and epimerization for
trans-1.
Although a certain chiral nitroxide was reported to
racemize under oxidizing conditions,5 there has been no
precedent for such spontaneous racemization and epimer-
ization in solution. Therefore, to clarify the mechanism of
this unexpected racemization and epimerization and to find
a way to prevent them, we investigated the effects of the
solvent, the solute concentration, the temperature, and the
light irradiation on the racemization and epimerization,
together with the kinetics of the racemization in solution.
† Graduate School of Global Environmental Studies.
‡ Graduate School of Human and Environmenetal Studies.
(1) Ikuma, N.; Tamura, R.; Shimono, S.; Kawame, N.; Tamada, O.; Sakai,
N.; Yamauchi, J.; Yamauchi, Y. Angew. Chem., Int. Ed. 2004, 43, 3677-
3682.
When a CHCl3 solution (45.0 mM) of (S)-enriched 2 of
42% ee was kept standing at 20 °C, the ee value of 2 in
solution decreased gradually to give an almost racemic
solution after one month, indicating the occurrence of
spontaneous racemization in solution. The racemization
(2) Ikuma, N.; Tamura, R.; Shimono, S.; Kawame, N.; Tamada, O.; Sakai,
N.; Yamauchi, J.; Yamauchi, Y. MendeleeV Commun. 2003, 109-111.
(3) Shimono, S.; Tamura, R.; Ikuma, N.; Takahashi, H.; Sakai, N.;
Yamauchji, J. Chem. Lett. 2004, 33, 932-933
(4) HPLC analysis was carried out by using a chiral stationary phase
column (Daicel Chiralcel OD-H, 0.46 × 25 cm), a mixture of hexane and
2-PrOH (9:1) as the mobile phase at a flow rate of 0.5 or 1.0 mL min-1
,
(5) Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.; Kwan, T. J.
Org. Chem. 1998, 63, 6363-6374.
and a UV-vis spectrometer (254 nm) as the detector.
10.1021/ol050401p CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/26/2005

occurred gradually in aprotic solvents such as benzene,
CHCl3, and CH2Cl2 at 25 °C (Figure 1) and was accelerated
Figure 2. Epimerization and racemization of trans-(2S,5S)-1 in
EtOAc (16.1 mM) but not in EtOH (32.2 mM).
To decide whether such spontaneous racemization and
epimerization occur intra- or intermolecularly, we have
measured the number-averaged molecular weights of (()-2
and trans-(()-3 in CHCl3 over a range of concentrations
from 5.0 to 40.0 mM at 35 °C by using a vapor pressure
osmometer and compared these data with those of nonphe-
nolic trans-(()-6 (Table 1).6 As a result, at concentrations
Figure 1. Racemization of (S)-rich 2 (42% ee) in various solvents
at a concentration of 45.0 mM except for in benzene (9.0 mM).
by increasing the solute concentration. In particular, race-
mization proceeded promptly in EtOAc or was dramatically
accelerated by irradiating with a 27 W fluorescent lamp in
CH2Cl2 at 25 °C, implying a radical mechanism. In contrast,
racemization was greatly suppressed in protic solvents or
hydrogen-bonding acceptor solvents such as EtOH or THF
(Figure 1), respectively, or at low temperatures such as -20
°C even in CH2Cl2.
Table 1. Number-Averaged Molecular Weight (NMW) of
(()-2, trans-(()-3, and trans-(()-6 Determined at 35 °C by
Vapor Pressure Osmometera
compound concn (mM) NMW NMW/FWb monomer/dimerc
(()-2
5.0
10.0
20.0
40.0
6.0
12.0
12.0
24.0
250
300
305
302
281
382
256
268
1.14
1.36
1.38
1.37
1.00
1.35
0.96
1.00
6.1
1.8
1.6
1.7
trans-(()-3
trans-(()-6
1.9
a Molecular weights were measured in CHCl3 using benzil as the standard
sample for calibration, and the results of the triplicate experiments were
reproducible. b FW: formula weight. c Ratio.
greater than 10.0 mM, where racemization and epimerization
occur appreciably, molecular association was noted for (()-2
and trans-(()-3 showing coexistence of the monomer and
the dimer in CHCl3, whereas no aggregation was observed
for trans-(()-6 over the same concentration range, indicating
an intermolecular origin of the spontaneous racemization and
epimerization and the participation of the OH group. It is
quite plausible that the dimer structure is formed by the
Likewise, both trans-(2S,5S)-3 of 96% ee and trans-(()-3
underwent partial epimerization gradually only at the C(2)
position bearing 4-hydroxyphenyl group in CH2Cl2 and
promptly in EtOAc to give partly cis-(2R,5S)-3 and cis-(()-
3, respectively, according to the equilibrium constant (trans/
cis 67:33).
(6) (a) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Gautier-Luneau, I.; Pierre,
J.-L. J. Org. Chem. 1997, 62, 9385-9388. (b) Benfaremo, N.; Steenbock,
M.; Klapper, M.; Mu¨llen, K.; Enkelmann, V.; Cabrera, K. Liebigs Ann.
Chem. 1996, 1413-1415.
For trans-(2S,5S)-1 of 97% ee, both spontaneous epimer-
ization and racemization were observed in EtOAc, while no
change was noted in EtOH (Figure 2).
1798
Org. Lett., Vol. 7, No. 9, 2005

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

of the five species for each set. The sum of residuals between
the observed and calculated concentrations of R and S was
employed to deduce the best rate constants. As can be seen
from Figure 3a, racemization of (S)-enriched 2 was satis-
factorily reproduced by the simulation using the best rate
constants shown in Scheme 2.
From the kinetic constants summarized in Scheme 2, the
observed spontaneous racemization of (S)-rich 2 can be
accounted for as follows. As shown in Figure 3c, in a solution
of (S)-rich 2 the homochiral dimerization of the monomers
2S occurs. The resultant S2 is slowly converted to the
heterodimer RS because the rate constant (k23) is smaller
than that of the competitive dissociation pathway to the initial
2S (k21). Nonetheless, once the heterodimer RS is formed,
the conversion from RS into either homodimer R2 or S2
occurs smoothly with identical probabilities because the
dissociation of RS to its component monomers R and S is
strongly hampered by the smaller rate constant k43 as
compared with the conversion to R2 or S2 (k32). As a final
step, R2 rapidly dissociates to its component monomers 2R
due to the large k21. The initial formation of S2 from 2S as
well as the subsequent conversion of S2 to RS are kinetically
unfavorable, whereas the involvement of these processes is
assumed to eventually decrease the ee value of 2 with the
aid of the kinetically favorable conversion of RS to R2 and
its dissociation to 2R. As a consequence, it was found from
kinetic considerations that the intermolecular association,
which triggered the subsequent multistep racemization
processes shown in Scheme 1, had a key role to play in the
observed spontaneous racemization of 2.
In summary, we have found that enantiomerically enriched
trans-1, 2, and trans-3 exhibit spontaneous racemization and/
or epimerization behavior in solution, which can be inter-
preted in terms of multistep equilibrations initiated by
intermolecular abstraction of the phenolic hydrogen atom by
the NO radical in aprotic solvents and have satisfactorily
been suppressed by the use of protic solvents or hydrogen
bonding acceptor solvents, which can prevent the NO radical
from approaching the phenolic OH group by solvation.
Figure 3. (a) Racemization of (S)-rich 2 (84% ee) in CHCl3 (20.0
mM) at 20 °C and the time course of the simulated ee value that
was evaluated by the equation ([S] + 2[S2] - [R] - 2[R2])/([S] +
2[S2] + [R] + 2[R2] + 2[RS]) × 100. (b) Changes in the
concentrations of the five species with the elapse of time. (c)
Enlargement of changes in the concentrations of R2, S2, and RS in
panel b.
Supporting Information Available: Experimental pro-
cedures and spectral data for trans-(2S,5S)-1, (2S)-2, trans-
(2S,5S)-3, (2S)-4, and (2S)-5 and chromatograms of HPLC
analysis for trans-(2S,5S)-1, (2S)-2, and trans-(2S,5S)-3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
generated one million sets of the six rate constants at random
and then simulated the time-courses of the concentrations
OL050401P
1800
Org. Lett., Vol. 7, No. 9, 2005