Organosulfur oxidation by hydrogen peroxide using a dinuclear Mn-1,4,7-trimethyl-1,4,7-triazacyclononane complex

Article abstract of DOI:10.1016/j.tetlet.2006.01.054

A mechanistic study of organosulfide oxidation by H₂O ₂, using a dinuclear manganese complex as the catalyst, has revealed an unusual switch in the philicity of the oxidant for the first and the second oxygen transfer steps; this switch has been exploited to tune selectivity for each of the products.

Full text of DOI:10.1016/j.tetlet.2006.01.054

Tetrahedron Letters 47 (2006) 2005–2008
Organosulfur oxidation by hydrogen peroxide using a
dinuclear Mn-1,4,7-trimethyl-1,4,7-triazacyclononane complex
a
a,
b
John R. Lindsay Smith,a,* Jane Murray, Paul H. Walton and Terry R. Lowdon
*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom
bC6 Solutions Ltd, Wheldon Road, Castleford, West Yorkshire WF10 2JT, United Kingdom
Received 15 December 2005; accepted 12 January 2006
Available online 7 February 2006
Abstract—A mechanistic study of organosulfide oxidation by H2O2, using a dinuclear manganese complex as the catalyst, has
revealed an unusual switch in the philicity of the oxidant for the first and the second oxygen transfer steps; this switch has been
exploited to tune selectivity for each of the products.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Sulfoxides and sulfones often display useful biological
and medicinal properties.1 Both compounds can be pre-
pared by oxidation of the corresponding sulfide; the ver-
satility of this synthetic route is limited, however, as
over-oxidation to the sulfone can be a problem. In addi-
tion, the mild and chemoselective oxidation of sulfides
to sulfones remains an important challenge in modern
synthetic chemistry. Accordingly, there is much interest
in developing selective catalytic methods to perform
these oxidations.2
(5 cm3) at 25 ꢁC. Aliquots (0.18 cm3) were removed at
selected time intervals, diluted with acetonitrile and ana-
lysed by UV–vis spectroscopy. Deconvolution of the
spectra from sulfide oxidations gives reaction profiles
showing [sulfide], [sulfoxide] and [sulfone] versus time
and provides initial rate data and maximum yields of
sulfoxides (see e.g., Fig. 1). The same procedure was
used to follow the sulfoxide oxidations. Under these
reaction conditions, the rates of the uncatalysed oxida-
tions of the substrates were at least two orders of mag-
nitude less than those of the corresponding catalysed
reactions. Repeating the sulfide oxidations using the
The dinuclear manganese 1,4,7-trimethyl-1,4,7-triaza-
cyclononane complex, ½ðMe3TACNÞ2MnI2Vðl-OÞ3ꢀðPF6Þ2
(1), has shown considerable potential as a catalyst for
oxidations with H2O2 in aqueous and organic solu-
tion.2–9 However, details of the mechanisms of many of
these reactions remain unclear. We report here a study
of the oxidation of methyl 4-substituted phenyl sulfides
and sulfoxides using this system, revealing an unusual
and atypical switch in the philicity of the oxidant from
electrophilic for sulfides to nucleophilic for sulfones.
100
90
80
70
60
50
40
30
20
10
0
In a typical oxidation, hydrogen peroxide (2.2 ·
10ꢁ3 mol, 31%, w/w) was added to a stirred solution
of sulfide or sulfoxide (1.5 · 10ꢁ4 mol) and manganese
complex 1 (3.7 · 10ꢁ7 mol, 0.25 mol %) in acetone
0
20
40
60
80
100
Time (min)
Keywords: Oxidation; Sulfide; Sulfoxide; Catalysis; Manganese 1,4,7-
Figure 1. Reaction profile for the oxidation of 4-methoxyphenyl
methyl sulfide using H2O2 (15 equiv) and 1 (1 mol %) in acetone, ( )
sulfide, ( ) sulfoxide and ( ) sulfone.
trimethyl-1,4,7-triazacyclononane complexes; Hydrogen peroxide.
*
Corresponding authors. Tel.: +44 (0)1904 432585; fax: +44 (0)1904
432516; e-mail: jrls1@york.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.054

2006
J. R. Lindsay Smith et al. / Tetrahedron Letters 47 (2006) 2005–2008
mononuclear Mn catalyst 2 gave identical reaction
profiles.
selectivity arises from the switch in the nature of the oxi-
dant for the two steps. Thus sulfoxides, which are
unreactive towards the electrophilic oxidant are relatively
susceptible to nucleophilic attack (see mechanism below).
2+
Me
N
Me
N
+
Me
To investigate the fate of complex 1 in the oxidation
system, ESI-MS was used to monitor the reaction. On
addition of H2O2 to 1, a new species with m/z 500,
corresponding to [ðMe3TACNÞ MnIII=IVðl-OÞ3ꢀþ (3)
O
N
OMe
IV
IV
Me
N
Mn
Mn
N
Me
O
O
Me
N
MnIV
Me
OMe
OMe
2
2
N
N
N
was detected. This one-electron reduction of 1 by H2O2
in acetone has previously been observed by Feringa
and coworkers using EPR spectroscopy.13 On sub-
sequent addition of phenyl methyl sulfide, new signals
at m/z 277 and 259 were also detected. These
cations, assigned to the mononuclear manganese species
[(Me3TACN)MnIV(OH)3]+ and [(Me3TACN)O@MnIV-
(OH)]+, respectively, have been observed before in the
equivalent oxidations of azo dyes14 and cinnamic acids,15
and suggest that the active oxidant is a mononuclear Mn
species.
Me
Me
1
2
Substituent effects on the initial rates of substrate con-
sumption were analysed using the Hammett equation.
The plot of log relative rate data versus r+, for the
monooxidation of methyl 4-substituted phenyl sulfides,
gives a good linear correlation with a negative q value
of ꢁ0.28 0.01 (r = 0.987) (Fig. 2a), indicating that
the active oxidant for the first oxidation step is an elec-
trophile. However, the comparable plot for sulfoxide
oxidations (vs r), performed under identical experimen-
tal conditions, has a positive slope (q = 0.2 0.01,
r = 0.990) (Fig. 2b). The change in the sign of q indi-
cates that there is a switch in the nature of the active oxi-
dant from electrophilic in the first oxidation step to
nucleophilic in the second. Bonchio et al. have reported
that sulfoxide–sulfone oxidations, using TiIV/homo-
chiral C3 symmetric trialkanolamine-hydroperoxo com-
plexes, can proceed by either an electrophilic or a
nucleophilic pathway.10 Similarly, Huang and Espen-
son, in their study of the methyltrioxorhenium-catalysed
oxidation of sulfines (thioketone S-oxides) with hydro-
gen peroxide, noted that the active oxidant changed
from electrophilic with electron-rich to nucleophilic with
electron-deficient sulfines.11 However, in our system the
linear Hammett plot suggests a uniquely nucleophilic
pathway operates in the sulfoxide oxidation step.
We next applied the reaction profiles, described above,
to improve the maximum sulfoxide yield using methyl
4-nitrophenyl sulfide, the most electron deficient sulfide,
with the poorest sulfoxide selectivity of all the substrates
screened. Changing the mole percent of catalyst from
1.0 to 0.25 increased the maximum yield of sulfoxide
from 28% to 47% and improved the sulfoxide:sulfone
ratio from 1.1 to 2.1 (Table 1). A similar improvement
in sulfoxide yield was observed for all methyl 4-substi-
tuted aryl sulfides. The selectivity for sulfoxide over
sulfone was further enhanced by switching the solvent
from acetone to acetonitrile and by adding carboxylic
acid/carboxylate co-catalysts (Table 1). The best of the
co-catalysts tested was 3,3-dimethylbutanoic acid, which
gave a sulfoxide:sulfone ratio of 13.3.
We can account for all the results above with the mech-
anism in Scheme 1. Reduction of L2MnIV=IV (1) by H2O2
2
generates the dinuclear L2MnIII=IV species (3), which fol-
Sulfide/sulfoxide oxidations that are performed using
2
lowing a second reduction is cleaved to give two LMnIII
species (Reaction 1). Subsequent oxidation yields the
proposed active oxidant, LMnV@O (Reaction 2).8,14–16
This reacts with the sulfide to form a LMnIII–sulfoxide
complex, 4, which is in equilibrium with free sulfoxide
and LMnIII (Reaction 3). The further oxidation to
electrophilic oxidants typically exhibit kS/kSO
ꢂ
103, due to the greater nucleophilicity of sulfide com-
pared with sulfoxide.12 However, in our system
kS/kSO ꢂ 1. We propose that this decrease in chemo-
4-MeO
3-NO2
3-CF3
0.1
4-Me
4-Cl
Table 1. The effect of solvents and co-catalysts on the maximum yield
of sulfoxide and yield of sulfone in the oxidation of methyl 4-
nitrophenyl sulfide with H2O2 (5 equiv) catalysed by complex 1
(0.25 mol %) at 25 ꢁC
0.1
-0.1
-0.3
4-H
4-Cl
4-H
4-Me
4-MeO
0.1
0
Solvent
Co-catalyst
Max
Yield (%) Sulfoxide/
yield (%) sulfone
sulfoxide
sulfone
ratio
4-NO2
Me2COa
Me2CO
MeCN
MeCN
MeCN
MeCN
—
—
—
28
47
55
60
70
26
22
14
11
8
1.1
2.1
3.9
5.5
8.8
-0.1
-0.3
-0.8
-0.3
0.2
0.7
0.5
0.9
σ+
σ
(a)
(b)
MeCO2H
MeCO2Na
tBuCH2CO2H 80
Figure 2. Hammett plots for the oxidation of methyl 3- and 4-
substituted phenyl sulfides (a) and sulfoxides (b) using H2O2 (15 equiv)
and (1) (0.25 mol %) in acetone.
6
13.3
a Complex 1, 1.0 mol %.

J. R. Lindsay Smith et al. / Tetrahedron Letters 47 (2006) 2005–2008
2007
+
.
H2O2
-H
.
HOOH + L2MnIV/IV
2 LMnIII
HO2 + L2MnIII/IV
(1)
(2)
L2MnIII/III
2
+
HO2
2
2
+
-H
LMnIII + H2O2
LMnV=O
R
R
R
+
LMnV=O +
S
LMnIII
LMnIII
LMnIII
O
S
+
O=S
(3)
(4)
R'
R'
R'
(4)
R
+
R
R
O
LMnIII
LMnIII
O
S
R'
O
S
+
S
R'
R'
O
O
O
HOOH
H
Scheme 1.
sulfone (Reaction 4) occurs by nucleophilic attack by
hydrogen peroxide on the positive sulfur in the Mn–sulf-
oxide complex, 4.
exchange with coordinated water in the oxo-manga-
nese(V) species. The latter reaction, has been observed
previously in oxidations with oxo-manganese(V) por-
phyrins23,24 and salens.25
An alternative electron-transfer oxidation of sulfide to
sulfoxide by the oxo-manganese(V) species would also
be in agreement with the measured q value. However,
this mechanism was ruled out by a competitive oxida-
tion, which showed that tert-butyl methyl sulfide is
>10-times more reactive than methyl phenyl sulfide.
Two-electron oxygen transfer is known to occur more
rapidly with dialkyl sulfides whereas single electron
transfer is faster with aryl sulfides.17
Hitherto, we had concentrated on performing reactions
under conditions that inhibited Mn–sulfoxide complex
formation in order to limit over-oxidation to the sul-
fone. However, by performing reactions under condi-
tions that favour formation of the Mn–sulfoxide
complex, sulfones can be prepared in a mild and chemo-
selective manner using our system.
Competition experiments revealed that sulfides could
be selectively oxidised to the corresponding sulfones
in the presence of other easily oxidised substrates/func-
tional groups, including alkenes and alcohols. For
example, sulfones 5 and 6 could be prepared in excel-
lent yields (94% and 91%, respectively), from the corre-
sponding sulfides by performing the reactions using
0.5 mol % catalyst, in acetone, in the absence of
co-catalyst.
The experimental changes leading to improved sulfoxide
selectivity (Table 1) can all be rationalised in terms of
discouraging the reaction of free sulfoxide with LMnIII
to form complex 4 that is needed for sulfone formation.
These include decreasing the catalyst concentration and
using a solvent or oxidatively stable co-catalyst that
competes with the sulfoxide as a ligand for the manga-
nese centre.15,17–22 The greater efficiency of sodium ace-
tate over acetic acid, in suppressing over-oxidation to
sulfone, is attributed to the ability of the Na+ counter-
ion to bind to the sulfoxide, which further inhibits
sulfoxide complexation to manganese. The improved
performance of 3,3-dimethylbutanoic acid over acetic
acid may arise from the steric bulk of the ligand
hindering sulfoxide ligation.
O
O
O
O
S
S
OH
5
6
Further support for the mechanism in Scheme 1 comes
from labelling experiments using H218O2/H216O and
H216O2/H218O. With labelled H2O2 (90 at %), the iso-
topic incorporation in sulfoxide and sulfone was 96.5%
and 89.2%, respectively, whereas with labelled water
(98 at %) it was 8.6% and 10.4%, respectively. These
results show that the large majority of the oxygen in
the products arises from hydrogen peroxide. For sulfox-
idation (Steps 2–3), this is in agreement with oxygen
atom-transfer being the main (if not the only), oxidation
route. The small amount of unlabelled oxygen in the
sulfoxide (ca. 5–8%) could arise from a minor elec-
tron-transfer pathway in which water traps the sulfide
cation radical or alternatively from protropic oxygen
In conclusion, we have shown that an unusual oxidation
mechanism operates in this system, which allows the
products to be tuned to either sulfoxide or sulfone.
The key to controlling the selectivity in these reactions
is the equilibrium between the (Me3TACN)MnIII–sulf-
oxide complex and (Me3TACN)MnIII and sulfoxide.
Conditions that disfavour complex formation lead to
sulfoxide and discourage sulfone—a common by-prod-
uct when performing sulfoxidation. Alternatively, con-
ditions that promote the complex can be used for the
chemoselective preparation of sulfones.

2008
J. R. Lindsay Smith et al. / Tetrahedron Letters 47 (2006) 2005–2008
11. Huang, R.; Espenson, J. H. J. Org. Chem. 1999, 64, 6374–
Acknowledgements
6379.
12. Patai, S. The Chemistry of Peroxides; John Wiley & Sons,
1983.
13. Zondervan, C.; Hage, R.; Feringa, B. L. Chem. Commun.
1997, 419.
J.M. thanks the EPSRC and C6 Solutions Ltd for a
CASE studentship.
14. Gilbert, B. C.; Lindsay Smith, J. R.; Newton, M. S.;
Oakes, J.; Pons i Prats, R. Org. Biomol. Chem. 2003, 1568–
1577.
References and notes
1. Page, P. Organosulfur Chemistry: Synthetic Aspects; John
Wiley & Sons: Chichester, 1994.
15. Gilbert, B. C.; Lindsay Smith, J. R.; Mairat i Payeras, A.;
Oakes, J.; Pons i Prats, R. J. Mol. Catal. A-Chem. 2004,
219, 265–272.
16. Gilbert, B. C.; Kamp, N. W. J.; Lindsay Smith, J. R.;
Oakes, J. J. Chem. Soc., Perkin Trans. 2 1998, 1841–1843.
17. Sevvel, R.; Rajagopal, S.; Srinivasan, C.; Alhaji, N. I.;
Chellamani, A. J. Org. Chem. 2000, 65, 3334–3340.
18. Feichtinger, D.; Plattner, D. A. Angew. Chem., Int. Ed.
1997, 36, 1718–1719.
2. Ba¨ckvall, J.-E. Modern Oxidation Methods; Wiley-VCH
Verlang GmbH & Co. KgaA: Weinheim, 2004.
3. Hage, R.; Iburg, J. E.; Kerschner, J.; Koek, J. H.;
Lempers, E. L. M.; Martens, R. J.; Racherla, U. S.;
Russell, S. W.; Swarthoff, T.; van Vliet, M. R. P.;
Warnaar, J. B.; van der Wolf, L.; Krijnen, B. Nature
1994, 369, 637–639.
4. Lindsay Smith, J. R.; Shul’pin, G. B. Tetrahedron Lett.
1998, 39, 4909–4912.
5. Brinksma, J.; La Crois, R.; Feringa, B. L.; Donnoli, M. I.;
Rosini, C. Tetrahedron Lett. 2001, 42, 4049–4052.
6. Shul’pin, G. B.; Suss-Fink, G.; Shul’pina, L. S. J. Mol.
Catal. A: Chem. 2001, 170, 17–34.
7. Bennur, T. H.; Sabne, S.; Deshpande, S. S.; Srinivas, D.;
Sivasanker, S. J. Mol. Catal. A: Chem. 2002, 185, 71–
80.
19. DeVos, D. E.; Sels, B. F.; Reynaers, M.; Rao, Y. V. S.;
Jacobs, P. A. Tetrahedron Lett. 1998, 39, 3221–3224.
20. Berkessel, A.; Sklorz, C. Tetrahedron Lett. 1999, 40, 7965–
7968.
21. Brinsksma, J.; Schmieder, L.; van Vliet, G.; Boaron, R.;
Hage, R.; De Vos, D. E.; Alsters, P. L.; Feringa, B. L.
Tetrahedron Lett. 2002, 43, 2619–2622.
22. Shul’pin, G. B.; Suss-Fink, G.; Lindsay Smith, J. R.
¨
Tetrahedron 1999, 55, 5345–5358.
8. Gilbert, B. C.; Lindsay Smith, J. R.; Mairata I Payeras,
A.; Oakes, J. Org. Biomol. Chem. 2004, 1176–1180.
9. Barker, J. E.; Ren, T. Tetrahedron Lett. 2004, 45, 4681–
4683.
23. Bernadou, J.; Fabiano, A.-S.; Robert, A.; Meunier, B. J.
Am. Chem. Soc. 1994, 116, 9375–9376.
24. Groves, J. T.; Lee, J.; Marla, S. S. J. Am. Chem. Soc. 1997,
119, 6269–6273.
10. Bonchio, M.; Bortolini, O.; Licini, G.; Moro, S.; Nugent,
W. A. J. Org. Chem. 2003, 507–511.
25. Srinivasan, K.; Michaud, P.; Kochi, J. K. J. Am. Chem.
Soc. 1986, 108, 2309–2320.