Tripodal bis(imidazole) thioether copper(I) complexes: Mimics of the Cu(B) site of hydroxylase enzymes

Article abstract of DOI:10.1021/ic052121b

Tripodal bis(imidazole) thioether ligands and the corresponding copper(I) complexes [(BIMT-OR)Cu(L)]PF₆ [L = CH₃CN (2), CO (3); R = H (a), CH₃ (b)] have been prepared as models for the Cu(B) site of copper hydroxylase enzymes. The IR ν(CO) values of 3a and 3b (L = CO) are comparable to those of the carbonylated enzymes. The reaction of 2a with O ₂ gives dinuclear complex 4 with bridging BIMT-O ligands and oxidized -SMe groups, whereas oxygenation of 2b affords [(BIMT-OMe)₂Cu ₂O(H)₂](CF₃SO₃)₂ (5) and Cu(BIMT-OMe)(DMF)₂](PF₆)₂ (6).

Full text of DOI:10.1021/ic052121b

Inorg. Chem. 2006, 45, 3840−3842
Tripodal Bis(imidazole) Thioether Copper(I) Complexes: Mimics of the
Cu(B) Site of Hydroxylase Enzymes
L. Zhou, D. Powell, and K. M. Nicholas*
Department of Chemistry and Biochemistry, UniVersity of Oklahoma, Norman, Oklahoma 73019
Received December 12, 2005
Tripodal bis(imidazole) thioether ligands and the corresponding
copper(I) complexes [(BIMT-OR)Cu(L)]PF6 [L CH3CN (2), CO
(3); R H (a), CH3 (b)] have been prepared as models for the
Cu(B) site of copper hydroxylase enzymes. The IR (CO) values
of 3a and 3b (L CO) are comparable to those of the carbonylated
enzymes. The reaction of 2a with O2 gives dinuclear complex 4
but only one CuI analogue has been reported.9 Given the
significantly different basicity10 and donor-acceptor proper-
ties11 of imidazole vis a vis the other common nitrogen lig-
ands, the most accurate structural and functional mimics for
histidine-rich metalloenzymes are likely to be provided by
incorporating the actual biological donor set. Toward this
goal, we report here the preparation of biomimetic tripodal
bis(imidazole) thioether (BIMT) ligands, the corresponding
CuI complexes, and their reactivity with CO and O2.
To provide the desired bis(imidazole) thioether donor set
of the Cu(B) center in a sterically encumbered environment
that could limit the formation of bimetallic species, we
targeted the phenylated tripodal ligands BIMT-OH (1a) and
BIMT-OMe (1b), which are conveniently prepared from 4,5-
diphenylimidazole (Scheme 1).12 Compounds 1a and 1b react
readily with [Cu(CH3CN)4]PF6 (CH2Cl2, rt) to afford the
somewhat air-sensitive [(BIMT-OR)Cu(CH3CN)]PF6 (2a,b);
the former was characterized spectroscopically.
)
)
ν
)
with bridging BIMT-O ligands and oxidized −SMe groups, whereas
oxygenation of 2b affords [(BIMT-OMe)2Cu2O(H)2](CF3SO3)2 (5)
and Cu(BIMT-OMe)(DMF)2](PF6)2 (6).
The copper hydroxylase enzymes, dopamine â-hydroxy-
lase (DâH) and peptidylglycine R-hydroxylating monooxy-
genase (PHM), catalyze the regio- and enantioselective hy-
droxylation of mildly activated C-H bonds by O2.1 These
enzymes appear to have very similar active-site structures,
featuring two Cu centers separated by ca. 11 Å, with the
Cu(A) site being ligated by three histidine-derived imidazoles
and the Cu(B) site by two histidines and a methionine re-
sidue.2 Spectroscopic and amino acid deletion studies suggest
that upon reduction both O2 and the substrate are activated
at the Cu(B) site.3 A recent X-ray structure of the O2-bound
PHM enzyme has revealed an unusual end-on coordination
mode to the Cu(B) center,4,5 contrasting with the more com-
mon side-on mononuclear and bridging bimetallic bonding
modes found in most synthetic complexes and in the O2-bind-
ing Cu-protein hemocyanin.6
Although many synthetic model complexes for these (and
other) Cu enzymes have been prepared with a variety of poly-
dentate amine and pyridine and pyrazolyl-based ligands,6 re-
markably few have incorporated the biologically most rele-
vant imidazole donors.7 Regarding the Cu(B) site of the hy-
droxylases, a few CuII complexes with mixed NxSy-polyden-
tate imidazole thioether ligands have been characterized,8
Complexes 2a and 2b are convenient precursors for inves-
tigating reactions with biorelevant substrates such as CO and
O2. Bubbling CO into a CH2Cl2 solution of 2a,b (3 h, rt)
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* To whom correspondence should be addressed. E-mail:
knicholas@ou.edu.
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are provided in the Supporting Information.
3840 Inorganic Chemistry, Vol. 45, No. 10, 2006
10.1021/ic052121b CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/11/2006

COMMUNICATION
Scheme 1
Scheme 2
Figure 2. Crystal structure for the cation of 4. Selected bond lengths (Å):
Cu1-O42′ 1.909(9), Cu1-O44 1.9369(18), Cu1-O38 1.9436(16), Cu1-
N1 1.958(2), Cu1-O38′ 1.9599(16), Cu1-Cu1A 3.0302(7).
Figure 1. Crystal structure of 3a. Selected bond lengths (Å) and angles
(deg): Cu1-C43 1.811(2), Cu1-N25 2.0005(19), Cu1-N1 2.0259(17),
Cu1-S1 2.4392(7), C43-O44 1.123(2); C43-Cu1-N25 122.90(9), C43-
Cu1-N1 132.84(10), C43-Cu1-S1 118.81(9), N25-Cu1-N1 90.67(7),
N25-Cu1-S1 93.37(6), N1-Cu1-S1 87.33(5), Cu1-C43-O44 177.4(2).
2) showed it to be a product of adventitious oxidation. The
centrosymmetric dinuclear structure of 4 (Figure 2)17 consists
of two five-coordinate CuII centers, each terminally coordi-
nated to one imidazole N, a DMF O, and a sulfoxide O,
with the Cu centers bridged by two alkoxo O atoms from
the deprotonated tripodal ligands. Thus, both the Cu and S
atoms are oxidized during the conversion of 2a to 4. This
facile S oxidation can be compared to known Cu-mediated
oxidations of thioethers18 and of the methionine residue of
the amyloid â-peptide (Aâ)19 but contrasted with the apparent
oxidative inertness of the Cu(B) active-site methionine in
DâH and PHM. Related tris(imidazole) carbinol ligands have
also been found to form polynuclear, alkoxo-bridged CuII
complexes.20
resulted in the appearance of a strong IR absorption near
2100 cm-1. Addition of ether-petroleum ether induced
crystallization of the colorless, air-sensitive carbonyl com-
plexes [(BIMT-OR)Cu(CO)]PF6 (3a,b; Scheme 1). The
molecular structure of 3a was established by X-ray diffraction
(Figure 1)13 and consists of a slightly distorted pyramidal
arrangement about the CuI center formed by the tridentate
BIMT and CO ligands. Notwithstanding the unique N2S-
(L)-CuI donor atom set and a bifurcated O-H-FPF5
hydrogen bond, the observed bond lengths and angles are
unexceptional relative to reported N3CuI-CO structures.14
A close electronic similarity of the Cu centers in the carbonyl
complexes 3a and 3b with the Cu(B) site of the carbonylated
copper hydroxylases is indicated by comparable CO vibra-
tional frequencies: PHM (2093 cm-1),15 DâH (2089 cm-1),16
3a (2102 cm-1), and 3b (2095 cm-1).
In contrast, room-temperature oxygenation of the BIMT-
OMe complexes 2b or 3b (1 atm of O2, CH2Cl2, 12 h), for
which alkoxide formation is blocked, followed by crystal-
lization from CH2Cl2-Et2O produced an amber compound
The reactions of the hydroxy and methoxy tripodal com-
plexes 2a and 2b with O2 produced remarkably different
results. Slow recrystallization of 2a from a dimethylforma-
mide (DMF)-ether solution over a week’s time afforded
green crystals of a new complex 4, whose electrospray ioni-
zation mass spectrum (ESI-MS) and X-ray structure (Scheme
(14) (a) Imai, S.; Fujisawa, K.; Kobayashi, T.; Shirasawa, N.; Fujii, H.;
Yoshimura, T.; Kitajima, N.; Moro-oka, Y. Inorg. Chem. 1998, 37,
3066-3070. (b) Reger, D. L.; Collins, J. E.; Rheingold, A. L.; Liable-
Sands, L. M. Organometallics 1996, 15, 2029-2032. (c) Dias, H. V.
R.; Lu, H. L. Inorg. Chem. 1995, 34, 5380-5382.
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(16) Blackburn, N. J.; Pettingill, T. M.; Seagraves, K. S.; Shigeta, R. T. J.
Biol. Chem. 1990, 265, 15383-15386.
(13) X-ray crystal data for 3a: (C38H36CuN4O2S)(PF6), fw ) 821.28, P21/n
(No. 14), a ) 13.066(2) Å, b ) 14.065(2) Å, c ) 20.789(3) Å, â )
100.227(5)°, V ) 3759.8(10) Å3, Z ) 4, T ) -173 °C, Dcalcd ) 1.451
g cm-3, λ ) 0.710 73 Å, µ ) 7.48 cm-1, R1obsd ) 0.0360, wR2all(F 2)
) 0.0930.
(17) X-ray crystal data for 4: (C80H84Cu2N10O6S2)(PF6)2(C3H7NO)2-
(C4H10O), fw ) 1983.02, P1h (No. 2), a ) 9.7020(12) Å, b ) 15.521(2)
Å, c ) 15.775(2) Å, R ) 83.976(5)°, â ) 79.171(5)°, γ ) 81.070(5)°,
V ) 2297.9(5) Å3, Z ) 1, T ) -173 °C, Dcalcd ) 1.433 g cm-3, λ )
0.710 73 Å, µ ) 6.31 cm-1, R1obsd ) 0.0457, wR2all(F 2) ) 0.1298.
Inorganic Chemistry, Vol. 45, No. 10, 2006 3841

COMMUNICATION
Figure 4. Crystal structure of the dication of 6. Selected bond lengths
(Å) and angles (deg): Cu1-O3 1.9474(18), Cu1-N2 1.952(2), Cu1-O2
1.9527(17), Cu1-N1 1.968(2), Cu1-S1 2.6892(8); O3-Cu1-N2 98.75(8),
O3-Cu1-O2 84.85(7), N2-Cu1-N1 84.70(9), O2-Cu1-N1, 91.45(8).
Figure 3. Crystal structure of the cation of 5. Selected bond lengths (Å):
Cu(1)-O(1)′ 1.917(3), Cu(1)-O(1) 1.931(3), Cu(1)-Cu(1)′ 3.0206(9),
Cu(1)-S(1) 2.868(3), O(1)-O(1) 2.383(3).
5, whose ESI-MS was indicative of a dinuclear complex that
had incorporated two oxygens.
noteworthy that 6 retains the N2S coordination mode of the
oxidized Cu(B) site of the hydroxylase enzymes.2,3 Further-
more, the CuII-S distance of 6 (2.69 Å) is considerably
longer than the CuI-S length of 3a (2.44 Å), suggestive of
tighter binding of the S ligand to the reduced Cu center. The
same effect has been seen with the oxidized (2.68 Å) and
reduced (2.27 Å) forms of PHM.25
The X-ray structure of 5 (Scheme 3 and Figure 3)21 re-
Scheme 3
vealed it to be a dinuclear complex having a Cu2O2 core
with each copper coordinated to a BIMT-OMe ligand and
forming a square pyramid at Cu. The Cu-O, O-O, and Cu-
Cu distances in 5 are indicative of either a µ-oxocopper(III)
or µ-hydroxocopper(II) formulation, which cannot be dis-
tinguished definitively with the available spectroscopic data.22
Thus, by capping the hydroxyl group, as in the BIMT-OMe
complexes, Cu-centered oxygenation proceeds to give 5,
avoiding not only the alkoxo-bridging tripod (as in 4) but
also S oxidation as well. The relatively unhindered S center
of the BIMT-OMe ligand apparently is insufficient (at least
at room temperature), however, to prevent the formation of
an O2-bridged dinuclear complex.
Lability of the Cu2O2 linkage of 5 was suggested during
its recrystallization from DMF-ether when blue crystals of
a new compound 6 were also obtained. The ESI-MS of 6
suggested a [(BIMT-OMe)CuII(DMF)n]2+ formulation. In-
deed, the X-ray structure of 6 (Figure 4)22 revealed a cationic
mononuclear CuII complex of square-pyramidal geometry
with its basal plane defined by the two imidazole N atoms
and two DMF O atoms with an apical -SMe group. It is
In conclusion, the biomimetic (BIMT-OR)Cu complexes
reported herein exhibit several close parallels with the Cu(B)
site of the copper hydroxylases, including the formation of
electronically similar carbonyl adducts and their Cu-centered
oxidation and oxygenation (when R ) Me). Our ongoing-
efforts are focused on identifying oxygenation reaction
intermediates, potentially including Cu-O2 adducts, and
exploring the stoichiometric and catalytic oxidation reactions
promoted by these and related poly(imidazole) complexes.
Acknowledgment. We are grateful for partial support
provided by the Petroleum Research Fund of the American
Chemical Society and for helpful discussions with Dr. G.
Richter-Addo.
Supporting Information Available: Listings of preparative and
characterizational data for compounds 1-6, including X-ray
crystallographic data for 3a, 4, 5, and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
IC052121B
(22) Average reported distances for µ-peroxo, -oxo (refs 6a-d), and
-hydroxo (ref 23) complexes, respectively: Cu-Cu, 3.51, 2.80, 3.00
Å; O-O, 1.42, 2.33, 2.40 Å; Cu-O, 1.92, 1.84, 1.93 Å.
(18) Firouzabadi, H.; Iranpoor, N.; Zolfigol, M. A. Synth. Commun. 1998,
28, 1179-1187.
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(21) X-ray crystal data for 5: (C76H76Cu2N8O4S2)(PF6)2(CH2Cl2)2(C4H10O),
fw ) 1890.56, Pc (No. 7), a ) 14.446(2) Å, b ) 18.150(3) Å, c )
18.005(3) Å, â ) 113.351(5)°, V ) 4334.2(12) Å3, Z ) 2, T )
(24) X-ray crystal data for 6: (C44H52CuN6O3S)(PF6)2(C4H10O), fw )
1172.58, P21/c (No. 14), a ) 12.448(2) Å, b ) 28.000(5) Å, c )
16.848(3) Å, â ) 100.739(5)°, V ) 5769.4(17) Å3, Z ) 4, T )
-173(2) °C, Dcalcd ) 1.350 g cm-3, λ ) 0.710 73 Å, µ ) 5.54 cm-1
R1obsd ) 0.0476, wR2all(F 2) ) 0.1193.
,
-173(2) °C, Dcalcd ) 1.449 g cm-3, λ ) 0.710 73 Å, µ ) 7.80 cm-1
.
The metal complex suffers from “whole-molecule” disorder. Appar-
ently, good quality intensity data from four crystals has led to
essentially this same model.
(25) (a) Eipper, B. A.; Quon, A. S. W.; Mains, R. E.; Boswell, J. S.;
Blackburn, N. J. Biochemistry 1995, 34, 2857-2865. (b) Reddy, B.
J.; Blackburn, N. J. J. Am. Chem. Soc. 1994, 116, 1924-1931.
3842 Inorganic Chemistry, Vol. 45, No. 10, 2006