Catalytic sulfoxidation by dinuclear copper complexes

Article abstract of DOI:10.1002/chem.200902451

The power of two: μ-η²:η²- Peroxodicopper(II) complexes with hexadentate diaminotetrabenzimidazole ligands can catalyze the sulfoxidation of aromatic sulfides by a direct oxygen-transfer mechanism (see scheme) in the presence of a sacrificial co-substrate, similarly to the enzyme tyrosinase. The yields and turnover numbers depend on the sulfide and co-substrate concentrations and the electron density on the sulfide S atom.

Full text of DOI:10.1002/chem.200902451

DOI: 10.1002/chem.200902451
Catalytic Sulfoxidation by Dinuclear Copper Complexes
Ilaria Gamba, Sara Palavicini, Enrico Monzani, and Luigi Casella*[a]
The ability of the copper enzyme tyrosinase to promote
catalytically, similarly to reactions promoted by tyrosinase.
The catalytic oxidation of sulfides is a process of considera-
ble interest because organic sulfoxides are synthetic inter-
mediates for the preparation of biologically active molecu-
les.[8a] However, the methods based on metal catalysis in
general make use of peroxides,[8b–e] whereas use of molecular
oxygen is less frequent.[8f] In any case, the nature of the cat-
alyst oxidizing species is often unknown. Of the catalytic
processes reported, only a few that concern the oxidation of
sulfides by CuII complexes in the presence of hydrogen per-
oxide have appeared,[9] and the catalytic reaction occurs
with high efficiency in only one case.[9c]
ꢀ
oxygen atom insertion into the aromatic C H bond of phe-
nolic substrates, and also the simpler oxidation of o-diphe-
[1]
nols, by O2 has stimulated an enormous number of bio-
mimetic studies based on copper complexes.[2] The enzymat-
ic reactions occur through a key oxygenated intermediate
that has been thoroughly characterized spectroscopically[3]
and, more recently, also structurally.[4] Synthetic copper–di-
oxygen complexes can be formed with different stoichiome-
tries and binding modes depending on the ligand, tempera-
ture, solvent, counterion, etc.[2] The enzymatic oxygen atom
transfer reaction to exogenous phenols has been reproduced
by using two types of copper–dioxygen complexes, namely,
the m-h2:h2-peroxodicopper(II) and bis
ACTHUNRTGENN(GU m-oxo)dicopperACHTUNTGREN(NUGN III)
species.[2] Recently, we reported a new reactivity for tyrosi-
nase: The asymmetric oxidation of sulfides to sulfoxides, in
which the enzyme behaves as an external monooxygenase,
with a co-substrate to support the catalytic reaction.[5] The
only precedent for the oxidation of an exogenous sulfide by
a synthetic copper complex is the report by Itoh et al. on
the stoichiometric sulfoxidation reaction promoted by a bis-
ACHTUNGTRENNUNG(m-oxo)dicopperACHTUNGTRENNUNG
(III) complex.[6] They found that the reac-
tion proceeds with fast substrate binding to the copper fol-
lowed by oxygen transfer, with the latter process occurring
through a direct oxygen transfer mechanism. Other exam-
ples are known in which the sulfide group undergoing oxida-
tion is part of the ligand supporting the CuI complex.[7]
Herein we report that m-h2:h2-peroxodicopper(II) complexes
derived from diaminetetrabenzimidazole ligands can also
support a sulfoxidation reaction with O2 and that with a suit-
able sacrificial co-substrate the reaction can be carried out
When thioanisole is added at low temperature to a solu-
tion of the m-h2:h2-peroxodicopper(II) complex [Cu2-
AHCTUNGTRENNUNG
(MeL66)O2]2+ in acetone,[10] the characteristic LMCT
(ligand-to-metal charge transfer) band of this complex at
l=362 nm slowly decreases in intensity at a rate that de-
pends on both the temperature and the amount of substrate.
The position of the LMCT band and its shape remain un-
altered as the reaction proceeds independent of the excess
of substrate, which suggests that no direct coordination of
the substrate to the Cu2O2 core occurs. At temperatures
above ꢀ608C, the competitive self-degradation of the dioxy-
gen complex becomes non-negligible, whereas below ꢀ808C
the extinction of the peroxo LMCT band is exceedingly
slow. Therefore, the reaction was studied at ꢀ728C, at which
the m-h2:h2-peroxodicopper(II) complex is quite stable and
the reaction with thioanisole occurs in a few hours. Analysis
[a] I. Gamba, S. Palavicini, E. Monzani, L. Casella
Dipartimento di Chimica Generale
Universitꢀ di Pavia
Via Taramelli 12
27100 Pavia (Italy)
Fax : (+39)0382-528544
E-mail: bioinorg@unipv.it
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Chem. Eur. J. 2009, 15, 12932 – 12936

COMMUNICATION
of the reaction products showed that the peroxo complex
converts thioanisole into the corresponding sulfoxide and is
itself reduced to the dicopper(II) form. When the experi-
ment was performed in the presence of 18O2, the sulfoxide
product contained 93% 18O. This result indicates that the re-
action occurs through direct oxygen transfer from the m-
h2:h2-peroxodicopper(II) complex to the sulfide with negligi-
ble contribution from any radical mechanism.
The kinetics of the reaction between the peroxo complex
and excess thioanisole is pseudo first-order, with kobs show-
ing a hyperbolic dependence on the substrate concentration
and saturation at [thioanisole]>50 mm (see Figure 1). These
from the four benzimidazole rings prevents the thioanisole
accessing the Cu2O2 moiety and the sulfide interacts with
the complex through p–p stacking with the benzimidazole
nuclei instead. In fact, binding of the sulfide to the bisACHTUNGTRENNUNG(m-
oxo)dicopperACTHUNTGRNEUNG(III) complex studied by Itoh et al. occurs with
an affinity that is an order of magnitude larger.[6] This
makes the sulfoxidation much more efficient because the
kSO is also about tenfold larger with respect to that reported
here for [Cu
Because the reaction of [Cu2ACHNUTTGRENNUNG
(MeL66)O2]2+
2ACHTUNGETRNNUNG .
(MeL66)O2]2+ is slow, we
thought that potential applications of this reaction with syn-
thetic copper complexes could be sought by using the relat-
[11]
ed dicopper system [Cu
(L55)]2+/4+
.
In fact, this provides
the most efficient copper complex in the catalytic oxidation
of catechols[2d,12] and is also active in the hydroxylation of
phenols.[13] However, the reactivity of the dioxygen complex
[Cu2ACHTNUGRTNEUNG
(L55)O2]2+ is extremely high and this species could not
be isolated at any temperature down to ꢀ808C in any sol-
vent.[11,14] On the other hand, the high reactivity of this com-
plex makes it an excellent candidate for use in a catalytic
sulfoxidation reaction, thereby modeling the behavior of ty-
rosinase.
When excess thioanisole is added to solutions of the di-
copper(II) complex [Cu2ACTHNUTRGNEUNG
(L55)]4+, no reaction occurs. Bind-
ing of the sulfide to the CuII centers can also be excluded in
this case because this would be signaled by the development
of a near-UV band attributable to a sulfide!CuII LMCT
transition.[15] However, if a reducing agent, such as ascorbic
acid, is added to the mixture the reaction proceeds catalyti-
cally with formation of sulfoxide. This suggests that the di-
oxygen adduct of the dicopper(I) complex is the active spe-
cies in the sulfoxidation and the reducing co-substrate is re-
Figure 1. Substrate concentration dependence of the first-order rate con-
stant of the reaction of [Cu2ACTHNUTRGNEUNG
(MeL66)O2]2+ with thioanisole in acetone at
ꢀ728C.
results can be accounted for by assuming pre-equilibrium
binding of thioanisole to the complex to give a ternary (non-
covalent) Cu2O2/sulfide adduct, followed by oxygen transfer
to the bound substrate. The reaction mechanism is described
by the following kinetic equation:
quired to regenerate the active [Cu
(L55)O2]2+ species from
2ACHTUNGTRENNUNG
[Cu2A
CTHUNGTRENNUNG
(Scheme 1). The choice of reducing agent is important be-
cause this competes with the sulfide in the reaction with
kSOKeq½Sꢁ
kobs
¼
ð1Þ
ð1 þ Keq½SꢁÞ
in which Keq represents the thi-
oanisole binding constant to the
m-h2:h2-peroxodicopper(II)
complex and kSO is the first-
order rate constant for oxygen
transfer to the sulfur atom in
the ternary adduct; kSO repre-
sents the saturation value in
Figure 1. Fitting of the experi-
mental data gives values of (9ꢂ
2)ꢂ10mꢀ1 for Keq and (12ꢂ1)ꢂ
10ꢀ5 sꢀ1 for kSO.
The small value of Keq con-
firms that the reaction occurs
even if no direct coordination
of the sulfide to the Cu centers
Scheme 1. Catalytic cycle of the sulfoxidation reaction with [Cu
ments (methanolic aqueous buffer at pH 5.1), the copper complex is probably a mixture of dibridged bis-
(aqua)- and monoaquamonohydroxo species.[11] For simplicity it is represented here as a monohydroxo species.
(L55)]4+. Under the conditions of the experi-
2ACHTUNGTRENNUNG
of [Cu2ACHTUNGTRENNUNG
(MeL66)O2]2+ occurs.
Presumably, steric hindrance
ACHTUNGTRENNUNG
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12933

L. Casella et al.
[Cu
G
In the second mechanism, the sulfoxidation may occur
through two consecutive one-electron oxidations by the cat-
alyst active species with two molecules of the substrate, with
formation of sulfur radical cations. Dismutation of the latter
species in solution in the presence of water (or methanol)
gives rise to the sulfoxide:
ascorbic acid, hydroxylamine, and l-Dopa. l-Dopa is the re-
agent of choice for the sulfoxidation catalyzed by tyrosi-
nase,[5] but in the present case its oxidation products simply
complicate the workup of the reaction. The best results
were obtained by using hydroxylamine, which proved to be
the most efficient co-catalyst in terms of sulfoxide yield and
gave no organic byproduct. Typically, a solution of thioani-
þC
½Cu2ðL55ÞO2ꢁ2þ þ 2 S þ 3 Hþ ! ½Cu2ðL55ÞOHꢁ3þ þ 2 S þ H2O
sole (10 mm) and [Cu2ACTHNUTRGNEUNG
(L55)]4+ (10 mm) in either methanol or
ð3Þ
methanol containing 1:3 (v/v) phosphate buffer (50 mm,
pH 5.1) was allowed to react with variable amounts of
NH2OH. At various times during the reaction, a sample of
the solution was withdrawn and analyzed by NMR spectros-
copy to monitor sulfoxide formation. The best and most re-
producible results were obtained in the solvent that con-
tained the aqueous buffer, probably because the consump-
tion of the reducing agent affects the pH of the solution. In
all cases, sulfoxide was the only product. Blank experiments
þ
þC
2 S þ H2O ! S þ SO þ 2 H
ð4Þ
This mechanism typically operates, for instance, in the sul-
foxidation catalyzed by peroxidases in the presence of
H2O2,[16] but in some cases a direct oxygen transfer can
occur even with these enzymes.[17] For catalytic sulfoxida-
tions by metal complexes with either O2, H2O2, or other O-
atom donors, in spite of the extensive literature, direct evi-
dence for the actual reaction pathway is scarce. However,
apparently both the one-electron sulfur oxidation and the
direct oxygen transfer mechanisms are possible,[8f,18] the
latter probably being predominant when the reactions occur
with high stereo- or enantioselectivity.
in the absence of the copper complex or with Cu
the catalyst gave negligible sulfoxide formation.
The catalytic reaction slowed down with time, and the
yield of sulfoxide reached a constant value after several
hours because the catalyst became inactivated. The inactiva-
tion process is likely due to radical species generated by the
action of the reducing agent. The number of catalytic cycles
depends on the amount of NH2OH, as shown in Table 1. It
The two mechanisms differ depending on the source of
the oxygen atom incorporated in the sulfoxide; in the first
mechanism it comes from O2, in the second from the sol-
vent. To discriminate between the two possibilities, an ex-
periment was performed in the presence of 18O2 that showed
98% incorporation of 18O into methylphenyl sulfoxide. This
is consistent with a direct oxygen transfer from the [Cu2-
Table 1. Yield of methylphenyl sulfoxide and product turnover number
as a function of the concentration of the co-substrate hydroxylamine.[a]
NH2OH [mm]
1
2
5
10
20
70
AHCTUNGTRENNUNG
(L55)O2]2+ species and excludes the radical mechanism.
This result is particularly important because the oxygenation
proceeds even if it is likely that the sulfide does not directly
bind to the copper centers of [Cu
(L55)O2]2+, as for [Cu2-
2ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[a] Reaction conditions: Thioanisole (10 mm) and [Cu2ACTHNUTRGNEUNG
(L55)]4+ (10 mm) in
cant steric crowding around the dicopper cores due to the
benzimidazole groups of the ligand.
3:1 (v/v) methanol/aqueous phosphate buffer (50 mm, pH 5.1) for 24 h at
258C.
The scope of the catalytic sulfoxidation by [Cu2ACHTUNGTRENNUNG
(L55)]4+
is interesting to note that the highest sulfoxide yield is ob-
tained when the substrate and co-substrate are used in equal
amounts. With a lower concentration of NH2OH the reac-
tion to restore the active form of the catalyst ([Cu2-
was further investigated with some other representative sul-
fides. By reacting the sulfide (10 mm) and NH2OH (10 mm)
under the same conditions as in Table 1, the turnover
number for the oxidation of methyl p-tolyl sulfide dropped
to 80 and that of 4-(methylthio)benzonitrile to 12, while the
reaction of 4-(methylthio)benzaldehyde gave only traces of
sulfoxide, which shows that both steric and electronic effects
influence the reaction. However, the reaction conditions for
each sulfide would need to be optimized in terms of nature
and amount of co-substrate of choice.
ACHTUNGTRENNUNG
(L55)O2]2+) is slower, whereas with larger amounts of
NH2OH the sulfoxide yield and turnover number are re-
duced. This reflects the double activity of the reducing
agents; it is necessary to generate the reduced complex
([Cu
2ACHTUNGTRENNUNG
(L55)]2+) but competes with the substrate in the reac-
tion with [Cu2ACHTUNGTRENNUNG .
(L55)O2]2+
The biomimetic monooxygenase reaction can occur
through two different mechanisms. In the first, a sulfide
molecule (S) reacts with the oxy form of the catalyst and un-
dergoes a direct incorporation of an oxygen atom, giving
rise to the sulfoxide (SO) in a single step:
In conclusion, dinuclear copper complexes capable of per-
forming biomimetic phenol hydroxylation are also able to
support the oxygenation of organic sulfides. While the sul-
foxidation activity of the mononuclear hydroperoxo-
AHCTUNGTRENNUNG
copper(II) complex studied by Masuda et al.[9c] is reminis-
cent of that of dopamine b-hydroxylase (which, however,
uses dioxygen instead of hydrogen peroxide[19]), the dinu-
clear peroxodicopper(II) complexes studied herein repro-
½Cu2ðL55ÞO2ꢁ2þ þ S þ Hþ ! ½Cu2ðL55ÞOHꢁ3þ þ SO
ð2Þ
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Catalytic Sulfoxidation
COMMUNICATION
duce the behavior of tyrosinase.[5] The maximum turnover
number reported for the sulfoxidation of thioanisole by the
Masuda system (300) was lower than that achieved herein,
but because the conditions of the experiment were different
a direct comparison with our system would be inappropria-
te.[9c] In general, however, the efficiency of the sulfoxidation
catalyzed by copper complexes compares favorably with
that of other transition-metal catalysts[8a,b] and opens new
possibilities for synthetic applications.
pounds was performed by using a HP.1 column (30ꢂ0.32 mm). The tem-
perature was raised from 70 up to 2708C with a linear gradient of
208Cminꢀ1, and then kept at 2708C for further 6 min. The MS spectrum
of the labeled methylphenyl sulfoxide obtained from 18O2 was compared
with that of a standard unlabelled sample, and the percentage of 18O in-
corporation was established by the intensity ratio of the molecular
peaks.[5]
Catalytic oxidation of thioanisole: In a standard reaction, thioanisole
(10 mm) and [Cu2ACHTNUGTRENNUG(L55)]ACHTUNTGREN(NUGN ClO4)4 (10 mm) were stirred at RT in 1 mL of a
3:1 (v/v) mixture of methanol and either aqueous phosphate or acetate
buffer (50 mm, pH 5.1). The reaction was started by addition of the de-
sired amount of hydroxylamine hydrochloride (1–70 mm). After the given
reaction time (usually 24 h), a sample of the reaction mixture was with-
drawn and quenched with dilute aqueous perchloric acid, then a known
amount of benzophenone in dichloromethane (20 mL, 10ꢀ2 m) was added
as the internal standard for HPLC and NMR spectroscopy analysis. The
methanol phase was removed by rotary evaporation.[20] The aqueous
phase was extracted three times with equal volumes of dichloromethane
and the organic extracts were combined. The solvent was removed by
rotary evaporation[20] (during which unreacted volatile thioanisole is par-
tially lost) and the residue dissolved in either CDCl3 for NMR spectro-
scopic analysis or in ethyl acetate for HPLC analysis, as described above.
Blank experiments were performed as above but in the absence of [Cu2-
Experimental Section
Materials: The synthesis of the [Cu2ACHTNUGTRNE(NUNG MeL66)]AHCTNURTGEG[NUNN PF6]2 and [Cu2ACHTNUGRTEN(NUGN L55)]-
ACHTUNGTRENNUNG
[ClO4]4 complexes has been described in the literature.[10,13] All the other
compounds were from Aldrich. 18O2 gas was at 15 atm and with 97%
content of 18O.
Stoichiometric oxidation of thioanisole by [Cu
dard reaction, a solution of copper(I) complex [Cu
(MeL66)O2]2+: In a stan-
2A(MeL66)][PF6]2 (5.1ꢂ
10ꢀ4 m) in dry and deoxygenated acetone (25 mL) was thermostated at
ꢀ728C in a Schlenk flask. Oxygenation of the complex was carried out
by gently bubbling oxygen (1 atm) into the cold solution. When the for-
mation of the oxygenated intermediate was complete, usually within 1
hour, a cooled solution of thioanisole (in variable amounts, from 20 to
200 equiv) in acetone was added. The final solution was then stirred at
low temperature for a period that depended on the concentration of thio-
anisole, typically 6–15 h. The progress of the reaction was monitored by
using a custom-designed fiber-optic quartz probe (Hellma) to record the
disappearance of the band at l=362 nm arising from the peroxo com-
plex. After the given reaction time, the reaction mixture was quenched
by the addition of aqueous perchloric acid (0.4m, 3 mL), then a known
amount of benzophenone in CH2Cl2 (20 mL, 10ꢀ2 m) was added as the in-
ternal standard for HPLC and NMR spectroscopic analysis. The acetone
component was removed by rotary evaporation.[20] The aqueous phase
was extracted with CH2Cl2 (3ꢂ10 mL) and the organic extracts were
combined. The solvent was removed by rotary evaporation[20] (during
which unreacted volatile thioanisole is partially lost) and the residue dis-
solved in either CDCl3 for NMR spectroscopy analysis (by using a
Bruker AVANCE 400 spectrometer) or in ethyl acetate for HPLC analy-
sis (by using a Jasco MD-1510 instrument with diode array detection) on
a Daicel chiral column OD (0.46ꢂ25 cm; although the product is clearly
racemic, this column gave an excellent separation of the product from
the sulfide and the internal standard). The product was eluted with n-
G
ACHUTNGTRENNG[U ClO4]4 or in the presence of CuCAHTUNGTRENNNUG
CTHUNGTRENNUNG
CHTUNGTRENNUNG
E
a
(50 mm, pH 5.1) mixture at RT was carefully degassed by using vacuum/
argon cycles in a small Schlenk flask; care was taken to avoid loss of thi-
oanisole. A degassed solution of hydroxylamine hydrochloride (20 mm)
was then added by using a gas-tight syringe. The reaction was started by
slowly bubbling 18O2 into the solution through
a gas-tight syringe
(10 mL), then allowed to run for 10 h. The reaction was then quenched
with aqueous perchloric acid (1 mL, 0.4m). The methanol phase was re-
moved by rotary evaporation[20] and the aqueous phase was extracted
three times with an equal volumes of dichloromethane. The combined or-
ganic extracts were evaporated to dryness,[20] then the residue was dis-
solved in methanol and analyzed by GC–MS as described above.
(L55)]4+
Catalytic sulfoxidation of other sulfide derivatives by [Cu2ACHTUNGTRENNUNG /
NH2OH: The catalytic oxidations of methyl p-tolyl sulfide, 4-(methyl-
thio)benzonitrile, and 4-(methylthio)benzaldehyde (10 mm) in the pres-
ence of [Cu2ACHTNUGTRENNUG(L55)]ACHTUNGTRNEN[UGN ClO4]4 (10 mm) were studied in the same conditions
described above for thioanisole oxidation. The reactions were started by
addition of hydroxylamine hydrochloride (10 mm final concentration).
After reacting for 72 h, a sample of the reaction mixture was withdrawn
and quenched with aqueous perchloric acid (0.4m), then a known amount
of benzophenone in CH2Cl2 (20 mL, 10ꢀ2 m) was added as the internal
standard for HPLC and NMR spectroscopy analysis. The methanol phase
was then removed by rotary evaporation. The aqueous phase was extract-
ed three times with equal volumes of dichloromethane and the organic
extracts were combined. The solvent was removed by rotary evaporation
hexane/isopropanol (85:15) and was used at a flow rate of 0.5 mLminꢀ1
,
with optical readings at l=242 nm; the peak of the internal standard was
evaluated by reading the absorbance at l=340 nm. The retention time of
the (R)-sulfoxide was 21.7 min and that of the (S)-sulfoxide was 24.8 min.
The sulfoxide yield was calculated by summing the equal areas of the
two peaks and from the NMR spectra. 1H NMR (400 MHz, CDCl3,
1
and the residue was dissolved in CDCl3 for H NMR spectroscopy analy-
ꢀ
TMS): d=2.76 (s, 3H; CH3), 7.50–7.62 (m, 3H; aromatic C H), 7.65–
sis.
ꢀ
7.69 ppm (m, 2H; aromatic C H).
Spectroscopic data for p-tolyl sulfoxide: 1H NMR (400 MHz, CDCl3,
TMS): d=2.39 (s, 3H; CH3-phenyl), 2.84 (s, 3H; CH3), 7.31 (d, 2H; aro-
matic C-H), 7.52 (d, 2H; aromatic C-H); MS: m/z: 153.98.
18O incorporation into thioanisole: A 10 mL sample of a solution contain-
ing thioanisole (100 mm) and [Cu2ACHTNUGTRENN(UG MeL66)]ACHTUNGTRNE[NUGN PF6]2 (0.5 mm) in dry and de-
oxygenated acetone (25 mL) was thermostated at ꢀ728C and then de-
gassed through vacuum/argon cycles in a small Schlenk flask. Care was
taken to prevent loss of the volatile thioanisole during this operation.
The mixture was held at low temperature and the reaction was started by
slowly bubbling 18O2 through a gas-tight syringe (5 mL) for a few minutes,
then left for 10 h under stirring. The reaction was then quenched by the
addition of diluted perchloric acid (1 mL, 0.4m). The acetone phase was
removed by rotary evaporation[20] and the aqueous phase was extracted
three times with equal volumes of dichloromethane. The combined or-
ganic extracts were evaporated to dryness,[20] then the residue was dis-
solved into dichloromethane and analyzed by GC–MS. The GC–MS anal-
ysis was performed by using an Agilent 6890 gas chromatograph
equipped with an Agilent 5973 MS detector. GC separation of the com-
1
Spectroscopic data for 4-(methylsulfinyl)benzonitrile: H NMR (400 MHz,
CDCl3, TMS): d=2.70 (s, 3H; CH3), 7.71 (d, 2H; aromatic C-H), 7.79 (d,
2H; aromatic C-H); MS: m/z: 164.99
Spectroscopic data for 4-(methylsulfinyl)benzaldehyde: 1H NMR
(400 MHz, CDCl3, TMS): d=2.69 (s, 3H; CH3), 7.21 (d, 2H; aromatic C-
H), 7.67 (d, 2H; aromatic C-H), 9.83 (s, 1H; CHO); MS: m/z: 168.01.
Chem. Eur. J. 2009, 15, 12932 – 12936
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12935

L. Casella et al.
Wu, X. Feng, Z. Zhang, Y. Li, Z. Wang, Inorg. Chim. Acta 2007,
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Acknowledgements
This work was supported by a PRIN Project of the Italian MIURand by
the University of Pavia through FAR.
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Keywords: homogeneous catalysis
activation · peroxo ligands · sulfoxidation · tyrosinase
·
copper
·
oxygen
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Received: September 4, 2009
Published online: October 28, 2009
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