Structural and functional mimic of galactose oxidase by a copper complex of a sterically demanding [N2O2] ligand

Article abstract of DOI:10.1039/b801496e

A structural and functional mimic of the galactose oxidase (GOase) enzyme active-site by a copper complex supported over a sterically demanding ligand having [N₂O₂] donor sites is reported. Specifically, the binding of the histidine (496 and 581) and tyrosine (272 and 495) residues to the copper center in a square-pyramidal fashion in the active-site of galactose oxidase (GOase) enzyme has been modeled in a copper complex, {[(3-tert-butyl-5-methyl-2-hydoxybenzyl)(3′-tert-butyl-5′-methyl- 2′-oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc)} (1b), stabilized over a sterically demanding ligand in which the two phenolate-O atoms mimicked the tyrosine binding while an amine-N and pyridyl-N atoms emulated the histidine binding to the metal center, similar to that in the enzyme active-site. Furthermore, the copper complex 1b is found to be an effective functional model of the enzyme as it efficiently catalyzed the chemoselective oxidation of primary alcohols to aldehydes in high turnover numbers under ambient conditions. An insight into the nature of the active-species was obtained by EPR and CV studies, which in conjunction with the DFT studies, revealed that the active-species is an anti-ferromagnetically coupled diamagnetic radical cation, ¹1b⁺, obtained by one electron oxidation at the equatorial phenolate-O atom of the ligand in the 1b complex. The Royal Society of Chemistry.

Full text of DOI:10.1039/b801496e

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Structural and functional mimic of galactose oxidase by a copper complex of
a sterically demanding [N O ] ligand†
2
2
a
b
a
Alex John, Mobin M. Shaikh and Prasenjit Ghosh*
Received 28th January 2008, Accepted 13th March 2008
First published as an Advance Article on the web 18th April 2008
DOI: 10.1039/b801496e
A structural and functional mimic of the galactose oxidase (GOase) enzyme active-site by a copper
complex supported over a sterically demanding ligand having [N ] donor sites is reported.
2
O
2
Specifically, the binding of the histidine (496 and 581) and tyrosine (272 and 495) residues to the copper
center in a square-pyramidal fashion in the active-site of galactose oxidase (GOase) enzyme has been
ꢀ
ꢀ
ꢀ
modeled in a copper complex, {[(3-tert-butyl-5-methyl-2-hydoxybenzyl)(3 -tert-butyl-5 -methyl-2 -
oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc)} (1b), stabilized over a sterically demanding ligand in
which the two phenolate-O atoms mimicked the tyrosine binding while an amine-N and pyridyl-N
atoms emulated the histidine binding to the metal center, similar to that in the enzyme active-site.
Furthermore, the copper complex 1b is found to be an effective functional model of the enzyme as it
efficiently catalyzed the chemoselective oxidation of primary alcohols to aldehydes in high turnover
numbers under ambient conditions. An insight into the nature of the active-species was obtained by
EPR and CV studies, which in conjunction with the DFT studies, revealed that the active-species is an
1
+
anti-ferromagnetically coupled diamagnetic radical cation, 1b , obtained by one electron oxidation at
the equatorial phenolate-O atom of the ligand in the 1b complex.
Introduction
shuttle, is uniquely bound to a nearby cysteine (228) residue
through a covalent thioether linkage. Interestingly, the active form
7
Galactose oxidase (GOase) is an important mononuclear Type II
copper fungal enzyme that effectively carries out conversion of
primary alcohols to aldehydes under ambient aerobic conditions.
The tertiary structure of the 68 kDa GOase enzyme exhibits three
domains (D1, D2 and D3) comprising of 43 b-strands and one
small a-helix built from a single polypeptide chain of 639 amino
acid residues. The active-site of the GOase consists of a distorted
square-pyramidal copper(II) center coordinated to two histidine
of the enzyme is an anti-ferromagnetically coupled diamagnetic
species that is EPR silent and which results from the coupling
of the radical cofactor, the tyrosine (272) residue, with the metal
1
8
based unpaired electron of the copper(II) center in the active-site.
A formidable challenge in designing synthetic models of GOase,
especially the functional ones, therefore lies in mimicking this tyro-
syl/tyrosinate and the Cu(II)/Cu(I) redox couple in small molecule
copper complexes. Furthermore, as the catalytic reactivity of the
synthetic model is largely dependent on the organic radical–
Cu(II/I) redox couple, the proper control of the organic radical
center in a model complex, particularly with respect to its stability,
magnetic properties and reactivity, are of prime importance.
The strategies often employed in fine-tuning the organic radical
reactivity thus involve varying several mutually dependent factors
like, the state of the phenol moiety (protonated vs. deprotonated),
the geometrical arrangement around the metal center (axial or
equatorial) and the electronic properties of the ligand stabilizing
(
496 and 581), and two tyrosine (272 and 495) residues of the
protein backbone along with an exogenous water (at pH = 7) or an
acetate (pH = 4.5) moiety and is located on the surface of domain
2,3
D2 in a hydrophobic region rich with aromatic residues. The
enzyme efficiently uses molecular oxygen in air in achieving a two-
electron oxidation of a wide variety of primary alcohol substrates
4
to aldehydes via a rare concerted redox cooperativity pathway
existing between a neighboring radical cofactor, a tyrosine (272)
residue, and the redox active copper(II/I) metal center in the
enzyme active-site. Worth noting that the radical cofactor,
tyrosine (272), which undergoes the rare tyrosyl/tyrosinate redox
5,6
9
the synthetic model. Towards this end, several ligand systems
having N
GOase biomimetic modeling studies.
the tripodal N O ligands with a pyridyl-N, a tertiary amine-N,
2
O
2
and N
3
O donor sets have been extensively used in the
9,10
Of special mention are
a
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
2
2
Mumbai, 400 076, India. E-mail: pghosh@chem.iitb.ac.in; Fax: +91-22-
and two phenolate-O donor atoms, which successfully emulated
the radical cofactor-Cu(II/I) redox couple in its synthetic model
complexes and did so specifically by selective deprotonation of the
equatorial phenolate-O, which transforms to a radical cofactor
upon oxidation during the catalysis, while the axial phenolate-
O remains protonated in these model complexes. This selective
deprotonation of the equatorial phenolate-O has not only been
achieved by distinguishing the two phenolate-O moieties by incor-
porating different substituents on the respective phenyl rings, as
2
572-3480; Tel: +91-22-2576-7178
b
National Single Crystal X-ray Diffraction Facility, Indian Institute of
Technology Bombay, Powai, Mumbai, 400 076, India
†
Electronic supplementary information (ESI) available: X-Ray metrical
data comparison table, the B3LYP coordinates of the optimized geometries
2
3
+
4
2+
for 1b, 1b , 1b , intermediate 1, intermediate 2 and intermediate 3 along
with the comparison tables, spin density table, frontier molecular orbital
diagrams, cyclic voltammogram and electronic spectroscopic data. CCDC
reference number 640145. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b801496e
This journal is © The Royal Society of Chemistry 2008
Dalton Trans., 2008, 2815–2824 | 2815

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ꢀ
ꢀ
in the {[(3-tert-butyl-5-methoxy-2-hydoxybenzyl)(3 -tert-butyl-5 -
functional attributes. Hence, we became interested in designing
ꢀ
11
nitro-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc) complex,
a structural and functional model of a N
butyl-5-methyl-2-hydroxybenzyl)(2-pyridylmethyl)amine
2
O
2
ligand, bis(3-tert-
(1a),
but also in a case where they are the same as observed
ꢀ
ꢀ
ꢀ
in the {[(3,5-di-tert-butyl-2-hydoxybenzyl)(3 ,5 -di-tert-butyl-2 -
possessing two same phenolate-O sidearms by fine-tuning its
steric and electronic properties.
12
oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc) complex. Because
of the aforementioned reasons, we decided to employ a new
In this regard, the tripodal ligand 1a was synthesized
by a Mannich condensation reaction of 2-tert-butyl-4-methyl-
phenol with 2-(aminomethyl)pyridine in 55% yield while the cor-
responding copper complex, {[(3-tert-butyl-5-methyl-2-hydoxy-
sterically demanding variant of the N
2
O tripodal ligand, bis(3-
2
tert-butyl-5-methyl-2-hydroxybenzyl)(2-pyridylmethyl)amine (1a)
for the purpose of our enzyme biomimetic studies. Furthermore,
we rationalized, particularly keeping the functional model of
GOase in mind, that the coupling of a stable ligand-based
redox center with an adjacent redox active and coordinatively
unsaturated Cu(II)/Cu(I) site in the copper complexes would result
in generation of novel catalysts capable of oxidation reactions.
Here in this contribution, we report a mononuclear copper
ꢀ
ꢀ
ꢀ
benzyl)(3 -tert-butyl-5 -methyl-2 -oxobenzyl)(2-pyridylmethyl)]-
amine}Cu(OAc) 1b, was obtained by the treatment of the ligand
1a with Cu(OAc)
2
·H
2
O in methanol in 43% yield (Scheme 1) and
the paramagnetic complex was characterized by IR, electronic
spectroscopy, EPR, elemental analysis and X-ray diffraction
studies.
complex supported over a tripodal N
2
O
2
ligand that not only
The most remarkable feature of the 1b complex is its similarity
with the GOase active-site (Fig. 1 and 2). Specifically, the Cu
center in 1b was found to bind with two O donors, mimicking the
tyrosine (Tyr 272 and Tyr 495) binding, and to two N donors, also
emulating the histidine (His 581 and His 496) binding, in a square
pyramidal fashion similar to that seen in the enzyme active-site
(Table S1, ESI†). The equatorial square plane around the central
structurally resembles the active-site of GOase, but also func-
tionally mimics the enzyme activity in carrying out two-electron
oxidation of a wide variety of primary alcohol substrates to the
corresponding aldehydes under ambient conditions, employing a
not so common organic radical–Cu(II/I) coupled redox pathway
similar to what is observed in the active enzyme.
2
+
Cu in 1b was thus formed by two N atoms (amine N and the
pyridine N), two O atoms (phenolate O and acetate O) while the
non-deprotonated phenol (phenyl-OH) was found to bind to the
metal from the axial position. Apart from the direct correlation
with the enzyme active-site, the copper complex 1b was also
found to be in good agreement with two other structurally similar
Results and discussion
The primary challenge in the biomimetic studies of GOase had
been in emulating the entire structural, spectroscopic and the
functional aspects of the enzyme in totality in small molecule
synthetic analogs. As a consequence, despite enormous body
11,12
GOase model complexes (Table S1, ESI†).
In this regard, worth
13,14
mentioning that the square pyramidal geometry around the Cu(II)
center in the active-site of GOase is vital to its function as it
orients the methylene hydrogen of the substrate alcohol in close
vicinity of the tyrosyl radical in the active enzyme to facilitate
of literature
that exist on the modeling studies of GOase,
the examples of metal complexes that simultaneously serve as
both the structural and the functional model of the enzyme,
particularly with respect to mimicking the unconventional radical
cofactor-Cu(II/I) redox coupled pathway as seen in the enzyme,
are strikingly few in number. For example, the representative
examples of a few copper complexes that would genuinely qualify
as both the structural and functional model of GOase are
1
0h,11,15–17
stabilized over N
2
O
2
ligands.
Interestingly enough, while
ꢀ
ꢀ
the {[(3-tert-butyl-5-methoxy-2-hydoxybenzyl)(3 -tert-butyl-5 -
ꢀ
11
nitro-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc) complex,
which is supported over a tripodal N
2
2
O ligand with two different
phenolate-O sidearms serves as an excellent structural and
functional model of GOase, a related analog, {[(3,5-di-tert-
ꢀ
ꢀ
ꢀ
butyl-2-hydoxybenzyl)(3 ,5 -di-tert-butyl-2 -oxobenzyl)(2-pyridyl-
12
methyl)]amine}Cu(OAc), stabilized over another variant of the
same N ligand but having same phenolate-O sidearms serves
only as a structural model and does not exhibit any biomimetic
2
O
2
Fig. 1
Scheme 1
2
816 | Dalton Trans., 2008, 2815–2824
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active enzyme, and subsequently yielding an antiferromagnetically
1
+
coupled diamagnetic species ( 1b ), instead of the expected lower
3
+
energy 1b species.
Indeed, removal of an electron from the copper complex 1b
2
results in a ligand based oxidation as opposed to the metal based
3
+
one resulting in the cationic 1b species. Inspection of the frontier
2
molecular orbitals of 1b displays a single vacancy in the valence
shell 150b (HOMO) located on the Cu dx2−y2 orbital, which is
consistent with a square pyramidal arrangement, while the next
th
lower 149 orbital (HOMO−1) being fully occupied (Fig. S1,
2
ESI†). Thus, the one-electron oxidation of 1b yielded the oxidized
3
+
1
b
species with two unpaired electrons, one on the Cu dx2−y2
orbital (150a) as seen from natural bond order (NBO) analysis
and the other on the equatorial phenolate ring (149 a) consistent
with the adjacent radical cofactor (Tyr 272) and the Cu(II/I) center
in the GOase active-site (Fig. 3).
◦
Fig. 2 ORTEP of 1b. Selected bond lengths ( A˚ ) and angles ( ):
Further support in favor of the one-electron ligand-based
oxidation comes from the Mulliken spin density analysis (Table
S9, ESI†) which revealed that the total spin density (both a and
Cu1–O1 1.8871(14), Cu1–O3 1.9582 (15), Cu1–N1 2.0340(18), Cu1–N2
1
1
1
.9967(18), O2–H102 0.75(3); O1–Cu1–O3 87.19(6), O1–Cu1–N2
66.86(7), O3–Cu1–N2 93.58(7), O1–Cu1–N1 94.12(7), O3–Cu1–N1
74.01(7).
2
b spins) on the Cu(II) center remains the same [Cu = 0.49 ( 1b),
3
+
0
.57 ( 1b )] while that on the equatorial phenolate-O moiety [0.26
2
3
+
the hydrogen atom transfer (HAT) process. Given the observation
that the coordination environment around 1b closely resembles
the active-site geometry of GOase, the copper complex is expected
( 1b), 1.01 ( 1b )] increases drastically upon one-electron oxidation
of 1b to the 1b species.
2
3
+
The clinching evidence in favor of the radical cofactor-Cu(II/I)
redox couple existing in the GOase model complex 1b came from
EPR studies, which showed that while the 1b complex displayed a
typical pattern corresponding to one unpaired electron on copper,
the electrochemically generated one-electron oxidized analog was
found to be diamagnetic as a result of antiferromagnetic coupling
between the organic radical (equatorial phenolate-O) and the
adjacent Cu(II) center (Fig. 4). Specifically, the EPR spectrum of
6c,18
to emulate the functional activity of the enzyme.
In order to obtain insight on the electronic structure of the
copper complex 1b, density functional theory studies were carried
out and the geometry optimized structure of the complex 1b
was computed at the B3LYP/LANL2DZ, 6–31G(d) level of
theory using the atomic coordinates adopted from X-ray analysis
and subsequently, single-point calculation was performed at the
same level of theory for detailed prediction of the electronic
1b recorded in the frozen state in CH CN showed a commonly
3
2
properties of the complex. The optimized structure of 1b (Fig.
observed axial pattern with three well resolved peaks in the low
S1, ESI†) exhibited a square pyramidal geometry around the
field region (g = 2.267; A = 160) due to splitting with the Cu
ꢁ
ꢁ
2
+
central Cu ion with the protonated phenol moiety occupying
the axial position in a manner similar to that observed in the
X-ray structure. Inspection of the frontier molecular orbitals of
the optimized structure reveals an arrangement characteristic of
square-pyramidal copper complexes with an one electron vacancy
in the 150b orbital localized on the Cu dx2−y2 orbital. In general,
the optimized bond lengths are in good agreement with those of
the crystallographic data (Table S8, ESI†).
As the enzyme is known to exist in three well defined oxidation
levels, (i) an EPR silent active form (cupric ion antiferromag-
netically coupled to the equatorial phenoxy radical), (ii) an
intermediate form and (iii) the reduced Cu(I) form (Scheme 2), we
became interested in investigating the relevance of these species
particularly with respect to the functioning of our GOase model
nucleus (I = 3/2) and a high intensity peak in the high field region
(g = 2.046; A = NR). The observed values are in concurrence
⊥
⊥
with not only the reported values for the inactive form of the
1
9
enzyme GOase (g = 2.277; g = 2.055; A = 175) but also with
ꢁ
⊥
ꢁ
related GOase synthetic models. For example, the g and A values
reported for a series of structural models of GOase based on
bis(pyridyl)alkyl amines are (g = 2.217–2.327; g = 2.04–2.098
ꢁ
⊥
and A = 147–187) while those exhibited by a series of phenol
ꢁ
containing TACN ligand (TACN = 1,4,7-triazacyclononane) lie
13c
in the range (g = 2.25–2.27; g = 2.02–2.06 and A = 157–175).
ꢁ
⊥
ꢁ
Furthermore, the g and A values exhibited by a related analog
ꢀ
namely, {[(3-tert-butyl-5-methoxy-2-hydoxybenzyl)(3 -tert-butyl-
ꢀ
ꢀ
5 -nitro-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc),
are
g
xx
= 2.042; g = 2.059; g = 2.256 and A = 1 mT; A = 2.5
yy
zz
xx
yy
11
1b complex. In particular, with the aim of exploring the feasibility
mT; A = 17.8 mT, respectively. In addition, the higher value of
zz
of the unconventional radical cofactor–Cu(II/I) redox coupled
pathway occurring in the GOase model 1b complex, we wanted to
look into the possibility of the ligand based one-electron oxidation
g (2.267) as compared to g (2.046) in the 1b complex indicates
ꢁ
⊥
that the unpaired electron of the Cu(II) center resides on the
metal dx
2−y2
orbital as was also confirmed by NBO studies. In this
2
occurring on the equatorial phenolate-O atom of 1b, thereby
regard it is worth mentioning that for the tetragonal and square
generating a organic radical center adjacent to the paramagnetic
Cu(II) center in the copper complex, similar to what is seen in the
planar Cu(II) complexes that exhibit g > g the unpaired electron
ꢁ
⊥
20
is reported to reside on the dx
2−y2
orbital.
More importantly, frozen-state EPR measurements carried out
on the electrochemically oxidized species of 1b showed it to be
diamagnetic in nature indicating a significant antiferromagnetic
2
+
Scheme 2
coupling occurring between the unpaired dx2−y2 electron on Cu
This journal is © The Royal Society of Chemistry 2008
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2
3
+
4
2+
Fig. 3 Frontier molecular orbitals of 1b, 1b and 1b showing the electronic arrangement; orbitals corresponding to molecular orbital number 150,
49 and 148 are shown (energy is given in Hartrees).
1
1
+
with the phenoxy-radical (suggesting the formation of 1b species)
similar to the tyrosyl (272) radical–Cu(II) redox couple seen in the
active enzyme (Fig. 4).
moiety to phenoxy radicals. For example, the structurally related
ꢀ
complex {[(3-tert-butyl-5-methoxy-2-hydoxybenzyl)(3 -tert-butyl-
ꢀ
ꢀ
5 -nitro-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc) showed
Further insights on the nature of the oxidized species of
the 1b complex were obtained from the cyclic voltammetry
CV) studies which were in concurrence with the EPR results.
Specifically, the cyclic voltammogram (CV) of the copper complex
1b) in CH CN–CH Cl (1 : 1) at room temperature, exhib-
ited two electrochemical processes in the anodic region on the
CV timescale, but no processes were observed in the negative
region [between 0 and −0.5 V vs. Ag/AgCl] (Fig. S2, ESI†
and Scheme 3). The first quasi-reversible electrochemical process
a reversible one-electron oxidation peaks at E1/2 = 0.075 V
+
(vs. FeCp
2
/FeCp
2
) {1 mM in CH
3
CN–CH
2
Cl (1 : 1), TBAP
2
−
1 11
(
(100 mM), scan rate 100 mV s } and another analo-
ꢀ ꢀ
gous complex namely, {[(3,5-di-tert-butyl-2-hydoxybenzyl)(3 ,5 -
ꢀ
(
3
2
2
di-tert-butyl-2 -oxybenzyl)(2-pyridylmethyl)]amine}Cu(OAc) ex-
hibited an irreversible one electron oxidation peaks at E1/2
=
−
1
12
0.62 V (vs. Ag/AgCl) {CH
2
Cl
2
, TBAP, scan rate 100 mV s }.
Apart from these structural analogues, another copper bisphe-
ꢀ
ꢀꢀ
nolate complex namely (N-benzyl-bis-N ,N -salicylidene)-cis-
appeared at E1/2 = 0.72 V (DE = 82 mV) [E1/2 = 0.21 V
1,3,5-triaminocyclohexanecopper(II) showed two reversible one-
+
+
vs. FeCp
2
/FeCp
2
] and the second quasi-reversible process at
electron oxidations at E1/2 = 0.89 V (0.34 V vs. Fc/Fc ) and E1/2
=
+
+
E
1/2 = 1.10 V (DE = 94 mV) [E1/2 = 0.60 V vs. FeCp
2
/FeCp
2
].
1.13 V (0.58 V vs. Fc/Fc ) {0.1 mM in CH
2
Cl , TBAB (500 mM),
2
−
1
14c
Comparison of the electrochemical nature of complex 1b with
scan rate 200 mV s }.
related copper bisphenolate complexes confirms that both the
The electronic spectroscopy studies corroborated the electro-
chemical results. Specifically, the electronic spectra of the copper
1b complex showed absorptions at 465 (e = 823) and 673 nm
oxidation processes (E1/2 = 0.21 V and E1/2 = 0.60 V; vs.
+
FeCp
2
/FeCp
2
) arise due to ligand based oxidation of the phenol
−
1
−1
(
e = 285 L mol cm ) in addition to the ligand based p–
p* transitions. The absorption at 465 nm is assigned to the
equatorial phenolate–metal charge transfer (CT) band and is
in agreement with similar absorption bands observed in the
range of 370–460 nm for related complexes having an equatorial
Scheme 3
2
818 | Dalton Trans., 2008, 2815–2824
This journal is © The Royal Society of Chemistry 2008

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and the axial phenolic-OH moieties with the loss of net spin
densities upon oxidation remaining confined to the respective
phenyl moieties, theoretical calculations carried out on another
ꢀ
ꢀꢀ
related GOase model namely (N-benzyl-bis-N ,N -salicylidene)-
22
cis-1,3,5-triaminocyclohexanecopper(II) showed that for both
the first as well as the second one-electron oxidations, the net spin
density due to the unpaired electron resulting from the oxidation
gets delocalized over the two phenol rings instead and this is
presumably due to the presence of a highly conjugated ligand
backbone attached to two symmetrical phenolate-O moieties.
An important structural parameter often used in indicating the
extent of distortion is given by the trigonal index that provides a
measure of the degree of trigonality in a five-coordinated complex
that may vary from a trigonal bipyramidal (s = 1) to square
23
pyramidal (s = 0) geometry. The trigonal index ‘s‘ is given by
s = (b − a)/60, where b is the larger of the two largest basal
angles, a and b, in a five-coordinated geometry. Comparison
2
of the optimized geometry of the neutral copper 1b complex
3
+
with the one-electron oxidized species 1b and the two-electron
4
2+
oxidized species 1b reveals that the two-electron oxidized species
4
2+
1
b
species (s = 0.57) is significantly distorted from the one-
3 +
electron oxidized 1b species (s = 0.11) and the neutral copper
2
1
b complex (s = 0.21). Indeed, a careful examination of the
4 2+
computed geometry optimized structure of 1b reveals that the
2
3
+
axial phenolic-OH moiety, present in 1b and 1b , underwent
deprotonation with a concomitant proton transfer to the metal
bound acetate moiety (Fig. S4 and Table S8, ESI†). Further
understanding of the proton transfer process occurring between
the axial phenolic-OH and the metal bound acetate moieties were
obtained from that the quasi-reversible cyclic voltammogram peak
Fig. 4 X-Band EPR spectra of (a) the copper complex 1b in CH
7
[
3
CN at
7 K and (b) electrochemically generated cationic 1b species in CH CN
TEAP (0.1 M)] at 77 K.
1
+
3
1
+
4
2+
phenolate moiety bound to a Cu(II) center (Table S10 and Fig.
for oxidation of 1b (verified by EPR studies) to 1b [E1/2
=
21,14n
S3, ESI†).
The other absorption band appearing at 673 nm
1.10 V vs. Ag/AgCl] that exhibited a DE of 94 mV for the redox
couple and is suggestive of a fast reversible proton transfer between
the two on a CV timescale.
is assigned to a d–d transition and also falls in the range (640–
1
4n
7
80 nm) observed in analogous complexes. The one-electron
1
+
oxidized species 1b (as verified by EPR studies) generated
Significantly enough, the 1b complex not only mimicked the
active-site structure and the anti-ferromagnetic coupling present
between the tyrosine (272) radical and the neighboring Cu(II)
center in the active form of the GOase, but also successfully
oxidized primary alcohols to aldehydes similar to the active
enzyme. Specifically, when a variety of substituted benzylic
electrochemically by exhaustive electrolysis carried out at +0.9 V,
2
1
+
showed a red shift in the CT band at 465 nm ( 1b) to 500 nm ( 1b )
and correlates with similar shift observed for a related analogue,
ꢀ
namely {[(3-tert-butyl-5-methoxy-2-hydoxybenzyl)(3 -tert-butyl-
ꢀ
ꢀ
5
4
-nitro-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc) (392 to
11
10 nm).
alcohols were stirred under O
copper catalyst and 2 mol% of base (NaOH) at room temper-
ature in CH CN, the corresponding aldehydes were obtained in
2
in presence of 0.1 mol% of the
The cyclic voltammetry results were substantiated by the density
functional theory studies that ascribed the first one-electron
3
oxidation to the loss of an electron from the equatorial phenolate-
moderate to high TONs (103–272) (Table 1). The broad substrate
specificity of 1b is underscored from its ability to successfully
oxidize a wide range of substituted benzylic alcohol substrates
to the corresponding aldehydes under ambient conditions. Quite
remarkably, the 1b complex reproduces the chemoselectivity of
the enzyme GOase as it only oxidizes primary alcohols but fails
in the case of secondary alcohols like cyclohexanol, for which no
conversion to the ketone was observed even after 24 h. Worth
noting that the efficiency of the 1b complex is comparable to,
and in many cases, even superior to that of other reported
examples. For instance, a structurally similar functional GOase
2
3
+
O moiety in 1b to give the lower energy 1b while the second
one-electron oxidation to that on the axial phenolic-OH moiety
4
2+
resulting in a dication 1b species. The three unpaired electrons
4
2+
of the dication 1b species reside on the Cu(II) dx2−y2 orbital
(
150a), the equatorial phenolate-O moiety (149a) and the axial
phenolic-OH moiety (148a) (Fig. 3). During the second one-
electron oxidation process, the Mulliken net spin density on the
Cu(II) (0.57) center and the equatorial phenolate (1.01) remains
almost unchanged, while that on the axial phenolic-OH moiety
3
+
4
2+
drastically increases [0.02 ( 1b ); 0.98 ( 1b )] upon oxidation
3
+
4
2+
ꢀ
of 1b to 1b species implying that the second oxidation is
occurring on the axial phenolic-OH moiety (Table S9, ESI†
and Fig. 3). In this context it is worth mentioning that unlike
what is observed in the 1b complex, where the two successive
one-electron oxidations occur on the equatorial phenolate-O
model namely, {[(3-tert-butyl-5-methoxy-2-hydoxybenzyl)(3 -tert-
ꢀ
ꢀ
butyl-5 -nitro-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc)
exhibited a maximum of 220 turnover numbers for the oxi-
11
dation of benzyl alcohol in 48 h (KOH used as base, RT),
while the same was achieved by the 1b complex in 24 h (272
This journal is © The Royal Society of Chemistry 2008
Dalton Trans., 2008, 2815–2824 | 2819

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a,b
ꢀ
Table 1 Selected results for the oxidation of primary alcohols by 1b
[where LH = 2,2 -selenobis-(4,6-di-tert-butylphenol)] effectively
2
carried out the oxidation of benzyl alcohol to benzaldehyde in up
Entry
1
Reagent
Product
TON
272
24
to 95 turnovers.
It is worth noting that though the copper 1b complex efficiently
oxidizes a variety of substituted benzylic alcohols, similar to the
other synthetic analogues, its activity is however, significantly
lower compared to that of the active GOase enzyme. This
difference in activity is ascribed to the better delocalization of
the phenoxy radical into the equatorial tyrosine ring (Tyr 272) of
2
124
25
the active enzyme relative to that in the models, where structural
constraints do not facilitate such substantial delocalization of the
phenoxy radical and thereby account for much subdued activity
in these synthetic mimics of GOase. Efficient delocalization of the
phenoxy radical by the phenolate ring is a prerequisite for the
3
4
103
163
26
subsequent rate determining H atom abstraction step (HAT).
Thus, the choice of suitable spacers and substituents on the
phenolate rings in the model complexes becomes important as
it plays a significant role in dictating the enzymatic activity. It is
noteworthy that the activation barrier for the alcohol oxidation
is estimated to reduce dramatically with the incorporation of
electron withdrawing substituents on the equatorial phenolate
27
moiety in small molecule synthetic GOase models.
The dominating effect of electron withdrawing phenolate
substituents on the enzymatic activity is very much evident
in the existing GOase synthetic analogues. In particular, {[(3-
5
6
7
162
126
10
ꢀ
ꢀ
ꢀ
tert-butyl-5-methoxy-2-hydoxybenzyl)(3-tert-butyl-5 -nitro-2 -oxo-
11
benzyl)(2-pyridylmethyl)]amine}Cu(OAc), which is an excellent
structural and functional mimic of GOase, contains an electron-
withdrawing nitro substituent on the para-position and a
bulky tert-butyl moiety on the ortho-position of the equatorial
ꢀ
ꢀ
phenolate ring while, {[(3,5-di-tert-butyl-2-hydoxybenzyl)(3 ,5 -di-
ꢀ
12
tert-butyl-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc), which
only serves as a structural model but do not exhibit any functional
characteristics, contains relatively more electron donating tert-
butyl group on the para-position with the ortho-substituent
remaining the same. The increased electron density due to
the combined inductive effects of the two tert-butyl groups
significantly diminishes the ability of the phenolate ring to
delocalize the phenoxy radical in the functionally inactive {[(3,5-
CH
3
(CH
2
)
6
OH
3 2 5
CH (CH ) CHO
a
Reaction conditions: Benzylic alcohol, NaOH and 1,2-dichlorobenzene
internal standard) in the molar ratio of 1 : 0.02 : 1 in CH CN (10 mL),
(
3
copper complex 1b (0.001 mmol), 24 h at room temperature under O
atmosphere. Determined by GC using 1,2-dichlorobenzene as an internal
standard.
2
b
ꢀ
ꢀ
ꢀ
di-tert-butyl-2-hydoxybenzyl)(3 ,5 -di-tert-butyl-2 -oxobenzyl)(2-
1
2
turnover numbers). Again, for the oxidation of benzyl alcohol
to benzaldehyde, the activity of 1b is also comparable to other
functional models such as (N-benzyl-bis-N ,N -salicylidene)-cis-
pyridylmethyl)]amine}Cu(OAc) complex. Quite understandably,
owing to the presence of less electron donating methyl substituent
on the para-position of the phenolate ring, complex 1b was
found to exhibit much superior activity than the inactive
ortho/para di-tert-butyl substituted {[(3,5-di-tert-butyl-2-hy-
ꢀ
ꢀꢀ
1
4
,3,5-triaminocyclohexanecopper(II) [44 turnover numbers in 24 h,
% base, chemical oxidant (Cu(CF
1
4c
3
SO
3
)
2
used, air, CH CN] and
3
ꢀ
ꢀ
ꢀ
[
bis(di-tert-butylsalicylimine)binaphthyl]copper(II) [40 turnover
doxybenzyl)(3 ,5 -di-tert-butyl-2 -oxobenzyl)(2-pyridylmethyl)]-
17
12
numbers in 20 h, 0.2 mol% base, O
2
, CH
3
CN]. In this context it
amine}Cu(OAc) complex.
ꢀ
is worth mentioning that another copper complex, [N,N -bis(2-
oxy-3,5-di-tert-butylbenzyl)-1,2-ethylenediamine]copper(II), too
showed similar broad substrate specificity like that of complex
Apart from its utility in the biomimetic chemistry of GOase, the
green aspect of the catalysis by the copper complex 1b is worth
commenting upon, particularly with regard to its potential use in
the development of green oxidation catalysts. As these functional
mimics were able to carry out controlled oxidation of several
benzylic alcohols to aldehydes at ambient conditions using molec-
1
b for a wide range of aliphatic primary alcohols [ROH, R =
CH , C , C , C ] but exhibited much lower turnover
3
2
H
5
3
H
7
4
H
9
1
6
numbers. Apart from above-mentioned complexes, which serve
as both structural and functional models of GOase, there are other
complexes which though do not structurally mimic the active-site
of GOase, but incorporates the other salient features of the GOase
like the organic radical–Cu(II/I) redox couple and also successfully
oxidizes primary alcohols to aldehydes under ambient aerobic
ular O (air), they offer potential solution towards circumventing
2
the hazards associated with the use of stoichiometric amounts of
traditional inorganic oxidants and waste disposal.
The most important feature of the copper complex 1b is that,
it not only mimics the structural and functional characteris-
tics of GOase but also precisely emulates the enzyme mode
1
0a,b,15
Se
conditions.
For example, the copper complex [CuL (NEt )]
3
2
820 | Dalton Trans., 2008, 2815–2824
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View Article Online
of action through an unconventional organic radical cofactor-
Cu(II/I) redox coupled pathway. In order to get further insight
about the catalytic cycle of the 1b model complex we decided
to model the oxidation of a specific alcohol substrate e.g. of
benzyl alcohol. The proposed intermediates in the oxidation
pathway were computed at the B3LYP/LANL2DZ 6–31G(d) level
of theory by geometry optimizing the structures obtained after
employing suitable modifications to the initial structure based on
the neutral 1b complex and taking into consideration other metal
bound moieties of the various intermediates in the catalytic cycle
in which the Cu(I) center of the intermediate 2 is oxidized back
to Cu(II) along with the oxidation of the equatorial phenolate-
O moiety to generate a phenolate-O radical, thereby resulting in
the intermediate 3 species bearing a metal bound hydroperoxide
moiety. The intermediate 3, again being paramagnetic in nature,
is significantly different from the diamagnetic intermediate 2
species (Fig, S7 and Table S11, ESI†). The last step in the proposed
26
catalytic cycle involves proton transfer from the PhCH OH to the
2
metal bound hydroperoxide moiety with the elimination of H
2
O
2
and generating back the intermediate 1 species.
(
Scheme 4).
As proposed in the first step of the catalytic cycle, the neutral
Conclusion
inactive 1b complex undergoes one-electron aerial oxidation to
3
+
generate the catalytically active radical cationic species 1b , which
In summary, the copper complex, {[(3-tert-butyl-5-methyl-
-hydoxybenzyl)(3 -tert-butyl-5 -methyl-2 -oxobenzyl)(2-
−
further binds to the alkoxide anion (PhCH
2
O moiety) with the
ꢀ
ꢀ
ꢀ
2
elimination of the metal bound acetate. The computed geometry
pyridylmethyl)]amine}Cu(OAc) 1b was found to be an excellent
structural and functional mimic of the enzyme GOase. Specifically,
the binding of the tyrosine (272 and 495) and the histidine (496
and 581) residues to the copper center in the GOase enzyme
were emulated by the two phenolate-O atoms and the amine N
and pyridine N, respectively. In addition, the copper 1b complex
efficiently catalyzed the chemoselective oxidation of primary
alcohols to the corresponding aldehydes in high turnover numbers
under ambient conditions and, more importantly, it did so by
employing a organic radical cofactor–Cu(II/I) redox couple
analogous to the active enzyme.
optimized structure of the intermediate 1 closely resembled the
3
+
precursor 1b species both structurally and electronically (Fig.
S5 and Table S11, ESI†). The step 2 involves a hydrogen atom
abstraction by the equatorial phenolate-O radical moiety from
the methylene hydrogens of the metal bound alkoxy group of
26
the intermediate 1 species and which in turn generates a metal
28
bound ketyl radical anion that undergoes fast single electron
transfer (SET) to give the aldehyde with concomitant reduction of
metal center [Cu(II) to Cu(I)] forming a diamagnetic intermediate
29
2
species (Fig. S6, ESI†). The kinetic isotope studies carried out
on the enzyme and its model complexes revealed that the hydrogen
atom transfer (HAT) is the rate-determining step as confirmed by
15,26,29
Experimental
its very high range (∼7–54) of k
H
/k
D
values.
On the other
hand, the single electron transfer (SET) is reported to be a rapid
General procedures
10a,b
process.
As expected, the structure and the electronic properties
of the diamagnetic intermediate 2 is significantly different from
that of the paramagnetic intermediate 1 species. Particularly, the
equatorial Cu–O and Cu–N bond lengths in the intermediate 2 are
comparatively larger than that of the intermediate 1 (Table S11,
ESI†). In step 3, a dioxygen molecule replaces the metal bound
aldehyde and subsequently carries out a two-electron oxidation
All manipulations were carried out using a combination of a
glovebox and standard Schlenk techniques. Solvents were purified
and degassed by standard procedures. 2-(Aminomethyl)pyridine
and 2-(tert-butyl)-4-methylphenol were purchased from Sigma
1
Aldrich, Germany and used without any further purification. H
1
3
1
and C { H} NMR spectra were recorded on a Varian 400 MHz
Scheme 4
This journal is © The Royal Society of Chemistry 2008
Dalton Trans., 2008, 2815–2824 | 2821

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1
NMR spectrometer. H NMR peaks are labeled as singlet (s)
2855 (w), 1745 (w), 1683 (w), 1609 (m), 1597 (m), 1574 (s), 1467 (s),
1439 (s), 1414 (s), 1397 (s), 1290 (m), 1260 (m), 1229 (m), 1155 (w),
1122 (w), 1089 (w), 1069 (w), 1028 (m), 976 (w), 914 (w), 860 (m),
and doublet (d). Infrared spectra were recorded on a Perkin
Elmer Spectrum One FT-IR spectrometer. Mass spectrometry
measurements were done on a Micromass Q-Tof spectrometer.
The EPR measurements were made with a Varian model 109C
E-line X-band spectrometer fitted with a quartz Dewar for
measurements at 77 K. The spectra were calibrated by using
tetracyanoethylene (tcne) (g = 2.0037). The electronic spectra were
recorded in acetonitrile–dichloromethane (1 : 1) by using a Perkin
Elmer Lambda 950 UV/VIS Spectrometer. GC spectra were
measured on a Shimadzu gas chromatograph GC-15A equipped
with a FID. Cyclic voltammetric and coulometric measurements
were carried out using a PAR model 273A electrochemistry
system. Platinum disc working (2 mm), auxiliary electrodes and
Ag/AgCl electrode were used in three-electrode configuration. A
platinum wire-gauze working electrode was used in coulometric
experiments. Elemental Analysis was carried out on Thermo Quest
FLASH 1112 SERIES (CHNS) Elemental Analyzer.
811 (w), 758 (w), 659 (m). Anal. Calc. for C32
C, 65.52; H, 7.28; N, 6.74. Found: C, 64.90; H, 8.15; N, 7.58%.
H
42CuN
2
O
4
·CH
3
CN:
Computational methods
Density functional theory calculations were performed on the
2
3
+
copper 1b complex ( 1b) and on its oxidized forms ( 1b and
4
2+
1
b ) as well as on the mechanistic intermediates 1, 2 and 3
30
using GAUSSIAN 03 suite of quantum chemical programs.
The Becke three-parameter exchange functional in conjunction
with Lee–Yang–Parr correlation functional (B3LYP) has been
3
1
employed in the study. The LANL2DZ basis set was used for Cu
atom while the 6–31G(d) basis set was used for all other atoms.
Stationary point calculations were carried out using the output
coordinates from the geometry optimization calculations. Natural
bond orbital (NBO) analysis was performed using the NBO 3.1
32
program implemented in the GAUSSIAN 03 package.
Synthesis of bis(3-tert-butyl-5-methyl-2-
hydroxybenzyl)(2-pyridylmethyl)amine (1a)
General procedure for the aerobic oxidation of alcohols
2
-Aminomethylpyridine (2.69 g, 24.9 mmol), 2-tert-butyl-4-
In a typical catalysis run, a Schlenk flask was charged with the
alcohol, NaOH and 1,2-dichlorobenzene (internal standard) in the
methylphenol (8.19 g, 49.9 mmol) and formalin (8.42 g of 37%
solution, 104 mmol) were taken in methnol (ca. 10 mL) and
the reaction mixture was refluxed for 24 h during which time a
precipitate was formed. The precipitate was isolated by filtration
to obtain the product 1a as a white powder (6.31 g, 55%). H
NMR (CDCl
molar ratio of 1 : 0.02 : 1 in CH
added the copper 1b complex (0.001 mmol). The reaction mixture
was stirred in an O atmosphere for 24 h after which it was diluted
with CH OH (10 mL) and analyzed by gas chromatography using
,2-dichlorobenzene as an internal standard.
3
CN (10 mL) and to this mixture was
1
2
◦
3
3
, 400 MHz, 25 C): d 10.2 (br, 2H, OH), 8.73 (d,
1
3
3
1
7
m-C
H, JHH = 8 Hz, o-C
5
H
4
N), 7.68 (t, 1H, JHH = 8 Hz, p-C
5
H N),
4
3
3
.27 (t, 1H, JHH = 8 Hz, m-C
N), 6.91 (s, 2H, m-C
H, CH ), 3.72 (s, 4H, CH
C(CH
N), 153.8 (o-C
37.0 (o-C ), 128.9 (p-C
23.6 (m-C N), 122.5 (o-C
5.2 (CH ), 34.7 (C(CH ), 29.5 (C(CH
5
H
4
N), 7.10 (d, 1H, JHH = 8 Hz,
Crystallography
5
H
4
6
H
2
), 6.66 (s, 2H, m-C
6
H
2
), 3.80 (s,
2
2
2
), 2.22 (s, 6H, CH
3
), 1.36 (s, 18H,
X-Ray diffraction data were collected on a Bruker P4 diffrac-
tometer equipped with a SMART CCD detector, and crystal data
collection and refinement parameters are summarized in Table 2.
The structures were solved using direct methods and standard
1
3
◦
3
)
3
). C NMR (CDCl
N), 148.1 (ipso-C
), 127.1 (m-C
), 122.0 (m-C
3
, 100 MHz, 25 C): d 156.0 (ipso-
C
5
H
4
5
H
4
6
H
2
), 137.3 (p-C
5
4
H N),
1
1
5
6
H
2
6
H
2
6
H
2
), 127.0 (m-C
H
6
H
2
),
),
5
H
4
6
H
2
5
4
N), 56.1 (CH
2
2
3
+
)
3
3
)
3
), 20.7 (CH ). LRMS
3
Table 2 X-Ray crystallographic data for 1b
+
(
ES): m/z 461 (M + H) 100%. HRMS (ES): calc. for [M + H]
−
1
4
2
1
61.3168, found m/z 461.3156. IR (cm , KBr pellet): 3048 (m),
952 (s), 2865 (s), 2824 (m), 2370 (w), 1597 (m), 1478 (s), 1435 (s),
375 (s), 1294 (m), 1236 (s), 1200 (s), 1151 (m), 1116 (m), 1010
Formula
64 2 4 8
C H84Cu N O
M
r
1164.43
Triclinic
¯
P1
12.3083(4)
14.719(2)
18.0662(15)
73.601(10)
74.338(5)
83.836(8)
3021.6(5)
2
120(2)
0.71073
1.280
Crystal system
Space group
(
C
m), 933 (w), 859 (m), 752 (m), 682 (w), 630 (w). Anal. Calc. for
·CH OH: C, 75.57; H, 9.00; N, 5.69. Found: C, 76.45;
H, 9.55; N, 6.42%.
˚
a/A
H
40
N
2
O
2
3
b/A˚
30
c/A
˚
◦
a/
b/
◦
ꢀ
◦
Synthesis of {[(3-tert-butyl-5-methyl-2-hydoxybenzyl)(3 -tert-
butyl-5 -methyl-2 -oxobenzyl)(2-pyridylmethyl)]amine}Cu(OAc)}
1b)
c /
V/A˚
3
ꢀ
ꢀ
Z
(
T/K
k(Mo-Ka)/A˚
To a stirred solution of Cu(OAc)
methanol (ca. 20 mL) was added a solution of bis(3-tert-butyl-
5
1
refluxed for 8 h after which it was filtered and the filtrate was
reduced under vacuum to obtain a dark solid. The residue was
2
·H
2
O (0.269 g, 1.35 mmol) in
−3
c
D /g cm
−1
l(Mo-Ka)/mm
0.760
32.5654
10584
◦
-methyl-2-hydroxybenzyl)(2-pyridylmethyl)amine (1a) (0.620 g,
.35 mmol) in methanol (ca. 10 mL). The reaction mixture was
h
max
/
No. of data
No. of parameters
Reflections collected/unique
Rint
729
25774/10584
0.0294
R indices (all data)
Final R indices [I > 2r(I)]
GOF
R1 = 0.0479, wR2 = 0.0853
R1 = 0.0320, wR2 = 0.0768
1.046
extracted with CH
was removed vacuum to obtain the product 1b as a dark green solid
3
CN (ca. 10 mL) and filtered and the solvent
−
1
(
0.338 g, 43%). IR (cm , KBr pellet): 3433 (w), 2958 (m), 2923 (m),
2
822 | Dalton Trans., 2008, 2815–2824
This journal is © The Royal Society of Chemistry 2008

View Article Online
difference map techniques, and were refined by full-matrix least-
squares procedures on F with SHELXTL (Version 6.10).
CCDC reference number 640145.
For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b801496e
Jazdzewski, S. Mahapatra, L. M. Berreau, E. C. Wilkinson, L. Que,
Jr. and W. B. Tolman, J. Am. Chem. Soc., 1997, 119, 8217–8227; (f) S.
Itoh, S. Takayama, R. Arakawa, A. Furuta, M. Komatsu, A. Ishida, S.
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Stack, J. Am. Chem. Soc., 1996, 118, 13097–13098.
2
33
1
1
1
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Acknowledgements
We thank the Department of Science and Technology, New
Delhi, for financial support of this research. We are grateful
to the National Single Crystal X-ray Diffraction Facility at IIT
Bombay for the crystallographic results. P. G. thanks Professor
G. K. Lahiri and Professor A. Q. Contractor, IIT Bombay, for
help with electrochemical studies. AJ thanks CSIR, New Delhi for
research fellowship. Computational facilities from the IIT Bombay
Computer Center are gratefully acknowledged.
4
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