Oxygenation chemistry at a mononuclear copper(II) hydroquinone system with O2

Article abstract of DOI:10.1021/ic101037v

Aerobic treatment of a copper(II) complex supported by a bis(pyridin-2-ylmethyl)amine ligand containing a p-hydroquinone moiety on one of the pyridine donor groups in CH₃OH induces oxygenation reaction of the ligand to give a hydroxylated p-quinone derivative.

Full text of DOI:10.1021/ic101037v

6820 Inorg. Chem. 2010, 49, 6820–6822
DOI: 10.1021/ic101037v
Oxygenation Chemistry at a Mononuclear Copper(II) Hydroquinone System with O2
Kae Tabuchi, Hideki Sugimoto, Atsushi Kunishita, Nobutaka Fujieda, and Shinobu Itoh*
Department of Material and Life Science, Division of Advanced Science and Biotechnology,
Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
Received May 21, 2010
Chart 1
Aerobic treatment of a copper(II) complex supported by a bis(pyridin-
2-ylmethyl)amine ligand containing a p-hydroquinone moiety on one of
the pyridine donor groups in CH3OH induces oxygenation reaction of
the ligand to give a hydroxylated p-quinone derivative.
In copper monooxygenases such as tyrosinase, peptidylgly-
cine R-hydroxylating monooxygenase, dopamine β-monoox-
ygenase, and particulate methane monooxygenase, molecular
mechanistic scenario has been proposed for the biogenetic
oxygen (O2) is activated at a mono- or dinuclear copper
reaction center to perform substrate oxygenation.1,2 In the
catalytic cycles of these enzymes, there is a distinct reduction
process of copper(II) to copper(I) by an external reductant
prior to O2 binding and activation for the following substrate
oxygenation.1-4 The structure, physicochemical properties,
and reactivity of several types of active oxygen species gener-
ated by the reaction of copper(I) complexes and O2 have been
studied extensively in model systems to provide significantly
important insights into catalytic mechanisms of the copper
monooxygenases.5,6
In copper dioxygenase such as quercetin 2,3-dioxygenase
(2,3-QD), on the other hand, sucha definite reduction process
of the mononuclear copper(II) reaction center is not observed
during the catalytic cycle. Thus, the enzymatic reaction is
believed to involve substrate activation prior to O2 binding.
Namely, inner-sphere electron transfer from the deprotonated
polyhydroxylated organic substrate (R-) to copper(II) initially
occurs to generate an organic radical intermediate (R•) of the
substrate and copper(I).7 Then, the generated R•/copper(I) spe-
cies readily reacts with O2 having a triplet ground state (S=1)
to promote the substrate oxygenation reaction.7 A similar
processes of a (trihydroxyphenyl)alanine quinone (TPQ)
cofactor of copper-containing amine oxidase and a lysyltyrosyl-
quinone (LTQ) cofactor of lysyl oxidase. In these cases,
oxidative modification of the active-site tyrosine (precursor of
the cofactor) is initiated by activation of tyrosinate (Tyr-, the
deprotonated form of tyrosine) to a tyrosyl radical (Tyr•) via
inner-sphere electron transfer to the active-site copper(II).
Then, the generated Tyr•CuI intermediate reacts with O2 to
induce the post-translational modification.8-11 However, such
substrate activation chemistry at a mononuclear copper(II)
reaction center has been less investigated in model systems
compared to the comprehensive copper(I) dioxygen model
studies for the copper monooxygenase systems. In this Com-
munication, we report a mononuclear copper(II) hydroquinone
system, which undergoes a similar oxygenation reaction at its
hydroquinone moiety to give hydroxylated p-quinone deriva-
tives under aerobic conditions.
Ligand L1H2 shown in Chart 1 (left) was synthesized accord-
ing to the synthetic procedures described in the Supporting
Information (SI; Scheme S1).12 The copper(II) complex [CuII-
(L1H)](ClO4) (CuIIL1H) was then prepared by treating the
ligand and CuII(ClO4)2 6H2O in acetonitrile. The crystal struc-
3
ture of CuIIL1H is shown in Figure 1, and the crystallographic
data and selected bond lengths and angles are summarized in
Tables S1 and S2 in the SI, respectively.
*To whom correspondence should be addressed. E-mail: shinobu@mls.
eng.osaka-u.ac.jp.
(1) Halcrow, M. A. Monocopper Oxygenases. In Comprehensive Coordi-
nation Chemistry II; Que, J. L., Tolman, W. B., Eds.; Elsevier: Amsterdam, The
Netherlands, 2004; pp 395-436.
Compound CuIIL1H exists as a dimeric form in crystal,
where one of the oxygen atoms of the hydroquinone moiety
O1 bridges two copper(II) ions, making a Cu2O2 rhombic
(2) Itoh, S. Dicopper Enzymes. In Comprehensive Coordination Chemistry
II; Que, J. L., Tolman, W. B., Eds.; Elsevier: Amsterdam, The Netherlands, 2004;
pp 369-393.
(3) Klinman, J. P. Chem. Rev. 1996, 96, 2541–2562.
(4) Solomon, E. I.; Sundaram, U. M.; Machonkin, T. E. Chem. Rev. 1996,
96, 2563–2606.
(8) Klinman, J. P. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 14766–14768.
(9) Okeley, N. M.; van der Donk, W. A. Chem. Biol. 2000, 7, R159–R171.
(10) Dooley, D. M. J. Biol. Inorg. Chem. 1999, 4, 1–11.
(11) Brazeau, B. J.; Johnson, B. J.; Wilmot, C. M. Arch. Biochem.
Biophys. 2004, 428, 22–31.
(12) Details of the experimental procedures are described in the SI.
(5) Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104,
1013–1045.
(6) Lewis, E. A.; Tolman, W. B. Chem. Rev. 2004, 104, 1047–1076.
(7) Pap, J. S.; Kaizer, J.; Speier, G. Coord. Chem. Rev. 2010, 254, 781–793.
r
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Published on Web 06/25/2010
2010 American Chemical Society

Communication
Inorganic Chemistry, Vol. 49, No. 15, 2010 6821
Figure 1. ORTEP drawing of CuIIL1H showing 50% probability
thermal ellipsoids. Counteranions, the solvent molecule, and hydrogen
atoms are omitted for clarity.
Figure 2. Spectral change observed upon introduction of an O2 gas into
a methanol solution of CuIIL1H (0.5 mM) at room temperature. Inset:
Time course of the absorption change at 410 nm.
core [—O1-Cu1-O1*=81.43(8)ꢀ and —Cu1-O1-Cu1*=
98.58(7)ꢀ]. The copper ion exhibits a distorted square-pyr-
amidal geometry (τ = 0.22),13 where the three nitrogen atoms
N1, N2, and N3 and the oxygen atom O1 from the same ligand
occupy the corners of the basal plane and the oxygen atom
O1* from another copper(II) monomer unit possesses the
ligand L2H) was isolated by an ordinary workup treatment
(demetalation) using an NH3 aqueous solution and following
SiO2 column chromatography. Figure S4 in the SI shows the
1H NMR spectrum of modified ligand L2H, where there are
two doublet peaks at δ 6.65 and 6.71, which are magnetically
coupled to each other with J = 10.0 Hz. Thus, there are two
neighboring olefinic protons in L2H. In addition, there is a
broad peak at δ 6.32, which disappeared upon the addition of
D2O. In the 13C NMR shown in Figure S5 in the SI, two
distinct carbonyl carbon atoms are observed at δ 183.8 and
184.2. Furthermore, in the IR spectrum, there are two CdO
stretching vibration peaks at 1682 and 1632 cm-1, together
with an intense O-H vibrational peak at 3417 cm-1. On the
basis of these spectral data, together with the detailed 2D
NMR analyses (HSQC, HH-COSY, and HMBC) shown in
Figure S6 in the SI, the structure of the modified ligand L2H
has been confirmed, as shown in Chart 1 (middle), and all of
the 1H and 13C NMR peaks have been completely assigned, as
indicated in Figures S4 and S5 in the SI, respectively.
˚
axial position [the Cu1-O1* distance is 2.463(2) A]. Because
there is only one counteranion ClO4- per monomer unit, the
hydroquinone oxygen atom O1 directly coordinating to the
˚
copper ion is deprotonated [Cu1-O1 distance is 1.893(2) A],
whereas another oxygen atom, O2, is protonated, thus making
the ligand monoanionic.
The electron spin resonance (ESR) spectrum of CuIIL1H
was taken in CH3OH at 77 K, as shown in Figures S3 in the
Supporting Information, which exhibited a typical spectrum
of copper(II) with a tetragonal geometry (g^ = 2.074, g|| =
2.245, and A|| = 155 G). However, the peak intensity was
relatively weak, and double integration of the ESR spectrum
indicated that the spin density of the solution was ∼40%.
These results indicated that there was an equilibrium between
the monomeric and dimeric forms in solution, where the
dimeric complex might be ESR-silent because of antiferro-
magnetic interaction between the two copper(II) ions bridged
by the phenolic oxygen atoms (Figure 1).
When the aerobic reaction of CuIIL1H was carried out for a
prolonged time (3 days), the methanol adduct [CuII(L3)](ClO4)
(CuIIL3) having a molecular weight of 579.1234 was obtained
as a major product (61% yield; see the Experimental Section).
An isotope labeling experiment using 18O2 unambiguously
demonstrated that one of the oxygen atoms in the complex
originated from O2 (Figure S7 in the SI).14 In this case as
well, the structure of the modified ligand L3H, which was iso-
lated by demetalation and SiO2 column chromatography, has
been determined as indicated in Chart 1 (right) by the IR, 1H
NMR (Figure S8 in the SI), 13C NMR (Figure S9 in the SI),
and 2D NMR (HSQC, HH-COSY, and HMBC; Figure S10
in the SI) analyses.
Furthermore, from an acetone/CH3CN (5:1, v/v) solution
of CuIIL3, another copper(II) complex, [CuII(L4H)](ClO4)
(CuIIL4H), crystallized after several days. The crystal struc-
ture of CuIIL4H is presented in Figure 3, and the crystal-
lographic data and selected bond lengths and angles are listed
in Tables S1 and S2 in the SI, respectively. As is clearly seen in
To examine the O2 reactivity of CuIIL1H, the complex was
treated in methanol under a O2 atmosphere. Figure 2 shows a
UV-vis spectral change of the reaction at room temperature.
The relatively intense ligand-to-metal charge-transferband at
410 nm (ε = 1830 M-1 cm-1) due to CuIIL1H gradually
shifted to 458 nm (ε = 540 M-1 cm-1) without any isosbestic
point between the two absorption bands (410 and 458 nm).
Thus, the reaction may involve several steps. Such a spectral
change was not observed at all in the absence of O2, clearly
demonstrating that O2 was involved to initiate the reaction.
Then, we tried to isolate products from a preparative-scale
reaction in methanol (see the SI). When the reaction was
quenched after 15 min, the initial product [CuII(L2)](ClO4)
(CuIIL2) having a molecular weight of 549.1345 was obtained
in 77% yield. The molecular weight of this product is larger
than that of the starting material CuIIL1H, 535.1337, by 14
mass units, suggesting that both monooxygenation (one oxy-
gen-atom insertion) and dehydrogenation (H2 elimination)
reactions took place. Then, the organic product (modified
(14) Computer simulation of electrospray ionization mass spectrometry
obtained with 18O2 indicated that only 44% 18O was incorporated into the
product. Such a relatively low value of 18O incorporation may be due to an
exchange reaction of the OH group with H2O in the solvent through a similar
mechanism, as shown in Scheme 2.
(13) Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.; Verschoor,
G. C. J. Chem. Soc., Dalton Trans. 1984, 1349–1356.

6822 Inorganic Chemistry, Vol. 49, No. 15, 2010
Tabuchi et al.
Scheme 1. Possible Mechanism for the Formation of CuIIL2 and
CuIIL3
Figure 3. ORTEP drawing of CuIIL4H showing 50% probability ther-
malellipsoids. Counteranions andhydrogenatomsare omittedforclarity.
Chart 2
Scheme 2. Possible Mechanism for the Formation of CuIIL4H
the crystal structure, the -OCH3 group in compound CuIIL3
is replaced by the -OH group in CuIIL4H and one of the oxy-
gen atoms, O1, of the modified ring consists of the equatorial
plane, together with the three nitrogen atoms N1, N2, and N3
of the supporting ligand. Another oxygen atom of the modified
ring, O2, acts as an axial ligand for another copper(II) com-
In the prolonged reaction time, Michael addition of the
solvent molecule methanol occurs at one of the nonsubsti-
tuted olefinic carbon atoms to give CuIIL3H2, which is
further oxidized by O2 to give CuIIL3. During the recrystalli-
zation process, hydrolysis of CuIIL3 may take place through
intermediate C to give CuIIL4H (Scheme 2).
In summary, the O2 reactivity of a copper(II) hydroqui-
none system ,CuIIL1H, has been examined to demonstrate
that the substrate activation could occur to induce oxidative
modification of a hydroxylated aromatic group at a mono-
nuclear copper reaction center. The reaction may involve the
key steps of TPQ and LTQ biogenesis such as inner-sphere
electron transfer, generating an organic radical copper(I)
species, formation of an alkylperoxocopper(II) intermediate,
and Michael addition of the solvent molecules. Further
mechanistic studies are now in progress using a series of
phenol-containing ligands.
˚
plex, Cu1* [O2-Cu1*=2.439(2) A], completing the square-
pyramidal geometry of each copper(II) center (τ = 0.10).13
Thus, in the crystal, oxygen atom O2 on the modified ring
bridges the neighboring copper(II) complexes, constructing a
one-dimensional polymer chain structure (see Figure S2 in
-
the SI). Because there is only one counteranion ClO4 per
monomer unit of complex CuIIL4H, the modified ligand exists
as a monoanionic compound (only one OH group is deproto-
˚
nated). Judging from each C-O and C-C bond length (in A)
of the quinone moiety [C1-O1, 1.266(5); C2-O2, 1.228(5);
C4-O3, 1.328(5); C5-O4, 1.229(5); C1-C2, 1.531(5); C2-
C3, 1.449(5); C3-C4, 1.330(6); C4-C5, 1.507(5); C5-C6,
1.445(5); C6-C1, 1.392(5)], the most plausible canonical form
of the modified ring in CuIIL4H is the one depicted in Chart 2.
A possible mechanism for the formation of complexes
CuIIL2 and CuIIL3 from CuIIL1H is shown in Scheme 1,
where a monomeric form dissociated from the dimer in the
solution is considered as the reactive starting material be-
cause of its coordinatively unsaturated structure. Inner-
sphere electron transfer from the deprotonated hydroqui-
none moiety to copper(II) in CuIIL1H may generate a
transient copper(I) semiquinone radical intermediate, A.
Then, O2 attacks A to generate an alkylperoxo-type inter-
mediate, B, from which heterolytic cleavage of the O-O
bond may occur to give the quinone derivative CuIIL2.
Acknowledgment. This work was financially supported
by Grants-in-Aid for Science Research on Priority Areas
(Grant 200360044, Synergy of Elements; Grant 21108515,
π-Space) from Ministry of Education, Culture, Sports,
Science and Technology, Japan, and also by the Asahi Glass
Foundation and Mitsubishi Foundation. We also thank
Dr. Kyoko Inoue of the analytical center of Osaka University
for her assistance in obtaining the 2D NMR data.
Supporting Information Available: Further details are given in
Tables S1 and S2, Figures S1-S10, and in a CIF file. This
material is available free of charge via the Internet at http://
pubs.acs.org.