Thioether sulfur oxygenation from O2 or H2O 2 reactivity of copper complexes with tridentate N2S thioether ligands

Article abstract of DOI:10.1021/ic060730t

To model thioether-copper coordination chemistry including oxidative reactivity, such as occurs in the copper monooxygenases peptidylglycine α-hydroxylating monooxygenase (PHM) and dopamine β-hydroxylase (DβH), we have synthesized new tridentate N₂S ligands L ^SEP and L^SBz [L^SEP = methyl(2- phenethylsulfanylpropyl)(2-pyridin-2-ylethyl)amine; L^SBz = (2-benzylsulfanylpropyl)methyl(2-pyridin-2-ylethyl)amine)]. Both copper(I) and copper(II) complexes have been prepared, and their respective O₂ and H₂O₂ chemistry has been studied. Under mild conditions, oxygenation of [(L^SEP)Cu^I]⁺ (1a) and [(L ^SBz)Cu^I]⁺ (2a) leads to ligand sulfoxidation, thus exhibiting copper monooxygenase activity. A copper(II) complex of this sulfoxide ligand product, [(L^SOEP)Cu^II(CH ₃OH)(OClO₃)₂], has been structurally characterized, demonstrating Cu-O_sulfoXide ligation. The X-ray structure of [(L^SEP)Cu^II(H₂O)(OClO ₃)]⁺ (1b) and its solution UV-visible spectral properties [S-Cu^II LMCT band at 365 nm (MeCN solvent); ε = 4205 M ^-1 cm^-1] indicate the thioether sulfur atom is bound to the cupric ion in both the solid (Cu^II-S distance: 2.31 A) and solution states. Reaction of 1b with H₂O₂ leads to sulfonation via the sulfoxide; excess hydrogen peroxide gives mostly sulfone product. These results may provide some insight into recent reports concerning protein methionine oxidation, showing the potential importance of copper-mediated oxidation processes in certain biological settings.

Full text of DOI:10.1021/ic060730t

Inorg. Chem. 2006, 45, 10098−10107
Thioether Sulfur Oxygenation from O2 or H2O2 Reactivity of Copper
Complexes with Tridentate N2Sthioether Ligands
Yunho Lee,† Dong-Heon Lee,‡ Amy A. Narducci Sarjeant,† Lev N. Zakharov,§
|
Arnold L. Rheingold,§, and Kenneth D. Karlin*,†
Departments of Chemistry, The Johns Hopkins UniVersity, 3400 North Charles Street,
Baltimore, Maryland 21218, Chonbuk National UniVersity, Jeonju, S. Korea 561-756, and
UniVersity of Delaware, Newark, Delaware 19716
Received April 28, 2006
To model thioether
monooxygenases peptidylglycine
have synthesized new tridentate N2S ligands LSEP and LSBz [LSEP
ylethyl)amine; LSBz
(2-benzylsulfanylpropyl)methyl(2-pyridin-2-ylethyl)amine)]. Both copper(I) and copper(II)
−
copper coordination chemistry including oxidative reactivity, such as occurs in the copper
-hydroxylating monooxygenase (PHM) and dopamine -hydroxylase (D H), we
methyl(2-phenethylsulfanylpropyl)(2-pyridin-2-
R
â
â
)
)
complexes have been prepared, and their respective O2 and H2O2 chemistry has been studied. Under mild conditions,
oxygenation of [(LSEP)CuI]+ (1a) and [(LSBz)CuI]+ (2a) leads to ligand sulfoxidation, thus exhibiting copper
monooxygenase activity. A copper(II) complex of this sulfoxide ligand product, [(LSOEP)CuII(CH3OH)(OClO3)2], has
been structurally characterized, demonstrating Cu
(1b) and its solution UV visible spectral properties [S
cm-1] indicate the thioether sulfur atom is bound to the cupric ion in both the solid (CuII
−
Osulfoxide ligation. The X-ray structure of [(LSEP)CuII(H2O)(OClO3)]+
1
−
−
CuII LMCT band at 365 nm (MeCN solvent); ꢀ ) 4285 M-
−S distance: 2.31 Å) and
solution states. Reaction of 1b with H2O2 leads to sulfonation via the sulfoxide; excess hydrogen peroxide gives
mostly sulfone product. These results may provide some insight into recent reports concerning protein methionine
oxidation, showing the potential importance of copper-mediated oxidation processes in certain biological settings.
Introduction
enzyme nitrous oxide reductase.3-5 Thioether methionine-
copper ion interactions also occur in the type 1 “blue”
electron-transfer proteins6,7 but also at the active site of
certain monooxygenases which effect substrate C-H bond
activation and oxygenation chemistry.
The investigation of sulfur atom containing ligands for
copper complexes is currently of considerable interest in
bioinorganic chemistry. Cysteine-thiolate-Cu ion interac-
tions are important in electron-transfer protein centers,1,2 and
sulfide-Cu interactions as a Cu4-S cluster occur in the
(3) Chen, P.; Gorelsky, S. I.; Ghosh, S.; Solomon, E. I. Angew. Chem.,
Int. Ed. 2004, 43 (32), 4132-4140.
* To whom correspondence should be addressed. E-mail: Karlin@jhu.edu.
† The Johns Hopkins University.
(4) For recent synthetic models of the N2OR copper center which are
(di)sulfido-copper complexes, see: (a) Brown, E. C.; Aboelella, N.
W.; Reynolds, A. M.; Aullon, G.; Alvarez, S.; Tolman, W. B. Inorg.
Chem. 2004, 43 (11), 3335-3337. (b) Brown, E. C.; York, J. T.;
Antholine, W. E.; Ruiz, E.; Alvarez, S.; Tolman, W. B. J. Am. Chem.
Soc. 2005, 127 (40), 13752-13753. (c) York, J. T.; Brown, E. C.;
Tolman, W. B. Angew. Chem., Int. Ed. 2005, 44, 7745-7748. (d)
Helton, M. E.; Chen, P.; Paul, P. P.; Tyekla´r, Z.; Sommer, R. D.;
Zhakarov, L. N.; Rheingold, A. L.; Solomon, E. I.; Karlin, K. D. J.
Am. Chem. Soc. 2003, 125, 1160-1161. (e) Helton, M. E.; Maiti, D.;
Zhakarov, L. N.; Rheingold, A. L.; Porco, J., John A.; Karlin, K. D.
Angew. Chem., Int. Ed. 2006, 45, 7, 1138-1141.
‡ Chonbuk National University.
§ University of Delaware.
| Current address: Department of Chemistry and Biology, University of
California, San Diego, La Jolla, CA 92093-0332.
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© 2006 American Chemical Society
Published on Web 11/10/2006

Cu Complexes with Tridentate N2Sthioether Ligands
Chart 1
Figure 1. Representation of the X-ray structure of the CuM center in the
PHM active site (PDB code 1PHM).10
Catalyzing hydroxylation reactions of substrates leading
to neurotransmitters/hormones, dopamine â-hydroxylase
(DâH) and a closely related enzyme, peptidylglycine R-hy-
droxylating monooxygenase (PHM), possess dicopper active
sites, with however the two copper centers, CuH and CuM,8
separated by ∼11 Å distance.9-12 CuH with (His)3-Cu
ligation is thought to shuttle electrons to the actual site of
O2-binding and substrate oxidation, CuM, which possesses a
(His)2(Met)-Cu coordination environment (Figure 1). Ex-
perimental13 and computational studies14 suggest a super-
and neurodegenerative disorders including Parkinson’s and
Alzheimer’s disease.23-29 Redox-active metals such as iron
and copper will likely facilitate Met oxidation (perhaps in
combination with O2, hydrogen peroxide, or other oxi-
dants).27,28,30 Derived products (e.g., methionine sulfoxide)
may strongly influence protein conformational changes,
including either enhancing or inhibiting deposition/aggrega-
tion of protein fibrils.31-33 There is even some discussion
concerning the direct production of reactive oxygen species
(ROS) as facilitated by methionine-copper chemistry.28
Thus, an area of research interest is to shed further light
on copper redox chemistry in the presence of thioether groups
(as models for protein methionine residues) directed toward
oxidative chemistry, i.e., emphasizing CuI/O2 or CuII/H2O2
reactions. Investigations in this area have been quite limited
(see further discussion below). Thus, in this report, we
describe copper(I) and copper(II) complexes and their
oxidative chemistry with new tridentate thioether containing
ligands, LSEP and LSBz, Chart 1. Copper(I)/O2 chemistry with
these ligands leads to stoichiometric sulfoxidations, while
addition of hydrogen peroxide to copper(II) complexes of
-
oxo-copper(II) [CuIIM-(O2 )] moiety may be responsible
for substrate hydrogen atom abstraction reaction.15 A cop-
per(II)-hydroperoxo moiety [CuIIM-(-O2H)] or higher-
valent copper-oxo moiety [CuIIIM-(O2-) T CuIIM-(O•-)]16
are also considered as relevant active species. Important
questions of interest which follow are (i) what is the role of
the thioether ligand in stabilizing or activating a center for
Cu-O2 binding, formation of a superoxo or hydroperoxo
copper(II) entity, and subsequent reactivity and (ii) how or
why does the methionine not itself become oxidized irrevers-
ibly, as sulfur oxidation is relatively facile?
Further impetus for the study of oxidative processes
involving methionine (Met) is the likely relevance to
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catalytic site, to avoid confusion with copper ion center labeling in
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Inorganic Chemistry, Vol. 45, No. 25, 2006 10099

Lee et al.
of [(LSEP)CuII(H2O)(OClO3)](ClO4) (1b) was mounted with epoxy
cement to the tip of a glass fiber. Intensity data were collected at
150(2) K with a Bruker SMART APEX CCD diffractometer with
graphite-monochromated Mo KR radiation (λ ) 0.71073 Å). An
absorption correction was applied using the SADABS program
(Sheldrick, G. M. SADABS (2.01), Bruker/Siemens Area Detector
Absorption Correction Program; Bruker AXS: Madison, WI,
1998). The structure was solved using direct methods and refined
using the Bruker SHELXTL (v6.1) software package (G. M.
Sheldrick, 2000). The H atoms in 1b were refined in calculated
positions except the H atoms in the water molecule involved in
O(1)-H(1)···O(7) hydrogen bonds which were found from the
F-map and refined with isotropic thermal parameters. Three O atoms
in one of the ClO4 anions and the CH2CHCH3 group are disordered
over two positions in ratios 71/29 and 56/54, respectively.
LSEP and LSBz leads to sulfoxide products in both cases and
additionally a sulfone for LSEP. The results show how copper
ion can facilitate thioether oxygenation reactions, which may
be relevant to biological processes.
Experimental Section
General Methods. All reagents and solvents used for this work
were commercial products and are of reagent quality unless
otherwise stated. Acetonitrile, dichloromethane, diethyl ether,
methanol, and tetrahydrofuran were purified and dried by passing
through a double alumina column solvent purification system by
Innovative Technologies, Inc. Deoxygenation of these solvents was
achieved by bubbling Ar for 30 min and/or followed by three freeze/
pump/thaw cycles. Air-sensitive compounds were handled under
Ar atmosphere with standard Schlenk techniques or within a
MBraun Labmaster 130 inert-atmosphere (N2 atmosphere; <1 ppm
O2, <1 ppm H2O) glovebox. [CuI(MeCN)4]ClO4 was prepared by
the literature procedure.34,35
Warning: While we have experienced no problems in working
with perchlorate compounds, they are potentially explosive and care
must be taken not to work with large quantities.
1H NMR and 13C NMR spectra were measured on a Varian
400 MHz or Bruker 400 MHz spectrometer, and chemical shifts
are reported in ppm (δ) downfield from an internal TMS reference.
Infrared spectra were recorded on a Mattson Instruments 4030
Galaxy Series FT-IR spectrometer.
Gas chromatography was carried out and recorded using a
Hewlett-Packard 5890 Series II gas chromatograph. The GC
conditions for the analysis of the resulting oxidation product mixture
were the following: injector port temperature, 250 °C; detector
temperature, 250 °C; flow rate, 50 mL/min.
X-band electron paramagnetic resonance (EPR) spectra were
recorded on a Bruker EMX CW-EPR spectrometer controlled with
a Bruker ER 041 XG microwave bridge operating at X-band (∼9
GHz). The low-temperature experiments were carried out via either
a continuous-flow He(l) cryostat and ITC503 temperature controller
made by Oxford Instruments, Inc., or N2(l) finger dewar.
Low-temperature UV-vis spectra were obtained with either
a Cary 50 Bio spectrophotometer equipped with a fiber optic coupler
(Varian) and a fiber optic dip probe (Hellma: 661.302-QX-UV-2
mm-for-low-temperature) or a Hewlett-Packard model 8453 diode
array spectrophotometer equipped with a custom-made quartz
Dewar flask filled with methanol. A low-temperature unit (Neslab
ULT-95 low-temperature circulator) is attached to the HP spectro-
photometer. Air-sensitive solutions were prepared in a glovebox
(N2 filled, MBraun) and carried out in custom-made Schlenk tubes
designed for the dip probe (Chemglass: JHU-0407-271MS) or
Schlenk cuvettes (Quark).
Elemental analyses were performed by Desert Analytics,
Tucson, AZ, for the air-sensitive samples or Quantitative Technolo-
gies Inc. (QTI), Whitehouse, NJ, for the non-air-sensitive samples.
Mass spectrometry was conducted at the mass spectrometry
facility either at the Johns Hopkins University or at The Ohio State
University. Chemical ionization (CI) and fast atomic bombardment
(FAB) mass spectra were acquired at the Johns Hopkins University
facility using a VG70S double-focusing magnetic sector mass
spectrometer (VG Analytical, Manchester, U.K., now Micromass/
Wasters) equipped with a Xe gas FAB gun (7.5 kV @ 1 mA) and
an off-axis electron multiplier.
Synthesis of Ligands. LSEP Ligand. 2-(2-Methylaminoethyl)-
pyridine (2.31 g, 17.0 mmol) and propylene sulfide (1.26 g, 17.0
mmol) were refluxed in acetonitrile (50 mL) for 4 h under Ar. After
the mixture has been cooled, solvent was removed by rotary
evaporator. The resulting crude yellow oil was dissolved in THF
(50 mL). With vigorous stirring upon addition of sodium (0.45 g,
19.6 mmol), the yellow solution turned to a dark orange color
slowly. (2-Bromoethyl)benzene (3.14 g, 17.0 mmol) was added
dropwise with stirring, and then the reaction mixture was refluxed
for 1 h under Ar. During this time solution color was changed to
yellow. After cooling of the sample to room temperature, ethanol
(10 mL) was added for deactivating the unreacted sodium and
solvent was removed by rotary evaporator. The solid residue was
dissolved in CH2Cl2 and washed with brine three times. The organic
layer was separated, dried over anhydrous MgSO4, filtered, and
concentrated under vacuum. The oil obtained was purified by
column chromatography (Al2O3, 9:1 hexane-ethyl acetate, Rf )
0.31). Yield: 2.6 g (8.27 mmol, 48.8%). 1H NMR (CDCl3): δ 8.51
(dq, J ) 4, 0.8 Hz, 1H), 7.56 (td, J ) 7.6, 2 Hz, 1H), ∼7.2 (m,
7H), ∼2.85 (m, 9H), 2.56 (dd, 1H), 2.40 (dd, 1H), 2.31 (s, 3H),
1.21 (d, J ) 6.4 Hz, 3H). 13C NMR (CDCl3): δ 161.6 (py), 150.3
(py), 141.8 (ph), 137.3 (py), 129.5 (ph), 127.3 (ph), 124.4 (py),
122.1 (py), 65.3 (NCH2), 59.1 (NCH2), 43.7 (NCH3), 39.3 (CH2-
ph), 37.7 (CH), 37.1 (pyCH2), 33.0 (SCH2), 20.7 (CH3). FAB mass
spectrum: m/z 315.3 (M + 1)+.
Cyclic voltammetry measurements were undertaken in freshly
distilled acetonitrile using a BAS 100B electrochemical analyzer
with a glassy carbon working electrode and a platinum wire
auxiliary electrode. Potentials were recorded versus a Ag/AgNO3
+/0
electrode. The voltammograms are plotted versus the Fe(Cp)2
potential which was measured as an external standard. Scans were
run at 50-500 mV/s under an argon atmosphere using ca. 0.1 M
[Bu4N][PF6] as the supporting electrolyte.
X-ray crystallography was performed at the X-ray diffraction
facility either at the Johns Hopkins University or University of
Delaware. A suitable blue single crystal of [(LSOEP)CuII(CH3OH)-
(OClO3)2] was mounted in Paratone-N oil on the end of a glass
fiber and transferred to the N2 cold stream (110 K) of an Oxford
Diffraction Xcalibur3 system equipped with Enhance optics [Mo
KR radiation (λ ) 0.71073 Å)] and a CCD detector. The frames
were integrated, and a face-indexed absorption correction and an
interframe scaling correction were also applied with the Oxford
Diffraction CrysAlisRED software package (CrysAlis CCD, Oxford
Diffraction Ltd.,version 1.171.27p5 beta). The structure was solved
using direct methods and refined using the Bruker SHELXTL (v6.1)
software package (G. M. Sheldrick, 2000). A suitable green crystal
(34) Liang, H.-C.; Kim, E.; Incarvito, C. D.; Rheingold, A. L.; Karlin, K.
D. Inorg, Chem. 2002, 41 (8), 2209-2212.
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Zuberbu¨hler, A. D. Inorg. Chem. 2000, 39 (26), 5884-5894.
10100 Inorganic Chemistry, Vol. 45, No. 25, 2006

Cu Complexes with Tridentate N2Sthioether Ligands
LSBz Ligand. 2-(2-Methylaminoethyl)pyridine (4.78 g, 35.1
mmol) and propylene sulfide (2.60 g, 35.1 mmol) were refluxed in
acetonitrile (50 mL) for 5 h under Ar. After the mixture was cooled,
solvent was removed. The crude yellow oil obtained was dissolved
in THF (50 mL). With vigorous stirring upon addition of sodium
(0.98 g, 42.6 mmol), slowly the yellow solution turned to dark
orange color. Benzyl chloride (4.75 g, 37.5 mmol) was added
dropwise with stirring, and then the mixture was refluxed for 1 h
under Ar. During this time solution color was changed form black
to yellow. After cooling of the sample to room temperature, ethanol
(10 mL) was added for deactivating the excess sodium and solvent
was removed by rotary evaporator. The product mixture was
dissolved in CH2Cl2 and washed with brine three times. The
resulting organic layer was separated, dried over anhydrous MgSO4,
filtered, and concentrated under vacuum. The oil was purified by
column chromatography (Al2O3, 4:1 hexane-ethyl acetate, Rf )
0.45) to give a yellow oil. Yield: 5.21 g (17.35 mmol, 49.5%). 1H
NMR (CDCl3): δ 8.40 (dt, J ) 4.8, 0.8 Hz, 1H), 7.44 (tq, J ) 7.6,
1.6 Hz, 1H), ∼7.1 (m, 7H), 3.65 (d, J ) 4 Hz, 2H), 2.81 (t, J )
7.4 Hz, 2H), 2.65 (m, 3H), 2.44 (dd, 1H), 2.29 (dd, 1H), 2.13 (s,
3H), 1.08 (d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ 160.5 (py),
149.2 (py), 138.7 (ph), 136.1 (py), 128.8 (ph), 128.4 (ph), 126.8
(ph), 123.2 (py), 121.0 (py), 64.0 (NCH2), 57.9 (NCH2), 42.5
(NCH3), 37.4 (CH), 35.9 (CH2ph), 34.9 (pyCH2), 19.5 (CH3). EI-
MS mass spectrum: m/z 301.2 (M + 1)+.
and concentrated under vacuum. The oil was purified by column
chromatography (Al2O3, 1:5 hexane-ethyl acetate, Rf ) 0.25).
Yield: 0.11 g (0.33 mmol, 47%). 1H NMR (CDCl3): δ 8.50 (dm,
J ) 4, 1 Hz, 1H), 7.54 (m, 1H), ∼7.2 (m, 7H), ∼2.9 (m, 10H),
2.48 (m, J ) 6 Hz, 1H), 2.32 (d, 3H), 1.20 (dd, J ) 3.6, 7.2 Hz,
3H). 13C NMR (CDCl3): δ 160.4 (py), 149.5 (py), 139.5 (ph), 136.5
(py), 128.9 (ph), 128.8 (ph), 126.8 (ph), 123.6 (py), 121.4 (py),
59.2 (CH2), 57.9 (CH2N), 57.2 (CH), 51.7 (SCH2), 42.7 (NCH3),
36.0 (CH2ph), 29.7 (pyCH2), 12.2 (CH3). CI-MS mass spectrum:
m/z 331.2 (M + 1)+. IR: SO (-SO-) band shows up at 1032
cm-1
.
[(LSEP)CuI]+ (1a) plus 18O2: 18O-LSOEP Formation. [(LSEP)CuI]-
(ClO4)(CH3CN)2/3 (0.10 g, 0.20 mmol) was dissolved in O2-free
acetonitrile (10 mL) under Ar in a 25 mL Schlenk flask connected
to a three-way valve, a vacuum was applied, and an 18O2 bulb (25
mL, 99 atom %, 1 atm from ICON, part no. IO 6393) was
connected. Labeled dioxygen 18O2 diffused into the reaction flask
after breaking the seal (room temperature). The reaction solution
was stirred overnight, and after the solvent was removed, the
residual green material was treated with NH4OH/CH2Cl2 to effect
demetalation of the ligand organic.36,37 The organic layer was
separated, washed with brine (3×), dried over anhydrous MgSO4,
filtered, and concentrated under vacuum. The identity of the
sulfoxide product was again confirmed by GC; subsequent mass
spectrometric analysis indicated a 62% incorporation of labeled
oxygen. (See Supporting Information.)
Synthesis of Cu(I) Complexes. [(LSEP)CuI](ClO4)(CH3CN)2/3
.
[(LSBz)CuI]+ (2a) plus O2: LSOBz Formation. [(LSBz)CuI](ClO4)-
(CH3CN)1/3 (0.30 g, 0.63 mmol) was dissolved in O2-free aceto-
nitrile (5 mL) under Ar. While O2 gas was bubbling for 5 min at
room temperature, the yellow solution was turning to green. The
resulting green solution was stirred overnight at room temperature.
Solvent was removed, and residual green material was treated by
NH4OH/CH2Cl2 for demetalation.36,37 The organic layer was
separated, washed by brine three times, dried over anhydrous
MgSO4, filtered, and concentrated under vacuum. The resulting oil
was purified by column chromatography (Al2O3, 1:1 hexane-ethyl
The ligand LSEP (0.47 g, 1.49 mmol) and [CuI(CH3CN)4]ClO4 (0.444
g, 1.36 mmol) were stirred for 1 h in O2-free acetonitrile (5 mL)
under Ar at room temperature. The complex was precipitated as a
yellow solid upon addition of (oxygen free) diethyl ether into the
reaction mixture. The supernatant was decanted. The resulting
yellow powder was washed two times with O2-free diethyl ether
and dried under vacuum. Yield: 0.63 g (1.25 mmol, 92%). 1H NMR
(Acetone-d6): δ 8.40 (d, 1H), 7.80 (td, 1H), ∼7.3 (m, 7H), 3∼2.4
(m, 14H), 1.94 (s, CH3CN), 1.29 (d, 3H). Anal. Calcd for C19H26-
ClCuN2O4S + 2/3CH3CN: C, 48.37; H, 5.59; N, 7.40. Found: C,
48.64; H, 5.41; N, 7.50. IR: 2019, 1602, 1316 (weak), 1090 (strong,
1
acetate, Rf ) 0.2). Yield: 0.06 g (0.19 mmol, 30%). H NMR
ClO4-), 931 (weak), 765, 701, 623 cm-1
.
(CDCl3): δ 8.51 (dm, J ) 4 Hz, 1H), 7.56 (td, J ) 7.2, 1.8 Hz,
1H), ∼7.3 (m, 5H), ∼7.1 (m, 2H), 3.91 (dd, 2H), ∼2.9 (m, 6H),
2.48 (dd, J ) 21.2, 12.8 Hz, 1H), 2.24 (s, 3H), 1.23 (d, J ) 6.4
Hz, 3H). 13C NMR (CDCl3): δ 160.2 (py), 149.2 (py), 136.2 (py),
131.0 (ph), 129.8 (ph), 128.8 (ph), 128.0 (ph), 123.3 (py), 121.1
(py), 58.9 (NCH2), 57.6 (CH2N), 55.8 (CH), 51.2 (SCH2), 42.2
(NCH3), 35.8 (pyCH2), 9.1 (CH3). CI-MS mass spectrum: m/z 317.2
(M + 1)+.
[(LSBz)CuI](ClO4)(CH3CN)1/3. The ligand LSBz (0.44 g, 1.46
mmol) and [CuI(CH3CN)4]ClO4 (0.45 g, 1.37 mmol) were stirred
for 1 h in O2-free acetonitrile (5 mL) under Ar at room temperature.
The complex was precipitated as a yellow solid upon addition of
diethyl ether into the reaction mixture. The supernatant was
decanted, and the yellow powder obtained was washed two times
with diethyl ether and dried under vacuum. Yield: 0.60 g (1.26
Synthesis of Cu(II) Complexes. [(LSEP)CuII(H2O)(OClO3)]-
ClO4‚H2O (1b). The ligand LSEP (0.429 g, 1.36 mmol) and CuII-
(ClO4)2‚6H2O (0.485 g, 1.31 mmol) were stirred in CH2Cl2 (5 mL)
at room temperature for 1 h. The complex was precipitated as dark
green solid on addition of diethyl ether into the reaction mixture.
The supernatant was decanted, and the resulting green powder was
washed two times with diethyl ether and dried under vacuum.
Yield: 0.622 g (1.01 mmol, 78%). UV-vis (MeCN; λmax, nm; ꢀ,
M-1 cm-1): 260, 7010; 365, 4285; 625, 265. Anal. Calcd for
C19H30Cl2CuN2O10S: C, 37.23; H, 4.93; N, 4.57. Found: C, 37.68;
H, 4.83; N, 4.33. An EPR spectrum of [(LSEP)CuII(H2O)(OClO3)]+
(1b) indicates a typical tetragonal copper environment. X-band
spectrometer (ν ) 9.186 GHz) in 2-methyltetrahydrofuran/MeCN
(1:1) at 77 K: g| ) 2.23, A| )170 G; g ) 2.03 (see Supporting
Information). X-ray-quality dark green crystals were obtained by
1
mmol, 92%). H NMR (CD3NO2): δ 8.45 (d, 1H), 7.92 (td, 1H),
∼7.3 (m, 7H), 4.0 (m, 2H), 3.44 (m, 1H), 3.18 (m, 1H), ∼2.8 (m,
4H), ∼ 2.5 (m, 4H), 2.10 (s, CH3CN) 1.47 (d, 3H). Anal. Calcd
for C18H24ClCuN2O4S + 1/3CH3CN: C, 46.99; H, 5.28; N, 6.85.
Found: C, 46.86; H, 5.33; N, 6.67. IR: 2015, 1603, 1316, 1248
(weak), 1083 (strong, ClO4-), 932 (weak), 771, 708, 623 cm-1
.
Dioxygen Reactivity Studies of LCu(I) Complexes. [(LSEP)-
CuI]+ (1a) plus O2: LSOEP Formation. [(LSEP)CuI](ClO4)(CH3CN)2/3
(0.35 g, 0.69 mmol) was dissolved in O2-free acetonitrile (5 mL)
under Ar. While O2 gas was bubbling for 5 min at room
temperature, the yellow solution was turning to green. The resulting
green solution was stirred overnight at room temperature. Solvent
was removed, and the residual green material was treated by NH4-
OH/CH2Cl2 for demetalation.36,37 The organic layer was separated,
washed by brine three times, dried over anhydrous MgSO4, filtered,
(37) Sanyal, I.; Mahroof-Tahir, M.; Nasir, S.; Ghosh, P.; Cohen, B. I.;
Gultneh, Y.; Cruse, R.; Farooq, A.; Karlin, K. D.; Liu, S.; Zubieta, J.
Inorg. Chem. 1992, 31, 4322-4332.
(36) Karlin, K. D.; Nasir, M. S.; Cohen, B. I.; Cruse, R. W.; Kaderli, S.;
Zuberbu¨hler, A. D. J. Am. Chem. Soc. 1994, 116, 1324-1336.
Inorganic Chemistry, Vol. 45, No. 25, 2006 10101

Lee et al.
dissolving a portion of this product in CH2Cl2 and layering with
diethyl ether.
analyzed by TLC (thin-layer chromatography), showing two more
spots (Rf ) 0.66, 0.22) in addition to one (Rf ) 0.9) for the original
ligand. After purification by column chromatography (Al2O3, eluent
1:1 hexane-ethyl acetate), 1H and 13C NMR spectroscopy and mass
spectrometric analyses indicate that those two additional spots on
the TLC correspond to a sulfoxide LSOEP (Rf ) 0.22) and a sulfone
LSO2EP (Rf ) 0.66), respectively. With 1 equiv of H2O2, the yields
determined were 34.5 mol % LSEP, 48.7 mol % LSOEP, and 16.8
mol % LSO2EP, while with 2 equiv of H2O2 reaction gave 19.9 mol
[(LSOEP)CuII(CH3OH)(OClO3)2]. LSOEP (0.360 g, 1.09 mmol)
and CuII(ClO4)2‚6H2O (0.404 g, 1.07 mmol) were stirred in CH3-
OH (5 mL) at room temperature for 1 h. The complex was
precipitated as a blue powder upon addition of diethyl ether into
the reaction mixture. The supernatant was decanted, and the blue
powder obtained was washed two times with diethyl ether and dried
under vacuum giving 0.40 g (0.64 mmol, 61%). UV-vis (MeCN;
% LSEP, 40.6 mol % LSOEP, and 39.5 mol % LSO2EP
.
λ
max, nm; ꢀ, M-1 cm-1): 262, 7286; 330 (shoulder), 1946; 665,
[(LSBz)CuII(H2O)(OClO3)]+ (2b) plus H2O2: LSOBz Formation.
[(LSBz)CuII(H2O)(OClO3)]ClO4 (49 mg, 0.0857 mmol) was dissolved
in methanol (5 mL). A color change to blue from green was
observed upon addition of excess hydrogen peroxide (560 mg,
29.6%, 4.8 mmol) at room temperature. After the 22 h reaction
time, solvent was removed and residual green material was treated
by NH4OH/CH2Cl2 for demetalation.36,37 The organic layer was
separated, washed by brine, dried over anhydrous MgSO4, filtered,
and concentrated under vacuum. The oil obtained was purified by
column chromatography (Al2O3, 1:1 hexane-ethyl acetate, Rf )
0.7, 0.2 for LSBz and sulfoxide ligand) to give 0.021 g (0.066 mmol,
77%) of product. The characterization of LSOBz ligand is described
above.
118. Anal. Calcd for C20H30Cl2CuN2O10S: C, 38.44; H, 4.84; N,
4.48. Found: C, 38.28; H, 4.73; N, 4.40. IR: ∼3400 (weak, br),
1615, 1082 (strong), 981 (weak, br), 930 (weak), 767, 622 cm-1
.
X-ray-quality blue single crystals were grown in from a CH3OH/
CH2Cl2 solution layered with diethyl ether. An EPR spectrum of
[(LSOEP)CuII(CH3OH)(OClO3)2] reveals a typical tetragonal environ-
ment. X-band spectrometer (ν ) 9.191 GHz) in 2-methyltetrahy-
drofuran/MeCN (3:1) at 8 K: g| ) 2.27, A| ) 162 G; g ) 2.04
(see Supporting Information).
[(LSBz)CuII(H2O)(OClO3)]ClO4 (2b). LSBz (0.31 g, 1.03 mmol)
and CuII(ClO4)2‚6H2O (0.38 g, 1.02 mmol) were stirred in MeCN
(5 mL) at room temperature for 1 h. The complex was precipitated
as dark green solid on addition of diethyl ether into the reaction
mixture. The supernatant was decanted, and the resulting green
powder was washed two times with diethyl ether and dried under
Results and Discussion
vacuum. Yield: 0.53 g (0.927 mmol, 91%). UV-vis (MeCN; λmax
,
Ligand Design, Syntheses, and Other Systems. In the
CuM active site of PHM and DâH, a (His)2(Met)-Cu
tridentate coordination environment is present (Figure 1).
There previously has been considerable synthetic modeling
activity on the structural, spectroscopic, and redox properties
of mixed nitrogen-Sthioether ligands,7,38-57 including extensive
studies on polythioether-containing macrocycles studied by
nm; ꢀ, M-1 cm-1): 372, 3756; 615, 334. Anal. Calcd for C18H24-
Cl2CuN2O8S·1/2H2O: C, 37.80; H, 4.41; N, 4.90. Found: C, 37.72;
H, 4.75; N, 5.17. IR: ∼3400 (weak, br, OH), 1612, 1049 (strong,
ClO4-) cm-1. An EPR spectrum of [(LSBz)CuII(H2O)(OClO3)]+ (2b)
indicates a typical tetragonal copper environment. X-band spec-
trometer (ν ) 9.186 GHz) in 2-methyltetrahydrofuran/MeCN (1:
1) at 77 K: g| ) 2.23, A| )170 G; g ) 2.03 (see Supporting
Information).
(38) Tubbs, K. J.; Fuller, A. L.; Bennett, B.; Arif, A. M.; Berreau, L. M.
Inorg. Chem. 2003, 42 (16), 4790-4791.
(39) Tubbs, K. J.; Fuller, A. L.; Bennett, B.; Arif, A. M.; Makowska-
Grzyska, M. M.; Berreau, L. M. Dalton Trans. 2003 (15), 3111-
3116.
(40) Su, C. Y.; Liao, S.; Wanner, M.; Fiedler, J.; Zhang, C.; Kang, B. S.;
Kaim, W. Dalton Trans. 2003 (2), 189-202.
(41) Otsuka, M.; Hamasaki, A.; Kurosaki, H.; Goto, M. J. Organomet.
Chem. 2000, 611 (1-2), 577-585.
(42) Ambundo, E. A.; Deydier, M.-V.; Grall, A. J.; Aguera-Vega, N.;
Dressel, L. T.; Cooper, T. H.; Heeg, M. J.; Ochrymowycz, L. A.;
Rorabacher, D. B. Inorg. Chem. 1999, 38, 4233-4242.
(43) Casella, L.; Gullotti, M.; Radaelli, R.; Di Gennaro, P. J. Chem. Soc.,
Chem. Commun. 1991, 1611-1612.
(44) Chaka, G.; Ochrymowycz, L. A.; Rorabacher, D. B. Inorg. Chem.
2005, 44 (24), 9105-9111.
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Bushendorf, J. D.; Heeg, M. J.; Ochrymowycz, L. A.; Taschner, M.
J.; Rorabacher, D. B. Dalton Trans. 2003 (8), 1577-1586.
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Chem. 2002, 41 (16), 4304-4304.
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Chim. Acta 2001, 324 (1-2), 123-130.
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M. J. Chem. Soc., Dalton Trans. 2001, (23), 3498-3506.
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1332-1342.
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M. J.; Howard, T. A.; Salhi, C. A.; Goldie, S. N.; Ochrymowycz, L.
A.; Rorabacher, D. B. Inorg. Chem. 1995, 34 (1), 357-369.
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(53) Solomon, E. I.; Penfield, K. W.; Wilcox, D. E. ActiVe Sites in Copper
Proteins: An Electronic Structure OVerView; Springer-Verlag: Berlin,
1983; Vol. 53.
Hydrogen Peroxide Reactivity Study of LCuII Complexes.
[(LSEP)CuII(H2O)(OClO3)]+ (1b) plus H2O2: LSO2EP Formation.
[(LSEP)CuII(H2O)(OClO3)]ClO4‚H2O (30 mg, 0.0489 mmol) was
dissolved in methanol (5 mL). A blue solution changing to green
was observed upon addition of excess hydrogen peroxide (70 mg,
29.6%, 0.61 mmol) at room temperature. After the 14 h reaction
time, solvent was removed and the residual green material was
treated by NH4OH/CH2Cl2 for demetalation.36,37 The organic layer
was separated, washed by brine, dried over anhydrous MgSO4,
filtered, and concentrated under vacuum. The oil was purified by
column chromatography (Al2O3, 1:1 hexane-ethyl acetate, Rf )
0.66 for the sulfone ligand). Yield of LSO2EP ligand: 0.012 g (0.033
1
mmol, >68%). H NMR (CDCl3): δ 8.46 (dm, J ) 4.8, 1 Hz,
1H), 7.46 (dt, J ) 7.6, 1.6 Hz, 1H), ∼7.2 (m, 7H), ∼3.0 (m, 10H),
2.47 (dd, 1H), 2.31 (s, 3H), 1.29 (d, J ) 6.8 Hz, 3H). 13C NMR
(CDCl3): δ 160.0 (py), 149.4 (py), 138.3 (ph), 136.4 (py), 128.9
(ph), 128.6 (ph), 127.0 (ph), 123.5 (py), 121.4 (py), 58.8 (NCH2),
57.8 (NCH2), 55.8 (CH), 54.0 (SCH2), 42.4 (NCH3), 35.8 (pyCH2),
27.8 (CH2ph), 11.1 (CH3). CI-MS: m/z ) 347.2 (M + 1)+. IR:
SO (-SO2-) band shows up at 1051 cm-1
.
Stoichiometric Hydrogen Peroxide Reactions with [(LSEP)-
CuII(H2O)(OClO3)]+ (1b). [(LSEP)CuII(H2O)(OClO3)]ClO4‚H2O
(1b) (∼100 mg scale) was dissolved in 5 mL of MeOH. The green
solution turned to blue immediately upon the addition of either 1
or 2 equiv of H2O2 at RT (room temperature). Reactions were
stopped after 18 h (1 h gives the same yield), and the solvent was
removed. The metal ions were removed by treating the residual
material with NH4OH/CH2Cl2.36,37 The organic layer was washed
with brine solution and dried under MgSO4. The oil obtained was
(54) Nikles, D. E.; Powers, M. J.; Urbach, F. L. Inorg. Chem. 1983, 22
(22), 3210-3217.
10102 Inorganic Chemistry, Vol. 45, No. 25, 2006

Cu Complexes with Tridentate N2Sthioether Ligands
Scheme 1
Figure 2. Synthesis of the tridentate thioether ligands LSEP and LSBz. See
Experimental Section for further details.
CH3CN, C, Scheme 1), a product with dicopper Cu2O2 core
for R ) CH3.
Kodera and co-workers62 demonstrated the formation of
a copper hydroperoxo species via H2O2 reaction with a
copper(II) complex of an N3Sthioether tetradentate ligand (D,
Scheme 1, R ) C6H5). However, for an alkyl thioether ligand
(R ) CH3 or iso-C3H7), sulfoxide and sulfone organic
products were instead detected. In a somewhat related system
(with disulfide ligand), Ohta et al.63 showed that a hydro-
peroxocopper(II) complex could be generated by reacting
H2O2 with complex E (Scheme 1).
For our own ligand design (LSEP and LSBz), we chose to
synthetically input ethylphenyl and benzyl groups on the
thioether sulfur donor, with the thought that placement of a
potential substrate, i.e., the benzylic methylene group (with
C-H BDE ) 85 kcal/mol), may lead to attack by a copper/
O2 derived species, thus providing a model system in which
Cu(I)/O2 chemistry in the presence of a thioether ligand might
allow the study of C-H activation. As described below, this
did not turn out to occur and sulfur oxidation chemistry
instead ensued.
The thioether ligands LSEP and LSBz were synthesized from
the precursor thiol (Figure 2), which was previously reported
from this laboratory.5 Introduction of sodium metal to the
thiol ligand in tetrahydrofuran led to the generation of the
strong thiolate nucleophile; the target ligands were then
synthesized by the addition of (2-bromoethyl)benzene or
benzyl chloride, respectively (Figure 2).
Rorabacher, Ochrymowycz, and co-workers.7,44,45 However,
as stated in the Introduction, it has become of considerable
interest to investigate CuI/O2 and CuII/H2O2 chemistry of
N2Sthioether tridentate ligands, such as LSEP and LSBz (Chart
1).
An early system of interest was studied by Casella and
co-workers,58 showing that C-H activation chemistry with
O2 could occur even in the presence of thioether-containing
ligands. Using a xylyl-containing binucleating ligand (fol-
lowing our own previously studied xylyl systems with all
nitrogen ligands),36,59 aromatic hydroxylation indeed takes
place (A, Scheme 1); only 15-20% sulfoxidation of the
ligand was observed.58 Very recently, Tolman and co-
workers60 described copper(I)/O2 reactivity with an anionic
â-diketiminate N2S-Cu(I) complex (B, Scheme 1); the
thioether ligand donor appears to influence the thermody-
namics of O2-binding, but it does not affect the ultimate
mononuclear ligand-Cu-O2 and bis(µ-oxo)dicopper(III)
products, where in fact S-ligand binding to copper does not
occur. Another recent report from Zhou et al.61 revealed 20%
of a sulfoxidation product derived from the oxygenation
reaction of a N2Sthioether-copper(I) complex (R ) H, L )
Copper(I) Complexes: Sulfoxidation of Thioether
Ligands with CuI/O2 Chemistry. Ligand-copper(I) com-
plexes were synthesized from the addition of the thioether
ligand to [CuI(MeCN)4]ClO4,34,35 in acetonitrile under Ar at
1
room temperature. Elemental analysis and H NMR spec-
troscopy (Experimental Section) are consistent with the
formulations given, [(LSEP)CuI]+ (1a) or [(LSBz)CuI]+ (2a)
with perchlorate as counterion.
Neither copper(I) complex [(LSEP)CuI]+ (1a) nor [(LSBz)-
CuI]+ (2a) is reactive toward O2 at -80 °C (CH2Cl2) or -40
°C (MeCN), as monitored by UV-vis spectroscopy. To
obtain insights, the cyclic voltammetric behavior of 1a and
2a were measured in acetonitrile as solvent, and while the
compounds turned out to be the best behaved in this solvent,
irreversible oxidations peaks in the region +400-450 mV
(55) Ferris, N. S.; Woodruff, W. H.; Rorabacher, D. B.; Jones, T. E.;
Ochrymowycz, L. A. J. Am. Chem. Soc. 1978, 100 (18), 5939-5942.
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(57) Miskowski, V. M.; Thich, J. A.; Solomon, R.; Schugar, H. J. J. Am.
Chem. Soc. 1976, 98 (26), 8344-8350.
(58) Alzuet, G.; Casella, L.; Villa, M. L.; Carugo, O.; Gullotti, M. J. Chem.
Soc., Dalton Trans. 1997, 4789-4794.
(59) Pidcock, E.; Obias, H. V.; Zhang, C. X.; Karlin, K. D.; Solomon, E.
I. J. Am. Chem. Soc. 1998, 120, 7841-7847.
(60) Aboelella, N. W.; Gherman, B. F.; Hill, L. M. R.; York, J. T.; Holm,
N.; Young, V. G.; Cramer, C. J.; Tolman, W. B. J. Am. Chem. Soc.
2006, 128 (10), 3445-3458.
(62) Kodera, M.; Kita, T.; Miura, I.; Nakayama, N.; Kawata, T.; Kano,
K.; Hirota, S. J. Am. Chem. Soc. 2001, 123 (31), 7715-7716.
(63) Ohta, T.; Tachiyama, T.; Yoshizawa, K.; Yamabe, T.; Uchida, T.;
Kitagawa, T. Inorg. Chem. 2000, 39, 4358-4369.
(61) Zhou, L.; Powell, D.; Nicholas, K. M. Inorg. Chem. 2006, 45 (10),
3840-3842.
Inorganic Chemistry, Vol. 45, No. 25, 2006 10103

Lee et al.
Figure 4. Possible course of reaction for ligand sulfoxidation by CuI/O2
with LSEP
.
Figure 3. Synthesis of thioether ligand-copper(I) complexes and their
reactivity toward O2, producing sulfoxide products.
reducing equivalents necessary for reaction, formally allow-
ing oxygen atom transfer (OAT), leaving behind two
copper(II) ions and a oxide (or OH- or H2O) derived from
O2 (Figure 4). The expected yield of sulfoxide is thus 50%
maximum. We therefore conclude that some type of mo-
nooxygenase chemistry is occurring in the present system,
since our yields (vide supra) approach the range expected
and the labeling study does indicate an oxygen atom from
O2 is the source of the sulfoxide oxygen.
+/0
vs Fe(cp)2 were observed (see Supporting Information).
These characteristics, complexes with very positive oxidation
potentials, are not untypical for thioether-containing ligands
bound to copper ion.7,44,64 Tridentate N3 and tetradentate N4
ligand-copper(I) compounds, with more negative redox
potentials, are normally very reactive toward dioxygen at
reduced temperatures, giving rise to peroxo- and/or bis(µ-
oxo)dicopper species.65-69
As mentioned above, Casella showed that Cu-O2 chem-
istry can lead to ligand sulfoxidation but as a side product
in his xylyl-hydroxylating system.58 However, Itoh and co-
workers75 showed that copper-dioxygen derived binuclear
products convert exogenously added sulfide substrates to the
corresponding sulfoxides via an oxygen atom transfer (OAT)
mechanism. In our thioether system, the soft thioether ligand
donor apparently stabilizes the cuprous complex at low
temperatures where we would hope to monitor Cun/O2
complex formation, such as A (Figure 4). However, we never
observed a discrete CuIn/O2-derived species even above -80
°C and must conclude that there is no buildup of such an
intermediate; once formed, it reacts very rapidly with the
ligand thioether substrate.
Structure of a Copper(II) Complex with LSOEP. To
complement the [(LSEP)CuI]+ (1a) plus O2 reaction chemistry,
we separately added cupric perchlorate to isolated ligand
sulfoxide LSOEP and were able to crystallize the resulting
product [(LSOEP)CuII(CH3OH)(OClO3)2]. Its X-ray structure
(Figure 5) reveals the sulfoxide oxygen atom as one of the
equatorial ligands coordinated to the Cu(II) ion, Cu-O )
1.9407(12) Å. The sulfoxide S-O bond distance is 1.5418
Å; the latter is in accord with values known from the
literature.76 In S-O-coordinated metal complexes, average
S-O bond distances are 1.492 (free), 1.527 (O-bound,
including copper(II)), and 1.472 Å (S-bound; no example
with copper is known). Metal-Osulfoxide binding reduces the
SdO double bond character. The LSOEP pyridine and aliphatic
amine nitrogen atoms are the other equatorial ligands, along
with a methanol oxygen atom, giving rise to a near planar
However, following low-temperature oxygenation and
warming to room temperature, solutions of [(LSEP)CuI]+ (1a)
or [(LSBz)CuI]+ (2a) did slowly change color from yellow to
green. To determine if there was a ligand transformation,
reaction mixtures were treated with NH4OH/CH2Cl2 to
demetalate the complexes formed and allow for analysis of
the organics present (see Experimental Section).36,37 In both
cases, sulfoxide products were obtained in moderately good
yield (see further discussion below) (Figure 3). For the 1a/
O2 system, isotope labeling experiments were carried out; a
62% incorporation of labeled oxygen was observed in the
isolated LSOEP product (see Supporting Information). This
18O incorporation under theses experimental conditions is
modest, but clearly the sulfoxide oxygen is derived from
molecular oxygen.
It is very common in copper/dioxygen chemistry for
substrate oxygenation reactions (including the copper ligands
themselves) to follow a monooxygenase type reaction
stoichiometry, wherein one of the two atoms of molecular
oxygen is transferred from a copper-O2-derived intermediate
(e.g., a dicopper(II) peroxide or bis(µ-oxo)dicopper(III)
complex)67,70-74 where the two copper(I) ions supply the
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Dressel, L. T.; Cooper, T. H.; Heeg, M. J.; Ochrymowycz, L. A.;
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10104 Inorganic Chemistry, Vol. 45, No. 25, 2006

Cu Complexes with Tridentate N2Sthioether Ligands
Figure 6. Synthesis of Cu(II)-thioether complexes and their reactivity
with H2O2. Primary products with excess peroxide are the sulfone and
sulfoxide, for the LSEP and LSBz ligand complexes, respectively. See text
for more details.
Figure 5. X-ray crystal structure of [(LSOEP)CuII(CH3OH)(OClO3)2]. The
hydrogen atoms have been omitted for clarity.
Table 1. Selected Bond Distances and Angles of the Crystal Structure
of [(LSOEP)CuII(CH3OH)(OClO3)2]
atoms
dist (Å)
atoms
angle (deg)
Cu(1)-O(1)
Cu(1)-N(1)
Cu(1)-O(2)
Cu(1)-N(2)
S(1)-O(1)
Cu(1)-O(3)
Cu(1)-O(7)
1.9407(12)
1.9980(14)
2.0098(13)
2.0545(14)
1.5418(13)
2.4740(15)
2.4684(15)
O(1)-Cu(1)-N(1)
O(1)-Cu(1)-O(2)
N(1)-Cu(1)-O(2)
O(1)-Cu(1)-N(2)
N(1)-Cu(1)-N(2)
O(2)-Cu(1)-N(2)
173.99(5)
84.90(5)
89.29(6)
87.96(5)
97.86(6)
172.86(6)
arrangement. Two perchlorate anions coordinate weakly to
the copper(II) ion as axial ligands, Cu-Operchlorate ) 2.468
and 2.474 Å, making for overall copper coordination in a
distorted (axially elongated) octahedral geometry as expected
for the Jahn-Teller d9 cupric ion. Other selected bond
distances and angles are listed in Table 1. This complex
exhibits an infrared absorption 980 cm-1, assigned as an S-O
stretching vibration, in the range (862-997 cm-1) for
sulfoxide-O-metal complexes.76
Figure 7. Crystal structure of [(LSEP)CuII(H2O)(OClO3)](ClO4) (1b).
Hydrogen atoms are omitted for clarity.
Corresponding CuI/O2 Chemistry with LSBz. As men-
tioned in the Introduction, each tridentate thioether ligand
LSEP and LSBz has a potential internal substrate for C-H
oxidation/oxygenation chemistry, the ethylphenyl or benzyl
group. Such groups are susceptible to oxidation via CuI/O2
chemistry, as previously studied in all nitrogen-containing
ligand systems.37,73 However no carbon-based oxidation
chemistry was observed, either from ligand-Cu(I)/O2 or
ligand-Cu(II)/H2O2 chemistry, presumably because the
thioether sulfur atom is much more easily oxidized. We do
note that in comparing LSEP with LSBz CuI/O2 chemistry, the
former exhibits considerably enhanced sulfoxidation
(yields: LSOEP ) 43%, LSOBz ) 30%, Figure 3).
equatorial ligand, coordinated to copper ion with Cu-S )
2.3128(10) Å. The pyridine and aliphatic amine nitrogen
atoms are equatorial ligands, along with a water molecule
which is hydrogen bonded to an oxygen atom of a perchlorate
anion. The other perchlorate group is coordinate to the
copper(II) as a unidentate axial ligand. The overall coordina-
tion geometry can be described as a distorted square pyramid
(τ ) 0.206, where τ ) 0.00 for a perfect square pyramid
and τ ) 1.00 for a trigonal bipyramidal geometry).77 Other
selected bond distances and angles are listed in Table 2.
Hydrogen Peroxide Reactivity of the Copper(II) Thio-
ether Complexes. The UV-vis spectrum of [(LSEP)CuII-
(H2O)(OClO3)]ClO4‚H2O (1b) in MeCN solvent (Figure 8)
shows a peak at 365 nm (ꢀ ) 4285 M-1 cm-1) and a weak
d-d band at 625 nm (ꢀ ) 265 M-1 cm-1). The strong UV-
absorption can be assigned as a Sthioether-to-Cu(II) LMCT
band; thus, the thioether group in 1b (and 2b) also coordi-
nates to the copper(II) ion in solution (and probably not as
Thioether Copper(II) Complexes: Structure of [(LSEP)-
CuII(H2O)(OClO3)]ClO4‚H2O. Cu(II) complexes [(LSEP)-
CuII(H2O)(OClO3)]ClO4‚H2O (1b) and [(LSBz)CuII(H2O)-
(OClO3)]ClO4 (2b) were synthesized by the addition of
thioether ligand (LSEP or LSBz) to CuII(ClO4)2‚6H2O in CH2Cl2
at room temperature. Each complex was isolated as a dark
green solid (Figure 6). An X-ray crystal structure of 1b
(Figure 7) shows the thioether sulfur atom of LSEP as an
(77) Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.; Verschoor, G.
C. J. Chem. Soc., Dalton Trans. 1984, 1349-1356.
Inorganic Chemistry, Vol. 45, No. 25, 2006 10105

Lee et al.
Table 2. Selected Bond Distances and Angles of the Crystal Structure
of [(LSEP)CuII(H2O)(OClO3)](ClO4)
atoms
dist (Å)
atoms
angle (deg)
Cu(1)-O(1)
Cu(1)-N(1)
Cu(1)-N(2)
Cu(1)-S(1)
Cu(1)-O(2)
H(01)-O(7)
1.980(3)
1.981(3)
2.038(3)
2.3128(10)
2.332(3)
1.945
O(1)-Cu(1)-N(1)
O(1)-Cu(1)-N(2)
N(1)-Cu(1)-N(2)
O(1)-Cu(1)-S(1)
N(1)-Cu(1)-S(1)
N(2)-Cu(1)-S(1)
O(1)-Cu(1)-O(2)
N(1)-Cu(1)-O(2)
N(2)-Cu(1)-O(2)
S(1)-Cu(1)-O(2)
88.27(12)
177.21(14)
91.43(12)
90.34(9)
164.83(9)
89.21(9)
86.11(13)
93.40(12)
96.67(14)
101.58(8)
Figure 8. UV-vis spectra of [(LSEP)CuII(H2O)(OClO3)]ClO4‚H2O in
MeCN. Inset: 365 nm band decrease while the temperature is increased
from -40 °C to RT after addition of H2O2.
an axial ligand, since the observed absorptivity is quite
large).46,47,50-57,62 Addition of H2O2 (5 equiv) to a solution
of 1b in MeCN at -40 °C does not result in any reaction
(as judged by observing no change in the UV-vis spectrum;
see Supporting Information), but warming to RT causes the
365 nm absorption to disappear (Figure 8, inset), suggesting
the interaction or reaction affects the Cu(II)-thioether
coordination. In fact, sulfone (RS(O)2R′) and/or sulfoxide
(RS(O)R′) formation takes place (Figure 6), as described
below.
On a synthetic scale, addition of excess hydrogen peroxide
(10 equiv) to [(LSEP)CuII(H2O)(OClO3)]ClO4‚H2O (1b), fol-
lowed by workup and spectroscopic analysis in a manner
similar to that carried out in the 1a (and 2a)/O2 chemistry
(vide supra), showed that the ligand LSEP was mostly
converted to the corresponding sulfone; only the sulfone
compound LSO2EP (Figure 6) was isolated and a trace of
sulfoxide was detected. By contrast, the (LSBz)CuII complex
2b showed only ligand sulfoxidation under the same reaction
conditions (Figure 6). We already mentioned (vide supra)
Kodera’s observation of alkyl thioether ligand sulfoxidation
(D, Scheme 1).62 Other groups have recently observed that
certain copper(II) complexes can catalytically oxidize added
sulfide substrates to corresponding sulfoxides in the presence
of hydrogen peroxide.78,79
Figure 9. Proposed course of the hydrogen peroxide reactions to give
sulfone product, via the initially formed copper(II)-sulfoxide complex.
Metal assistance via CuII-OOH intermediates is suggested. See text.
+ H2O2 gives the sulfoxide (100% yield). But, without
copper ion present, even excess H2O2 plus LSEP does not yield
any sulfone. Thus, it seems likely that sulfone formation
proceeds by H2O2 reaction with the copper(II)-sulfoxide.
This may occur by Cu(II)-OOH formation on the metal-
sulfoxide moiety (i.e., such as that found in the X-ray
structure of [(LSOEP)CuII(CH3OH)(OClO3)2] (Figure 5)), or
it could simply proceed by nucleophilic attack of hydrogen
peroxide on the sulfoxide ligand,80,81 with Lewis acid
activation by the cupric ion, Figure 9.
While the (LSEP)CuII complex (1b) reacts with excess H2O2
to give only sulfone, an interesting contrast is that the (LSBz)-
CuII complex (2b) produces only a sulfoxide ligand product
(Figure 6). At this time, we do not understand if this variation
in reactivity is due to a steric or perhaps an electronic effect
of the benzyl versus ethylphenyl group on the thioether
sulfur.
To try to clarify whether the sulfone forms via the
sulfoxide, the reactivity of [(LSEP)CuII(H2O)(OClO3)]ClO4‚
H2O (1b) with various amounts of hydrogen peroxide was
studied. A blue solution of 1b in MeOH turned to green
immediately upon the addition of either 1 or 2 equiv of H2O2.
Separation from the metal ion and analysis of the mixture
by column chromatography and NMR spectroscopy showed
that the products included LSEP, LSOEP, and LSO2EP. With 1
equiv of H2O2, the yields determined were 34.5 mol % LSEP
48.7 mol % LSOEP, and 16.8 mol % LSO2EP, while 2 equiv of
H2O2 reaction gave 19.9 mol % LSEP, 40.6 mol % LSOEP
,
,
Summary/Conclusions
and 39.5 mol % LSO2EP. The results suggest that the sulfoxide
forms first, by either direct attack H2O2 on the thioether or
via metal-assisted chemistry such as formation of a cop-
per(II)-OOH species, which attacks the nearby thioether in
an intramolecular fashion (Figure 9). The former explanation
may be sufficient, since without any metal ion present, LSEP
The chemistry of the copper complexes with tridentate N2S
ligands, LSEP and LSBz, has been described. Under mild
conditions, ligand sulfoxidation is observed in the reactions
of ligand-CuI complexes with dioxygen. The yield of
sulfoxide products are suggestive of an overall copper
monoooxygenase stoichiometry. No copper-dioxygen in-
(78) Velusamy, S.; Kumar, A. V.; Saini, R.; Punniyamurthy, T. Tetrahedron
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Jitsukawa, K.; Nagatomo, S.; Kitagawa, T.; Masuda, H. Chem.
Commun. 2003, (21), 2700-2701.
(80) Adam, W.; Haas, W.; Lohray, B. B. J. Am. Chem. Soc. 1991, 113,
6202-6208.
(81) Adam, W.; Durr, H.; Haas, W.; Lohray, B. Angew. Chem., Int. Ed.
1986, 25 (1), 101-103.
10106 Inorganic Chemistry, Vol. 45, No. 25, 2006

Cu Complexes with Tridentate N2Sthioether Ligands
termediate or low-temperature stabilized species could be
detected (by UV-vis spectroscopy), suggesting that if one
forms, it very rapidly reacts with the internal sulfur-based
substrate. A structure was obtained for a copper(II) complex
of a separately isolated sulfoxide ligand LSOEP; this exhibits
sulfoxide oxygen coordination. X-ray crystallography of the
cupric thioether complex [(LSEP)CuII(H2O)(OClO3)](ClO4)
(1b) and UV-visible spectroscopy on solutions show that
the thioether sulfur atom coordinates to the cupric ion in
both phases. Reactions of 1b with H2O2 gives both sulfoxide
and sulfone product mixtures; most likely the sulfoxide is
formed first, while cupric binding to this facilitates nucleo-
philic attack by hydrogen peroxide to give the sulfone. No
C-H bond oxidation of the benzyl or ethylphenyl group on
sulfur is observed in any ligand-Cu(I)/O2 or ligand-Cu(II)/
H2O2 reactions, presumably due to the much more facile
sulfur oxygenation chemistry.
biological events (see Introduction). As for the active-site
chemistry in PHM or DâH, if anything, this work just leads
to even more questions about the true role of the Met
thioether ligand and how Nature prevents its irreversible
oxidation to sulfoxide or sulfone, as observed here.
Acknowledgment. K.D.K. is grateful to the National
Institutes of Health (Grant GM 28962) for support of this
research. D.-H.L. is grateful to Chonbuk National University
for support.
Supporting Information Available: Crystallographic informa-
tion files (CIF) for [(LSOEP)CuII(CH3OH)(OClO3)2] and 1b, cyclic
voltammograms of 1a and 2a, mass spectra following 18O2 reaction
of 1a, EPR spectra of 1b, 2b, and [(LSOEP)CuII(CH3OH)(OClO3)2],
and UV-vis spectra for H2O2 reaction with 1b. This material is
available free of charge via the Internet at http://pubs.acs.org.
Clearly, copper ion can facilitate sulfoxide formation with
either O2 or H2O2, which may be relevant to various
IC060730T
Inorganic Chemistry, Vol. 45, No. 25, 2006 10107