Copper(I) complex O2-reactivity with a N3S thioether ligand: A copper-dioxygen adduct including sulfur ligation, ligand oxygenation, and comparisons with all nitrogen ligand analogues

Article abstract of DOI:10.1021/ic700541k

In order to contribute to an understanding of the effects of thioether sulfur ligation in copper-O₂ reactivity, the tetradentate ligands L^N3S (2-ethylthio-N,N-bis(pyridin-2-yl)methylethanamine) and L ^N3S′ (2-ethylthio-N,N-bis(pyridin-2-yl)ethylethanamine) have been synthesized. Corresponding copper(I) complexes, [Cu^I(L ^N3S)]CIO₄ (1-CIO₄), [Cu^I-(L ^N3S)]B(C₆F₅)₄ (1-B(C ₆F₅)4), and [Cu^I(L^N3S′)] CIO₄ (2), were generated, and their redox properties, CO binding, and O₂-reactivity were compared to the situation with analogous compounds having all nitrogen donor ligands, [Cu^I-(TMPA)(MeCN)] ⁺ and [Cu^I(PMAP)]⁺ (TMPA = tris(2- pyridylmethyl)amine; PMAP = bis[2-(2-pyridyl)ethyl]-(2-pyridyl)-methylamine). X-ray structures of 1-B(C₆F₅)₄, a dimer, and copper(II) complex [Cu^II(L^N3S)(MeOH)](CIO ₄)₂ (3) were obtained; the latter possesses axial thioether coordination. At low temperature in CH₂CI₂, acetone, or 2-methyltetrahydrofuran (MeTHF), 1 reacts with O₂ and generates an adduct formulated as an end-on peroxodicopper-(II) complex [{CU^II(L^N3S)}₂(μ-1,2-O₂ ^2-)]²⁺ (4)){λ_max = 530 (ε ≈ 9200 M^-1 cm^-1) and 605 nm (ε ≈ 11 800 M^-1 cm^-1)}; the number and relative intensity of LMCT UV-vis bands vary from those for [{Cu^II(TMPA)}₂(O₂ ^2-)]²⁺ {λ_max = 524 nm (ε = 11 300 M^-1 cm^-1)} and 615 nm (ε = 5800 M^-1 cm^-1)} and are ascribed to electronic structure variation due to coordination geometry changes with the L^N3S ligand. Resonance Raman spectroscopy confirms the end-on peroxo-formulation {ν_(O-O) = 817 cm^-1 (^16-18O₂ Δ = 46 cm^-1) and ν_(Cu-O) = 545 cm^-1 (^16-18O₂ Δ = 26 cm^-1); these values are lower in energy than those for [{Cu^II(TMPA)}₂(O₂^2-)]²⁺ {μ(Cu-O) = 561 cm^-1 and Δ(O-O) = 827 cm^-1} and can be attributed to less electron density donation from the peroxide π* orbitals to the Cu(II) ion. Complex 4 is the first copper-dioxygen adduct with thioether ligation; direct evidence comes from EXAFS spectroscopy {Cu K-edge; Cu-S = 2.4 A}. Following a [Cu^I(L ^N3S)]⁺/O₂ reaction and warming, the L ^N3S thioether ligand is oxidized to the sulfoxide in a reaction modeling copper monooxygenase activity. By contrast, 2 is unreactive toward dioxygen probably due to its significantly increased Cu^II/Cu ^I redox potential, an effect of ligand chelate ring size (in comparison to 1). Discussion of the relevance of the chemistry to copper enzyme O₂-activation, and situations of biological stress involving methionine oxidation, is provided.

Full text of DOI:10.1021/ic700541k

Inorg. Chem. 2007, 46, 6056−6068
Copper(I) Complex O2-Reactivity with a N3S Thioether Ligand: a
Copper Dioxygen Adduct Including Sulfur Ligation, Ligand
−
Oxygenation, and Comparisons with All Nitrogen Ligand Analogues
Dong-Heon Lee,†,‡ Lanying Q. Hatcher,† Michael A. Vance,§ Ritimukta Sarangi,§ Ashley E. Milligan,§
|
Amy A. Narducci Sarjeant,† Christopher D. Incarvito,£ Arnold L. Rheingold,£, Keith O. Hodgson,§
Britt Hedman,§ Edward I. Solomon,§ and Kenneth D. Karlin*,†
Department of Chemistry, The Johns Hopkins UniVersity, Baltimore, Maryland 21218, Department
of Chemistry, Chonbuk National UniVersity, Jeonju, Korea, 561-756, Department of Chemistry,
Stanford UniVersity, Stanford, California 94305, Department of Chemistry, UniVersity of
Delaware, Newark, Delaware 19716
Received March 21, 2007
In order to contribute to an understanding of the effects of thioether sulfur ligation in copper−O2 reactivity, the
tetradentate ligands LN3S (2-ethylthio-N,N-bis(pyridin-2-yl)methylethanamine) and LN3S′(2-ethylthio-N,N-bis(pyridin-
2-yl)ethylethanamine) have been synthesized. Corresponding copper(I) complexes, [CuI(LN3S)]ClO4 (1-ClO4), [CuI-
(LN3S)]B(C6F5)4 (1-B(C6F5)4), and [CuI(LN3S′)]ClO4 (2), were generated, and their redox properties, CO binding, and
O2-reactivity were compared to the situation with analogous compounds having all nitrogen donor ligands, [CuI-
(TMPA)(MeCN)]+ and [CuI(PMAP)]+ (TMPA
) tris(2-pyridylmethyl)amine; PMAP ) bis[2-(2-pyridyl)ethyl]-(2-pyridyl)-
methylamine). X-ray structures of 1-B(C6F5)4, a dimer, and copper(II) complex [CuII(LN3S)(MeOH)](ClO4)2 (3) were
obtained; the latter possesses axial thioether coordination. At low temperature in CH2Cl2, acetone, or
2-methyltetrahydrofuran (MeTHF), 1 reacts with O2 and generates an adduct formulated as an end-on peroxodicopper-
2
+
1
1
(II) complex [
{
CuII(LN3S
)}
(
2 µ-1,2-O2 -)]2 (4)){λmax
)
530 (ꢀ ≈ 9200 M- cm-1) and 605 nm (ꢀ ≈ 11 800 M-
1
2
+
cm-
)
}
; the number and relative intensity of LMCT UV
−
vis bands vary from those for [
{
CuII(TMPA)
}
2(O2 -)]2
1
1
1
{λmax
)
524 nm (ꢀ ) 11 300 M- cm-1) and 615 nm (ꢀ ) 5800 M- cm-
)}
and are ascribed to electronic
structure variation due to coordination geometry changes with the LN3S ligand. Resonance Raman spectroscopy
1
16-
1
confirms the end-on peroxo-formulation {ν(O
)
817 cm-
(
18O2 ∆ ) 46 cm-1) and ν(Cu
)
−
545 cm-
-O)
-O)
16
-
2
(
18O2 ∆ ) 26 cm-1); these values are lower in energy than those for [
{
CuII(TMPA)
}
2(O2 -)]2+ {ν(Cu
O) 561
)
cm- and
orbitals to the Cu(II) ion. Complex 4 is the first copper
comes from EXAFS spectroscopy Cu K-edge; Cu
ν
(O
−O)
)
827 cm-
}
and can be attributed to less electron density donation from the peroxide
dioxygen adduct with thioether ligation; direct evidence
2.4 Å
. Following a [CuI(LN3S)]+/O2 reaction and warming,
π*
1
1
−
{
−S
)
}
the LN3S thioether ligand is oxidized to the sulfoxide in a reaction modeling copper monooxygenase activity. By
contrast, 2 is unreactive toward dioxygen probably due to its significantly increased CuII/CuI redox potential, an
effect of ligand chelate ring size (in comparison to 1). Discussion of the relevance of the chemistry to copper
enzyme O2-activation, and situations of biological stress involving methionine oxidation, is provided.
Introduction
involved in copper-protein O2 binding/activation and for
ultimately designing better/more specific or “green” practical
reagents or catalysts for substrate oxidations. A great deal
of knowledge has been obtained from (low-temperature)
dioxygen reactivity studies of copper(I) complexes, and a
number of spectroscopic/structural Cun-O2(H) and reactivity
types are now well established.1-4 The first crystallographi-
The reactivity of copper(I) ion and molecular oxygen is
of considerable interest for insights into intermediates
* To whom correspondence should be addressed. E-mail: karlin@jhu.edu.
† The Johns Hopkins University.
‡ Chonbuk National University.
§ Stanford University.
£ University of Delaware.
| Current address: Department of Chemistry and Biochemistry, University
of California, San Diego, La Jolla, CA 92093-0332.
(1) Itoh, S. Curr. Opin. Chem. Biol. 2006, 10, 115-122.
6056 Inorganic Chemistry, Vol. 46, No. 15, 2007
10.1021/ic700541k CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

Tetradentate N3S Ligands for Copper-O2 ReactiWity
enzymological studies7,14 have led to suggestions that a
copper dioxygen adduct (a CuII-O2- superoxide species) is
the likely active site species effecting substrate hydrogen-
atom abstraction, as in the mechanism outlined in Figure
1.7,11,13,15 In fact, a recent protein X-ray structure9 revealed
a superoxide-copper moiety at the CuM site when in the
presence of a bound substrate analogue (an inhibitor); this
entity perhaps closely resembles the enzyme’s catalytically
active species. However, there are other computational
investigations suggesting a ‘cupryl’ (CuIIIdO, CuII-O•, or
[CuO]2+)16 H-atom abstracting agent (following O-O cleav-
age).17,18
The uncommon presence of a methionine ligand clearly
plays a key role in tuning the dioxygen chemistry and
effecting C-H hydroxylation. Yet the precise role and
influence of thioether coordination on copper-dioxygen
binding and chemistry12,13,15 remains a subject of continuing
interest. Why is the presence of a methionine (Met) so
important to the coordination and/or electronic structure in
this situation of oxidative reactivity, especially as copper ion
can readily mediate the irreversible oxidation of organic
sulfides to sulfoxides (or sulfones)?19-21 Copper-dioxygen
reactivity studies in cases with concurrent copper-sulfur
coordination are uncommon in comparison to the extensive
literature on CunO2 adducts with all nitrogen donors.1-4
Certainly, spectroscopic, coordination, or redox studies on
copper complexes with thioether ligands have been carried
out. Rorabacher, Ochrymowycz, and co-workers22-24 have
carried out extensive coordination chemistry and redox
studies with copper(I/II) thioether containing macrocycles.
Other selected ligand examples are shown in Figure 2. Ligand
A was utilized in conjunction with a bypyridine ligand to
synthesize a copper(II) complex that structurally models the
oxidized form of the CuM active sites of DâH and PHM with
its axial Cu-thioether coordination.25 The Met-derived
thioether and amine containing ligand B (Figure 2) was
Figure 1. PHM active site and proposed mechanism of monooxygenase
activity.
cally characterized dicopper-peroxide adduct came from
early studies in our laboratory with the tetradentate amine
ligand TMPA (tris(2-pyridyl)methylamine) (see below).5,6 To
date, most ligands utilized for CuI/O2 reactivity studies are
various forms of bi-, tri-, and tetradentate amine ligands,
including alkyl, pyridyl, secondary, and tertiary amine
donors, with each ligand feature in some way modulating
the O2 reactivity and subsequent Cu-dioxygen structure.1-4
However, other heteroatom ligand donors besides nitrogen
can also coordinate to copper with the result being effective
copper complex dioxygen activation/O-atom insertion reac-
tions. Key biological examples occur at the active sites of
dopamine â-hydroxylase (DâH) and peptidyl glycine R-hy-
droxylating monooxygenase (PHM), two enzymes involved
in neurotransmitter biosynthesis/hormone regulation.7 The
two enzymes possess a high degree of sequence homology,
each containing two functionally related but physically
separated mononuclear copper centers. (X-ray structural
information is available for PHM.8-10) CuM (also referred
to as CuB), ligated by two histidines and a methionine residue,
is the O2 binding site forming a substrate H-atom abstracting
active species. The other copper active site, CuH (also referred
to as CuA), lies ∼11 Å away; it is ligated by three histidine
residues and is the source of the second reducing electron
required for the monooxygenase activity (Figure 1).
(14) Evans, J. P.; Ahn, K.; Klinman, J. P. J. Biol. Chem. 2003, 278, 49691-
49698.
Theoretical/computational analyses profiling CuII-OOR
(i.e., peroxide) reactivity11-13 and separate mechanistic
(15) Chen, P.; Solomon, E. I. Proc. Nat. Acad. Sci., U.S.A. 2004, 101,
13105-13110.
(16) Decker, A.; Solomon, E. I. Curr. Opin. Chem. Biol. 2005, 9, 152-
163.
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683.
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Karlin, K. D. J. Am. Chem. Soc. 1993, 115, 2677-2689.
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Chem. Soc. 1988, 110, 3690-3692.
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Jacobson, R. R.; Blackburn, N. J.; Strange, R. W.; Zubieta, J. J. Am.
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S.; Fukuzumi, S. J. Am. Chem. Soc. 2002, 124, 6367-6377.
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Jitsukawa, K.; Nagatomo, S.; Kitagawa, T.; Masuda, H. Chem. Comm.
2003, 2700-2701.
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Dressel, L. T.; Cooper, T. H.; Heeg, M. J.; Ochrymowycz, L. A.;
Rorabacher, D. B. Inorg. Chem. 1999, 38, 4233-4242.
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Bushendorf, J. D.; Heeg, M. J.; Ochrymowycz, L. A.; Taschner, M.
J.; Rorabacher, D. B. Dalton Trans. 2003, 1577-1586.
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(25) Santra, B. K.; Reddy, P. A. N.; Nethaji, M.; Chakravarty, A. R. Inorg.
Chem. 2002, 41, 1328-1332.
(7) Klinman, J. P. J. Biol. Chem. 2006, 281, 3013-3016.
(8) Prigge, S. T.; Kolhekar, A.; Eipper, B. A.; Mains, R. E.; Amzel, M.
Science 1997, 278, 1300-1305.
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Life Sci. 2000, 57, 1236-1259.
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10177-10193.
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43, 5735-5747.
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Inorganic Chemistry, Vol. 46, No. 15, 2007 6057

Lee et al.
Figure 3. Tetradentate ligands for copper ion and chemistry discussed
herein.
(C6F5)4 (1-B(C6F5)4), and [CuI(LN3S′)]ClO4 (2) (LN3S
)
2-ethylthio-N,N-bis(pyridin-2-yl)methylethanamine and LN3S′
) 2-ethylthio-N,N-bis(pyridin-2-yl)ethylethanamine, Figure
3). By directly comparing them to analogous and well-studied
systems, [CuI(TMPA)(MeCN)]+ and [CuI(PMAP)(MeCN)]+
(see Figure 3),5,33,34 we seek to gain a better understanding
of the role a thioether donor plays in the CuI redox properties
and O2-chemistry. The only difference between LN3S and
LN3S′ is the alkyl spacer between the central amine and the
pyridyl arms, which increases the copper chelate-rings size
from five to six. We show that the thioether donor in LN3S
raises the redox potential of the CuI complex relative to
analogues with only nitrogen donors, yet is still reactive
toward O2 at low temperature and forms an “end-on” µ-1,2-
peroxodicopper(II) species with a new UV-vis absorption
pattern. Furthermore, the room-temperature oxygenation of
[CuI(LN3S)]+ (1) behaves as a monooxygenase model system
as the ligand becomes oxygenated in ca. 50% yield. By
contrast, as expected from the observations of Reglier,28 the
“long armed” complex, 2, is unreactive toward O2. A
preliminary report on some aspects of the work has ap-
peared.35
Figure 2. Selected thioether/disulfide ligands previously used for copper
ligation and reactivity. See text.
synthesized by Casella and co-workers,26,27 and they dem-
onstrated that CuI2/O2 reactivity studies still allowed mo-
nooxygenase type chemistry, i.e., m-xylyl ligand hydroxy-
lation; a minor fraction of the ligand was oxidized to the
sulfoxide, attributable to the occurrence of a secondary
process resulting from reaction of H2O2 and CuII. Reglier
and co-workers28 also observed ligand sulfoxidation from
the reaction of a CuII complex with ligand C (Figure 2) with
H2O2. However, no dioxygen intermediates were observed
for the reaction of the CuI complex of the same ligand even
at low temperature. Copper-hydroperoxo species generated
from the reaction of H2O2 and copper(II) complexes (with
ligands having a thioether sulfur coordination (ligands D and
E, Figure 2) have been characterized in a few instances.29,30
Recently, Tolman and co-workers31 reported CuI/O2 chem-
istry with ligand F; however, they observed that the
thioether-S donor does not coordinate to copper in O2-adduct
products which form. Also, the group of Nicholas32 employed
a new imidazolyl N2S-type ligand G; unfortunately, there
was no copper(I)-dioxygen reactivity.
Experimental Section
General Considerations and Instrumentation. Resonance
Raman (rR) data were collected using a Princeton Instruments ST-
135 back-illuminated CCD detector on a Spex 1877 CP triple
monochromator with 1200, 1800, and 2400 grooves/mm holo-
graphic spectrograph gratings. Excitation was provided by Coherent
I90C-K Kr+ and Innova Sabre 25/7 Ar+ CW ion lasers. The spectral
resolution was <2 cm-1. Sample concentrations were ∼1 mM in
Cu2O2. Samples were run at 77 K in a liquid N2 finger Dewar
(Wilmad) and were hand spun to minimize sample decomposition
during scan collection. Isotopic substitution was achieved by
oxygenating with 18O2 (Icon, Summit, NJ). Elemental analyses were
performed by Desert Analytics, Tucson, AZ. Mass Spectrometry
was conducted at the mass spectrometry (MS) facility at either The
In an effort to extend copper-dioxygen reactivity to
copper(I) complexes of thioether-amine ligands, we hereby
describe the CuII/I redox properties and dioxygen reactivity
of the complexes [CuI(LN3S)]ClO4 (1-ClO4), [CuI(LN3S)]B-
(26) Casella, L.; Gullotti, M.; Bartosek, M.; Pallanza, G.; Laurenti, E. J.
Chem. Soc. Chem. Commun. 1991, 1235-1237.
(27) Alzuet, G.; Casella, L.; Villa, M. L.; Carugo, O.; Gullotti, M. J. Chem.
Soc. Dalton Trans. 1997, 4789-4794.
(28) Champloy, F.; Benali-Cherif, N.; Bruno, P.; Blain, I.; Pierrot, M.;
Reglier, M.; Michalowicz, A. Inorg. Chem. 1998, 37, 3910-3918.
(29) Ohta, T.; Tachiyama, T.; Yoshizawa, K.; Yamabe, T.; Uchida, T.;
Kitagawa, T. Inorg. Chem. 2000, 39, 4358-4369.
(33) Schatz, M.; Becker, M.; Thaler, F.; Hampel, F.; Schindler, S.; Jacobson,
R. R.; Tyekla´r, Z.; Murthy, N. N.; Ghosh, P.; Chen, Q.; Zubieta, J.;
Karlin, K. D. Inorg. Chem. 2001, 40, 2312-2322.
(34) Zhang, C. X.; Kaderli, S.; Costas, M.; Kim, E.-i.; Neuhold, Y.-M.;
Karlin, K. D.; Zuberbu¨hler, A. D. Inorg. Chem. 2003, 42, 1807-1824.
(35) Hatcher, L. Q.; Lee, D. H.; Vance, M. A.; Milligan, A. E.; Sarangi,
R.; Hodgson, K. O.; Hedman, B.; Solomon, E. I.; Karlin, K. D. Inorg.
Chem. 2006, 45, 10055-10057.
(30) Kodera, M.; Kita, T.; Miura, I.; Nakayama, N.; Kawata, T.; Kano,
K.; Hirota, S. J. Am. Chem. Soc. 2001, 123, 7715-7716.
(31) 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, 3445-3458.
(32) Zhou, L.; Powell, D.; Nicholas, K. M. Inorg. Chem. 2006, 45, 3840-
3842.
6058 Inorganic Chemistry, Vol. 46, No. 15, 2007

Tetradentate N3S Ligands for Copper-O2 ReactiWity
Johns Hopkins University or at The Ohio State University. CI
spectra were acquired at the Johns Hopkins University MS facility
using a VG70S double focusing magnetic sector mass spectrometer
(VG Analytical, Manchester, UK, now Micromass/Waters) equipped
with a Xe gas FAB gun (7.5 kV at 1 mA) and an off-axis electron
multiplier. Samples were introduced into the CI source (block
temperature ) 200 °C) using a heated direct insertion probe using
a deep quartz cup, at a rate of 0.5 °C/s. Methane reagent gas was
used with an electron energy of 70 eV. High-boiling perfluoro-
kerosene was used as the reference mass for accurate mass analyses.
For accurate mass analyses, the matrix contained 10% PEG mass
calibrant. Data was acquired using a MSS Data system (MasCom,
Bremen, Germany) for subsequent processing. High-resolution
electrospray ionization (ESI) mass spectrometry analyses were
performed at the Ohio State University (MS) facility with a 3-T
Finnigan FTMS-2000 Fourier transform mass spectrometer. Samples
were sprayed from a commercial Analytical electrospray ionization
source and then focused into the FTMS cell using a home-built set
of ion optics. X-ray diffraction was performed at the X-ray
diffraction facility either at the Johns Hopkins University or the
University of Delaware. The X-ray absorption spectrum of {[(LN3S)-
CuII}2(µ-1,2-O22-)]2+ (4) was carried out as previously described.35
1H NMR and 13C NMR spectra were measured on a Varian 400
MHz spectrometer and chemical shifts are reported in ppm (δ)
downfield from an internal TMS reference. Infrared spectra of
carbonyl adducts (as a solution in CH2Cl2) were recorded on a
Mattson Instruments 4030 Galaxy Series FT-IR spectrometer using
a solution IR cell. Low-temperature UV-vis spectra were taken
either with a Hewlett-Packard model 8453 diode-array spectropho-
tometer equipped with a custom-made quartz Dewar filled with
cold (-78 °C) methanol (maintained and controlled by a Neslab
ULT-95 low-temperature circulator), or using a -78 °C methanol
bath (CC-100 immersion cooler and Agitainor, Neslab) and taking
measurements with a Cary 50 Bio spectrophotometer equipped with
a fiber optic coupler (Varian) and a fiber optic dip probe (Hellma:
661.302-QX-UV-2mm-for-low-temperature). Air-sensitive solutions
were prepared in a nitrogen atmosphere in a glove box (MBraun)
and carried out in Schlenk 2 mm cuvettes (Quark) or custom-made
Schlenk tubes designed for the dip probe (Chemglass: JHU-0407-
271MS). rR spectroscopy measurements were undertaken on a
Princeton Instruments ST-135 back-illuminated CCD detector on
a Spex 1877 CP triple monochromator with 1200, 1800, and 2400
grooves/mm holographic spectrograph gratings. Excitation was
provided by a Coherent I90C-K Kr+ ion laser (λex ) 620). The
spectral resolution was <2 cm-1. Sample concentrations were ∼3
mM in Cu2O2. Samples were run at 77 K in a liquid N2 finger
Dewar (Wilmad) and were hand spun to minimize sample decom-
position during scan collection. Isotopic substitution was achieved
by oxygenating with 18O2 (Icon). X-Band EPR spectra were
recorded on a Bruker EMX CW-EPR spectrometer. The cavity was
maintained at ∼4 K with the use of a He cryostat. Cyclic
voltammetry measurements were undertaken in freshly distilled
acetonitrile with a BAS 100B electrochemical analyzer with a glassy
carbon working electrode and a platinum wire auxiliary electrode.
Potentials were recorded versus a Ag/AgNO3 electrode. The
3 GeV and 80-100 mA. A Si(220) double crystal monochromator
was used for energy selection. A Rh-coated harmonic rejection
mirror and a cylindrical Rh-coated bent focusing mirror were used
for beam line 9-3 to reject components of higher harmonics. A
2-MeTHF solution of 4 was loaded into a lucite XAS cell with a
precooled syringe. The temperature of the solution was maintained
below -120 °C during this process. The sample was immediately
frozen thereafter and stored under liquid N2. During data collection,
it was maintained at a constant temperature of 10 K using an Oxford
Instruments CF 1208 liquid helium cryostat. Fluorescence mode
was used to measure data to k ) 13.4 Å-1 employing a Canberra
Ge 30-element solid array detector. Internal energy calibration was
accomplished by simultaneous measurement of the absorption of a
Cu foil placed between two ionization chambers situated after the
sample.36 The first inflection point of the foil spectrum was assigned
to 8980.3 eV. Data represented here are an eight-scan (4) and six-
scan (temperature induced decay product of 4) average spectrum,
which was processed by fitting a second-order polynomial to the
pre-edge region and subtracting this from the entire spectrum as
background. A three-region spline of orders 2, 3, and 3 was used
to model the smoothly decaying post-edge region. The data were
normalized by subtracting the cubic spline and by assigning the
edge jump to 1.0 at 9000 eV using the PySpline program.37
Theoretical EXAFS signals ø(k) were calculated using FEFF
(version 7.0)38,39 and fit to the data using EXAFSPAK.40 The
structural parameters varied during the fitting process were the bond
distance (R) and the bond variance σ2, which is related to the
Debye-Waller factor resulting from thermal motion, and static
disorder. The nonstructural parameter E0 (the energy at which k )
0) was also allowed to vary but was restricted to a common value
for every component in a given fit. Coordination numbers were
systematically varied in the course of the fit but were fixed within
a given fit.
Synthesis of Ligands and Copper Complexes. Reagents and
solvents used were of commercially available reagent quality unless
otherwise stated. Methylene chloride, methanol, and diethyl ether
were purified/dried by passing through a double alumina column
solvent purification system by Innovative Technologies, Inc.
Methanol was also distilled from Mg turnings. Acetone was distilled
from Drierite under argon. [CuI(CH3CN)4]ClO4 was synthesized
according to previously published procedures.41,42 Air-sensitive
compounds were synthesized and handled under an argon atmo-
sphere using standard Schlenk techniques and stored in an MBraun
drybox filled with N2. Deoxygenation of solvents was achieved
either by bubbling argon through the solution for 30-45 min or
by three freeze-pump-thaw cycles.
2-Ethylthio-N,N-bis(pyridin-2-yl)methylethanamine (LN3S).
These ligands have in fact been previously reported22 and also
described in our preliminary communication.34
2-Ethylthio-N,N-bis(pyridin-2-yl)ethylethanamine (LN3S′). LN3S′
was synthesized according to the method of Ambundo, et al.22 N,N-
(36) DuBois, J. L.; Mukherjee, P.; Stack, T. D. P.; Hedman, B.; Solomon,
E. I.; Hodgson, K. O. J. Am. Chem. Soc. 2000, 122, 5775-5787.
(37) Tenderholt, A. PySpline; Stanford University: Stanford, CA, 2005.
(38) Deleon, J. M.; Rehr, J. J.; Zabinsky, S. I.; Albers, R. C. Phys. ReV. B
1991, 44, 4146-4156.
(39) Rehr, J. J.; Deleon, J. M.; Zabinsky, S. I.; Albers, R. C. J. Am. Chem.
Soc. 1991, 113, 5135-5140.
(40) George, G. N. EXAFSPAK; EDG_FIT; Stanford Synchrotron Radiation
Laboratory: Stanford, CA, 2000.
(41) Liang, H.-C.; Kim, E.; Incarvito, C. D.; Rheingold, A. L.; Karlin, K.
D. Inorg. Chem. 2002, 41, 2209-2212.
(42) Liang, H.-C.; Karlin, K. D.; Dyson, R.; Kaderli, S.; Jung, B.;
Zuberbu¨hler, A. D. Inorg. Chem. 2000, 39, 5884-5894.
+/0
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.
XAS Data Acquisition. The X-ray absorption spectra of 4 and
of the temperature-induced decay product of 4 were measured at
the Stanford Synchrotron Radiation Laboratory on the focused 16-
pole 2.0 T wiggler beam line 9-3 under standard ring conditions of
Inorganic Chemistry, Vol. 46, No. 15, 2007 6059

Lee et al.
1
bis-(2-pyridin-2-yl-ethyl)-amine43 (9.21 g, 40.4 mmol) and 1-chloro-
2-ethylthioethane (5.0 g, 40.1 mmol) were dissolved in toluene.
Excess NaHCO3 was added, and the reaction was heated to 80 °C
for 3 days. The reaction was then filtered and the solvent removed
in vacuo to isolate the crude oil. The product was purified by
column chromatography using 2.5% to 4% (incrementally) MeOH/
CH2Cl2 on silica gel. 1H NMR (CDCl3): δ 8.52 (2 H, py-6, d, J )
4.8 Hz), 7.55 (2 H, py-5, t, J ) 7.8 Hz), 7.10 (2 H, py-3,4 m), 2.94
(8 H, m), 2.79 (2 H, m), 2.52 (4 H, m), 1.23 (3 H, t, J ) 7.4 Hz).
High-resolution ESI-MS m/z (M + H+): Calcd: 316.184193,
Found: 316.18469.
evaporation. The remaining yellow oil was analyzed by H NMR
spectroscopy. The oxidized ligand, LN3Sox, was purified by column
chromatography on silica gel with 5% CH3OH in CH2Cl2 and was
identified as the sulfoxide derivative of LN3S by 1H NMR and high-
1
resolution mass spectrometry. The H NMR spectrum indicated a
chiral center according to the splitting of the methyl protons adjacent
to the thioether-S atom, suggesting that the lone pairs on the sulfur
were no longer equivalent and had been modified. The mass
spectrum displayed a mass of 16 units more than LN3S and fit the
calculated value for the ligand sulfoxide. Characterization for
LN3Sox 1H NMR (CDCl3): δ 8.52 (2 H, py-6, d, J ) 4.0 Hz), 7.67
:
[CuI(LN3S)]ClO4 (1-ClO4) and [CuI(LN3S)]B(C6F5)4 (1-B(C6F5)4).
The syntheses of these complexes were described in our preliminary
communication.35
(2 H, py-5, td, J ) 7.6, 2.0 Hz), 7.50 (2 H, py-3 d, J ) 4.3 Hz),
7.14 (2 H, py-4, m), 3.87 (4 H, s), 3.06 (2 H, m), 2.87 (2 H, m),
2.63 (2 H, m), 1.24 (3 H, t, J ) 7.4 Hz). CI-MS m/z (M + H+):
Calcd: 304.14836, Found: 304.14788 (Using labeled 18O2, found:
306.15329, 58% 18O2 incorporation based on the 304 vs 306 m/z
peak intensities). IR: Following an oxidation reaction, the yields
of ligand sulfoxidation was found to be 44% based on the relative
1H NMR signal intensities for LN3Sox and LN3S. The reaction was
repeated in triplicate.
[CuI(LN3S′)]ClO4 (2). Under an Ar atmosphere, LN3S′ (0.366 g,
1.16 mmol) in 10 mL of MeCN was added with stirring to solid
[Cu(MeCN)4]ClO4 (0.375 g, 1.16 mmol). The solution was stirred
for 30 min and was then filtered through a medium-porosity frit to
collect a clear, golden-yellow solution. It was layered with
deoxygenated ether at 0 °C after which a brown oil separated from
the solution. The organic solvents were decanted and the oil was
redissolved in 2 mL of dichloromethane. To this solution was added
5 mL of petroleum ether, and oil separated from solution which
was dried in vacuo to collect 0.250 g (45% yield) of yellow solid.
Anal. Calcd for (C18H25ClCuN3O4S): C, 45.18; H, 5.27; N, 8.78.
Found: C, 45.60; H, 5.15; N, 8.94. 1H NMR (CD3CN): δ 8.59 (2
H, d, J ) 5.0 Hz), 7.81 (4 H, m), 2.93 (4 H, br m), 2.83 (4 H, br
m), 2.77 (8 H, m), 2.08 (2 H, br s), 2.65 (2 H, m), 1.21 (3 H, t, J
) 7.4 Hz).
H2O2 Reactivity of 3. The copper(II) complex was dissolved in
methanol. Then, 10 equiv of H2O2 was added. The reaction was
stirred for 2 h at room temperature during which time the color
remained blue. The methanol was then removed by rotary evapora-
tion, and the blue residue was redissolved in CH2Cl2. The metal
was then removed from the ligand by shaking the organic layer
with 35% NH4OH. The organic layer was then dried, and the solvent
was removed by rotary evaporation. The remaining yellow oil was
analyzed by 1H NMR spectroscopy and identified as LN3Sox
.
[CuII(LN3S)(MeOH)](ClO4)2 (3). CuII(ClO4)2‚6H2O (0.310 g,
0.84 mmol) was added to 0.240 g of LN3S in 5 mL of acetonitrile,
and the mixture was stirred for 2 h. Then, 50 mL of diethyl ether
was added in order to precipitate the copper(II) complex. After
sitting overnight, a deep blue oil separated out from the solution.
The oil was washed with ether and was then crystallized by
dissolving it in 5 mL of methanol layered with ca. 10 mL of ether.
A blue crystalline solid (0.3571 g, 73% yield) was collected. The
crystals were of suitable quality for X-ray crystallography. Anal.
Calcd for (C17H25Cl2CuN3O9S): C, 35.09; H, 4.33; N, 7.22.
Found: C, 34.78; H, 4.26; N, 7.29. UV-vis (MeOH) 670 nm (ꢀ )
90 M-1 cm-1): EPR (4K, DMF/toluene frozen glass): g ) 2.079,
g ) 2.257, A ) 181 × 10-4 cm-1, also see Figure S1.
Following an oxidation reaction, the yields of ligand sulfoxidation
was found to be 74% based on the relative 1H NMR-signal
intensities for LN3Sox and LN3S. The reaction was repeated in
triplicate.
Results and Discussion
Synthesis. Thioether-amine N3S ligands LN3S and LN3S′
have been previously synthesized and studied by Rorabacher
and co-workers22,24 for ligand-copper ion binding and redox
properties. Ligand LN3S or derivatives have also been utilized
by Berreau and co-workers44 for copper(II) complex hydro-
lytic chemistry and by Zubieta and co-workers45 for Re/Tc
complex studies. The preparation of LN3S used for the present
studies was recently published,35 and that for LN3S′ is given
in the Experimental Section. The air-sensitive complexes
1-ClO4,35 1-B(C6F5)4,35 and 2 were synthesized and handled
using standard Schlenk techniques. The structures of
1-B(C6F5)4, as well as a copper(II) complex, 3, were
confirmed by X-ray crystallography (vide infra).
X-ray Crystal Structures. Reaction of LN3S and [CuI(CH3-
CN)4](B(C6F5)4) under anaerobic condition in CH2Cl2 gives
a off-white air-sensitive complex, formulated as 1-B(C6F5)4
on the basis of elemental analysis and NMR spectroscopy.
Attempts to grow crystals of this complex in CH2Cl2/
diethylether lead to the isolation of a dinuclear complex,
[{CuI(LN3S)}2](B(C6F5)4)2 (1-(B(C6F5)4)2, Figure 4). Crystal
data and details of the structure determination for 1-(B(C6F5)4)2
||
||
Carbon Monoxide Binding and In Situ Cu-CO IR Monitor-
ing. Using a syringe, excess CO(g) was bubbled through a 5.0 mM
solution of [CuI(LN3S)]ClO4 (1-ClO4) in degassed dichloromethane
or acetonitrile. The immediate formation of the carbonyl complex
[CuI(LN3S)(CO)]+ (1-CO), was observed by the appearance of a
corresponding CO stretching frequency: νCO ) 2094 cm-1 in
acetonitrile (see Supporting Information, Figure S1) and 2096 cm-1
(data not shown) in dichloromethane. The CO stretch was identified
by comparing with the IR spectrum of the starting material, 1-ClO4,
recorded under the same conditions.
Dioxygen reactivity of 1 and 2. In the glove box, the copper(I)
complex solutions were prepared by dissolving in CH2Cl2, and
reaction flasks sealed with a rubber septa. Out on the benchtop, O2
was bubbled through the solution for ca. 60 s at room temperature.
The solution quickly changed from yellow to aqua. After 5 min,
the metal ion was then removed from the ligand by shaking the
organic layer with 35% NH4OH. The organic layer was then dried
over MgSO4 and filtered, and the solvent was removed by rotary
(44) Tubbs, K. J.; Fuller, A. L.; Bennett, B.; Arif, A. M.; Berreau, L. M.
Inorg. Chem. 2003, 42, 4790-4791.
(45) Lazarova, N.; Babich, J.; Valliant, J.; Schaffer, P.; James, S.; Zubieta,
J. Inorg. Chem. 2005, 44, 6763-6770.
(43) Brady, L. E.; Freifelder, M.; Stone, G. J. Org. Chem. 1961, 26, 4757-
4758.
6060 Inorganic Chemistry, Vol. 46, No. 15, 2007

Tetradentate N3S Ligands for Copper-O2 ReactiWity
Figure 4. ORTEP diagram of the cationic component of [{CuI(LN3S)}2]-
(B(C6F5)4)2 (1-(B(C6F5)4)2). Thermal ellipsoids are drawn by ORTEP and
represent 50% probability surfaces.
Figure 6. Cyclic voltammograms of 1-ClO4 (top) and 2 (bottom) in
acetonitrile.
These Cu(I) and Cu(II) complexes possess certain aspects
of the structural features of PHM. Extended X-ray absorption
fine structure (EXAFS) spectroscopic studies of PHM and
DâH indicate that the Cu-SMet distance is 2.2-2.3 Å for
reduced enzyme forms,49,50 and thus, the Cu-S distance
(2.2023 Å) in the present complex 1-(B(C6F5)4)2 is fairly
similar. On the other hand, X-ray diffraction studies indicate
an oxidized PHM form has the CuM site coordinated by two
histidine residues and a solvent molecule on the basal plane,
with an elongated Cu-SMet bond (or distance) of 2.68 Å.8
The axial CuII-Sthioether bond in the hexacoordinate structure
3 is elongated CuII (Cu-S ) 2.655 Å), which in fact is
typical for related structures, being 2.63-2.94 Å.25,30,51 For
other geometries or lower coordination numbers, Cu(II)-
thioether bond lengths fall in the 2.33-2.53 Å range,28,52-54
where the higher end values arise from highly distorted
trigonal bipyramidal structures.53
Redox Comparisons. As part of our efforts to evaluate
the effects of the thioether ligand on copper complex O2-
reactivity, we measured the redox potentials of 1-ClO4 and
2 by cyclic voltammetry (Figure 6). Both species exhibit
quasi-reversible behavior; 2 behaves much more poorly,
possessing a very large separation between cathodic and
anodic waves, indicating slow electron-transfer kinetics at
the electrode surface; however the ratio of current amplitudes
(ipa/ipc) is close enough to unity (Figure 6) to consider that a
one-electron process occurs. The slow electrode electron-
transfer kinetic behavior (for 2) is a common occurrence for
Figure 5. ORTEP diagram of the cationic component of [CuII(LN3S)-
(MeOH)](ClO4)2 (3). Thermal ellipsoids are drawn by ORTEP and represent
50% probability surfaces.
are provided in Supporting Information (Table S1). Selected
bond lengths and bond angles of this complex are listed in
Table 1.
Dimer 1-(B(C6F5)4)2 is a centrosymmetric structure (Figure
4), where each copper ion is coordinated by one ligand via
the three N-donors and by the other ligand via the thioether
atom, thus giving the overall dinuclear structure. Each copper
ion shows a pyramidal arrangement of ligands, with the three
nitrogens comprising the basal plane and the apical position
occupied by one S-atom. Other tetra- or pentacoordinate
copper(I) complexes containing at least one thioether ligand
exhibit Cu-Sthioether bond distances between 2.2 and 2.44
Å.22,29,32,46-48 Thus, the Cu-S distance of 2.2023 Å in
1-(B(C6F5)4)2 is fairly typical.
Complex 3 adopts a distorted octahedral copper(II)
structure (Figure 5) with all three amine ligands and a
methanol oxygen atom donor in the equatorial plane. Weak
thioether and perchlorate oxygen atom interactions with the
copper(II) ion occur via the axial positions with Cu-S )
2.655 Å and Cu-O ) 2.57 Å. Table 1 also contains selected
bond distance and angle information for 3. Crystal data and
details of the structure determination for 3 are provided in
the Supporting Information (Table S2).
(49) Eipper, B. A.; Quon, A. S. W.; Mains, R. E.; Boswell, J. S.; Blackburn,
N. J. Biochemistry 1995, 34, 2857-2865.
(50) Reedy, B. J.; Blackburn, N. J. J. Am. Chem. Soc. 1994, 116, 1924-
1931.
(51) Prochaska, H. J.; Schwindinger, W. F.; Schwartz, M.; Burk, M. J.;
Bernarducci, E.; Lalancette, R. a.; Potenza, J. a.; Schugar, H. J. J.
Am. Chem. Soc. 1981, 103, 3446-3455.
(52) Ruf, M.; Pierpont, C. G. Angew. Chem., Int. Ed. 1998, 37, 1736-
1739.
(53) Otsuka, M.; Hamasaki, A.; Kurosaki, H.; Goto, M. J. Organomet.
Chem. 2000, 611, 577-585.
(54) Klein, E. L.; Khan, M. A.; Houser, R. P. Inorg. Chem. 2004, 43, 7272-
7274.
(46) Karlin, K. D.; Dahlstrom, P. L.; Stanford, M. L.; Zubieta, J. J. Chem.
Soc. Chem. Commun. 1979, 465-466.
(47) Karlin, K. D.; Hayes, J. C.; Hutchinson, J. P.; Zubieta, J. Inorg. Chim.
Acta 1983, 78, L45-L46.
(48) Karlin, K. D.; Dahlstrom, P. L.; Hyde, J. R.; Zubieta, J. J. Chem.
Soc. Chem. Commun. 1980, 906-908.
Inorganic Chemistry, Vol. 46, No. 15, 2007 6061

Lee et al.
Table 1. Selected Bond Distances and Angles for [{CuI(LN3S)}2](B(C6F5)4)2 (1-(B(C6F5)4)2) and [CuII(LN3S)(MeOH)](ClO4)2 (3)
1-(B(C6F5)4)2
3
Bond Lengths (Å)
2.2023(9)
Cu-S
Cu(1)-S(1)
Cu(1)-N(2)
Cu(1)-N(1)
Cu(1)-N(4)
Cu(1)-S(1)
Cu(1)-N(1)
Cu(1)-N(2)
Cu(1)-N(3
Cu(1)-O(1)
Cu(1)-O(8)
2.6551 (7)
Cu-Namine
Cu-Npy
2.2556(18)
2.0158(18)
2.0646(19)
2.0302 (19)
1.981 (2)
1.983 (2)
2.0009 (17)
2.57
Cu-O
Bond Angles (deg)
115.52(7)
N(1)-Cu(1)-N(4)
N(1)-Cu(1)-S(1)
N(4)-Cu(1)-S(1)
N(1)-Cu(1)-N(2)
N(4)-Cu(1)-N(2)
S(1)-Cu(1)-N(2)
N(2)-Cu(1)-N(3)
N(2)-Cu(1)-O(1)
N(3)-Cu(1)-O(1)
N(2)-Cu(1)-N(1)
N(3)-Cu(1)-N(1)
N(2)-Cu(1)-O(8)
O(1)-Cu(1)-N(1)
N(2)-Cu(1)-S(1)
N(3)-Cu(1)-S(1)
O(1)-Cu(1)-S(1)
N(1)-Cu(1)-S(1)
O(8)-Cu(1)-S(1)
164.01 (8)
96.36 (8)
96.93 (8)
84.41 (8)
82.20 (8)
94.0
178.94 (8)
90.00 (6)
98.11 (6)
93.13 (6)
87.61 (6)
175.6
129.81(6)
112.82(6)
80.80(7)
78.62(7)
121.88(5)
Table 2. CuII/CuI Redox Potential (E1/2) Values Measured on Copper(I)
constants for the corresponding ligand-CuI species are
generally unaffected by the chelate ring size or donor atom.
Complexesa
N3S ligand
complexes
E
1/2 vs
N4 ligand
complexes
E1/2 vs
Fe(cp)2
Carbon Monoxide Binding. As another means of com-
paring complexes 1 and 2 with the corresponding amine-
ligand counterparts, we measured the C-O stretching
frequencies for the respective carbonyl adducts. The prepara-
tion of 1-CO was performed in situ by bubbling excess CO-
(g) into a dichloromethane or acetonitrile solution of 1-ClO4
(eq 1). Interestingly, the same preparation was unsuccessful
for generating an analogue [CuI(LN3S′)(CO)]+ (2-CO), indi-
cating a distinct difference between 1 and 2 in the ability to
bind CO (eqs 1 and 2). The [CuI(PMAP)]+ amine analogue,
however, does react with CO and forms a carbonyl adduct
[CuI(PMAP)(CO)]+ (ν(C-O) ) 2090 cm-1),55 indicating that
the sulfur ligation is influencing the CO binding ability of
2.
+/0
+/0
Fe(cp)2
[CuI(LN3S)]+
[CuI(LN3S′)]+
-0.25 V
-0.12 V
[CuI(TMPA)(MeCN)]+
[CuI(PMAP)]+
-0.40 V
-0.25 V
a Acetonitrile solvent.
tripodal tetradentate ligand copper complexes with six-
membered chelate rings.33 The complex containing the “short
armed” ligand (1-ClO4) exhibits an E1/2 value which is ∼0.37
V more negative than that for 2, Table 2. As both LN3S and
LN3S′ are close analogues to complexes with TMPA and
PMAP ligands, whereby one pyridyl arm is substituted by a
CH2CH2-S-Et group (Figure 3), it is worthwhile to compare
copper(I) complex redox potentials. In acetonitrile, [CuI-
(TMPA)(MeCN)]+ has a CuII/CuI redox potential of -0.40
+/0
V vs Fe(cp)2 while that for [CuI(PMAP)]+ is -0.25 V
(Table 2).55 Hence, the thioether donor in 1 raises the redox
potential by 0.15 V in comparison to the copper(I) complex
of TMPA having only amine donors; similarly 2 has an E1/2
which is 0.13 V higher than that for the analogous [Cu-
(PMAP)]+ complex (Table 2).
[Cu(LN3S)]+ + CO(g) f [Cu(LN3S)(CO)]+
[Cu(LN3S′)]+ + CO(g) f No Reaction
(1)
(2)
The solution (acetonitrile) IR spectrum of [CuI(TMPA)-
(CO)]+ exhibits two ν(C-O) stretching frequencies at 2092
and 2077 cm-1, which has been previously attributed to a
dynamic equilibrium involving a pyridyl arm binding or
coming off of the copper(I) ion.5,55,60 The 2092 cm-1 peak
has been assigned as the [CuI(TMPA)(CO)]+ complex
wherein only three amine ligands of the TMPA ligand
coordinated, and the lower energy peak is assigned as the
[CuI(TMPA)(CO)]+ complex with all four amine ligands
coordinated to the copper(I).5,55,60 The IR spectrum of a
solution of in situ generated 1-CO exhibits a sharp carbonyl
vibration at 2094 cm-1 in acetonitrile and 2096 cm-1 in
dichloromethane. Because these values are almost identical
to those of [CuI(TMPA)(CO)]+, where the TMPA provides
tridentate coordination, we propose that LN3S behaves as a
Thus, these studies confirm two facets of previously known
factors that raise the redox potentials of copper(I) complexes,
the thioether donor and the Cu-chelate ring size of six. The
latter trend was observed in a number of individual
studies,33,56-59 and has been examined and analyzed by
Rorabacher and co-workers.22,24 The effect has been shown
to arise from the differences in the formation constants of
the ligand-CuII complexes (from copper(II) ion and free
ligand) of a five- versus a six-membered ligand chelate ring;
binding of the five-membered ring chelate ligand to copper-
(II) is thermodynamically favored. By contrast, formation
(55) Fry, H. C. Ph.D. Dissertation, Johns Hopkins University, 2004.
(56) Nikles, D. E.; Powers, M. J.; Urbach, F. L. Inorg. Chem. 1983, 22,
3210-3217.
(57) Karlin, K. D.; Yandell, J. K. Inorg. Chem. 1984, 23, 1184-1188.
(58) Karlin, K. D.; Sherman, S. E. Inorg. Chim. Acta 1982, 65, L39-L40.
(59) Karlin, K. D.; Hayes, J. C.; Shi, J.; Hutchinson, J. P.; Zubieta, J. Inorg.
Chem. 1982, 21, 4106-4108.
(60) Kretzer, R. M.; Ghiladi, R. A.; Lebeau, E. L.; Liang, H.-C.; Karlin,
K. D. Inorg. Chem. 2003, 42, 3016-3025.
6062 Inorganic Chemistry, Vol. 46, No. 15, 2007

Tetradentate N3S Ligands for Copper-O2 ReactiWity
“tridentate” ligand in the presence of CO in solution, with
the thioether not coordinated (see diagram).61
This makes the three amine ligands of LN3S creating a
copper(I) environment equivalent to that of [CuI(TMPA)-
(CO)]+. Overall tetra- compared to pentacoordination for
copper(I) is generally preferred and this coordination property
contributes to the lack of thioether ligation in 1-CO.
However, the thioether S-atom is thought to coordinate and
influence the properties of the O2-adduct of 1, as described
below.
Figure 7. Absorbance spectra of µ-1,2-peroxodicopper(II) complexes [CuII-
(TMPA)}2(µ-1,2-O22-)]2+ (5, purple) with N4 TMPA ligand, and 4 (blue)
with thioether N3S ligand LN3S
.
Copper-Dioxygen Reactivity of 1. While the “short arm”
[CuI(TMPA)(MeCN)]+ complex forms a low-temperature
stable “end-on” µ-1,2-peroxodicopper(II) species [{CuII-
(TMPA)}2(µ-1,2-O22-)]2+ (5) (diagram),5,6 the “long arm”
Figure 8. UV-vis spectra demonstrating the reversible O2-binding
behavior of [CuI(LN3S)]+ (1-B(C6F5)4) in Me-THF. A colorless solution of
1 (λmax ) 340 nm, spectrum 1) bubbled with O2 (at -127 °C) leads to the
dark blue dioxygen adduct [{(LN3S)CuII}2(µ-1,2-O22-)]2+ (4) (λmax ) 605
nm, spectrum 4). Application of a vacuum while warming to -90 °C leads
to solution decoloration and 1 is cleanly regenerated (O2 dissociation as
monitored by UV-vis spectroscopy is observable even at -127 °C but it
occurs very slowly). Four cycles are shown, and these are virtually
overlapped; thus, there appears to be no detectable decomposition.
amine complex [CuI(PMAP)]+ (Figure 3) does not react with
O2 at low temperature, presumably due to the fact that the
CuII/I redox potential is considerably more positive than that
for [CuI(TMPA)(MeCN)]+.33 Interestingly, 1-ClO4 exhibits
essentially the same redox potential as [CuI(PMAP)]+ (-0.25
V vs Fe(cp)2+/0, Table 2), yet it does react with O2 and forms
what we formulate as an end-on peroxo complex, 4 (Scheme
1),62 as observed by UV-vis and rR spectroscopy (vide
infra).
to formation of a stable species (Figure 7, blue spectrum);
the new dioxygen adduct, formulated as a µ-1,2-peroxodi-
copper(II) complex 4 (see the following section), has
absorption transitions with similar energies and total intensi-
ties to those of 5 with λmax ) 530 (ꢀ ≈ 9200 M-1 cm-1) and
605 nm (ꢀ ≈ 11 800 M-1 cm-1) (Figure 7). The binding of
O2 to 1-B(C6F5)4 is reversible, as evidenced by reactions
interconverting complexes 1-B(C6F5)4 and 4 (Figure 8).
One notable feature in the absorbance spectrum of 4 is
that the 16 560 cm-1 (604 nm) band is more intense than
the 18 870 cm-1 (530 nm) band, which is opposite to that
observed for [{CuII(TMPA)}2(µ-1,2-O22-)]2+ and other end-
on peroxo dicopper(II) complexes.1-4,63-66 While the thio-
ether S-donor in the N3S donor set of LN3S is not coordinated
in the [Cu(LN3S)(CO)]+ complex (vida supra), the UV-vis
characteristics suggest that it is coordinated to the copper-
(II) ion in the end-on peroxo species 4. If it were not, then
Scheme 1
At -80 °C, reaction of 1-ClO4 with O2 in CH2Cl2, acetone,
or 2-methyltetrahydrofuran (MeTHF) results in a rapid
change to a dark blue solution. The solution color persists
for only 10-20 min and slowly decompose to a green
species. However, oxygenation of 1-B(C6F5)4, instead of
1-ClO4, under colder conditions (-125 °C in MeTHF) leads
the remaining “tridentate amine” ligand (N3 portion of LN3S
)
would, according to precedent, likely form a very unstable
bis-µ-oxo complex (λmax ≈ 385 nm).67 EXAFS studies
(63) Henson, M. J.; Vance, M. A.; Zhang, C. X.; Liang, H.-C.; Karlin, K.
D.; Solomon, E. I. J. Am. Chem. Soc. 2003, 125, 5186-5192.
(64) Komiyama, K.; Furutachi, H.; Nagatomo, S.; Hashimoto, A.; Hayashi,
H.; Fujinami, S.; Suzuki, M.; Kitagawa, T. Bull. Chem. Soc. Jap. 2004,
77, 59-72.
(65) Becker, M.; Heinemann, F. W.; Schindler, S. Chem. Eur. J. 1999, 5,
3124-3129.
(66) Bol, J. E.; Driessen, W.; Ho, R. Y. N.; Maase, B.; Que, J., L.; Reedijk,
J. Angew. Chem., Int. Ed. Engl. 1997, 36, 998-1000.
(61) Supporting evidence (unpublished) comes from our observation that
when a copper(I)-ligand analogue of LN3S where the ligand does not
possess the -CH2CH2SEt arm, but a benzyl or methyl group instead
(i.e., thus with just N3 ligation), the CO stretching frequency also comes
at 2093 cm-1
.
(62) Hatcher, L. Q.; Vance, M. A.; Narducci Sarjeant, A. A.; Solomon, E.
I.; Karlin, K. D. Inorg. Chem. 2006, 45, 3004-3013.
Inorganic Chemistry, Vol. 46, No. 15, 2007 6063

Lee et al.
Figure 10. rR profile of ν(O-O) (pink triangles) and ν(Cu-O) (blue
stars) of [{CuII(LN3S)}2(µ-1,2-O22-)]2+ (4) in CH2Cl2. The absorbance
spectrum (black) and Gaussian fit transitions (gray, cyan, red, and green)
are also shown. See text for further discussion and explanation.
but it is in the expected range for the antisymmetric ν(Cu-
O) mode.63,69 There is another isotope-sensitive vibration at
∼250 cm-1
(
16-18O2 ∆ ) ∼4 cm-1; Figure 9B). This is likely
a bending motion with Cu-O character. The remaining
resonance enhanced modes show no 18O2 isotope shift and
are thus associated with the Cu-N ligands. The 419 cm-1
vibration (Figure 9B) has been assigned as the ν(Cu-N)
mode of the tertiary amine.63,69 Additional weak features at
∼393, 365, 330, 305, and 263 cm-1 are likely (Cu-N)/(Cu-
S) stretching and bending or other internal ligand modes
(Figure 9B).
Figure 9. rR spectra of [{CuII(LN3S)}2(µ-1,2-O22-)]2+ (4) in CH2Cl2 (λex
) 620 nm) with 16O2 (in red) and 18O2 (in blue) isotopic substitution. Solvent
peaks are overlaid in black. Inset of B: Blow-up of the 250 cm-1 peak and
isotope shifting observed. See text for further description.
To investigate for the possible presence of a thioether-to-
Cu LMCT, the broad visible absorption feature was profiled
between 458 and 752 nm (∼22 000 and ∼13 000 cm-1) by
rR spectroscopy (Figure 10).70 The ν(O-O) mode profiles
weakly across the ∼19 200 cm-1 transition (Figure 10, cyan),
strongly in the ∼15 500 cm-1 transition (Figure 10, green),
and not at all at ∼22 000 cm-1 (Figure 10, gray); ν(Cu-
O)S shows almost no resonance intensity at ∼19 200 cm-1,
but has strong enhancement in the ∼15 500 cm-1 transition
(Figure 10, green) and no enhancement at ∼22 000 cm-1.63,70
These enhancement patterns are similar to those observed
in [{CuII(TMPA)}2(µ-1,2-O22-)]2+,69 allowing assignment of
the ∼15 500 cm-1 transition (Figure 10, green) as a π*v-to-
Cu charge transfer, the ∼19 200 cm-1 transition (Figure 10,
cyan) as a π*σ-to-Cu charge transfer, and the ∼22 000 cm-1
band (Figure 10, gray) as the spin-forbidden triplet charge-
transfer transition from the π*v orbital. These three transitions
alone are not sufficient for a good Gaussian fit of the
absorbance spectrum. Another band is needed, and both the
ν(Cu-O) and ν(O-O) profiles exhibit a shoulder at ∼17 200
cm-1 (Figure 10, red). Given that the ∼17200 cm-1 shoulder
shows ν(Cu-O)S mode enhancement similar to that observed
in the ∼15,500 cm-1 band (Figure 10, green), this shoulder
is assigned as a second π*v-to-Cu charge-transfer transition.
Other rR peaks show much weaker enhancement. Impor-
tantly, no modes show enhancement consistent with the
presence of a S-Cu stretch, which would be associated with
a thioether-to-Cu(II) CT transition. Thus, the thioether-to-
confirm thioether ligation in 4 (vide infra). The origin of
the atypical absorption spectrum was further investigated by
rR spectroscopy.
Resonance Raman Spectroscopy of 4. As described in
our preliminary communication,35 rR spectra of 4 in CH2-
Cl2 with 16O2 and 18O2 isotopic substitution were collected
with 620 nm excitation. The primary features were the ν-
(O-O) band at 817 cm-1 (18O2 ∆ ) -46 cm-1) and the
symmetric ν(Cu-O) vibration at 545 cm-1 (18O2 ∆ ) -26
cm-1; Figure 9A).68 These values are similar to those
previously observed for 569 {ν(O-O) ) 827 cm-1 and νsym
-
(Cu-O) ) 561 cm-1} and allow the assignment of 4 as an
end-on peroxide-bridged structure.1-3 The lower (compared
to 5) vibrational frequencies indicate that O-O and Cu-O
bonding is weaker overall in 4 than in the TMPA complex;
the lower ν(Cu-O) frequency indicates less electron-
donation to copper from the peroxide π* orbital, which in
turn also weakens the O-O bond (i.e., more electron density
in the O-O antibonding orbital) and lowers ν(O-O) as well.
As discussed below, these effects can be ascribed to thioether
(instead of pyridyl nitrogen) ligation in 4.
Additional broad and weak vibrational features at ∼500
cm-1 (Figure 9A) also shift with dioxygen isotopic substitu-
tion. The magnitude of the shift is not clear due to overlap
with the νsym(Cu-O) mode and possible Fermi interactions,
(67) Osako, T.; Ueno, Y.; Tachi, Y.; Itoh, S. Inorg. Chem. 2003, 42, 8087-
8097.
(68) We here note that the 16O2 derived features were slightly split (with
additional peaks at ∼800 and ∼560 cm-1) which gain some intensity
through Fermi mixing; they were not present in the 18O2 prepared
sample.
(70) The possibility of multiple species being present was dismissed after
inspection of the ν(O-O) stretch overlaid across the laser lines profiled.
The peak shape did not change over the profile, so the sample is likely
composed of just one end-on peroxo species.
(69) Baldwin, M. J.; Ross, P. K.; Pate, J. E.; Tyekla´r, Z.; Karlin, K. D.;
Solomon, E. I. J. Am. Chem. Soc. 1991, 113, 8671-8679.
6064 Inorganic Chemistry, Vol. 46, No. 15, 2007

Tetradentate N3S Ligands for Copper-O2 ReactiWity
Cu(II) CT transition must be at >30 000 cm-1 as is observed
in other Cu(II) complexes.48,53,56,71,72
As described above, there are significant absorption
spectral differences between 4 and 5 which can provide
insight into structure. First, the relative intensities of the π*σ/
π*v transitions are reversed in 4 relative to the TMPA
complex with the π*v transition being more intense in 4
(Figure 10). This indicates that the π*v orbital has more
overlap with the half-occupied orbital on the Cu(II) than in
the TMPA complex, supporting the assertion of a distorted
ligand field around the Cu center. The π*σ orbital is,
however, at a deeper energy as it is involved in σ bonding
with the Cu. Although the position of the π*σ charge-transfer
band remains essentially unchanged, the lower intensity
indicates that it has less overlap with the half-occupied orbital
on the Cu(II). The more intense π*v transition has shifted to
lower energy, indicating weaker π*v bonding and weaker
Cu-O bonding overall. This is consistent with the observed
rR data.
Figure 11. Normalized Cu K-edge XAS spectrum of 4. Inset shows the
expanded pre-edge region and the 1sf3d transition at ∼8979 eV.
ligands having (i) six-substituted pyridyl arms,76 (ii) length-
ened arms,59,77 or (iii) an arm with thioether instead of a
methylpyridyl,46 including 3 (vide supra), are distorted toward
a square pyramidal geometry with the modified ligand at
the apex of the pyramid to minimize steric interaction with
the fifth ligand (here dioxygen). This distortion leads to
decreased π*σ overlap, greater π*v overlap, and a weakened
Cu-O bond.
EXAFS Spectroscopy. The most compelling evidence for
the presence of thioether ligation in 4 is the EXAFS
spectrum, obtained from frozen (MeTHF) solution. The
results were described in our preliminary communication.35
A more detailed analysis of the Cu K-edge and EXAFS data
of 4 is presented here. A comparison of the EXAFS data of
4 is made with that of the decomposition product.
Cu K-Edge. The normalized X-ray absorption Cu K-edge
and pre-edge (as inset) spectra of 4 are shown in Figure 11.
These data have been analyzed to estimate the conversion
of the Cu(I) starting material to the end-on Cu2O2 dimer.
The pre-edge feature observed at ∼8979 eV is characteristic
of a Cu(II) complex and corresponds to the electric dipole-
forbidden quadrupole-allowed 1sf3d transition.78 The pres-
ence of this feature indicates that 4 contains significant Cu(II)
character. The XAS spectra of a Cu(I) species display an
intense feature at ∼8984 eV which is assigned to the dipole
allowed 1sf4p transition.79 Comparison of the Cu K-edge
data of 4 with XAS spectral simulations of several Cu(II)
complexes with different amounts of Cu(I) contamination
indicate that 4 contains <5% of the unconverted Cu(I)
species.
Another notable spectral difference between 4 and 5 is
the ∼17 000 cm-1 splitting of the π*v transition into two
components, which is similar in magnitude to the charge-
transfer splitting observed in other bridged copper com-
plexes.73 Assuming at least C2 symmetry in the Cu2O2 unit,
the π*v CT state would be split by interaction of the charge-
transfer transitions to the two Cu(II) into A and B compo-
nents with the B component being at lower energy.74,75 This
allows assignment of the ∼15 500 cm-1 band as a π*v -to-
Cu (B) transition and the ∼17 200 cm-1 band as a π*v -to-
Cu (A) transition. The two π*σ-to-Cu(II) charge-transfer
transitions would also couple to form two split states in the
bridged dimer. However, because excited-state splitting is
derived from ligand overlap with the half-occupied metal
d-orbitals and the π*σ transition is less intense, a smaller
splitting would be expected and is not observed.
Application of a transition dipole-vector coupling model
to the intensity distribution of the π*v transitions can provide
insight into the degree of distortion of the Cu2O2 unit.74 The
integrated intensity ratio of the π*v transitions (IA/IB
)
∼0.36) relates to the angle between the transition dipoles
and the C2 axis, which is calculated to be ∼60° for 4. This
indicates a high degree of Cu2O2 core distortion, likely an
out-of-plane bend, compared to the nearly planar Cu2O2
found in the TMPA complex, which has intensity in only
one component of the π*v charge transfer (indicating that
the monomer dipoles are both perpendicular (90°) to the C2
axis). This distortion is likely due to steric effects. 5 and
[CuII(TMPA)Cl]+ maintain a trigonal bipyramidal geom-
etry.5,59 However, other complexes with tripodal tetradentate
EXAFS. The k3-weighted Cu K-edge EXAFS data and
their Fourier transforms (FT) for 4 are presented in Figure
S3. The EXAFS fit parameters are given in Table S1. The
first shell EXAFS was fit with 1 Cu-O/N contribution at
(71) Whittaker, M. M.; Chuang, Y. Y.; Whittaker, J. W. J. Am. Chem.
Soc. 1993, 115, 10029-10035.
(76) Lucchese, B.; Humphreys, K. J.; Lee, D.-H.; Incarvito, C. D.; Sommer,
R. D.; Rheingold, A. L.; Karlin, K. D. Inorg. Chem. 2004, 43, 5987-
5998.
(72) Huys, C. T.; Hoste, S.; Goeminne, A. M.; Vanderkelen, G. P.
Spectrochim. Acta A 1983, 39, 631-633.
(73) Tuczek, F.; Solomon, E. I. Inorg. Chem. 1993, 32, 2850-2862.
(74) Eickman, N. C.; Himmelwright, R. S.; Solomon, E. I. Proc. Natl. Acad.
Sci. U.S.A. 1979, 76, 2094-2098.
(75) Westre, T. E.; Di Cicco, A.; Fillipponi, A.; Natoli, C. R.; Hedman,
B.; Solomon, E. I.; Hodgson, K. O. J. Am. Chem. Soc. 1994, 116,
6757-6768.
(77) Wei, N.; Murthy, N. N.; Karlin, K. D. Inorg. Chem. 1994, 33, 6093-
6100.
(78) Shulman, R. G.; Yafet, Y.; Eisenberger, P.; Blumberg, W. E. Proc.
Nat. Acad. Sci., U.S.A. 1976, 73, 1384-1388.
(79) Kau, L.-S.; Spira-Solomon, A. J.; Penner-Hahn, J. E.; Hodgson, K.
O.; Solomon, E. I. J. Am. Chem. Soc. 1987, 109, 6433-6442.
Inorganic Chemistry, Vol. 46, No. 15, 2007 6065

Lee et al.
Figure 12. Cu K-edge EXAFS data (left panels) and non-phase-shift-
corrected Fourier transforms (right panels). Panels (A) and (B) give fits
with a long Cu-O and a Cu-S contribution, respectively. A lower reduced
ø2 error (FC) reflects a better fit. Data (black), fit (red), and residual (blue).
Figure 13. Cu K-edge EXAFS data (inset) and non-phase-shift-corrected
Fourier transform of 4 (red) and the temperature-induced decay product
(black).
LN3S Chemistry: Modeling DBH and PHM. In contrast
to tyrosinase or catechol oxidase, which involve a magneti-
cally coupled dicopper(II) side-on peroxo species as the
electrophilic oxidant,80 the non-coupled binuclear nature of
the PHM and DâH active sites (i.e., 11 Å distance between
CuM and CuH in PHM, Figure 1) directs the chemistry to
occur at only one mononuclear active site while still
providing another reducing electron from a distant CuI ion.15
What is the role of the thioether donor at the mononuclear
CuM active site? Recent results from our laboratories suggest
that a CuI complex [CuI(Me2N-TMPA)]+ having strong
amine donors (by way of added dimethylamino electron
donor 4-pyridyl substituents on TMPA) can better stabilize
1.89 Å, 3 Cu-N/O at 2.03 Å, and 1 Cu-S at 2.41 Å. The
FT shows intense peaks in the R ) 2-3 and 3.5-4.5 Å
ranges, indicating strong contribution from the LN3S ligand.
These second and third shell contributions were fit using
single scattering (SS) and multiple scattering (MS) contribu-
tions from the LN3S ligand pyridine rings (Table S3). The
first shell Cu-S contribution at 2.41 Å was required to obtain
a good fit. Replacement of the Cu-S path by single or
multiple Cu-O or Cu-C paths resulted in worse fits to the
data and clearly indicated a residual in the fits to the EXAFS
data. A comparison of the best fit with a long Cu-O path
(2.62 Å, in Panel A) and Cu-S path (2.41 Å, in Panel B) is
shown in Figure 12.
-
a mononuclear superoxo species [CuII(NMe2-TMPA)(O2 )]+
as compared to the unsubstituted [CuI(TMPA)]+ complex.81
The edge data for 4 indicate that essentially no unconverted
Cu(I) is present. However, 4 is extremely temperature
sensitive and could arguably decay to a Cu(II) complex
which could contain a Cu-S interaction at ∼2.4 Å. To
evaluate this possibility, Cu K-edge EXAFS data were
collected on a sample cell containing 4 which had been
allowed to warm up to room temperature for ∼2 h. The
EXAFS data and Fourier transforms of this decay product
are compared to those of 4 in Figure 13. The EXAFS data
are clearly different, and this is also manifested in differences
in the Fourier transform data. In particular, the peak at ∼2.0
Å in the non-phase-shift-corrected data of 4 is missing in
the decay product. Since the calculated phase shift is ∼0.4
Å, this difference in the EXAFS is indicative of the absence
of the Cu-S bond in the decay product. The MS contribution
from the LN3S ligand system at ∼3.8 Å is also smaller in the
decay product, likely indicating a more disordered site
compared to 4. The k3-weighted Cu K-edge EXAFS data,
and their FTs of the decay product are presented in Figure
S4. The EXAFS fit parameters are given in Table S4. The
first shell EXAFS data were fit with 4 Cu-O/N contributions
at 2.0 Å and a long Cu-O at 2.55 Å. The second and third
shell components are similar to those of 4 but have higher
Debye-Waller factors indicating an increase in disorder. The
first shell analysis of the decay product clearly indicates that
the Cu-S bond observed in the EXAFS analysis of 4 is only
present in the end-on Cu2O2 species.
-
The CuII-(O2 ) moiety forms faster (larger kon in the CuI/
O2 reaction) and is thermodynamically more stable (larger
K
formation), and the reverse reaction involving Cu-O bond-
breaking (in [CuII(NMe2-TMPA)(O2 )]+) possesses a larger
activation enthalpy.34 The corresponding end-on peroxo
species, [{CuII(NMe2-TMPA)}2(O22-)]2+, also has a weak-
ened bond, ν(O-O) ) 813 cm-1, similar to that of 4.63 The
result presented here, that the thioether group of LN3S may
act as a relatively stronger donor ligand in 4 (vide supra),
suggests that the methionine sulfur ligand at CuM in DâH
and PHM could well facilitate both kinetic and thermody-
namic stabilization of a CuIIM-superoxo intermediate, the
active species thought to effect substrate hydrogen-atom
abstraction (see Introduction). Chen and Solomon12 also point
out that the CuM Met ligand contributes to the stabilization
of the CuII-oxyl species produced later (following O-O
bond cleavage) in the reaction mechanism (Figure 1, bottom
left).
-
Ligand Substrate Reactivity of 4. The room-temperature
O2-reactivity of 1 is also noteworthy giving further insight
into Cu-dioxygen bonding and reactivity in the presence
of a thioether ligand; complex 1-ClO4 exhibits copper-
(80) Solomon, E. I.; Sundaram, U. M.; Machonkin, T. E. Chem. ReV. 1996,
96, 2563-2605.
(81) Maiti, D.; Fry, H. C.; Woertink, J. S.; Vance, M. A.; Solomon, E. I.;
Karlin, K. D. J. Am. Chem. Soc. 2007, 129, 264-265.
6066 Inorganic Chemistry, Vol. 46, No. 15, 2007

Tetradentate N3S Ligands for Copper-O2 ReactiWity
Scheme 2
Scheme 4
reaction occurs from the reaction of 3 with 10 equiv of H2O2
(eq 3). In this “peroxide shunt” reaction, we observe 74%
ligand oxidation. Sulfoxidation reactions mediated by CuII
and H2O2 are not uncommon.29,30
Scheme 3
(LN3S)CuII + H2O2 f (LN3Sox)CuII + H2O
(3)
It has been previously established that, for the most part,
end-on peroxo dicopper(II) compounds are nucleophilic or
basic by their nature.85,86 They react with PPh3 displacing
O2 and subsequently form CuI(PPh3) moieties; they also
protonate releasing H2O2.85,86 By contrast, side-on peroxo
dicopper and bis(µ-oxo) isomer species are known to be
electrophilic, carrying out ligand or substrate oxygen atom
transfer or oxidation (e.g., H-atom abstraction) reactions.4,85,86
Thus, to account for the sulfoxidation of LN3S via formation
of 4, we suggest that it may be a side-on µ-η2:η2 peroxodi-
copper or bis-µ-oxo dicopper(III) isomer form which could
be in equilibrium with the end-on peroxo complex 4 and
which effects the oxygen-atom transfer reaction (Scheme 4).
Such equilibrium mixtures are known.87,88 The end-on peroxo
structure 4 equilibrium form would be favored at low
temperature, in line with the UV-vis and rR spectroscopic
properties (vide supra). However, warming would perhaps
favor a N3-ligated-thioether dangling form (Scheme 4),
wherein intramolecular attack of the thioether substrate then
occurs. This hypothesis could also account for the observa-
tion that prolonged standing of 4 at low temperature (-80
°C), even followed by warming, results in significantly
reduced yields (<25%) of sulfoxide. We should also note
that Itoh and co-workers89 have demonstrated bis-µ-oxodi-
copper(III) sulfoxidation of exogenously added (but also
demonstrated to bind to copper) thioether substrates.
mediated oxygen atom transfer to the ligand in high yields.
Upon addition of O2 to 1-ClO4 in CH2Cl2, the solution
quickly turns aqua/blue. After demetallation with NH4OH-
(aq), analysis of the recovered ligand showed that 44% of
the thioether-amine ligand was oxidized to the sulfoxide
derivative (LN3Sox) (according to 1H NMR and high-resolution
MS, see Experimental Section), Scheme 2.
As observed in other chemical systems,4,82-84 a 50% yield
is all that is expected for a monooxygenase model system
where a four-electron reduction of O2 is accomplished with
(formally) one oxygen atom derived from the O2 molecule
being incorporated into a substrate and where the other
O-atom is reduced to the oxidation state level of water. In
the monooxygenase reaction of 1, as two electrons are needed
from the two copper(I) ions, only one of the ligands on one
copper can become oxidized and the theoretical maximum
is a 50% yield (Scheme 3).
Lack of Copper-Dioxygen Reactivity with 2. In contrast
to the oxidative chemistry observed for the copper complexes
of the “short arm” LN3S, complex 2 does not react with
dioxygen. Addition of O2 at low temperature leads to no
spectroscopic changes, and even at room temperature, there
is no immediate color change. Demetallation after 1 day
following a 2/O2 reaction showed that the ligand remained
unaffected (Scheme 2). Thus, a seemingly minor ligand
We find that when the reaction is carried out using labeled
18O2, 18O is incorporated into the sulfoxide ligand to the
extent of 58%, a relatively low level of oxygen atom
incorporation, but still indicating the sulfoxide O-atom
derives from O2 and a copper-dioxygen species. Also
consistent with this result is the finding that a sulfoxidation
(85) Hatcher, L. Q.; Karlin, K. D. J. Biol. Inorg. Chem. 2004, 9, 669-
683.
(82) Karlin, K. D.; Gultneh, Y.; Hayes, J. C.; Cruse, R. W.; McKown, J.
W.; Hutchinson, J. P.; Zubieta, J. J. Am. Chem. Soc. 1984, 106, 2121-
2128.
(83) Itoh, S.; Nakao, H.; Berreau, L. M.; Kondo, T.; Komatsu, M.;
Fukuzumi, S. J. Am. Chem. Soc. 1998, 120, 2890-2899.
(84) Mahapatra, S.; Halfen, J. A.; Tolman, W. B. J. Am. Chem. Soc. 1996,
118, 11575-11586.
(86) Paul, P. P.; Tyekla´r, Z.; Jacobson, R. R.; Karlin, K. D. J. Am. Chem.
Soc. 1991, 113, 5322-5332.
(87) Wick, P. K.; Karlin, K. D.; Suzuki, M.; Zuberbuhler, A. D. Micron
2004, 35, 137-139.
(88) Wick, P. K.; Karlin, K. D.; et al. Manuscript in preparation.
(89) Taki, M.; Itoh, S.; Fukuzumi, S. J. Am. Chem. Soc. 2002, 124, 998-
1002.
Inorganic Chemistry, Vol. 46, No. 15, 2007 6067

Lee et al.
modification (i.e., the change/addition of one methylene
group), essentially shuts off copper-mediated O2 chemistry.
We presume this has to do with the positively shifted redox
potential of 2 (vide supra), precluding binding of O2 to Cu-
(I); the latter process requires a significant degree of copper-
to-O2 electron-transfer.2,90 As noted (see Introduction), the
closely related ligand C was apparently not examined for
CuI/O2 reactivity but did undergo H2O2 mediated ligand-
copper(II) complex sulfoxidation.28
in order to generate synthetically derived mononuclear
copper-dioxygen adducts possessing thioether-nitrogen
ligands, i.e., models for the leading candidates for active-
site reactive intermediates.
The chemistry presented here also has some relevance to
the methionine oxidation implicated in the oxidative stress
pathogenesis of Alzheimer’s disease (AD)91,92 and other age-
related diseases.93 Amyloid â-peptides (Aâ, 1-42 residues
in length) can coordinate copper and lead to the generation
of reactive oxygen species (ROS) and cell toxicity.94-96 The
chemistry (sulfoxidation, or not) of Met-35 appears to be
crucial in neurotoxic situations and in polymer/plaque
formation; Met-sulfoxides are found in AD amyloid
plaques.97,98 In fact, methionine oxidation appears to be a
recurrent theme in biology (formed quite likely from ROSs
and redox metal mediated processes) and protein Met
residues may be present as sacrificial reductants to scavenge
ROSs and then be recycled back with methionine sulfoxide
reductases.93,99 Methionine oxidation is also implicated in
cellular regulation.100,101 Thus, the study of copper ion
mediated sulfoxidation chemistry has a strong biological
basis.
Conclusion
We have performed the first systematic study of the effects
of a thioether donor on the properties and chemistry of
copper(I) complexes and on their O2 reactivity, in direct
comparison to closely related copper(I) complexes having a
pyridyl ligand donor counterpart. We observe here that the
sulfur donor raises the redox potential of 1-ClO4 by ∼0.15
V versus the analogous [CuI(TMPA)(MeCN)]+ copper(I)
complex. Despite this increase in E1/2, 1 reacts with O2 at
low temperature to generate the first copper-dioxygen
adduct also possessing thioether ligation, an “end-on” peroxo
complex, 4, proven from EXAFS spectroscopy to possess
Cu-Sthioether bonding. This possesses a novel absorption
spectrum depicting an additional π*v-Cu(II) transition
indicating distortion away from trigonal bipyramidal struc-
ture. rR data for 4 show that Cu-O and O-O stretching
frequencies are lowered in comparison to those of 5. Thus,
the thioether ligand weakens the Cu-O and O-O bonds by
imposing a structural modification and/or by providing
greater electron density to the CuII center relative to the
nitrogen donors in TMPA. As discussed, enhanced thioether
donation/structural distortion thus may contribute to CuII-
superoxo active-species formation and stabilization at the
DâH or PHM CuM site.
Future studies of copper-thioether complexes and their
reactivity with O2 and H2O2 may further contribute to our
understanding of enzymatic and other biological processes.
Acknowledgment. We are grateful to the National
Institutes of Health (K.D.K., GM28962; E.I.S., DK31450;
K.O.H, RR-01209) for support of this research. SSRL
operations are funded by the Department of Energy, Office
of Basic Energy Sciences. The SSRL Structural Molecular
Biology program is supported by the National Institutes of
Health, National Center for Research Resources, Biomedical
Technology Program, and by the Department of Energy,
Office of Biological and Environmental Research.
1/O2 displays monooxygenase activity at room temperature
whereby 44% (out of a 50% theoretical maximum) of the
total ligand recovered after a CuI + O2 reaction is the ligand-
derived sulfoxide product. The same is observed for the
reaction of 3 with H2O2 but in higher yields. As discussed
above, DâH and PHM are unique copper-containing enzymes
because of their chemistry occurring at a mononuclear copper
site with an accompanying Met sulfur ligand. Thus, it may
seem surprising that DâH or PHM CuM site destruction (via
irreversible sulfoxide formation) does not appear to occur.
This may be due to (i) the lack of facile electron transfer
from the distant CuH (which could lead to a peroxide level
intermediate) and (ii) very tight control and coupling of active
species formation with substrate attack,13 such that no leakage
of reactive oxygen species occurs. Further structural, spec-
troscopic, and reactivity mechanistic studies are warranted
Supporting Information Available: Crystallographic informa-
tion file (CIF) of 1-(B(C6F5)4)2 and 3, EPR spectrum of 3 and IR
spectrum of 1-CO. This material is available free of charge via the
Internet at http://pubs.acs.org.
IC700541K
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6068 Inorganic Chemistry, Vol. 46, No. 15, 2007