Mechanistic studies of aliphatic ligand hydroxylation of a copper complex by dioxygen: A model reaction for copper monooxygenases

Article abstract of DOI:10.1021/ja972809q

Mechanistic studies on the aliphatic ligand hydroxylation in a copper complex of tridentate ligand la {N,N-bis[2-(2-pyridyl)ethyl]-2- phenylethylamine} by O₂ have been performed in order to shed light on the structure and reactivity of the active oxygen species of our functional model for copper monooxygenases (Itoh, S.; et al. J. Am. Chem. Soc. 1995, 117, 4714). When the copper complex [Cu(II)(1a)(ClO₄)₂] was treated with an equimolar amount of benzoin and triethylamine in CH₂Cl₂ under O₂ atmosphere, efficient hydroxylation occurred selectively at the benzylic position of the ligand to provide oxygenated product 2a {N,N-bis[2- (2pyridyl)ethyl]-2-phenyl-2-hydroxyethylamine} quantitatively. An isotope labeling experiment using ¹⁸O₂ confirms that the oxygen atom of the OH group in 2a originates from molecular oxygen. Spectroscopic analyses using UV-vis, resonance Raman, and ESR on the reaction of [Cu(I)(la)]⁺ and O₂ at low temperature show that a μ-η²:η²-peroxodicopper(II) complex is an initially formed intermediate. Kinetic analysis on the peroxo complex formation indicates that the reaction of the Cu(I) complex and the monomeric superoxocopper(II) species is rate-determining for the formation of the μ- η²:η²-peroxodicopper(II) intermediate. When ligand 1a is replaced by 1,1,2,2-tetradeuterated phenethylamine derivative 1a-d₄, a relatively small kinetic deuterium isotope effect (k(H)/k(D) = 1.8 at -40 °C) is observed for the ligand hydroxylation step. The rate of the hydroxylation step is rather insensitive to the p-substituent of the ligand [(PyCH₂CH₂)₂NCH₂CH₂Ar, 1a Ar = C₆H₅; 1b Ar = p-CH₃C₆H₄, 1c Ar = p-ClC₆H₄, and 1d Ar = p- NO₂C₆H₄)], but it varies depending on the solvent (THF > acetone > CH₃OH > CH₂Cl₂). The p-substituent, the solvent, and the kinetic deuterium isotope effects suggest that O-O bond homolysis of the μ-η²:η²- peroxodicopper(II) intermediate is involved as a rate-determining step in the aliphatic ligand hydroxylation process. Based on the results of the kinetics and the crossover experiments, we propose a mechanism involving intramolecular C-H bond activation in a bis-μ-oxodicopper(III) type intermediate for the ligand hydroxylation reaction.

Full text of DOI:10.1021/ja972809q

2890
J. Am. Chem. Soc. 1998, 120, 2890-2899
Mechanistic Studies of Aliphatic Ligand Hydroxylation of a Copper
Complex by Dioxygen: A Model Reaction for Copper
Monooxygenases
Shinobu Itoh,*,† Hajime Nakao,† Lisa M. Berreau,‡ Toshihiko Kondo,†
Mitsuo Komatsu,† and Shunichi Fukuzumi*,†
Contribution from the Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity,
2-1 Yamada-oka, Suita, Osaka 565, Japan, and the Department of Chemistry, UniVersity of Minnesota,
207 Pleasant Street SE, Minneapolis, Minnesota 55455
ReceiVed August 11, 1997
Abstract: Mechanistic studies on the aliphatic ligand hydroxylation in a copper complex of tridentate ligand
1a {N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine} by O2 have been performed in order to shed light on the
structure and reactivity of the active oxygen species of our functional model for copper monooxygenases
(Itoh, S.; et al. J. Am. Chem. Soc. 1995, 117, 4714). When the copper complex [CuII(1a)(ClO4)2] was treated
with an equimolar amount of benzoin and triethylamine in CH2Cl2 under O2 atmosphere, efficient hydroxylation
occurred selectively at the benzylic position of the ligand to provide oxygenated product 2a {N,N-bis[2-(2-
pyridyl)ethyl]-2-phenyl-2-hydroxyethylamine} quantitatively. An isotope labeling experiment using 18O2
confirms that the oxygen atom of the OH group in 2a originates from molecular oxygen. Spectroscopic analyses
using UV-vis, resonance Raman, and ESR on the reaction of [CuI(1a)]+ and O2 at low temperature show that
a µ-η2:η2-peroxodicopper(II) complex is an initially formed intermediate. Kinetic analysis on the peroxo complex
formation indicates that the reaction of the Cu(I) complex and the monomeric superoxocopper(II) species is
rate-determining for the formation of the µ-η2:η2-peroxodicopper(II) intermediate. When ligand 1a is replaced
by 1,1,2,2-tetradeuterated phenethylamine derivative 1a-d4, a relatively small kinetic deuterium isotope effect
(kH/kD ) 1.8 at -40 °C) is observed for the ligand hydroxylation step. The rate of the hydroxylation step is
rather insensitive to the p-substituent of the ligand [(PyCH2CH2)2NCH2CH2Ar, 1a Ar ) C6H5; 1b Ar )
p-CH3C6H4, 1c Ar ) p-ClC6H4, and 1d Ar ) p-NO2C6H4)], but it varies depending on the solvent (THF >
acetone > CH3OH > CH2Cl2). The p-substituent, the solvent, and the kinetic deuterium isotope effects suggest
that O-O bond homolysis of the µ-η2:η2-peroxodicopper(II) intermediate is involved as a rate-determining
step in the aliphatic ligand hydroxylation process. Based on the results of the kinetics and the crossover
experiments, we propose a mechanism involving intramolecular C-H bond activation in a bis-µ-oxodicopper-
(III) type intermediate for the ligand hydroxylation reaction.
Introduction
using simple metal complexes have been also performed to
provide valuable insight into the O2-binding mode and its
activation mechanism at several metal centers not only in the
enzymatic systems but also in catalytic processes of organic
synthesis.
During the past decade, there has been much progress in Cu/
O2 chemistry. Karlin and co-workers reported the first example
of aromatic ligand hydroxylation in a dinuclear copper(I)
complex by O2 (Scheme 1), opening the current research field
of Cu/O2 bioinorganic chemistry.1a,4,7,8 Reversible O2-binding
There has been considerable interest in O2-binding and
-activation by non-heme metalloenzymes.1-5 Several types of
mono- and multinuclear iron/copper centers of O2 carrier
enzymes and oxygenases have been characterized by extensive
spectroscopic studies, and some of their deoxy and oxy forms
have been structurally identified by recent X-ray crystallographic
investigations.6 Model studies on O2-binding and activation
† Osaka University.
‡ University of Minnesota.
(1) (a) Fox, S.; Karlin, K. D. In ActiVe Oxygen in Biochemistry; Valentine,
J. S., Foote, C. S., Greenberg, A., Liebman, J. F., Eds.; Chapman and Hall:
London, 1995; pp 188-231. (b) Que, L., Jr. In ActiVe Oxygen in
Biochemistry; Valentine, J. S., Foote, C. S., Greenberg, A., Liebman, J. F.,
Eds.; Chapman and Hall: London, 1995; pp 232-275. (c) Nelson, M. J.;
Seitz, S. P. In ActiVe Oxygen in Biochemistry; Valentine, J. S., Foote, C.
S., Greenberg, A., Liebman, J. F., Eds.; Chapman and Hall: London, 1995;
pp 276-312. (d) Funabiki, T., Ed. Oxygenase and Model Systems; Kluwer
Academic Publishers: Dordrecht/Boston/London, 1997.
(2) Feig, A. L.; Lippard, S. J. Chem. ReV. 1994, 94, 759.
(3) Que, L., Jr. In Bioinorganic Catalysis; Reedijk, J., Ed.; Marcel
Dekker: New York, 1993; pp 347-393.
(6) (a) Holm, R. H.; Kennepohl, P.; Solomon, E. I. Chem. ReV. 1996,
96, 2239. (b) Klinman, J. P. Chem. ReV. 1996, 96, 2541. (c) Solomon, E.
I.; Sundaram, U. M.; Machonkin, T. E. Chem. ReV. 1996, 96, 2563. (d)
Que, L., Jr.; Ho, R. Y. N. Chem. ReV. 1996, 96, 2607. (e) Wallar, B. J.;
Lipscomb, J. D. Chem. ReV. 1996, 96, 2625. (f) Kappock, T. J.; Caradonna,
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Tyekla´r, Z.; Karlin, K. D. Acc. Chem. Res. 1989, 22, 241. (c) Karlin, K.
D.; Tyekla´r, Z. AdV. Inorg. Biochem. 1993, 9, 123. (d) Karlin, K. D.;
Kaderki, S.; Zuberbu¨hler, A. D. Acc. Res. Chem. 1997, 30, 139.
(8) (a) Karlin, K. D.; Dahlstrom, P. L.; Cozzette, S. N.; Scensny, P. M.;
Zubieta, J. J. Chem. Soc., Chem. Commun. 1981, 881. (b) Karlin, K. D.;
Hayes, J. C.; Gultneh, Y.; Cruse, R. W.; McKown, J. W.; Hutchinson, J.
P.; Zubieta, J. J. Am. Chem. Soc. 1984, 106, 2121.
(4) Karlin, K. D., Tyekla´r, Z., Eds.; Bioinorganic Chemistry of Copper;
Chapman and Hall: New York, 1993.
(5) Solomon, E. I.; Lowery, M. D. Science 1993, 259, 1575.
S0002-7863(97)02809-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/17/1998

A Model Reaction for Copper Monooxygenases
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2891
Scheme 1
Scheme 2
Chart 1
Chart 2
to a series of dinuclear copper(I) complexes9 and the first crystal
structure of trans-µ-1,2-peroxodicopper(II) complex A (in Chart
1)10 have attracted many researchers in the related area.
Kitajima and Moro-oka’s group reported another type of
µ-peroxodicopper(II) complex having a µ-η2:η2 core (B)11 that
is finally concluded to exist in the enzyme active site of
oxyhemocyanin.12 Introduction of a sterically hindered sub-
stituent such as the tert-butyl group into the ligand face of the
O2-binding pocket made it possible to isolate a monomeric
superoxocopper(II) species in a similar side-on fashion (C).13,14
Tolman and co-workers have further extended the Cu/O2
chemistry to provide valuable information about the O2-
activation mechanism at copper ion centers (Scheme 2).15-18
They also observed formation of a µ-η2:η2-peroxodicopper(II)
species (D) in the reaction of [(i-Pr3TACN)Cu(CH3CN)]+ (i-
Pr3TACN ) 1,4,7-triisopropyl-1,4,7-triazacyclononane) with O2
in CH2Cl2 at -80 °C, where a hydrogen atom abstraction occurs
only from the methine carbon of the isopropyl substituent with
a little amount of N-dealkylation (<15%).15 When the sub-
stituent of the TACN ligand is replaced by benzyl group, O-O
bond homolysis takes place to afford bis-µ-oxodicopper(III)
intermediate E under the same experimental conditions.16 More
interestingly, interconversion between the µ-η2:η2-peroxodi-
copper(II) species and the bis-µ-oxodicopper(III) species is
observed just by changing the solvent between CH2Cl2 and THF,
where the oxidative N-dealkylation occurs efficiently from the
bis-µ-oxodicopper(III) intermediate.17,18 Stack and co-workers
have recently demonstrated that a similar bis-µ-oxodicopper-
(III) species (F) can be generated by starting with a copper(I)
complex with a bidentate ligand such as ethylenediamine
derivatives (Chart 2).19a,b In this case, a novel trinuclear Cu-
(9) (a) Karlin, K. D.; Haka, M. S.; Cruse, R. W.; Gultneh, Y. J. Am.
Chem. Soc. 1985, 107, 5828. (b) Karlin, K. D.; Cruse, R. W.; Gultneh, Y.;
Farooq, A.; Hayes, J. C.; Zubieta, J. J. Am. Chem. Soc. 1987, 109, 2668.
(c) Karlin, K. D.; Haka, M. S.; Cruse, R. W.; Meyer, G. J.; Farooq, A.;
Gultneh, Y.; Hayes, J. C.; Zubieta, J. J. Am. Chem. Soc. 1988, 110, 1196.
(10) (a) Jacobson, R. R.; Tyekla´r, Z.; Farooq, A.; Karlin, K. D.; Liu, S.;
Zubieta, J. J. Am. Chem. Soc. 1988, 110, 3690. (b) Tyekla´r, Z.; Jacobson,
R. R.; Wei, N.; Murthy, N. N.; Zubieta, J.; Karlin, K. D. J. Am. Chem.
Soc. 1993, 115, 2677.
(11) (a) Kitajima, N.; Fujisawa, K.; Moro-oka, Y.; Toriumi, K. J. Am.
Chem. Soc. 1989, 111, 8975. (b) Kitajima, N.; Fujisawa, K.; Fujimoto, C.;
Moro-oka, Y.; Hashimoto, S.; Kitagawa, T.; Toriumi, K.; Tatsumi, K.;
Nakamura, A. J. Am. Chem. Soc. 1992, 114, 1277.
(12) (a) Magnus, K. A.; Hazes, B.; Ton-That, H.; Bonaventura, C.;
Bonaventura, J.; Hol, W. G. J. Proteins: Struct., Funct., Genet. 1994, 19,
302. (b) Magnus, K. A.; Ton-That, H.; Carpenter, J. E. Chem. ReV. 1994,
94, 727.
(13) Fujisawa, K.; Tanaka, M.; Moro-oka, Y.; Kitajima, N. J. Am. Chem.
Soc. 1994, 116, 12079.
(14) A superoxocopper(II) complex with a end-on fashion was reported
by Harata et al. (Harata, M.; Jitsukawa, K.; Masuda, H.; Einaga, H. J. Am.
Chem. Soc. 1994, 116, 10817), but its structure has been recently claimed
to be questionable by Berreau et al. (Berreau, L. M.; Mahapatra, S.; Halfen,
J. A.; Young, V. G., Jr.; Tolman, W. B. Inorg. Chem. 1996, 35, 6339).
(15) Mahapatra, S.; Halfen, J. A.; Wilkinson, E. C.; Que, L., Jr.; Tolman,
W. B. J. Am. Chem. Soc. 1994, 116, 9785.
(16) (a) Mahapatra, S.; Halfen, J. A.; Wilkinson, E. C.; Pan, G.; Cramer,
C. J.; Que, L., Jr.; Tolman, W. B. J. Am. Chem. Soc. 1995, 117, 8865. (b)
Mahapatra, S.; Halfen, J. A.; Wilkinson, E. Z.; Pan, G.; Wang, X.; Young,
V. G., Jr.; Cramer, C. J.; Que, L., Jr.; Tolman, W. B. J. Am. Chem. Soc.
1996, 118, 11555. (c) Mahapatra, S.; Young, Jr., V. G.; Kaderli, S.;
Zuberbuhler, A. D.; Tolman, W. B. Angew. Chem., Int. Ed. Engl. 1997,
36, 130. (d) Tolman, W. B. Acc. Chem. Res. 1997, 30, 227.
(17) (a) Halfen, J. A.; Mahapatra, S.; Wilkinson, E. C.; Kaderli, S.;
Young, V. G., Jr.; Que, L., Jr.; Zuberbu¨hler, A. D.; Tolman, W. B. Science
1996, 271, 1397. (b) Cramer, C. J.; Smith, B. A.; Tolman, W. B. J. Am.
Chem. Soc. 1996, 118, 11283.
(18) Mahapatra, S.; Halfen, J. A.; Tolman, W. B. J. Am. Chem. Soc.
1996, 118, 11575.

2892 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Itoh et al.
(II)Cu(ΙΙ)Cu(III) mixed valence complex with two µ3-oxo
bridges (G) is also formed, probably due to the reaction between
the bis-µ-oxodicopper(III) intermediate and another Cu(I)
species.19c Krebs and co-worker reported another type of
tetranuclear Cu(II)4 µ4-peroxo species H which was produced
by the treatment of Cu(II) ion and the bidentate phenolate
diamine ligand with 3,5-di-tert-butyl catecolate (reductant) under
aerobic conditions.19d
Scheme 3
In contrast to the quantitative aromatic ligand hydroxylation
reaction observed in a series of dinuclear copper(I) complex-
O2 systems,8,20 quantitatiVe aliphatic ligand hydroxylation is
still very rare.18,19a,21 In this context, we have recently found
that quantitative ligand hydroxylation occurs selectively at the
benzylic position of the substrate moiety of the ligand, when
[CuII(1a)(ClO4)2] (I, 1a ) N,N-bis[2-(2-pyridyl)ethyl]-2-phe-
nylethylamine) is treated with an equimolar amount of benzoin
and triethylamine under O2 atmosphere (Scheme 3).22 Such a
system can be regarded as a functional model for copper
monooxygenases catalyzing alkane hydroxylation reactions such
as particulate methane monooxygenase (pMMO), dopamine
â-hydroxylase (DâH), or peptidylglycine R-amidating mo-
nooxygenase (PAM). Here, we have performed mechanistic
studies of the aliphatic ligand hydroxylation reaction (Scheme
3) to demonstrate that the benzylic hydroxylation occurs via a
rate-determining O-O bond homolysis of a µ-η2:η2-peroxodi-
copper(II) complex formed from [CuI(1a)]+ and O2 during the
course of the reaction. Mechanisms of the hydroxylation
process are discussed on the basis of the results of kinetics and
product analyses of the crossover experiments.
ascorbate,25 in CH2Cl2 at room temperature for 2 h under Ar.
The mixture was then stirred under an atmospheric pressure of
O2 for 24 h. The hydroxylated ligand 2a was isolated
quantitatively (100%) after an ordinary workup treatment of the
reaction mixture with aqueous NH4OH and following extraction
by CH2Cl2 (Scheme 3).24
The mass spectroscopic analysis of the modified ligand 2a
obtained in the same reaction with 18O2 (96% content) clearly
showed that the oxygen atom of the OH group came from
molecular oxygen (more than 95% of 18O was incorporated;
peak height of M+:(M++ 2) ) 11:100). The stoichiometry of
O2 to Cu(II) in this reaction was determined as 1:1 by a
manometric measurement. The ligand hydroxylation was only
observed in the presence of all reaction components together,
i.e., benzoin, triethylamine, and O2 in addition to the copper
complex.
The same reaction as shown in Scheme 3 occurred when
[CuΙ(1a)]PF6 was treated with O2 in CH2Cl2. In this case,
however, the yield of hydroxylation was not more than 50%
based on the Cu ion, and the stoichiometry of Cu:O2 became
2:1. Such a stoichiometry indicates clearly that 2 equiv of
electrons and 1 equiv of O2 are required for the single ligand
hydroxylation process (50% conversion). Starting from Cu(I),
the isolated yield of the hydroxylated ligand reached the
maximum value (50%) in about 5 h, while starting from Cu(II)
in the presence of benzoin and triethylamine, it took about 24
h to reach completion. When hydroquinone (1 equiv), a more
powerful reductant than benzoin, was used as an electron donor,
the rate of the reaction became as fast as that starting from Cu-
(I). The yield of hydroxylation was lower (62%), however,
probably because hydroquinone itself reacted with O2 to be
oxidized to benzoquinone under the present reaction conditions.
These results indicate that the reduction of Cu(II) to Cu(I) is
the rate-determining step in the benzoin/triethylamine system
at room temperature.
Results and Discussion
Aliphatic Ligand Hydroxylation (Product Analysis and
Stoichiometry). During the course of O2-activation process in
enzymatic systems, electrons are injected into O2 at a metal
center from an external electron donor, such as ascorbate in
DâH and PAM.23 To mimic such a process, we first tried to
examine the reaction of the Cu(II) complex of tridentate ligand
1a and O2 in the presence of a reductant (Scheme 3). The Cu-
(II) complex [CuII(1a)(ClO4)2] (I in Scheme 3)24 was treated
with an equimolar amount of the 1,2-enediolate derived from
benzoin and triethylamine, which is used as a model of
(19) (a) Mahadevan, V.; Hou, Z.; Cole, A. P.; Root, D. E.; Lal, T. K.;
Solomon, E. I.; Stack, T. D. P. J. Am. Chem. Soc. 1997, 119, 11996. (b)
DuBois, J. L.; Mukherjee, P.; Collier, A. M.; Mayer, J. M.; Solomon, E. I.;
Hedman, B.; Stack, T. D. P.; Hodgson, K. O. J. Am. Chem. Soc. 1997,
119, 8578. (c) Cole, A. P.; Root, D. E.; Mukherjee, P.; Solomon, E. I.;
Stack, T. D. P. Science 1996, 273, 1848. (d) Reim, J.; Krebs, B. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1969.
(20) (a) Gagne, R. R.; Gall, R. S.; Lisensky, G. C.; Marsh, R. E.; Speltz,
L. M. Inorg. Chem. 1979, 18, 771. (b) Nasir, M. S.; Karlin, K. D.; McGowty,
D.; Zubieta, J. J. Am. Chem. Soc. 1991, 113, 698. (c) Casella, L.; Gullotti,
M.; Pallanza, G.; Rigoni, L. J. Am. Chem. Soc. 1988, 110, 4221. (d) Gelling,
O. J.; Meetsma, A.; Feringa, B. L. Inorg. Chem. 1990, 29, 2816. (e) Sorrell,
T. N.; Vankai, V. A.; Garrity. M. L. Inorg. Chem. 1991, 30, 207.
(21) (a) Sprecher, C. A.; Zuberbu¨hler, A. D Angew. Chem. 1977, 89,
185. (b) Urbach, F. L.; Knopp, U.; Zuberbu¨hler, A. D. HelV. Chim. Acta
1978, 61, 1097. (c) Thompson, J. S. J. Am. Chem. Soc. 1984, 106, 8308.
(d) Patch, M. G.; McKee, V.; Reed, C. A. Inorg. Chem. 1987, 26, 776. (e)
Koziol, A. E.; Palenik, R. C.; Palenik, G. J. J. Chem. Soc., Chem. Commun,
1989, 650. (f) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1991, 32,
3831. (g) Amade´i, E.; Alilou, E. H.; Eydoux, F.; Pierrot, M.; Re´glier, M.;
Waegell, B. J. Chem. Soc., Chem. Commun. 1992, 1782. (h) Allen, W. E.;
Sorrell, T. N. Inorg. Chem. 1997, 36, 1732.
Reaction Intermediate. The hydroxylated ligand 2a was
also obtained in 33% yield when [CuII(1a)(ClO4)2] was treated
with H2O2 (10 equiv) in CH3OH for 18 h under Ar. On the
(22) Itoh, S.; Kondo, T.; Komatsu, M.; Ohshiro, Y.; Li, C.; Kanehisa,
N.; Kai, Y.; Fukuzumi, S. J. Am. Chem. Soc. 1995, 117, 4714.
(23) Stewart, L. C.; Klinman, J. P. Annu. ReV. Biochem. 1988, 57, 551.
(24) Crystal structures of the copper(II) complex I and dimeric copper-
(II) complex J of the hydroxylated ligand 2a (Scheme 3) have been reported
in ref 22.
(25) Itoh, S.; Mure, M.; Ohshiro, Y. J. Chem. Soc., Chem. Commun.
1987, 1580.

A Model Reaction for Copper Monooxygenases
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2893
Figure 1. Spectral change observed upon introduction of O2 gas into the THF solution of [CuI(1)]PF6 (2.5 × 10-3 M) at -80 °C in a 1 mm path
length UV cell: (A) O2-adduct formation, 30 s interval; (B) ligand hydroxylation, 5 min interval.
Figure 2. Resonance Raman spectra obtained with 514.5 nm excitation
on frozen (77 K) acetone solutions of (A) [CuII2(µ-16O2)(1a-d4)2](PF6)2
and (B) [CuII2(µ-18O2)(1a-d4)2](PF6)2.
Figure 3. Time course of the absorption change at 362 nm in the
reaction of [CuI(1)]PF6 (2.5 × 10-3 M) and O2 in THF at -80 °C.
Inset: second-order plot based on the absorbance change at 362 nm.
other hand, the reaction with tert-butyl hydroperoxide, cumene
hydroperoxide, or m-chloroperoxybenzoic acid (m-CPBA) gave
no hydroxylation product under the same experimental condi-
tions as those with H2O2.26 These results together with the
stoichiometry mentioned above (Cu(I):O2 ) 2:1) indicate that
a µ-peroxodicopper(II) species is involved as a reaction
intermediate.
Figure 1 shows the spectral change observed upon introduc-
tion of O2 gas into a THF solution of [CuI(1a)]PF6 at -80 °C.
The Cu(I) complex itself has no characteristic absorption in the
visible region, but introduction of O2 gas into the solution causes
a drastic spectral change. After a few minutes, we obtained a
spectrum with a strong absorption at 362 nm together with a
small one around 526 nm (Figure 1A). The final spectrum
shown in Figure 1A is very close to that reported for µ-η2:η2-
species B in Chart 1 and D in Scheme 2. Essentially the same
spectrum was obtained independently in the reaction of [CuII-
(1a)(ClO4)2] and H2O2 (10 equiv) in the presence of a base such
as triethylamine. Furthermore, this species was ESR silent,
indicating that there is a strong anti-ferromagnetic interaction
between the two cupric ions as seen in the case of other µ-η2:
η2 core systems.11,15
Figure 2 shows the resonance Raman spectrum obtained with
514.5 nm excitation on a frozen (77 K) acetone solution of
[CuII (µ-16O2)(1a-d4)2](PF6)2 (1a-d4 ) N,N-bis[2-(2-pyridyl)-
2
ethyl]-1,1,2,2-tetradeuterio-2-phenylethylamine). A character-
istic absorption is observed at 746 cm-1 that shifts to 704 cm-1
upon 18O2 substitution.27 The observed νO-O value at 746 cm-1
and the isotopic shift (∆ν ) 42 cm-1) are very close to those
reported for the structurally characterized µ-η2:η2-peroxodicop-
per(II) complex by Kitajima et al.11 and other related sys-
tems,15,28 confirming that µ-peroxodicopper(II) complex formed
in the present system has a µ-η2:η2 core. There is, however,
no evidence for formation of the bis-µ-oxodicopper(III) inter-
mediate at around 600 cm-1
.
At the prolonged reaction time, the characteristic spectrum
of the µ-η2:η2-peroxodicopper(II) species gradually decreases
even at the low temperature as shown in Figure 1B, which
corresponds to the ligand hydroxylation reaction as discussed
below.
O2-Binding Process. Figure 3 shows the time course of the
absorption change due to formation of the µ-η2:η2-peroxodi-
copper(II) complex at the low temperature in THF. In order to
keep the O2 concentration constant, dioxygen gas was continu-
Resonance Raman spectra of the intermediate provided a
further evidence of the µ-η2:η2-peroxodicopper(II) core structure.
(27) High reactivity of the µ-peroxodicopper(II) complex has precluded
getting a solution resonance Raman spectrum at -80 °C: Itoh, S.; Nakao,
H.; Fukuzumi, S.; Mukai, M.; Kitagawa, T. Unpublished results.
(28) Sorrell, T. N.; Allen, W. E.; White, P. S. Inorg. Chem. 1995, 34,
952.
(26) Re´glier et al. reported that the ligand hydroxylation occurs only at
the o-position of one pyridine nucleus in the reaction of Cu(I) complex of
the same ligand 1a with iodosylbenzene: Re´glier, M.; Amade¨ı, E.; Tadayoni,
R.; Waegell, B. J. Chem. Soc., Chem. Commun. 1989, 447.

2894 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Itoh et al.
Figure 4. Eyring plot for the formation of the µ-η2:η2-peroxodicopper-
(II) intermediate in THF.
Figure 5. First-order plot for the ligand hydroxylation process in THF
at -80 °C.
Scheme 4
oxocopper(II) intermediate and another Cu(I), is rate-determin-
ing. The activation parameters for the formation of the
monomeric superoxocopper(II) intermediate (the first step) and
the formation of the trans-µ-1,2-peroxodicopper(II) complex (the
second step) were reported as ∆Hq ) 32 ( 4 kJ mol-1, ∆Sq )
14 ( 18 JK-1 mol-1 and ∆Hq ) 14 ( 1 kJ mol-1, ∆Sq ) -78
( 2 J K-1 mol-1, respectively.31 In the case of i-Pr3TACN
ligand system (see, Scheme 2), superoxocopper(II) complex
formation (the first step) is the rate-determining step and the
activation parameters are ∆Hq ) 37.2 ( 0.5 kJ mol-1 and ∆Sq
ously supplied by gentle bubbling. Although there is a small
lag phase at the very beginning of the reaction due to the time
required for O2-saturation into the solution,29 the time course
after the lag phase can be fitted by second-order kinetics. The
second-order rate constant was obtained as the slope of the linear
line of the second-order plot shown in the inset of Figure 3.
The observed second-order rate constant was essentially constant
) -62 ( 2 J K-1 mol-1 17a
These values are close to those of
.
the superoxocopper(II) complex formation with sterically more
hindered BQPA [bis(2-quinolyl)(2-pyridyl)methylamine] ligand.31b
Thus, the present system is closer to that of the Karlin’s system
with regard to the O2-binding,30 although the overall O2-binding
process is irreversible at the low temperature. When the solution
of the µ-η2:η2-peroxodicopper(II) complex of the present system
was subjected to vacuum at the low temperatures (from -80 to
-60 °C), there was no spectral change due to the dissociation
of O2 from the peroxo intermediate.32 Several factors such as
steric hindrance, hydrophobicity in the O2-binding pocket, and
the redox potential of the copper center may be responsible for
such differences in reactivity of the Cu(I) complexes toward
O2.
Kinetics of the Benzylic Ligand Hydroxylation. In contrast
to the bimolecular O2-binding process, the ligand hydroxylation
reaction (the second-phase process, Figure 1B) obeys first-order
kinetics with respect to the peroxo complex as indicated in
Figure 5. The activation parameters are determined as ∆Hq )
28.1 ( 1.0 kJ mol-1 and ∆Sq ) -155 ( 5 J K-1 mol-1 by the
Eyring plot shown in Figure 6 (line H). Such a large negative
∆Sq value suggests that the rate-determining step of the
hydroxylation reaction requires a highly constrained transition
state as discussed below.
(11 ( 1 M-1 -1
s ) within a wide range of the initial concentrations
of the Cu(I) complex from 0.45 to 5.9 mM. Thus, it can be
concluded that the bimolecular reaction between the monomeric
superoxocopper(II) complex [CuII(1a)(O2-)]+ and another Cu-
(I) complex is rate-determining (Scheme 4), although direct
detection of such a monomeric superoxo species has not been
successful yet.29 From the dependence of the rate constants on
the reaction temperature shown as an Eyring plot in Figure 4
were obtained the activation enthalpy (∆Hq) of 19.3 ( 0.4 kJ
mol-1 and the activation entropy (∆Sq) of -91.6 ( 2.0 J K-1
mol-1 for the µ-η2:η2-peroxodicopper(II) complex formation.
In the Karlin’s system shown in Scheme 1, reversible
dioxygen binding to the dinuclear Cu(I) site occurs in a single
observable step with the low activation enthalpy (∆Hq ) 8.2 (
0.1 kJ mol-1) and the largely negative activation entropy (∆Sq
) -146 ( 1 JK-1 mol-1).30 They suggested that the µ-peroxo
intermediate had a bent µ-η2:η2 core that underwent the aromatic
ligand hydroxylation reaction in Scheme 1. They also inves-
tigated the reversible formation of trans-µ-1,2-peroxodicopper-
(II) complex using the monomeric Cu(I) complex with a
tetradentate ligand (see A in Chart 1), where they detected a
monomeric superoxocopper(II) intermediate. In such a case,
the second step, the reaction between the monomeric super-
Kinetic deuterium isotope effect on the ligand hydroxylation
process was examined using 1a-d4 as a ligand. As in the case
of 1a, only the benzylic position of the phenethylamine sidearm
was hydroxylated in a 50% yield, when [CuI(1a-d4)]PF6 was
treated with O2 in CH2Cl2 at room temperature for 24 h. The
1H NMR spectrum of the organic product obtained in a similar
workup treatment clearly showed that the ethylene group of the
pyridine sidearms remained intact and that all proton peaks of
(29) Direct injection of a concentrated solution of the Cu(I) starting
materials into the solvent saturated with dioxygen at the low temperature
may remove the lag phase observed in Figure 3, enabling us to detect the
initially formed Cu(I)-superoxo intermediate (Scheme 4). However, the
limited solubility of the Cu(I) starting materials in THF has precluded doing
this experiment.
(30) (a) Cruse, R. W.; Kaderli, S.; Karlin, K. D.; Zuberbu¨hler, A. D. J.
Am. Chem. Soc. 1988, 110, 6882. (b) 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.
(31) (a) Karlin, K. D.; Wei, N.; Jung, B.; Kaderli, S.; Zuberbu¨hler, A.
D. J. Am. Chem. Soc. 1991, 113, 5868. (b) Karlin, K. D.; Wei, N.; Jung,
B.; Kaderli, S.; Niklaus, P.; Zuberbu¨hler, A. D. J. Am. Chem. Soc. 1993,
115, 9506.
(32) The follow-up reaction (ligand hydroxylation) prevents us from
examining the reversibility of the O2-binding at higher temperature (>-40
°C).

A Model Reaction for Copper Monooxygenases
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2895
Table 1. Solvent and Counteranion Effects on the UV-Vis
Spectrum and the Formation and Decay Rate Constants (k1 and k2)
of the µ-η2:η2-Peroxodicopper(II) Complex at -80 °C
run solvent counteraniona λmax
k1 (M-1 s-1
)
104k2 (s-1
)
b
-
1
2
3
4
5
6
7
THF
PF6
PF6
PF6
PF6
362
362
362
362
362
360
362
10.0
2.0
2.0
0.14
2.1
0.61
1.9
8.1
4.8
3.1
0.86
3.2
3.0
2.8
-
-
-
acetone
CH3OH
CH2Cl2
CH3OH
CH3OH
CH3OH
-
ClO4
CF3SO3
BPh4
-
-
a The counteranion effect was investigated mainly in CH3OH because
of the low solubility of the ClO4- and BPh4- salts in THF. b Although
the ꢀmax value could not be determined directly because of the
subsequent ligand hydroxylation reaction (k2 process), the ꢀmax values
were estimated to be (1.56 ( 0.06) × 104 M-1 cm-1 by computer curve
fitting of the second-order plot for the k1 process.
Figure 6. Eyring plot for the ligand hydroxylation of (H) [CuI(1a)]-
PF6 and (D) [CuI(1a-d4)]PF6 by O2 in THF.
formation of the µ-η2:η2-peroxodicopper(II) complex (k1) and
the ligand hydroxylation step (k2) were then determined in each
solvent system. It is obvious that both k1 and k2 values vary
significantly depending on the solvent. Although both of the
rate constants have no relation with dielectric constant (ꢀ) or
dipole moment of the solvents, a solvent having an oxygen donor
ability such as THF enhances both processes. Interestingly, the
ligand hydroxylation (k2 process) proceeds most efficiently in
THF (run 1) which is the most favorable solvent for the
formation of bis-µ-oxodicopper(III) species in the reaction of
[(i-Pr3TACN)Cu(CH3CN)]+ and O2 (Scheme 2), while it
proceeds most slowly in CH2Cl2 (run 4) in which µ-η2:η2-
peroxodicopper(II) complex is a major component in the i-Pr3-
TACN system.
the hydroxylated ligand from 1a-d4 were identical to those of
2a. An Eyring plot for the ligand hydroxylation reaction of
[CuI(1a-d4)]PF6 by O2 is also shown in Figure 6 (line D). The
kinetic isotope effect (KIE) for the ligand hydroxylation process
was 5.9 at -80 °C in THF, but the KIE value decreases to 1.8
at -40 °C. The small KIE value shows a sharp contrast with
the case of [Cu2(µ-O)2(L)2]2+ (Scheme 2 and Chart 2), where
significant kinetic deuterium isotope effects were observed: kH/
kD ) 26 for L ) i-Pr3-TACN and kH/kD ) 40 for L ) Bn3-
TACN at -40 °C in THF and kH/kD ) 3.0 for L ) N,N,N′,N′-
tetraethylcyclohexanediamine at 20 °C for the oxidative
N-dealkylation process (C-H bond cleavage).18,19a,33 Similarly,
Que et al. recently reported a very large kinetic deuterium
isotope effect of kH/kD ) 20 at -40 °C for the hydrocarbon
hydroxylation by a high-valent [Fe2(µ-O)2(TAP)2]3+ species
[TAP ) tris(2-pyridylmethyl)amine].34 From the Eyring plot
shown in Figure 6 are determined the activation parameters as
Counteranions have been also demonstrated to affect the ratio
of µ-η2:η2-peroxodicopper(II) to bis-µ-oxodicopper(III) species.16b
-
-
Tolman et al. reported that ClO4 and PF6 gave only bis-µ-
-
-
oxo species in THF but that CF3SO3 and BPh4 gave a 4:1
mixture of µ-η2:η2-peroxodicopper(II) complex and bis-µ-
oxodicopper(III) complex. As seen in Table 1 (compare runs
3 and 5-7), the major species formed in the present system is
always µ-η2:η2-peroxodicopper(II) complex, and the absorption
ratio A362/A430 is almost constant within the experimental error
(10 ( 0.5). The counteranion effects on both the O2-adduct
formation process (k1) and the ligand hydroxylation reaction
(k2) were, however, relatively small as compared to the solvent
effects mentioned above.
∆HD ) 40.3 ( 1.3 kJ mol-1 and ∆SD ) -107 ( 6 J K-1
mol-1. The extrapolation of the Eyring plots gives the KIE
value being unity at -16 °C, when the rate-determining step
may be a process that precedes the hydrogen transfer.35 Thus,
the O-O bond cleavage may be involved as a rate-determining
step which is followed by the facile hydrogen transfer at the
higher temperature (>-16 °C) as discussed in more detail
below.
Solvent and counteranion effects of the reaction of [CuI(1a)]+
and O2 at -80 °C are summarized in Table 1. The spectrum
of active oxygen intermediate obtained in each solvent system
(THF, acetone, CH3OH, and CH2Cl2) has essentially the same
feature having a λmax at 362 nm due to the µ-η2:η2 core.
Interconversion between the µ-η2:η2-peroxodicopper(II) species
and the bis-µ-oxodicopper(III) species (Scheme 2) is not
observed by changing the solvent in the present system, since
the absorption ratio between 362 and 430 nm in each solvent is
nearly constant (A362/A430 ) 10 ( 0.4). This is consistent with
the resonance Raman spectrum of the frozen acetone solution
(Figure 2), where no feature due to bis-µ-oxodicopper(III)
species around 600 cm-1 can be seen.16 The rate constants for
q
q
Electronic effects of the p-substituents (X ) H, CH3, Cl, NO2)
on the benzene ring of the ligand (1a-d) have been also
examined both on the k1 and k2 processes as summarized in
Table 2. Because of the low solubility of [CuI(1d)]PF6 in CH3-
OH, the substituent effect of the nitro group was examined in
acetone by comparing the reactivity of [CuI(1d)]PF6 to that of
[CuI(1a)]PF6 under the same experimental conditions (runs 4
and 5). While the electron-donating substituent retards the O2-
adduct formation process (k1),36 the electronic effect on the
ligand hydroxylation process (k2) is negligible. Little effect of
the p-substituent on the k2 process also suggests that the benzylic
(33) For the electrophilic aromatic hydroxylation reaction in the dinuclear
Cu(I) complex shown in Scheme 1, Karlin et al. reported the absence of
kinetic deuterium isotope effect.30a This is reasonable since the electrophilic
attack of the peroxo species upon the proximate aromatic substrate is the
rate-determining step in their system: Nasir, M. S.; Cohen, B. I.; Karlin,
K. D. J. Am. Chem. Soc. 1992, 114, 2482.
(34) Kim, C.; Dong, Y.; Que, L., Jr. J. Am. Chem. Soc. 1997, 119, 3635.
(35) The direct hydrogen abstraction mechanism in the µ-η2:η2-perox-
odicopper(II) core can be ruled out, since a large kinetic isotope effect (kH/
kD ) 18 at 25 °C) was detected in the direct C-H bond cleavage in the
µ-η2:η2 core of [Cu2(µ-O2)(i-Pr3-TACN)2]2+ in CH2Cl2.15

2896 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Itoh et al.
Formation of the µ-η2:η2-peroxodicopper(II) complex (K) as
an initial O2-adduct is evident from the stoichiometry of Cu:O2
) 2:1 and the spectroscopic characterization using UV-vis,
resonance Raman, and ESR. Generation of an identical UV-
vis spectrum in the reaction of [CuII(1a)(ClO4)2] and H2O2 to
that obtained in the reaction between [CuI(1a)]PF6 and O2 is
also an evidence for the formation of the µ-η2:η2-peroxodicop-
per(II) complex. Involvement of the following O-O bond
homolysis of the peroxo intermediate prior to the ligand
hydroxylation reaction is implicated by (i) the small KIE values
(kD/kH ) 1.8 at -40 °C and the extrapolated value of 1.0 above
-16 °C) and (ii) no p-substituent effect (Table 2) on the k2
process. The solvent effects (THF > acetone > CH3OH > CH2-
Cl2) on the k2 process shown in Table 1 also suggest a significant
contribution of the O-O bond homolysis of the peroxo
intermediate as demonstrated in the Tolman i-Pr3TACN ligand
system.17 In other words, µ-η2:η2-peroxodicopper(II) complex
(K) is not a real active species for the C-H bond activation.
The O-O bond homolysis of the µ-η2:η2 core will produce a
bis-µ-oxodicopper(III)-type intermediate (L)39 and/or a mono-
meric Cu(II)-O• species (M). However, the largely negative
activation entropy (∆Sq ) -155 ( 5 J K-1 mol-1) observed
on the k2 process may rule out the direct formation of the
monomeric Cu(II)-O• species from the µ-η2:η2-peroxodicopper-
(II) complex (K), since such a process is entropically favorable,
producing a positive ∆Sq value. Formation of the isotope
scrambling products, 2a(16OH) and 2c(18OH), in the double-
labeling experiment, however, indicates that the monomeric Cu-
(II)-O• species (M) is also involved somewhere in the
mechanism of the ligand hydroxylation reaction. We assume
that the monomeric Cu(II)-O• species (M) is formed from the
bis-µ-oxodicopper(III) intermediate (L), and M is in equilibrium
with L. The isotope scrambling between 16O and 18O may occur
in this stage. The hydrogen abstraction from the benzylic
position of the ligand sidearm producing N and O or concerted
oxygen atom insertion producing P and O occurs from
intermediate L intramolecularly.40 No ligand scrambling in the
Table 2. p-Substituent Effects on the Formation and Decay Rate
Constants (k1 and k2) of the µ-η2:η2-Peroxodicopper(II) Complex at
-80 °Ca
run
X (ligand)
solvent
λmax
k1 (M-1 s-1
)
104k2 (s-1
)
1
2
3
4
5
CH3 (1b)
H (1a)
Cl (1c)
H (1a)
NO2 (1d)
CH3OH
CH3OH
CH3OH
acetone
acetone
360
362
362
362
362
0.39
2.0
4.1
1.8
7.1
3.1
3.1
3.7
4.8
5.1
-
a Counteranion: PF6
.
hydrogen transfer is not involved in the rate-determining step
of the benzylic hydroxylation process.
Crossover Experiment. The oxidative N-dealkylation reac-
tion in the Tolman bis-µ-oxodicopper(III) system (Scheme 2)
has been shown to be an intramolecular process in its diamond
core.18 On the other hand, Kitajima and co-workers reported
that µ-η2:η2-peroxodicopper(II) complex [Cu[HB(3,5-Me2pz)3]]2-
(O)2 (B in Chart 1; R ) Me) spontaneously decomposes into
the corresponding µ-oxodicopper(II) complex via rate-determin-
ing O-O bond homolysis of the µ-peroxo species. In the later
case, they proposed that the O-O bond homolysis resulted in
formation of a monomeric Cu(II)-O• species, which would react
rapidly with the remained Cu(I) species via an intermolecular
pathway to provide the final µ-oxodicopper(II) product.37 Thus,
to determine whether the present ligand hydroxylation reaction
proceeds via an intramolecular pathway through a bis-µ-
oxodicopper(III)-type intermediate or via the C-H bond activa-
tion involving an intermolecular process with a monomeric
Cu(II)-O• species, we performed a double-labeling experiment
by mixing CH2Cl2 solutions of [CuII (1a)2(µ-18O2)]2+ and [CuII -
2
2
(1c)2(µ-16O2)]2+ as has been done in the R3TACN system.18
Only 2a(18OH) and 2c(16OH) in 1:1 ratio would be obtained if
the reaction occurs solely via the intramolecular pathway,
whereas a mixture comprised of equivalent amounts of 2a(18-
OH), 2a(16OH), 2c(16OH), and 2c(18OH) would be produced if
the hydroxylation reaction proceeds via the intermolecular
process.
crossover experiment between [CuII(1a)(ClO4)2]2+ and [CuII -
The double-labeling experiment using [CuII (1a)2(µ-18O2)]2+
2
2
(1c)2(µ-16O2)]2+ may rule out the intermolecular attack by bis-
µ-oxo species L or by monomeric Cu(II)-O• species M on the
ligand sidearm of another molecule. Thus, the intramolecular
process in the bis-µ-oxodicopper(III) type intermediate (L) is
the only pathway for the benzylic ligand hydroxylation, and
we propose that the monomeric Cu(II)-O• species (M) is
contributed only in the isotope scrambling between 16O and 18O.
and [CuII (1c)2(µ-16O2)]2+ at -80 °C gave us a mixture of 2a(18-
2
OH), 2c(16OH), 2a(16OH), and 2c(18OH) in a 0.87:1:0.36:0.37
ratio. The two peroxo complexes prepared separately were
mixed after removal of excess amounts of 18O2 and 16O2 by
placing the reaction vessel under vacuum. Formation of 2a(18-
OH) and 2c(16OH) in nearly 1:1 ratio as the major products
indicates that the intramolecular process is the major pathway
for the ligand hydroxylation reaction. On the other hand, mixing
of a CH2Cl2 solution of [CuII(1a)(ClO4)2]2+ and an equimolar
(38) In this paper, the monomeric species formed from the peroxo
intermediate by O-O bond homolysis is described as Cu(II)-O•, although
another canonical form Cu(III)dO is also possible. In the present system,
however, we could not characterize such a monomeric copper-oxygen
species, since it is just a transient reactive intermediate, if it is formed.
(39) When [CuI(Py2CH2CH2CH2Ph)](ClO4) (Py2CH2CH2CH2Ph ) N,N-
bis[2-(2-pyridyl)ethyl]-3-phenylpropylamine) was used instead of [CuI(1a)]-
(ClO4), the k2 process significantly slowed (k2 ) 5.1 × 10-5 s-1 in CH3OH
at -80 °C) and the absorption ratio between 358 nm vs 430 nm became
smaller (A358/A430 ) 5.8) as compared to that of [CuII2(1a)2(µ-O2)](ClO4)2
(A362/A430 ) 10). These results suggest that bis-µ-oxodicopper(III) inter-
mediate (λmax ) ca. 430 nm) can be accumulated to some extent when the
ligand hydroxylation process becomes slow. Our attempt to detect the bis-
µ-oxodicopper(III) intermediate in this system by resonance Raman spectrum
was not successful though (Berreau, L. M.; Tolman, W. B.; Que, L., Jr.
Unpublished result). The low-temperature (-80 °C) UV-vis examination
on the reactions of [CuI(L)]+ and O2 in THF {L ) Py2CH2Ph (N,N-bis[2-
(2-pyridyl)ethyl]benzylamine) and Py2CH2CH2CH2CH3 (N,N-bis[2-(2-py-
ridyl)ethyl]butylamine)} also showed the predominant formation of the µ-η2:
η2-peroxodicopper(II) species.
amount of [CuII (1c)2(µ-16O2)]2+ in CH2Cl2 at -80 °C gave us
2
only 2c(16OH) as the oxygenated product. This result suggests
that neither exchange of 18O2 and 16O2 at the peroxo stage nor
the intermolecular ligand hydroxylation occurs. Thus, we
assume that the ligand hydroxylation reaction proceeds intramo-
lecularly in a bis-µ-oxo diamond core intermediate and the
isotope scrambling products 2a(16OH) and 2c(18OH) are pro-
duced by isotope exchange between 16O and 18O through the
monomeric Cu(II)-O• species38 as discussed below.
Mechanistic Consideration. On the basis of all the results
described above, we propose a mechanism for the aliphatic
ligand hydroxylation reaction, as illustrated in Scheme 5.
(36) The electron-donating substituent would increase the d-π interaction
between the copper center and the benzene ring, which may prevent the
interaction of the copper center with dioxygen by a steric hindrance. Details
about such interaction in the copper complexes will be reported elsewhere.
(37) Kitajima, N.; Koda, T.; Iwata, Y.; Moro-oka, Y. J. Am. Chem. Soc.
1990, 112, 8833.
(40) With regard to the mechanism of the ligand hydroxylation process
in the bis-µ-oxodicopper(III) core, Tolman et al. have proposed that both
the “hydrogen abstraction-oxygen rebound” and “direct oxygen insertion”
mechanisms are possible.18

A Model Reaction for Copper Monooxygenases
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2897
Scheme 5
If the O-O bond homolysis is solely the rate-determining
step in the ligand hydroxylation process, the KIE value would
be 1.0. The observed small KIE values in the present system
suggest that the O-O bond homolysis (kh) is much slower than
the back reaction (k-h) which competes with the facile C-H
bond activation (kCH). In such a case, the observed rate constant
(k2) is given by eq 1.
species between our system and the Tolman or Stack systems.
In fact, Kitajima’s hydrotris(pyrazolyl)borate ligands afford only
µ-η2:η2-peroxodicopper(II) species and the O-O bond homoly-
sis becomes the rate-determining step in its decomposition
process.37 Recent ligand modification experiments also dem-
onstrated that sterically less hindered amine ligands stabilized
bis-µ-oxo dicopper(III) species.16d,19a Thus, this steric factor
must also be taken into account for the difference in reactivity
of the Cu/O2 species between our system and others. Nonethe-
less, all of our kinetic results including kinetic deuterium isotope
effect, solvent effects, and p-substituents effects as well as the
product analyses of the crossover experiments support our
proposed mechanism.
Very recently, Que and co-workers have reported that
intermediate Q of sMMO (soluble methane monooxygenase)
has an FeIV-(µ-O)2-FeIV diamond core structure.41 Chan et
al. have also proposed that a bis-µ-oxo-Cu(II)Cu(III) core
corresponds to the methane hydroxylation in pMMO (particulate
methane monooxygenase),42 suggesting the mechanistic viability
of the bis-µ-oxo high-valent dimetallic diamond core for the
dioxygen activation and hydrocarbon oxygenation.
k2 ) khkCH/(k-h + kCH
)
(1)
The O-O bond homolysis may be largely the rate-determin-
ing step, i.e., kCH . k-h, but the ligand perdeuteration may result
in a significant decrease in the rate of the C-D cleavage (kCD),
which becomes partially rate-determining. Little p-substituent
effect observed on the k2 process is also consistent with the
proposed mechanism where the ligand hydroxylation process
is not a rate-determining step.
The oxygenated product P dimerizes to from a thermody-
namically stable product J as has been demonstrated by the
X-ray analysis.22 For the [CuII(1a)(ClO4)2]/benzoin/triethy-
lamine system, the CuII-OH complex (O) is reduced to a
cuprous state by the reductant that may participate in the
hydroxylation reaction again until all the ligand is hydroxylated.
According to this mechanism, the stoichiometry of 1a:O2:
benzoin is 1:1:1, agreeing with the experimental results. The
autoxidation mechanism (reaction between the carbon center
radical and external O2 to generate an alkylsuperperoxo species
which undergoes radical chain reactions) has been ruled out
since the benzylic hydroxylation reaction occurs in the same
yield (50%) when the solution of µ-η2:η2-peroxodicopper(II)
complex (I) is allowed to stand at -80 °C after removal of the
excess amount of O2 under vacuum.
In summary, we have demonstrated that the efficient benzylic
hydroxylation of the copper complex proceeds via the rate-
determining O-O bond homolysis of the µ-η2:η2-peroxodicop-
per(II) intermediate (K) which is formed from the Cu(I) complex
and O2 or from the Cu(II) complex with H2O2. We propose
the intramolecular hydrogen atom abstraction and oxygen
rebound or direct oxygen insertion mechanism through the bis-
µ-oxodicopper(III) type intermediate (L) for the efficient
benzylic hydroxylation reaction,40 although such an intermediate
could not be detected directly in our system probably because
of its high reactivity and/or instability. We believe that the
lower electron donor ability of the aromatic nitrogens as
compared to that of the aliphatic amine nitrogens is one of the
critical points for such a difference in reactivity of the Cu/O2
Experimental Section
All chemicals used in this study except the ligands and the copper
complexes were commercial products of the highest available purity
and were further purified by the standard methods.43 IR spectra were
recorded with a Hitachi 270-30 spectrophotometer or a Shimadzu
FTIR-8200PC. UV-vis spectra were measured using a Hewlett-
Packard HP8452A diode array spectrophotometer with a Unisoku
thermostated cell holder designed for low-temperature experiments.
Mass spectra were recorded with a JEOL JNX-DX303 HF mass
spectrometer. 1H and 13C NMR spectra were recorded on a JEOL FT-
NMR EX-270 spectrometer. ESR measurements were performed on
a JEOL JES-ME-2X spectrometer at -196 °C (liquid N2 temperature).
Synthesis of Ligands. All ligands used in this study were prepared
according to the established procedures using benzylamine, phenethy-
lamine, or p-substituted phenethylamines (X ) CH3, Cl, NO2) and
vinylpyridine in methanol containing acetic acid and purified by flash
column chromatography (SiO2).44 The structures of the products were
confirmed by the following analytical data.
(41) Shu, L.; Nesheim, J. C.; Kauffman, K.; Mu¨nck, E.; Lipscomb, J.
D.; Que, L., Jr. Science 1997, 275, 515.
(42) Elliott, S. J.; Zhu, M.; Tso, L.; Nguyen, H.-H. T.; Yip, J. H.-K.;
Chan, S. I. J. Am. Chem. Soc. 1997, 119, 9949.
(43) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon Press: Elmsford, NY, 1966.
(44) Sorrell, T. N. Tetrahedron 1989, 45, 3 and references therein.

2898 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Itoh et al.
N,N-Bis[2-(2-pyridyl)ethyl]-2-phenylethylamine (1a): pale yellow
oil; IR (neat, cm-1) 3150-2800 (aromatic and aliphatic C-H), 1594,
1572, 1496, 1478 (aromatic CdC and CdN), 750, and 700 (C-H);
1H NMR (270 MHz, CDCl3) δ 2.71-3.01 (12 H, m, -CH2-CH2-),
7.00-7.28 (9 H, m, C6H5, Hpy-3, and Hpy-5), 7.53 (2 H, dt, J ) 2.0
and 7.6 Hz, Hpy-4), 8.52 (2 H, d, J ) 4.0 Hz, Hpy-6); MS [EI (pos),
m/z] 332 (M+ + 1). Anal. Calcd for C22H25N3: C, 79.72; H, 7.60; N,
12.68. Found: C, 79.54; H, 7.72; N, 12.60.
7.0 Hz, Hpy-4), 8.46 (2 H, br s, Hpy-6); FTIR (KBr, cm-1) 1090 and
623 (ClO4-). Anal. for ([CuI(1a)]ClO4). Calcd for C22H25O4ClCuN3:
C, 53.44; H, 5.10; N, 8.50. Found: C, 53.41; H, 5.22; N, 8.20.
[CuI(1a)]CF3SO3 was prepared in a similar manner using [CuI(CH3-
CN)4]CF3SO3 instead of [CuI(CH3CN)4]PF6. However, the Cu(I)
46
complex could be obtained only as an oily pale yellow material. Thus,
after the treatment of [CuI(CH3CN)4]CF3SO3 with exactly the same
amount of ligand 1a in deaerated CH2Cl2 for 15 min, the solvent was
removed under a reduced pressure. The purity of the complex was
The 1,1,2,2-tetradeuterated derivative (1a-d4) was prepared with
PhCD2CD2NH2 instead of PhCH2CH2NH2, and its purity (> 99%) was
1
checked by H NMR [(400 MHz, CD3CN) δ 2.89-3.02 (12 H, m,
1
confirmed by the H NMR and mass spectra.
-CH2-CH2-), 7.21-7.35 (9 H, m, C6H5, Hpy-3, and Hpy-5), 7.83 (2
H, t, J ) 7.8 Hz, Hpy-4), 8.43 (2 H, br s, Hpy-6)] and FTIR [(KBr,
cm-1): 1225, 1153, 1030, and 640 (CF3SO3-)].
N,N-Bis[2-(2-pyridyl)ethyl]-2-(p-tolyl)ethylamine (1b): pale yellow
oil; IR (neat, cm-1) 3090-2770 (aromatic and aliphatic C-H), 1591,
1473, 1435 (aromatic CdC and CdN), and 752 (C-H); 1H NMR (400
MHz, CDCl3) δ 2.31 (3H, s, CH3), 2.66-2.82 (4 H, m, -CH2-CH2-
), 2.90-3.02 (8 H, m, -CH2-CH2-), 7.00-7.11 (8 H, m, Ho, Hm,
[CuI(1a)]BPh4 was prepared according to the reported procedure16b
and was obtained as an oily pale yellow material. The purity of the
complex was checked by 1H NMR [(270 MHz, CD3CN) δ 2.86-3.02
(12 H, m, -CH2-CH2-), 6.83 (4 H, t, J ) 7.2 Hz), 6.98 (8 H, t, J )
7.2 Hz), 6.18-7.37 (17 H, m), 7.81 (2 H, dt, J ) 1.8 and 7.8 Hz,
H
py-3, and Hpy-5), 7.53 (2 H, dt, J ) 2.0 and 7.6 Hz, Hpy-4), 8.52 (2 H,
d, J ) 4.0 Hz, Hpy-6); MS (EI, m/z) 346 (M+ + 1).
H
py-4), 8.46 (2 H, d, J ) 3.5 Hz, Hpy-6) and FTIR [(KBr, cm-1) 735
N,N-Bis[2-(2-pyridyl)ethyl]-2-(p-chlorophenyl)ethylamine (1c):
pale yellow oil; IR (neat, cm-1) 3090-2770 (aromatic and aliphatic
C-H), 1590, 1568, 1491, 1474, 1435 (aromatic CdC and CdN), 1091
(C-Cl), and 748 (C-H); 1H NMR (400 MHz, CDCl3) δ 2.64-2.79 (4
H, m, -CH2-CH2-), 2.87-3.00 (8 H, m, -CH2-CH2-), 6.97-7.01
(4 H, m, Hpy-5, Hm), 7.10 (2 H, ddd, J ) 1.2, 4.8, and 7.6 Hz, Hpy-3),
7.18 (2 H, d, J ) 8.4 Hz, Ho), 7.53 (2 H, dt, J ) 2.0 and 7.6 HZ,
and 704 (BPh4-)].
[CuI(1b)]PF6 was obtained in a manner similar to that for the
synthesis of [CuI(1a)]PF6 using ligand 1b instead of ligand 1a in 60%
as a pale yellow powder: 1H NMR (270 MHz, CD3CN) δ 2.29 (3 H,
s, CH3), 2.89-3.03 (12 H, m, -CH2-CH2-), 7.11 (4 H, br s, C6H4),
7.34-7.36 (4 H, m, Hpy-3 and Hpy-5), 7.83 (2 H, t, J ) 7.0 Hz, Hpy-4),
8.47 (2 H, d, J ) 4.3 Hz, Hpy-6); FTIR (KBr, cm-1): 837 (PF6-). Anal.
([CuI(1b)]PF6‚H2O). Calcd for C23H29CuF6N3OP: C, 48.30; H, 5.11;
N, 7.35. Found: C, 48.72; H, 4.88; N, 7.51.
H
py-4), 8.52 (2 H, ddd, J ) 0.8, 2.0, and 4.8 Hz, Hpy-6); MS (EI, m/z)
365 (M+).
N,N-Bis[2-(2-pyridyl)ethyl]-2-(p-nitrophenyl)ethylamine (1d): yel-
low oil; IR (neat, cm-1) 3100-2770 (aromatic and aliphatic C-H),
1592, 1473, 1436 (aromatic CdC and CdN), 1517, 1344, 857 (NO2),
[CuI(1c)]PF6 was obtained in a manner similar to that for the
synthesis of [CuI(1a)]PF6 using ligand 1c instead of ligand 1a in 55%
as a pale yellow powder: 1H NMR (270 MHz, CD3CN) δ 2.88-3.05
(12 H, m, -CH2-CH2-), 7.20-7.38 (8 H, m, C6H4, Hpy-3, and Hpy-5),
7.84 (2 H, dt, J ) 1.6 and 7.8 Hz, Hpy-4), 8.49 (2 H, dd, J ) 1.6 and
5.1 Hz, Hpy-6); FTIR (KBr, cm-1): 1086 (C-Cl) and 841 (PF6-). Anal.
([CuI(1c)]PF6). Calcd for C22H24ClCuF6N3P: C, 46.00; H, 4.21; N,
7.32. Found: C, 45.31; H, 4.16; N, 7.28.
[CuI(1d)]PF6 was obtained in a manner similar to that for the
synthesis of [CuI(1a)]PF6 using ligand 1d instead of ligand 1a in 87%
as a pale orange powder: 1H NMR (270 MHz, CD3CN) δ 2.90 (8 H,
br s, -CH2-CH2-), 3.06 (4 H, br s, -CH2-CH2-), 7.34-7.38 (4 H,
m, Hpy-3, and Hpy-5), 7.45 (2 H, d, J ) 8.8 Hz, Hm), 7.83 (2 H, dt, J
) 1.4 and 7.4 Hz, Hpy-4), 8.15 (2 H, d, J ) 8.8 Hz, Ho), 8.49 (2 H, d,
J ) 4.1 Hz, Hpy-6); FTIR (KBr, cm-1) 1515, 1344 (NO2), and 843
(PF6-). Anal. ([CuI(1d)]PF6). Calcd for C22H24CuF6N4O2P: C, 45.17;
H, 4.14; N, 9.58. Found: C, 44.83; H, 4.18; N, 9.14.
1
and 748 (C-H); H NMR (400 MHz, CDCl3) δ 2.75-2.85 (4 H, m,
-CH2-CH2-), 2.86-3.01 (8 H, m, -CH2-CH2-), 6.98 (2 H, d, J )
7.9 Hz, Hpy-3), 7.11 (2 H, ddd, J ) 0.8, 4.9, and 7.9 Hz, Hpy-5), 7.17
(2 H, d, J ) 8.6 Hz, Hm), 7.53 (2 H, dt, J ) 1.4 and 7.9 Hz, Hpy-4),
8.04 (2 H, d, J ) 8.6 Hz, Ho), 8.52 (2 H, dd, J ) 1.4 and 4.9 Hz,
H
py-6); MS (EI, m/z) 376 (M+).
Synthesis of Copper Complexes. [CuII(1a)(ClO4)2]. To a CH3-
OH solution (6 mL) of ligand 1a (1.19 g, 3.58 mmol) was added an
equimolar amount of Cu(ClO4)2‚6H2O, and the mixture was stirred for
15 min. The mixture was then poured into a large amount of Et2O.
The resulting oily blue material was separated and dissolved in 600
mL of CH2Cl2. Addition of Et2O (300 mL) into the CH2Cl2 solution
gave a blue solid which was collected by filtration and washed with
Et2O several times (1.50 g, 71%): UV-vis [CH2Cl2, λmax, nm (ꢀ, M-1
cm-1)] 266 (15 400), 664 (234); FTIR (KBr, cm-1); 1123, 1090, and
625 (ClO4-). Anal. ([CuII(1a)(ClO4)2]). Calcd for C22H25Cl2-
CuN3O8: C, 44.49; H, 4.24; N, 7.08. Found: C, 44.33; H, 4.23; N,
7.00.24
Ligand Hydroxylation Reaction. [CuII(1a)]2+/Benzoin/Triethy-
lamine/O2 System. The Cu(II) complex [CuII(1a)(ClO4)2] (84 µmol)
was treated with an equimolar amount of benzoin and triethylamine in
CH2Cl2 (5 mL) at room temperature for 2 h under Ar, and then the
mixture was stirred under an atmospheric pressure of O2 for several
hours. The modified ligand 2a was isolated quantitatively after an
ordinary workup treatment of the reaction mixture with NH4OH aq
and following extraction by CH2Cl2: 1H NMR (270 MHz, CDCl3, δ,
TMS) 2.57-3.16 (m, 10 H, -CH2- × 5), 4.60 (dd, J ) 3.5 and 9.7
Hz, 1 H, -CHOH-), 7.02 (d, J ) 7.7 Hz, 2 H, py-H3), 7.10 (dd, J )
4.8, 7.7 Hz, 2 H, py-H5), 7.22-7.38 (m, 5 H, -Ph), 7.54 (dt, J ) 1.7,
[CuI(1a)]PF6 was prepared according to the reported procedures45
as follows. To a deaerated CH2Cl2 solution (6 mL) of ligand 1a (99
mg, 0.33 mmol) was added [CuI(CH3CN)4]PF6 (112 mg, 0.3 mmol)
46
under Ar atmosphere. After 15 min of stirring at room temperature,
addition of deaerated ether (50 mL) with a syringe gave a pale yellow
Cu(I) complex which was precipitated by standing the mixture for
several minutes. The supernatant was then sucked up with a syringe,
and the remained pale yellow solid was washed with deaerated ether
three times under anaerobic conditions and dried under vacuum (79%
yield): 1H NMR (270 MHz, CD3CN) δ 2.80-3.08 (12 H, m, -CH2-
CH2-), 7.17-7.38 (9 H, m, C6H5, Hpy-3, and Hpy-5), 7.83 (2 H, t, J )
7.7 Hz, 2 H, py-H4), 8.52 (d, J ) 4.8 Hz, 2 H, py-H6); IR (neat, cm-1
3396 (OH); MS (CI, m/z) 348 (M+ + 1).
)
[CuI(L)]+/O2 System (L ) 1a-d). Typically, [CuI(1a)]PF6 (61 mg,
0.10 mmol) was dissolved into deaerated CH2Cl2 (5 mL) under
anaerobic conditions, and the solution was cooled to - 78 °C using a
dry ice/acetone bath. O2 gas was introduced into the solution by
bubbling for 1 h, when the color of the solution turned dark brown
due to the formation of the µ-peroxodicopper(II) complex. Then the
excess amount of O2 gas was replaced with Ar by letting the system
under reduced pressure and flashing Ar gas (three cycles) at the low
temperature. The reaction temperature was then gradually increased
to room temperature, and the mixture was stirred for additional 3 h. A
mixture of 1a and 2a was obtained after an ordinary workup treatment
of the reaction mixture with NH4OH aq and following extraction by
CH2Cl2. Yield of 2a was determined as 47% by using an integral ratio
7.3 Hz, Hpy-4), 8.47 (2 H, d, J ) 7.3 Hz, Hpy-6); FTIR (KBr, cm-1
839 (PF6-). Anal. ([CuI(1)]PF6‚0.75CH2Cl2). Calcd for C22.75H26.5
)
-
Cl1.5CuN3PF6: C, 45.26; H, 4.42; N, 6.96. Found: C, 45.62; H, 4.45;
N, 7.27.
[CuI(1a)]ClO4 was obtained in a similar manner using [CuI(CH3-
CN)4]ClO4 instead of [CuI(CH3CN)4]PF6 in 71% as a pale yellow
46
powder: 1H NMR (400 MHz, CD3CN) δ 2.85-3.05 (12 H, m, -CH2-
CH2-), 7.21-7.36 (9 H, m, C6H5, Hpy-3, and Hpy-5), 7.82 (2 H, t, J )
(45) Sanyal, I.; Mahroof-Tahir, M.; Nasir, M. S.; Ghosh, P.; Cohen, B.
I.; Gultneh, Y.; Cruse, R. W.; Farooq, A.; Karlin, K. D.; Liu, S.; Zubieta,
J. Inorg. Chem. 1992, 31, 4322.
(46) Kubas, G. J. Inorg Synth. 1979, 19, 90; 1990, 28, 68.

A Model Reaction for Copper Monooxygenases
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2899
1
in the H NMR spectrum between the methine proton (-CHOH-) at
nm). The spectra were obtained at 77 K using a backscattering
geometry. The samples were frozen onto a gold-plated copper
coldfinger in thermal contact with a dewar containing liquid nitrogen
for data collection. Raman frequencies were referenced to the intense
feature at 806 cm-1 from frozen acetone.
Kinetic Measurements. The reaction of the copper(I) complex and
O2 was carried out in a 1 mm path length UV-vis cell that was held
in a Unisoku thermostated cell holder designed for low-temperature
experiments (a desired temperature can be fixed within ( 0.5 °C). After
the deaerated solution of the copper(I) complex (2.5 × 10-3 M) in the
cell was kept at the desired temperature for several minutes, dry
dioxygen gas was continuously supplied by gentle bubbling from a
thin needle. The formation and decay of the µ-peroxodicopper complex
intermediate were monitored by following the increase and decrease
in the absorption at 362 nm.
δ 4.60 of 2a and the pyridine protons at the 6-position (py-H6, δ 8.52)
from both 1a and 2a (py-H6s of 1a and 2a are overlapped); (-CHOH-
):(py-H6) ) 0.47:2.00.
The reactions of the copper(I) complexes of other ligands (1b-d)
were carried out in a similar manner, and the yields of the ligand
hydroxylation were determined as 49%, 48%, and 47% for 2b, 2c, and
2d, respectively: for 2b, [-CHOH-, δ 4.57 (dd, J ) 3.8 and 9.4 Hz)]:
[py-H6, δ 8.52 (d, J ) 4.6 Hz)] ) 0.49:2.00; for 2c, [-CHOH-, δ
4.58 (dd, J ) 3.0 and 9.7 Hz)]:[py-H6, δ 8.51 (d, J ) 4.6 Hz)] )
0.48:2.00; for 2d, [-CHOH-, δ 4.72 (dd, J ) 3.8 and 9.4 Hz)]:[py-
H6, δ 8.52 (d, J ) 4.7 Hz)] ) 0.47:2.00. In all the cases, there is no
byproduct other than the benzyl hydroxylated ligand (2b-d).
O2-Uptake Measurements were carried out according to the
reported procedure using CH2Cl2 as a solvent at 21 °C.47 The volume
of O2 consumed during the oxygenation reaction was obtained as a
difference of the O2 consumption between the ligand hydroxylation
reaction and the blank solution without the reactants under exactly the
same conditions. For the reaction system of [CuII(1)(ClO4)2]/benzoin/
NEt3, Cu:O2 was 1:0.96 ( 0.1, and for the reaction with [CuI(1)]PF6,
Cu:O2 was 2:0.97 ( 0.1.
Acknowledgment. The present study was financially sup-
ported in part by a Grant-in-Aid for Scientific Research on
Priority Area (Molecular Biometallics, 08249223 and 09235218)
and a Grant-in-Aid for General Scientific Research (08458177)
from the Ministry of Education, Science, Sports, and Culture
of Japan. Our special thanks are due to Professors William B.
Tolman and Lawrence Que Jr. (University of Minnesota) for
their help in obtaining resonance Raman data at 77 K and also
for their very helpful discussions and valuable comments. We
also thank Professor Teizo Kitagawa and co-workers, especially
Dr. Masahiro Mukai, of Okazaki Institute for Molecular Science
for their help in trying to obtain the resonance Raman spectra
at -80 °C and Professors Nobumasa Kitajima and Yoshihiko
Moro-oka and Dr. Kiyoshi Fujisawa of Tokyo Institute of
Technology for their helpful discussions.
Resonance Raman Measurements. The 16O2 sample was prepared
via bubbling of dry dioxygen into an acetone solution of [CuI(1a-d4)]-
PF6 (0.02 M) at -80 °C. The 18O2 analogue was prepared via
condensation of 18O2 into a previously evacuated Schlenk flask
containing a frozen acetone solution (77 K) of [CuI(1a-d4)]PF6 (0.02
M). The flask was then allowed to warm to -80 °C and was maintained
at this temperature for about 30 min to allow for complete formation
of the dioxygen complex. Resonance Raman spectra were collected
on a SPEX 1403 spectrometer interfaced with a DM3000 data collection
system using a Spectra-Physics Model 2030-15 argon ion laser (514.5
(47) Karlin, K. D.; Ghosh, P.; Cruse, R. W.; Farooq, A.; Gultneth, Y.;
Jacobson, R. R.; Blackburn, N. J.; Strange, R. W.; Zubieta, J. J. Am. Chem.
Soc. 1988, 110, 6769.
JA972809Q