Thermal and photochemical racemization of chiral aromatic sulfoxides via the intermediacy of sulfoxide radical cations

Article abstract of DOI:10.1021/ol070500y

Efficient racemization of enantiomerically pure methyl aryl sulfoxides was obtained by N-methylquinolinium tetrafluoborate (NMQ+) sensitized photolysis and by one-electron oxidation catalyzed by tris(2,2′-bipyridyl)ruthenium(III) hexafluorophosphate.

Full text of DOI:10.1021/ol070500y

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1939-1942
Thermal and Photochemical
Racemization of Chiral Aromatic
Sulfoxides via the Intermediacy of
Sulfoxide Radical Cations
Claudia Aurisicchio,† Enrico Baciocchi,*,‡ Maria Francesca Gerini,† and
Osvaldo Lanzalunga*,†,‡
Dipartimento di Chimica and Istituto di Metodologie Chimiche (IMC-CNR), Sezione
Meccanismi di Reazione c/o Dipartimento di Chimica, UniVersita` degli Studi di Roma
“La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy
osValdo.lanzalunga@uniroma1.it
Received February 27, 2007
ABSTRACT
+
Efficient racemization of enantiomerically pure methyl aryl sulfoxides was obtained by N-methylquinolinium tetrafluoborate (NMQ ) sensitized
photolysis and by one-electron oxidation catalyzed by tris(2,2′-bipyridyl)ruthenium(III) hexafluorophosphate.
Enantiopure sulfoxides are attracting continuous attention for
their importance as bioactive compounds, valuable inter-
mediates in organic synthesis, and ligands for asymmetric
transformations.1 Recently, some chiral sulfoxides have also
found important application as drugs.2 Studies concerning
the optical stability of sulfoxides and the experimental
conditions which may lead to their stereomutation are
therefore of interest.
The thermal racemization or epimerization of sulfoxides
has been investigated in detail for many years,3 and it has
been established that the process can occur by pyramidal
inversion at the sulfur, a process requiring 38-41 kcal/mol,
or can involve C-S bond scission and recombination of the
radical fragments, depending on the structure. Generally,
quite drastic conditions (temperatures around 200 °C or
highly acidic media) are required. Inversion of the sulfur
center is also possible by direct irradiation of the sulfoxide.4
However, in this case too, photoracemization through
R-cleavage is also possible.5 The possibility to assist pho-
toracemization through sensitization has been investigated
by Mislow and Hammond.6 Naphthalene was used as the
sensitizer, and it was concluded that in this case sulfur
inversion occurs in an exciplex between naphthalene and
sulfoxide. More recently, this conclusion has been supported
by a study of the quenching rate by sulfoxides of the excited
(3) (a) Rayner, D. R.; Gordon, A. J.; Mislow, K. J. Am. Chem. Soc.
1968, 90, 4854-4860. (b) Miller, E. G.; Rayner, D. R.; Thomas, H. T.;
Mislow, K. J. Am. Chem. Soc. 1968, 90, 4861-4868. (c) Johnson, C. R.;
McCants, D. J. Am. Chem. Soc. 1964, 86, 2935-2936. (d) Mislow, K.;
Schneider, P.; Ternay, A. L. J. Am. Chem. Soc. 1964, 86, 2957-2958.
(4) (a) Vos, B. W.; Jenks, W. S. J. Am. Chem. Soc. 2002, 124, 2544-
2547. (b) Lee, W.; Jenks, W. S. J. Org. Chem. 2001, 66, 474-480.
(5) (a) Guo, Y.; Jenks, W. S. J. Org. Chem. 1997, 62, 857-864. (b)
Guo, Y.; Jenks, W. S. J. Org. Chem. 1995, 60, 5480-5486.
(6) (a) Cooke, R. S.; Hammond, G. S. J. Am. Chem. Soc. 1970, 92,
2739-2745. (b) Cooke, R. S.; Hammond, G. S. J. Am. Chem. Soc. 1968,
90, 2958-2959. (c) Mislow, K.; Axelrod, M.; Rayner, D. R.; Gotthardt,
H.; Coyne, L. M.; Hammond, G. S. J. Am. Chem. Soc. 1965, 87, 4958-
4960.
* Corresponding author: Phone: (+39) 0649913683. Fax: (+39)
06490421.
† Dipartimento di Chimica, Universita` “La Sapienza”.
‡ IMC-CNR.
(1) (a) Pellissier, H. Tetrahedron 2006, 62, 5559-5601. (b) Bentley, R.
Chem. Soc. ReV. 2005, 34, 609-624. (c) Fernandez, I.; Khiar, N. Chem.
ReV. 2003, 103, 3651-3705. (d) Carreno, M. C. Chem. ReV. 1995, 95,
1717-1760. (e) The Chemistry of Sulfones and Sulfoxides; Patai, S.,
Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley & Sons: Chichester,
England, 1988.
(2) (a) Legros, J.; Dehli, J. R.; Bolm, C. AdV. Synth. Catal. 2005, 347,
19-31. (b) Shin, J. M.; Cho, Y. M.; Sachs, G. J. Am. Chem. Soc. 2004,
126, 7800-7811.
10.1021/ol070500y CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/17/2007

state of naphthalene and substituted naphthalenes,7 and the
formation of a complex with a significant charge-transfer
character was suggested.
electron transfer to regenerate the neutral sulfoxide and
NMQ+. It is therefore reasonable to suggest that sulfoxide
radical cations are key intermediates in the racemization
process and that the racemization mechanism can be that
described in Scheme 1 (upper part). The reduced N-
We now want to show that the racemization of chiral
sulfoxides can also be performed by electron-transfer pro-
cesses involving the reversible formation of sulfoxide radical
cations. This possibility, which has been overlooked so far,
is clearly suggested by DFT calculations on methyl phenyl
sulfoxide radical cation, which showed that the pyramidal
inversion of the SOMe group in the radical cation requires
a much lower energy (ca. 10 kcal/mol) than in the neutral
parent substrate.
Scheme 1
Thus, a smooth and efficient photoracemization of enan-
tiomerically pure methyl aryl sulfoxides is promoted by
N-methylquinolinium tetrafluoborate (NMQ+) sensitized
photolysis, a process leading to the formation of a sulfoxide
radical cation.8 Moreover, racemization of sulfoxides can also
be accomplished in a thermal reaction by catalysis with tris-
(2,2′-bipyridyl)ruthenium(III) hexafluorophosphate [RuIII-
(bpy)3], and in this case too, evidence was obtained that an
electron-transfer process occurs.
DFT Calculations. The geometry of the methyl phenyl
sulfoxide radical cation was optimized by DFT calculations
performed with the Gaussian 98 program using the three-
parameter hybrid functional B3LYP with the 6-311G* basis
set. The sulfur atom exhibits a pyramidal geometry with a
degree of pyramidalization of 28.4°.9 The transition state
geometry for the inversion was found by optimizing a planar
structure (degree of pyramidalization 0°). The analysis of
the vibrational frequencies found that the planar conformer
was a first-order saddle point on the energy hypersurface.
The barrier for the sulfur pyramidal inversion (10.9 kcal/
mol) was calculated as the energy difference between the
total energy of the planar and pyramidal conformation (details
in the Supporting Information). When the same type of
calculations were carried out for the neutral methyl phenyl
sulfoxide, an inversion barrier of 42.7 kcal/mol was ob-
tained.10
methylquinolinium radical (NMQ•) is formed together with
the (S)-sulfoxide radical cation (path a), which then can
racemize (path b) before or in competition with back electron
transfer (path c).11 In line with this interpretation, when the
photoreaction was carried out in the presence of toluene, used
as co-sensitizer to increase the efficiency of the process (the
yield of radical cations),12 a substantial increase in the extent
of racemization was observed, with the enantiomeric ratio
(R)-1/(S)-1 being 0.5 after only 5 min of irradiation. In this
case, as shown in the lower part of Scheme 1, the actual
electron acceptor is the toluene radical cation (path e), which
shows that the racemization observed in the presence of
NMQ+ is not due, as in the naphthalene case, to the formation
of an exciplex between excited NMQ+ and the sulfoxide.
Racemization Catalyzed by RuIII(bpy)3. Racemization
of a series of chiral p-substituted methyl phenyl sulfoxides,
synthesized as described in Scheme 2,13 has been shown to
NMQ+ Photosensitized Racemization. A solution of
NMQ+ (8 × 10-3 M) and (S)-methyl p-tolyl sulfoxide (S)-1
(1.6 × 10-2 M) in N2-saturated CH3CN was irradiated in a
photoreactor (360 nm) for 10 min at 25 °C. HPLC analysis
on a Chiralcel OB column showed the presence of the two
enantiomers (S)-1 and (R)-1. The enantiomeric ratio [(R)-1/
(S)-1], determined by the integration of the two peaks, was
equal to 0.33. No photoproducts aside from stereoisomers
Scheme 2
1
of 1 were observed by HPLC and HNMR analysis of the
reaction mixtures. As already mentioned, our previous laser
photolysis study has shown the formation of sulfoxide radical
cations by excited NMQ+;8 moreover, it was found that the
main fate of the radical cation is that of undergoing back
occur in MeCN, at room temperature, in the presence of the
bona fide outer sphere oxidant tris(2,2′-bipyridyl)ruthenium-
(III) hexafluorophosphate [RuIII(bpy)3], for brevity also
indicated as Ru(III). This oxidant is characterized by a a
(7) Charlesworth, P.; Lee, W.; Jenks, W. S. J. Phys. Chem. 1996, 100,
15152-15155.
(8) Baciocchi, E.; Del Giacco, T.; Gerini, M. F.; Lanzalunga, O. J. Phys.
Chem. A 2006, 110, 9940-9948.
(11) With a barrier of 10 kcal/mol, an inversion rate larger than 105 s-1
can be estimated, fast enough to be competitive with back electron transfer
(9) Degree of pyramidalization equals 360 - ∑ bond angles to the S
atom (Ganguly, B.; Freed, D. A.; Kozlowski, M. C. J. Org. Chem. 2001,
66, 1103).
given the very low concentration of radical cations and NMQ• (ca. 10-5
M
in the laser flash photolysis experiments8). Of course, this holds even more
in the steady state experiments where the radical ion concentration is much
lower.
(10) This value is comparable to the experimentally observed activation
energy of 38.4 kcal/mol for methyl p-tolyl sulfoxide.3
1940
Org. Lett., Vol. 9, No. 10, 2007

reduction potential of 1.24 V vs SCE,14 much lower than
that of the aryl sulfoxides.
After the complete loss of optical activity (Figure 1),
Table 1. Sulfoxide Oxidation Potentials, kobs and k2 Values for
the Racemization of Chiral Aromatic Sulfoxides (S)-1/(S)-5
(0.013 M) with Ru(bpy)3(PF6)3 (0.0013 M) at 20 °C in CH3CN
Ep
kobs
k2
sulfoxide
(V vs SCE)a
(s-1
)
(M-1 s-1
)
(S)-1
1.95
4.7 × 10-4
4.4 × 10-4b
4.1 × 10-4c
3.3 × 10-4d
2.2 × 10-4e
5.2 × 10-3
1.5 × 10-4
2.6 × 10-5
1.6 × 10-6
0.36
(S)-2
(S)-3
(S)-4
(S)-5
1.90
2.01
2.05
2.16
4.0
0.12
0.02
1.3 × 10-3
a From ref 8. b [Bu4NBF4] ) 1.3 × 10-3 M. c [Bu4NBF4] ) 3.3 ×
10-3 M. d [Ru(bpy)3(PF6)2] ) 6.0 × 10-4 M. e [Ru(bpy)3(PF6)2] ) 1.2 ×
10-3 M.
Figure 1. Loss of optical activity as a function of time for the
reaction of (S)-2 with RuIII(bpy)3.
3), whereas a very slight decrease was noted in the presence
of RuII(bpy)3 (Table 1, entries 4 and 5).
The reactivity data reported in Table 1 show that the
reaction rate is very sensitive to the oxidation potential of
the sulfoxide as well as the electron-donating power of the
substituent, increasing as the former decreases and the latter
increases. A good linear correlation is obtained by plotting
log k2 against the substituent σ+ constants (F+ ) -2.4, r2 )
0.984), as shown in Figure 2.
spectrophotometric analysis of the mixtures indicates that
the oxidant that shows a strong absorption in the visible
region of the spectrum (λmax ) 520 nm)15 is not consumed
during the racemization process. [RuIII(bpy)3], therefore,
behaves as an actual catalyst. Moreover, after solvent
1
evaporation, HPLC, and HNMR analysis, no oxidation
products aside from stereoisomers of 1 were observed, thus
indicating that the loss of optical activity was not due to
substrate decomposition.
Racemization rates were shown to follow first-order
16
kinetics, and pseudo-first-order rate constants, kobs (Table
1), were determined from the slope of the straight line
obtained when -ln(Rt/Ro) is plotted against time in accord
with eq 1 (see Figure S5 in the Supporting Information).
-ln(Rt/Ro) ) kobs
t
(1)
where Rt is the rotation at time t and Ro is the initial rotation.
It also turned out that the racemization rate linearly increases
with the initial and constant Ru(III) concentration, indicating
a process first order in sulfoxide and first order in Ru(III)
(Table S1 and Figure S2 in the Supporting Information), and
the second-order rate constants, k2, can be calculated as usual
(eq 2).
Figure 2. Dependence of the rate constants of electron transfer
(k2) in the oxidation of chiral aromatic sulfoxides (S)-1/(S)-5 with
Ru(bpy)3(PF6)3 at 20 °C in CH3CN upon the Hammett σ+ constants.
kobs ) k2[RuIII(bpy)3]0
(2)
This relative high and negative F value is consistent with
an electron-transfer mechanism which may be that described
The values of kobs and k2 are reported in Table 1, together
with the oxidation potentials of the investigated sulfoxides.
Very small effects were observed when the reaction was
carried out in the presence of salts (Table 1, entries 2 and
(14) Fukuzumi, S.; Nakanishi, I.; Tanaka, K.; Suenobu, T.; Tabard, A.;
Guilard, R.; Van Caemelbecke, E.; Kadish, K. M. J. Am. Chem. Soc. 1999,
121, 785-790.
(15) (a) Kitaguchi, H.; Ohkubo, K.; Ogo, S.; Fukuzumi, S. J. Phys. Chem.
A 2006, 110, 1718-1725. (b) Kitaguchi, H.; Ohkubo, K.; Ogo, S.;
Fukuzumi, S.; Inada, O.; Suenobu, T. J. Am. Chem. Soc. 2003, 125, 4808-
4816.
(16) The value of kobs refers to the rate of formation of the racemized
sulfoxide. It is twice the rate constant for the inversion process.
(12) Dockery, K. P.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.; Gould,
I. R.; Todd, W. P. J. Am. Chem. Soc. 1997, 119, 1876-1883.
(13) (a) Drago, C.; Caggiano, R. F.; Jackson, F. Angew. Chem., Int. Ed.
2005, 44, 7221-7223. (b) Legros, J.; Bolm, C. Chem.sEur. J. 2005, 11,
1086-1092.
Org. Lett., Vol. 9, No. 10, 2007
1941

(reactants and solvent) reorganization energy associated with
the transfer of one electron from aromatic sulfoxides (S)-1/
(S)-5 to RuIII(bpy)3.
Scheme 3
Since the reorganization energy for the RuII(bpy)3/RuIII-
(bpy)3 self-exchange reaction is 32 kcal/mol in MeCN,19
a
reorganization energy as low as 14 kcal/mol can be calculated
+•
for the ArSOCH3/ArSOCH3 self-exchange reaction.
Whereas there should be little doubt that a low reorganiza-
tion energy is required for the ArSOCH3/ArSOCH3+• couple
(slight variations in bond distances and bond angles have
been estimated by DFT calculations on passing from the
neutral aromatic sulfoxide to the radical cation8), the value
given should be seen with some caution being based on ∆G°′
values calculated by the peak potentials of the sulfoxides.
In conclusion, this study has shown for the first time that
a mild racemization of chiral aromatic sulfoxides can occur
in the presence of electron-transfer reagents that leads to the
reversible formation of sulfoxide radical cations.20 This is
due to the fact that the inversion barrier in the SOR group is
much lower in the radical cation (ca. 10 kcal/mol) than in
the neutral sulfoxide (38-41 kcal/mol) as well as to the low
reorganization energy for the ArSOCH3/ArSOCH3+• couple.
The racemization can take place both by photosensitized and
thermal electron transfer. Interestingly, in the latter case, the
racemization can be performed by outer sphere one-electron-
transfer oxidants with a reduction potential significantly
lower than the oxidation potential of the aromatic sulfoxide.21
Apart from the theoretical interest, these results suggest that
an optical activation of racemic sulfoxides might be obtained
via an electron-transfer process induced by a chiral metal
complex. Another implication is that our observations may
raise some concern about the optical stability of chiral
aromatic sulfoxide drugs in the presence of oxidizing
metalloenzymes or metal ions.
in Scheme 3. We suggest that the racemization rate (kr) of
the radical cation is substantially faster than k-2 × [RuII-
(bpy)3] due to the extremely low concentration of Ru(II),17
so that the rate is practically determined in the electron-
transfer step. This is also indicated by the very small effect
of Ru(II) concentration on the reaction rate, certainly not
compatible with an electron-transfer process in which the
rate is equilibrium controlled.18
In line with a rate-determining electron-transfer mechanism
is also the satisfactory fit (Figure 3) obtained when the
Acknowledgment. MiUR, University “La Sapienza” of
Rome, are thanked for financial support. We thank Prof. P.
Mencarelli for the assistance in the theoretical calculations.
Figure 3. Diagram of ln k2 versus ∆G°′ for the reactions of chiral
aromatic sulfoxides (S)-1/(S)-5 with RuIII(bpy)3(PF6)3. The solid
circles correspond to the experimental values; the curve is calculated
by nonlinear least-squares fit to the Marcus equation with Z ) 6 ×
1012.
Supporting Information Available: Starting materials,
NMQ+ photosensitized racemization, racemization catalyzed
by RuIII(bpy)3, DFT calculations, and determination of the
reorganization energy. This material is available free of
charge via the Internet at http://pubs.acs.org.
reactivity data are reported against ∆G°′ (the standard free
energy for the electron-transfer step corrected for the
electrostatic interaction arising from the charge variation in
the reactants upon electron transfer) according to the Marcus
equation (see Supporting Information).
OL070500Y
(19) Chan, M.-S.; Wahl, A. C. J. Phys. Chem. 1978, 82, 2542-2549.
(20) Of course, the racemization process for chiral ArSOR compounds
can occur only if no other competitive routes, in particular, the fragmentation
to an alkyl carbocation (R+) and a sulfinyl radical (ArSO•), are available
for the radical cations. In that case, it is of paramount importance to know
the fragmentation rate that may be higher or lower than the racemization
rate. Laser and steady state photolysis studies underway in our laboratory
are showing that the fragmentation rate is extremely low when R is a primary
or secondary alkyl group.
The best fit of the experimental data is obtained for a λ
value of 23.3 kcal mol-1, which represents the overall
(17) No Ru(III) is reduced in the process. Thus the maximum Ru(II)
concentration is that at the equilibrium, i.e., ca 10-9 M.
(18) If the rate would be controlled by the electron-transfer equilibrium
constant, a much higher effect of Ru(II) would be expected as [Ru(II)] passes
from the equilibrium concentration (ca. 10-9 M, no Ru(II) added) to a
concentration of 0.0012 M, entry 5 in Table 1.
(21) We have observed that the racemization also occurs with Ce(IV)
ammonium nitrate. The rate is slower than with RuIII(bpy)3, in line with
the lower reduction potential of Ce(IV).
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Org. Lett., Vol. 9, No. 10, 2007