Hammett Correlations in the Photosensitized Oxidation of 4-Substituted Thioanisoles

Article abstract of DOI:10.1021/jo035679e

Singlet oxygen is quenched by a series of 4-substituted thioanisoles (methoxy to nitro), with rate constant k_t = 7 × 10⁴ to 7 × 10⁶ M^-1 s^-1, close to the value observed for the myoglobin-catalyzed sulfoxidation of the same sulfides. Correlations with σ (ρ = -1.97) and with E_ox (slope -3.9 V^-1) are evidence for an electrophilic mechanism. In methanol sulfoxides are formed (85%) via an intermediate quenched by diphenyl sulfoxide; competing minor paths lead to arylthiols, arylsulfenic acid, and aryl sulfoxides. In aprotic solvents, the sulfoxidation is quite sluggish, but carboxylic acids (mostly ≤0.1 M) enhance the rate by a factor of > 100. The protonated persulfoxide is formed in this case and acts as an electrophile with sulfides, again with a rate constant correlating with σ (ρ = -1.78).

Full text of DOI:10.1021/jo035679e

Ha m m ett Cor r ela tion s in th e P h otosen sitized Oxid a tion of
-Su bstitu ted Th ioa n isoles
4
Sergio M. Bonesi, Maurizio Fagnoni, and Angelo Albini*
Department of Organic Chemistry, University of Pavia, via Taramelli 10, 27100 Pavia, Italy
angelo.albini@unipv.it
Received November 14, 2003
Singlet oxygen is quenched by a series of 4-substituted thioanisoles (methoxy to nitro), with rate
4
6
-1 -1
constant k
t
) 7 × 10 to 7 × 10 M
s , close to the value observed for the myoglobin-catalyzed
-
1
sulfoxidation of the same sulfides. Correlations with σ (F ) -1.97) and with Eox (slope -3.9 V )
are evidence for an electrophilic mechanism. In methanol sulfoxides are formed (85%) via an
intermediate quenched by diphenyl sulfoxide; competing minor paths lead to arylthiols, arylsulfenic
acid, and aryl sulfoxides. In aprotic solvents, the sulfoxidation is quite sluggish, but carboxylic
acids (mostly e0.1 M) enhance the rate by a factor of >100. The protonated persulfoxide is formed
in this case and acts as an electrophile with sulfides, again with a rate constant correlating with
σ (F ) -1.78).
The oxidation of sulfides to sulfoxides is an important
process from both the synthetic and mechanistic points
of view, and many reagents are available for the conver-
sion.1 The reaction with singlet oxygen is an appealing
procedure, in view of the mild conditions, but the outcome
is highly dependent on the reagent structure and on the
conditions, and the reaction has proved to be mechanisti-
cally intricate. In fact, according to the solvent chosen,
formation of the sulfoxide involves different intermedi-
ates, the structure of which has been clarified through
trapping studies and computations.4 The Hammett
criterion was used early to establish the electrophilic
SCHEME 1
,2
7
been performed by using a variety of inorganic reagents,
enzymes,8 and photochemical methods not involving
singlet oxygen.9 This prompted us to investigate the
reaction of singlet oxygen with a series of thioanisoles,
taking advantage of the fact that direct measurement of
the quenching of O
3
1
2
allows the determination of a larger
character of initial attack of singlet oxygen onto thioani-
span of k
t
than previous less sensitive methods. In
5
soles (rate constant k
t
, Scheme 1), though the span of σ
10
addition, recent evidence suggest that protic additives,
explored has been relatively small. The Hammet crite-
rion, however, has not been used to determine the
electronic character of the second step (k ).
r
11
12
zeolites, and clays can make reluctant photooxidations
of sulfides more efficient, thus broadening the scope of
the reaction as a preparative method.
In general, aryl alkyl (as well as diaryl) sulfides appear
to be less reactive and have received less attention than
dialkyl derivatives, though some thioanisoles have been
Resu lts
6
considered in important mechanistic papers. On the
Qu en ch in g of Sin glet Oxygen . Thioanisole (1a ) and
a series of ring-substituted derivatives (1b-f) were
other hand, the (enantioselective) oxidation of thioani-
2
soles is quite important for several applications and has
(
7) Acquaye, J . H.; Muller, J . G.; Takeuchi, K. J . Inorg. Chem. 1993,
(
1) Uemura, S. In Comprehensive Organic Synthesis; Trost, M. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 7, p 758.
2) Carre n˜ o, M. C. Chem. Rev. 1995, 95, 1717. Baumstark, A. L.
Bioorg. Chem. 1986, 14, 326.
3) (a) Liang, J . J .; Gu, C. L.; Kacher, M. L.; Foote, C. S. J . Am.
Chem. Soc. 1983, 105, 4717. (b) Clennan, E. L. Acc. Chem. Res. 2001,
4, 875. (c) Clennan, E. L. Suflur Rep. 1996, 19, 171. (d) Clennan, E.
32, 160. Satyanarayana, P. V. V.; Rao, Y. N.; Rao, N. N. Indian J .
Chem., A 1985, 24A, 34. Baciocchi, E.; Lanzalunga, O.; Marconi, F.
Tetrahedron Lett. 1997, 53, 9771. Ganesan, T. K.; Rajagopal, S.;
Bharathy, J . B.; Sheriff, A. I. M. J . Org. Chem. 1998, 63, 21.
Santyanarayana, P. V. V.; Rao, B. N. M.; Ramana, G. V. J . Indian
Chem. Soc. 1989, 66, 198.
(
(
3
(8) Perez, U.; Dunford, H. D. Biochim. Biophys. Acta 1990, 1038,
98.
L. Adv. Oxygenated Processes 1995, 4, 49. (e) Ando, W.; Takada, T. In
Singlet Oxygen; Frimer, A. A., Ed.; CRC: Boca Raton, FL, 1985; Vol.
(9) Ramkumar, D.; Sankararaman, S. Synthesis 1993, 1057. Zen,
J . M.; Liou, S. L.; Kumar, A. S.; Hsia, M. S. Angew. Chem., Int. Ed.
2003, 42, 577. Bhalerhao, U. T.; Sridhar, M. Tetrahedron Lett. 1994,
35, 1413. Somasundaram, N.; Srnivasan, C. J . Photochem. Photobiol.,
A 1998, 115, 169. Baciocchi, E.; Del Giacco, T.; Ferrero, M. I.; Rol, C.;
Sebastiani, G. V. J . Org. Chem. 1997, 62, 4015.
(10) (a) Clennan. E. L.; Greer, A. J . Org. Chem. 1996, 61, 4793. (b)
Bonesi, S. M.; Albini, A. J . Org. Chem. 2000, 65, 4532.
(11) Clennan, E. L.; Zhou, W.; Chan, J . J . Org. Chem. 2002, 67, 9368.
(12) Madhavan, D.; Pitchumani, K. Tetrahedron 2001, 57, 8391.
3
, p 1.
(4) (a) J ensen, F.; Greer, A.; Clennan, E. L. J . Am. Chem. Soc. 1998,
1
1
20, 4439. Kenzen, F.; Greer, A.; Clennan, E. L. J . Am. Chem. Soc.
998, 120, 4439. (b) McKee, M. L. J . Am. Chem. Soc. 1998, 120, 3963.
(
5) (a) Kacher, M. L.; Foote, C. S. Photochem. Photobiol. 1979, 29,
65. (b) Monroe, B. M. Photochem. Photobiol. 1979, 29, 761.
6) (a) Watanabe, Y.; Kuriki, N.; Ishiguro, K.; Sawaki, Y. J . Am.
7
(
Chem. Soc. 1991, 113, 2677. (b) Ishiguro, K.; Hayashi, M.; Sawaki, Y.
J . Am. Chem. Soc. 1996, 118, 7265.
1
0.1021/jo035679e CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/09/2004
9
28
J . Org. Chem. 2004, 69, 928-935

Oxidation of 4-Substituted Thioanisoles
F IGURE 1. Correlation of the rate constants for singlet oxygen quenching by thioanisoles 1 with (a) σ coefficients and (b) oxidation
potentials.
TABLE 1. Qu en ch in g Con sta n ts (kt) of Sin glet Oxygen
examined. The quenching rates of singlet oxygen were
by Su lfid es 1a -f a n d Am ou n t of Th ioa n isole Rea cted
determined by laser flash photolysis by measuring the
(
[S]r ) in Meth a n ol a n d in Aceton itr ile a s Com p a r ed to
1
O
2
emission lifetime at 1270 nm after oxygen sensitiza-
Th a t of Dieth yl Su lfid e u n d er th e Sa m e Con d ition s
tion. This allowed the acquisition of precise measure-
ments even for poor quenchers. Thus, compounds bearing
a strong electron-withdrawing group such as 4-cyano (1e)
and 4-nitro (1f) were examined. Table 1 and Figure 1
demonstrate that the rate constants span a 2 orders of
magnitude range and are linearly correlated with both
Eox,a
V vs SCE
c
[S]r,d
MeOH
kt,
[SO]r,
MeCN
IPb
M-1 s-1
X
6
6
6
6
4
4
1
1
1a
1d
1
1
b
c
OMe
Me
H
Br
CN
NO2
1.13
1.24
1.34
1.41
1.61
7.8
7.87
8.07
7.6 × 10
4.6 × 10
2.3 × 10
0.22
0.25
0.046
0.011
0.004
0.0014
0.00034
0.00014
0.00014
7.8, 8.4e 1.1 × 10
f
f
e
f
7.3 × 10
0.0004
0.0002
σ and Eox
.
1.70
8.5g
8.44
8.7 × 10
0.002
1
f
f
P h otooxygen a tion in Meth a n ol. Rose Bengal (RB)-
sensitized oxygenation of 1a in methanol gave the
sulfoxide as the main product (2a , 85%) with minor
amounts of the sulfone (3a , 5%), diphenyl disulfide (4a ,
1.65h
i
7 j
Et2S
2 × 10
0.05
a
Reference 13. b Reference 14. c In CDCl3. d Amount of thio-
anisole reacted relative to that of diethyl sulfide reacted in MeOH
e
in the same time; starting concentration 0.01 M. Reference 15.
f
i
Starting concentration 0.1 M. Reference 16. h Reference 5a.
g
1
%), and methyl benzenesulfenate (5a , 4%) and benzene-
j
sulfinate (6a , 3%, Scheme 2). The product distribution
did not change during the reaction, up to >80% conver-
sion, except for 6a , which increased with increasing
conversion (see Figure 2). The same results were obtained
Reference 17. Reference 18.
in ethanol, with the only difference that products 5a and
6a were replaced by the corresponding ethyl esters.
J . Org. Chem, Vol. 69, No. 3, 2004 929

Bonesi et al.
TABLE 2. Ra tios kSO/kP h O a n d Resp ectively k′SO/k′P h O
Obta in ed fr om th e [Ar MeO]/[P h 2SO2] vs 1/[P h 2SO] P lots
in th e Cooxid a tion of Dip h en yl Su lfoxid e a n d
Th ioa n isoles 1a -f in Meth a n ol (F igu r e 3) a n d
Aceton itr ile, Resp ectively, Con ta in in g 0.5 M Acetic Acid
(
F igu r e 6)
k′SO/k′PhO,M, AcOH
X
kSO/kPhO, M, MeOH
(0.5 M in MeCN)
1
1
1
1
1
1
b
c
a
d
e
f
OMe
Me
H
Br
CN
NO2
1.5
3.2
4.2
1.5
0.5
0.4
14
11
7.3
4.2
0.5
0.5
F IGURE 2. Reaction of thioanisole (1a , b) and formation of
sulfoxide (2a , O), sulfone (3a , 9), diphenyl disulfide (4a , 3),
and methyl benzensulfenate (5a , 0) and sulfinate (6a , 1) upon
RB-sensitized photooxygenation in methanol. Inset: the four
last compounds on an expanded scale (right-hand side).
SCHEME 2
F IGURE 3. Ratio of sulfoxide 2a vs diphenyl sulfone formed
upon photooxygenation of thioanisoles in methanol in the
presence of diphenyl sulfoxide 1a : 0.1 ([), 0.071 (2), 0.05 (9),
0
.03 (b) M.
dized in the presence of thioanisoles. The arylmethyl
sulfoxide/diphenyl sulfone ratio ([ArMeSO]/[Ph SO ])
showed a reverse correlation with [Ph SO] under these
2
2
2
conditions, and the slope (see Table 2) depended on the
starting thioanisole concentration (see the case of 1a in
Figure 3).
Control experiments showed that sulfoxide 2a was not
significantly oxidized on this time scale, while thiophenol
reacted at a rate comparable to that of 1a , giving disulfide
P h otooxygen a tion in Ap r otic Med ia . Oxygenation
of 1a in other solvents was also attempted, but both the
RB-sensitized irradiation in acetonitrile (Table 1) and
tetraphenylporphine-sensitized irradiation in benzene
were exceedingly sluggish (rate <1/100 that in methanol)
when the solvents were freshly dried. The only product
at moderate conversion was the sulfoxide. Previous
researchers likewise found the sulfoxide with a yield of
4
a as virtually the only product.
RB-sensitized oxygenation of both 4-methoxythioani-
sole (1b) and 4-cyanothioanisole (1e) proceeded analo-
gously to that of the parent compound, giving the
sulfoxide (=85%) accompanied by small amounts of the
sulfoxide and the sulfinate (1b also gave the sulfenate
and traces of the sulfonate). The sulfoxide was also
formed in about 85% yield with the other substituted
thioanisoles examined (4-methyl, 1c; 4-bromo, 1d ; 4-ni-
tro, 1f). The amount of sulfide reacted was compared to
that measured for diethyl sulfide under the same condi-
6,11
sulfone ranging from <1% to 32% in these solvents.
The RB-sensitized oxygenation in acetonitrile was ex-
tended to the above substituted thioanisoles, and all of
them were converted to the sulfoxide, although the
reaction was quite slow particularly with those bearing
r
tions. The relative amounts of thioanisole reacted ([S] )
are reported in Table 1. No reaction occurred in the
absence of oxygen.
(14) Chmutova, G. A.; Vtyurina, N. N.; Komina, T. V.; Gazizov, I.
The role of oxygenated intermediates has been often
investigated through their oxygen-transfer properties to
appropriate acceptors. As done with other sulfur deriva-
tives,3 we used diphenyl sulfoxide, which per se is not
significantly photoreactive, and found that it was cooxi-
G.; Bock, H. Zh. Obsch. Khim. 1979, 49, 192. Dewar, P. S.; Ernstbrun-
ner, J . R.; Gilmore, M.; Godfrey, M.; Mellor, J . M. Tetrahedron 1974,
3
0, 2455.
15) Baker, B. J .; Armer, G. H.; Guang-di, Y.; Liotta, D.; Flannegan,
N. J . Org. Chem. 1981, 46, 4127.
16) Gazizov, I. G.; Chmutova, G. A. Zh. Obsch. Khim. 1980, 50,
063.
17) Zvezev, V. V.; Musin, B. M.; Yanilskin, V. V. Zh. Obsch. Khim.
(
,18
(
2
(
(
13) Goto, Y.; Matsui, T.; Ozaki, S.; Watanabe, Y.; Fukuzumi, S. J .
1997, 67, 1337.
Am. Chem. Soc. 1999, 121, 9497.
(18) Clennan, E. L.; Zhang, H. J . Am. Chem. Soc. 1995, 117, 4218.
9
30 J . Org. Chem., Vol. 69, No. 3, 2004

Oxidation of 4-Substituted Thioanisoles
F IGURE 4. Ratio of the yield of sulfoxide in the presence vs in the absence of acids in the RB-photosensitized oxidation of
thioanisole 1c: Diphenylacetic (b), acetic (O), and pivalic (1) acid added.
TABLE 3. Ra tio of Rea cted Moles of th e Su lfid e in th e
P r esen ce vs in th e Absen ce of Ca r boxylic Acid s: Slop es
of Su ch Ra tios vs th e Acid Con cen tr a tion (kH/kx; See
F igu r e 4) in Aceton itr ile
kH/kx, M-
1
X
t-BuCO2H
AcOH
Ph2CHCO2H
3
3
3
1
1
1
1
1
1
b
c
a
d
e
f
OMe
Me
H
Br
CN
NO2
1.8 × 10
3.7 × 10
22.8 × 10
2.8
8.3
8.0
0.8
0.6
4.7
34.9
33.7
10.4
1.1
9.3
10.1
1.1
0.7
0.7a
a
PhCH2CO2H.
an electron-withdrawing group, e.g., 20 h for a 0.2%
conversion with 1f (0.1 M).
Previous experiments with aliphatic sulfides had shown
1
0a
that protic additives such as alcohols and, much more
efficiently, carboxylic acids1 considerably speeded up the
photooxygenation in aprotic solvents. Some effect of the
alcohols was obtained also with thioanisoles; e.g., 2 M
methanol in MeCN increased the oxygenation of 1a by a
factor of 10, and 2 M trifluoroethanol led to an oxygen-
ation as fast as in neat methanol. These effects were
lower than those found with aliphatic sulfides. The effect
with carboxylic acids was more marked, but the acidity
window available for the exploration was limited, since
the oxygenation still required a rather long irradiation
time, and under these conditions the sensitizer was
unstable to acids as strong as chloroacetic acid. Pivalic,
acetic, and diphenylacetic acid could be used with no
inconvenience and were chosen for examination of the
series 1a -f. With these additives, the rates of oxygen-
ation were increased by a factor of >100 already at a 0.1
M concentration or below. The ratio of the moles of
sulfoxide formed in the presence vs in the absence of the
acid linearly correlated with the acid concentration, as
shown for a representative sulfide (1c) in Figure 4.
F IGURE 5. Dependence of the slopes in Figure 4 on the pK
of the acid added: 1a (1), 1b (b), 1c (O), 1d (3), 1e (9), 1f (0).
a
0b
by plotting the slopes of the linear plots obtained as above
vs the pK of the acids used for sulfides 1a -f. The same
a
acids also increased the rate of the TPP-sensitized
photooxygenation of 1a in benzene, with an effect quali-
tatively similar to that in MeCN, though much less
marked.
The reasonably rapid photooxidation in acid-containing
acetonitrile suggested the exploration of trapping by
diphenyl sulfoxide under these conditions. Indeed, cooxy-
2 2 2
genation of Ph SO was obtained, and the ratio [2]/[Ph SO ]
showed a reciprocal dependence on the concentration of
the acids, as shown for thioanisole 1a in MeCN contain-
ing 0.05 M acetic acid in Figure 6. The slope of the plots
depended on the concentration of both thioanisole and
the sulfoxide. The investigation was extended to the other
sulfides, as shown in Table 2.
Discu ssion
H x
The slopes are reported as k /k (see the Discussion)
in Table 3, where it appears that the effect varied with
the acid and the sulfide. This is illustrated in Figure 5
Qu en ch in g of Sin glet Oxygen . The data above
afford information concerning three aspects of the reac-
J . Org. Chem, Vol. 69, No. 3, 2004 931

Bonesi et al.
SCHEME 3
Indeed, the values obtained (varying over 2 orders of
magnitude) correlate satisfactorily (r ) 0.99) with σ,
+
giving F ) -1.97 (Figure 1a; the correlation with σ , on
the other hand, is poor, r ) 0.96). This is somewhat
higher than previously found with a series of thioanisoles
not containing strong electron-withdrawing substituents
F IGURE 6. Ratio of sulfoxide 2a vs diphenyl sulfone formed
upon photooxygenation of thioanisole in methanol in the
presence of diphenyl sulfoxide 1a : 0.075 (2), 0.05 (9), 0.03
(
F ) -1.6, -1.67).5
The k
(b) M.
t
values for the series 1a -f also correlate, though
1
-
tion as summarized in Scheme 1, viz., (1) interaction with
singlet oxygen generating the first intermediate, (2)
formation of the sulfoxide from it, and (3) competing
chemical paths. The rate constants for singlet oxyen
less satisfactorily, with Eox (slope -3.9 V , r ) 0.977,
Figure 1b). This is again a higher value than found in a
5
more limited series, but confirms the notion that the
process does not involve full electron transfer (which
-
1
24
quenching by the para-substituted thioanisoles (k
t
; see
would require a slope of -16.4 V ). In fact, ∆G° for
1
2
Table 1) show that these compounds, as in general aryl
alkyl (and diaryl) sulfides, are poor oxygen quenchers
compared to dialkyl derivatives (e.g., the rate constant
for 1a is lower by a factor of 10 than that measured for
diethyl sulfide), despite the fact that they have a lower
IP, as was earlier noted.5 The features of the thioanisole
PE spectrum suggest that there is an equilibrium be-
tween a (largely predominant) planar rotamer and a
perpendicular rotamer.19 The first one has maximum
electron transfer from 1a to O is markedly endothermic
(26.4 kcal/mol).25
These results have a bearing on the current debate on
the mechanism of cytochrome P450 catalyzed sulfoxida-
tion,26 viz., either electron transfer/oxygen coupling (over-
all two electrons oxo transfer) or sequential electron
transfer. Interestingly, the present absolute rates closely
match those measured for the oxidation of the same
sulfides by the His64Ser myoglobin mutant, which are
a
4
6
-1 -1
n(p
participate in the complexation with tetracyanoethylene
TCNE).20 The stability constant of the complex between
y
)-π(b
1
) conjugation, and it is the only one that can
also in the range 10 -10 M
s , though showing a less
-
1
13
steep dependence on Eox (slope -2.2 V ).
(
Synthetic models, such as oxoferryl tetramesithylpor-
phyrin dianion show a dependence on Eox similar to that
of myoglobin, but rates are slower by a factor of 100. On
the other hand, when S-oxidation proceeds via an electron-
transfer mechanism, as with the horseradish peroxidase
1
a and TCNE is 2 orders of magnitude lower than with
2
1,22
diethyl sulfide.
Complexation with this π acceptor can
be taken as a reasonable model for the formation of a
weakly bound adduct with singlet oxygen (see below), in
view of the similar redox characteristics; Ered(TCNE) )
compound I system, rates are much lower (e.g., kobs
)
1
23
+
0.23 and Ered( O
2
) ) +0.16 V vs SCE. This supports
-1 -1
1
M
s
for 1a ), though the dependence of Eox is much
1
that the reaction with electrophilic O
2
is slower than
-1 13
steeper (-10 V ). Thus, singlet oxygen is a simple and
appropriate model for the oxygen-transfer mechanism in
cytochrome P450 oxygenation of thioanisoles (see the
with dialkyl sulfides because the HOMO in thioanisole
is only partially localized on the sulfur atom, making this
a poor nucleophile. This also leads to the expectation that
parallel reactions of 1 in Scheme 3), and the easy
1
ring substituents will affect the rate of reaction with O
2
.
1
determination of k
t
( O
2
) may be used to test the reactivity
of a sulfurated biomolecule.
Su lfoxid a tion . While the overall rate of reaction with
singlet oxygen (k ) closely matches that of the enzymatic
t
oxidation process, the fundamental difference remains
(
19) Dewar, P. S.; Schweig, A.; Thon, N. Chem. Phys. Lett. 1976,
3
4
8, 482. Glass, R. S.; Broeker, J . L.; J atcko, M. E. Tetrahedron 1989,
5, 1263.
(
20) Frey, J . E.; Aiello, T.; Beaman, D. N.; Hutson, H.; Lang, S, R.;
Puckett, J . J . J . Org. Chem. 1995, 60, 2981.
21) Aloisi, G. G.; Santini, S.; Sorriso, S. J . Chem. Soc., Faraday
Trans. 1974, 70, 208.
22) (a) Similar results have been obtained for the iodine com-
(
(24) Rehm, D.; Weller, A. Ber. Bunsen-Ges. Phys. Chem. 1969, 73,
(
834.
plexes: Tsobumura, H.; Lang, R. P. J . Am. Chem. Soc. 1961, 83, 4329.
Kroll, M. J . Am. Chem. Soc. 1968, 90, 1097. (b) Satisfactory correlations
with σ have been found for the complexes of thioanisoles and diaryl
sulfides, e.g., with iodine: Santini, S.; Reichenbach, G.; Mazzuccato,
U. J . Chem. Soc., Perkin Trans. 2 1974, 494. See also ref 16.
(25) ∆G° for electron transfer from 1a to 1
O is obtained through
2
the Rehm-Weller equation, ref 24: ∆G° ) 23.04[Eox(1a ) - Ered(O
0.04] - ∆E°°. The values required are in Table 1 and ref 23.
2
) -
(26) Ortiz de Montellano, P. R. Cytochrome P450. Structure, Mech-
anism and Biochemistry, 2nd ed.; Plenum Press: New York, 1995.
P e´ rez, U.; Dunford, H. B. Biochemistry 1990, 29, 2757. Watanabe, Y.;
Iyamagi, T.; Oae, S. Tetrahedron Lett. 1982, 23, 533. Winkler, J . J .;
Dmchowski, I. J .; Dawson, J . H.; Winkler, J . R.; Gray, H. B. Angew.
Chem., Int. Ed. 1999, 38, 90. Baciocchi, E.; Gerini, M. F.; Lanzalunga,
O.; Lapi, A.; Lo Piparo, M. G. Org. Biomol. Chem. 2003, 1, 422.
(
23) (a) The reduction potential of singlet oxygen is taken as that
of triplet oxgyen (ref 23b) plus the electronic excitation energy; Ered
-
1
1
(
O
2
) ) Ered( O
2
) + ∆E°° ) -0.84 + (22.5/23.04) ) 0.15 V vs SCE. (b)
Clennan, E. L.; Noe, L. J .; Szneler, E.; Wen, T. J . Am. Chem. Soc. 1990,
12, 5080.
1
9
32 J . Org. Chem., Vol. 69, No. 3, 2004

Oxidation of 4-Substituted Thioanisoles
SCHEME 4
SCHEME 5
(kSO/kPhO ) 2.77), and only with strongly-electron-
withdrawing-substituted derivatives such as 1e and 1f
the ratio drops to 0.4-0.5, since these sulfides are poorer
nucleophiles.
that interaction with singlet oxygen does not lead neces-
sarily to sulfoxidation, since physical quenching (k
competes with chemical reaction (k , Scheme 1). Table 1
provides evidence that sulfoxidation is much less efficient
than with Et S. The amounts of sulfide transformed ([S]
Table 1) are not proportional to the rate constants for
chemical reaction, k , since, in contrast to the case of Et S,
q
)
r
On the other hand, the nonstabilized persulfoxide is
not sufficiently long-lived to react directly, and the only
path operating in aprotic solvents involves (inefficient)
rearrangement to a second intermediate, for which both
computational and experimental evidence suggest the
structure of S-hydroxypersulfonium ylide.3 A drastic
drop in efficiency occurs also with thioanisoles in MeCN
or benzene (Table 1), supporting that ylide 11 is inef-
2
r
,
r
2
singlet oxygen is not completely quenched by thioani-
soles, particularly by the electron-withdrawing-substi-
tuted derivatives even at a 0.1 M starting concentration.
,4,6
r d
However, k appears to be in most cases lower than k .
ficiently formed (k
sulfoxide has been used as a probe for the second
nucleophilic) intermediate, but with the present deriva-
x
, k
q 2
, Scheme 5). With Et S, diphenyl
This is not surprising, since with dimethyl sulfides it
has been demonstrated that the first intermediate,
persulfoxide 7 (Scheme 4), is formed as the first station-
(
tives oxygenation is too slow to adopt this course.
However, the effect of acids is informative. As men-
tioned in the Introduction, the addition of small amounts
of carboxylic acids to aprotic solvents strongly enhances
the sulfoxidation of diethyl sulfide, and the observed rate
is proportional to the acid strength, supporting that
general-acid catalysis is operating via protonation of the
weakly basic persulfoxide.1 Indeed also with thioani-
soles sulfoxidation is strongly enhanced by acids. Al-
though for the reasons mentioned above only a limited
4
ary point on a very flat surface and rapidly decays to
q
the sulfide and oxygen (k ), so that the predominant
process (g95%) is physical quenching, not sulfoxidation.
The same reasons that make thioanisole a poorer nu-
cleophile than dialkyl sulfide suggest that the S-O bond
in persulfoxide is if anything weaker with these sub-
strates, and suggest that k dominates over k , as indeed
q r
observed in aprotic solvents. However, the reaction
0b
becomes significant in methanol, where it is 10 to >100
times faster than in MeCN with both Et S and ArSMe.
2
a
pK range could be explored, the data in Table 3 and
Figure 3 show that there is a marked dependence on the
acid strength. This supports that protonated persulfoxide
Detailed work on dialkyl sulfides by Foote and by
3
Clennan has long demonstrated that reaction in alcohols
involve an intermediate, arising from persulfoxide 7 by
hydrogen bonding (structure 8, Scheme 4), nucleophile
addition (alkoxyperoxysulfurane 9), or both hydrogen
bonding and nucleophile stabilization (10). This reacts
both as an electrophile, forming 2 mol of sulfoxide by
reaction with a sulfide, and as a nucleophile, forming
sulfones from sulfoxides.
1
2 (Schemes 3 and 5) is the intermediate.
The amount of sulfoxide formed in a given time is
determined by competition between protonation and
decay (eq 2), and the ratio of sulfoxide formed in the
H
presence ([ArMeSO] ) vs in the absence of the acid is
proportional to the acid concentration (eq 3, valid in the
simplified form because the large increase in the oxi-
dation rate in the presence of acids supports that
This model perfectly fits the case of thioanisole in
methanol (R ) Ar, R′ ) Me, Scheme 4). Diphenyl
k
H
[HA] . k
x
).
sulfoxide is indeed cophotooxidized under these condi-
a
tions, similarly to the Et
eq 1 is valid.
2
S case. As Foote has shown,3
2
kH[HA] + 2kx
[
ArMeSO] ) K
(2)
(3)
k + k + k [HA]
q
x
H
[
RR′SO]
2kSO[RR′S]
)
1 +
(1)
[
ArMeSO]H kH[HA] + kx kH[HA]
[Ph SO ]
kPhO[Ph SO]
2
2
2
)
=
[
ArMeSO]
kx
kx
The slope of the [ArMeSO]/[Ph
2
SO
2
] vs [Ph
2
SO] plots
(
e.g., Figure 3) allows evaluation of the ratio kSO/kPhO
.
In fact, linear plots according to eq 3 are obtained
(Figure 4), and the ratios k /k are measured. These
ratios are on the order of 10 , consistently with the fact
The values obtained (Table 2) for thioanisoles 1a -d
oscillate around the value observed with diethyl sulfide
H
x
3
J . Org. Chem, Vol. 69, No. 3, 2004 933

Bonesi et al.
SCHEME 6
F IGURE 7. Correlation of the log(k′SO/k′PhO) values with σ
oxidant such as perbenzoic acid (F ) -2.50),28b though
low values have been obtained with some metal-catalyzed
hydrogen peroxide oxidations.2
coefficients.
8c
that rearrangement 7 f 11 (k
with non-electron-withdrawing-substituted anisoles (1a -
c) there is a clear increase of the ratio with the pK of
the acid, supporting that acid catalysis is operating via
2 (k in Scheme 5; see Figure 5). With electron-
withdrawing substituents the ratio k /k is lower and
does not depends on pK , reasonably because the less
basic persulfoxides make a weaker hydrogen bond with
x
) is slow. Furthermore,
Com p etin g Ch em ica l P a th s. The third point in-
volves different paths from the persulfoxide. As men-
tioned above, with dialkyl sulfides there is evidence that
an S-hydroxypersulfonium ylide is the key intermediate
in aprotic solvents. Sawaki found support for the ylide
involvement in the formation of the sulfone (not the
sulfoxide) from thioanisole in benzene containing trace
water.6 We did not further investigate the very slow
oxidation in aprotic media. In the reaction in methanol,
however, about 15% of the thioanisole is converted to
products different from the sulfoxide, viz., the sulfone
(3a ), diphenyl disulfide (4a ), and methyl benzene-
sulfenate (5a ). These appear to result from parallel paths
via a common intermediate, since the yields change little
during the progress of the reaction (Figure 2). The paths
are gathered in Scheme 6, following predictions based
on calculation with dimethyl sulfide,4 which consider
ylide 11 the key intermediate, although this may be
envisaged also as the hydrogen-bonded persulfoxide
under these conditions. The sulfone, expected to arise via
OH group migration to the sulfur atom (path a, inter-
mediate 13), is the most abundant of the products. An
alternative path involves migration of the OOH group
a
1
H
H
x
a
a
the acids and the relation with pK cannot be appreciated
in the small span explored.
Support of this mechanism comes from the cooxidation
studies. Thus, experiments with diphenyl sulfoxide in
0
.05 M acetic acid in acetonitrile (Figure 6) show that,
just as it occurs in alcohols, the [ArMeSO]/[Ph ] ratio
depends on the concentration of both thioanisole and Ph
SO, and thus both reagents compete for a single inter-
mediate. This is clearly protonated sulfoxide 12. The k′SO
2
O
2
2
-
/
k′PhO ratio shows a regular trend, decreasing by a factor
of 30 from electron-donating-substituted 1b to nitro-
substituted 1f. The values log(k′SO) - log(k′PhO) linearly
correlate with σ (Figure 7, slope -1.78, r ) 0.989, no
+
correlation with σ ).
The similarity with Figure 1a suggests that k′PhO does
not change appreciably while k′SO decreases regularly in
electrophilic OH transfer to the less-electron-rich sulfides;
to the R carbon (path b, Pummerer-type rearrangement
4
thus, there is a close parallelism between the electrophilic
to hydroperoxythioacetal 14), as calculated for Me
2
S and
1
attack of sulfides 1 by O
2
and by 12 (see Scheme 3). A
evidenced through the isolation of products resulting
from R-hydroxylation29 or C-S bond fragmentation in
other cases. Hydrolysis of 14 forma thiophenol 15, which
under the conditions is converted to the disulfide as
shown by independent experiments, and is well estab-
lished by analogy to benzyl sulfides.
30
trend in the same direction, but not a clear dependence,
is noticed in alcohols, since here hydrogen bonding is
weaker and possibly the balance between kSO and kPhO
is more complex. Previous measurements of the oxidation
of substituted diphenyl sulfides by the oxidized interme-
diates from diethyl sulfide and cyclohexene sulfide in
methanol had indeed given lower F values (-0.61 and
Formation of phenylsulfenic acid 16 is revealed through
the identification of the corresponding esters in MeOH
and EtOH and has been previously suggested on the
basis of the isolation of thiosulfinates from some sul-
-
0.74, respectively).27 The value obtained with pro-
tonated persulfoxide 12 is quite close to that observed
with flavin 4a-hydroperoxide (F ) -1.68)2 and ap-
proaches that obtained with a classical electrophilic
8a
31
fides, and on the results of calculations in the case of
Me
2
S.4b The conversion of sulfenic (5) to sulfinic (6) (and
(
27) Ando, W.; Kabe, Y.; Miyazaki, H. Photochem. Photobiol. 1980,
1, 191. Akasaka, T.; Kako, M.; Sonobe, H.; Ando, W. J . Am. Chem.
Soc. 1988, 110, 494.
28) (a) Miller, A. E.; Bischoff, J . I.; Bizub, C.; Luminoso, P.; Smiley,
(29) Toutchkine, A.; Clennan, E. L. J . Am. Chem. Soc. 2000, 122,
1834. Takata, T.; Tamura, Y.; Ando, W. Tetrahedron 1985, 41, 2133.
(30) Corey, E. J .; Ouann e` s, C. Tetrahedron Lett. 1976, 4263. Takata,
T.; Ishibashi, K.; Ando, W. Tetrahedron Lett. 1985, 26, 4689. Bonesi,
S. M.; Mella, M.; d’Alessandro, N.; Aloisi, G. G.; Vanossi, M.; Albini,
A. J . Org. Chem. 1998, 63, 9946. Bonesi, S. M.; Torriani, R.; Mella,
M.; Albini, A. Eur. J . Org. Chem. 1999, 1723, 3.
3
(
S. J . Am. Chem. Soc. 1986, 108, 7773. (b) Ponec, R.; Prochazka, M.
Collect. Czech. Chem. Commun. 1974, 39, 2088. (c) See e.g.: Oae, S.;
Wataabe, Y.; Fujimori, K. Tetrahedron Lett. 1982, 23, 1189.
9
34 J . Org. Chem., Vol. 69, No. 3, 2004

Oxidation of 4-Substituted Thioanisoles
ultimately sulfonic) derivatives has been previously well
characterized.32 Neither the proportion with respect to
tetraphenylporphine (in benzene) or of Rose Bengal (in acetone
or acetonitrile). The solutions were contained in rubber-
stoppered, 1 cm diameter Pyrex tubes. These were exposed to
four phosphor-coated 15 W lamps emitting from 350 to 700
nm while a steam of dry oxygen saturated with the appropriate
solvent was passed into the solution through a needle.
The products were determined by GC on the basis of
calibration curves in the presence of dodecane as the internal
standard and by HPLC with biphenyl as internal standard.
sulfoxide formation nor that of each of the individual
cleavage processes is dramatically affected by ring sub-
stitution in the photoreactions in methanol, as shown by
the fact that both cyano- and methoxythioanisole give a
product distribution similar to that obtained with the
parent compound 1a . This suggests that no strongly basic
3
5
or polar intermediate is involved on the various paths,
The identification of the minor products (disulfides, benzen-
sulfenates,36 and benzensulfinates) was based on the com-
parison of the GC/MS characteristics to those of samples
prepared through published procedures. The photooxidation
of diethyl sulfide was carried out in parallel experiments in
the same (mixed) solvents and likewise monitored by both by
GC and by HPLC.
37
as indeed suggested by calculation.4
Con clu sion
The nonlocalized nature of the HOMO makes thioani-
soles react less efficiently than dialkyl sulfides with a
moderate electrophile such as singlet oxygen. The effect
of substituents in a series of 4-substituted thioanisoles
Qu en ch in g Measu r em en ts. Rate constants for the quench-
ing of singlet oxygen were obtained from the shorthening of
1
the (O
2
) ∆
g
emission lifetime at 1.27 µm in the presence of
allows a better characterization of the initial reaction
known amounts of sulfides in aerated CDCl
3
. Singlet oxygen
1
with O
2
, of the basicity of the resulting persulfoxide, and
was generated by energy transfer to O from the triplet state
2
of electrophilic OH transfer from protonated persulfoxide
to sulfides. Minor paths have been characterized in
methanol, including the cleavage to arylsulfenates, but
account for e15%. The Hammet criterion allows a better
framing of sulfoxidation via singlet oxygen among other
chemical and biochemical oxidations. The availability of
a general mechanistic frame and the fact that small
of TPP, populated by laser excitation (Nd:YAG laser, 532 nm).
The near-IR luminescence of molecular oxygen was observed
at 90° geometry through a 5 mm thick AR-coated silicon metal
filter with wavelength pass >1.1 µm and an interference filter
at 1.27 µm by means of a preamplified (low-impedance) Ge
photodiode cooled at 77 K (time resolution 300 ns). Single-
exponential analysis of the emission decay was performed with
the exclusion of the initial part of the signal, affected by
scattered light, sensitizer fluorescence, and the formation
profile of the emission signal itself.
1
1
amounts of acids (or, as shown by Clennan, of zeolites)
make the reaction reasonably fast give more interest to
the hitherto scarcely utilized singlet oxygen path for the
sulfoxidation of these derivatives, which is useful for the
preparative point of view and for comparison with
biological oxidations.
Ack n ow led gm en t. We are greatly indebted to Dr.
S. Monti (FRAE, Bologna) for help in measuring the rate
contants for singlet oxygen quenching. Partial support
of this work by the Department of Education (MIUR),
Rome, is gratefully aknowledged. S.M.B. (permanent
address Department of Organic Chemistry and Conicet,
University of Buenos Aires, Ciudad Universitaria, CP
Exp er im en ta l Section
Ma ter ia ls. Thioanisoles and diphenyl sulfone were com-
mercial products or were synthesized via published proce-
1
428 Buenos Aires, Argentina) acknowledges a fellow-
3
3
dures. Sulfoxides and sulfones used as reference compounds
ship in the frame of an Argentine-Italian collaboration
plan sponsored by the Department of Foreign Affairs
3
4
were prepared via published procedures.
P h otor ea ction s. The photooxidations were carried out by
using 0.01-0.1 M solutions of the sulfides in the presence of
(
MAE), Rome, and administered by the Interuniversity
Consortium INCA, Venice.
(
31) Toutchkine, A.; Clennan, E. L. J . Am. Chem. Soc. 2000, 122,
J O035679E
1
834. J ensen, F.; Foote, C. S. J . Am. Chem. Soc. 1987, 109, 1478. Oae,
S. In Organic Sulfur Chemistry; Oae, S., Ed.; Kagaludojin: Kyoto,
J apan, 1982; Vol. 2, Chapter 5, p 131.
(35) Aido, T.; Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem. Soc.
J pn. 1976, 49, 1441.
(36) Armitage, D. A. Synthesis 1984, 1042.
(37) Grossert, J . S.; Dubey, P. K.; Elwood, T. Can. J . Chem. 1985,
63, 1263.
(
(
32) Clennan, E. C.; Chen, M. F. J . Org. Chem. 1995, 60, 6444.
33) Bauld, N. L.; Aplin, J . T.; Yueh, W.; Loinez, T. J . Am. Chem.
Soc. 1997, 119, 47.
34) Bordwell, F. G.; Boutan, P. J . Am. Chem. Soc. 1957, 79, 717.
(
J . Org. Chem, Vol. 69, No. 3, 2004 935