Reactions of a copper(II) superoxo complex lead to C-H and O-H substrate oxygenation: Modeling copper-monooxygenase C-H hydroxylation

Article abstract of DOI:10.1002/anie.200704389

(Chemical Equation Presented) Donor makes the difference: The mononuclear η¹-superoxo copper(II) complex 1 undergoes dioxygen activation with the addition of hydrogen-atom donors. Net O₂-derived O-atom insertion into the N-methyl group of the ligand leads to formation of a copper(II)-alkoxide product 2. The cupric superoxo species 1 itself is not capable of the observed hydroxylation reaction.

Full text of DOI:10.1002/anie.200704389

Communications
DOI: 10.1002/anie.200704389
Copper Superoxo Complexes
ꢀ
ꢀ
Reactions of a Copper(II) Superoxo Complex Lead to C H and O H
Substrate Oxygenation: Modeling Copper-Monooxygenase C H
Hydroxylation**
ꢀ
Debabrata Maiti, Dong-Heon Lee, Katya Gaoutchenova, Christian Würtele, Max C. Holthausen,
Amy A. Narducci Sarjeant, Jörg Sundermeyer, Siegfried Schindler, and Kenneth D. Karlin*
Mononuclear species derived from copper(I) and dioxygen
such as cupric superoxide CuII(O2Cꢀ), cupric hydroperoxide
CuII(OOHꢀ), or even high-valent copper oxo species have all
been considered as possible active-site reactive intermediates
in the copper monooxygenases dopamine b-monooxygenase
(DbM) and peptidylglycine a-hydroxylating monooxygenase
(PHM).[1] These enzymes effect neurohormone and neuro-
CuO species are predicted to be the hydroxylating agent by
some researchers.[1f,g]
Synthetically derived 1:1 dioxygen–copper(I) adducts are
best described as superoxo copper(II) or peroxo copper(III)
complexes, with the O2 moiety bound either in an h1 (end-on)
or h2 (side-on) metal coordination mode.[1e,7] Recent efforts
employing nitrogenous N4 tripodal tetradentate ligands have
led to the crystallographic characterization of the mononu-
clear CuII(O2Cꢀ) complex with an end-on superoxo ligand
[CuII(TMG3tren)(h1-O2Cꢀ)]+ (1, TMG3tren = tris(2-(N-tetra-
ꢀ
transmitter biosynthesis through active-site substrate C H
hydroxylation, which involves H-atom abstraction. However,
synthetic investigations have to date revealed only very
limited substrate reactivity with CuII(O2Cꢀ) or CuII(OOHꢀ)
ꢀ
methylguanidyl)ethyl)amine; a(Cu-O-O) = 123.58, d(Cu
complexes,[2] especially with C H-containing substrates.
O) = 1.927 Š, d(O O) = 1.280 Š, and n˜O-O = 1118 cmꢀ1 (res-
ꢀ
ꢀ
There are as yet no discrete examples of, nor evidence for,
onance Raman spectroscopy)), which is formed reversibly
from the corresponding cuprous analogue.[8] Spectroscopic
analysis showed that a related dioxygen–copper adduct,
[CuII(NMe2-tmpa)(h1-O2Cꢀ)]+ (2, NMe2-tmpa = tris(4-dime-
thylaminopyrid-2-ylmethyl)amine), also possesses an end-on
superoxo ligand; the chemistry of 2 provided the first clear
demonstration of CuII(O2Cꢀ) oxidative reactivity with exoge-
nous substrates (substituted phenols), resulting in their
oxidation, oxygenation, or hydroperoxylation.[2a] Herein, we
report our initial findings concerning the reactivity of 1. It also
oxygenates or oxidizes phenols in a manner similar to that
found for 2. Of greater interest and importance is our
demonstration that starting with the cupric superoxide
[3]
high-valent copper oxo species CuIIOCꢀ ($CuIII O) or
=
CuIIIOCꢀ (i.e. {CuO}2+).[1e] On the basis of a recent X-ray
structure of PHM,[4] an entity with h1-coordination (end-on)
of a superoxo ligand to copper(II) is formulated and
suggested to also apply to DbM. Such a cupric superoxo
complex capable of effecting an enzymatic substrate hydrox-
ylation by H-atom abstraction has drawn experimental[5] and
theoretical[1d,6] support, although, as mentioned, higher-valent
[*] D. Maiti, Prof. Dr. D.-H. Lee,[+] Dr. A. A. Narducci Sarjeant,
Prof. K. D. Karlin
Department of Chemistry, The Johns Hopkins University
Baltimore, MD 21218 (USA)
Fax: (+1)410-516-7044
ꢀ
complex 1, addition of a H-atom (HC) donor leads to C H
activation, O-atom insertion into an N-methyl group on the
TMG3tren ligand, and formation of a copper(II) alkoxide
product.
E-mail: karlin@jhu.edu
Dr. K. Gaoutchenova, Prof. Dr. J. Sundermeyer
Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
When 4-MeO-2,6-tBu2-phenol was added to a solution of
a newly synthesized tetraarylborate salt [CuII(TMG3tren)-
(O2Cꢀ)]B(C6F5)4 (1, excess O2 removed)[9] at ꢀ808C in 2-
methyltetrahydrofuran (MeTHF) and the mixture kept cold
for 48 h, the color changed from the initial light green to
bright green. A sharp, strong peak was observed at 407 nm in
the absorption spectrum of the reaction solution, and EPR
spectroscopy revealed a g ꢁ 2 signal, both of which indicate
the formation of the corresponding stabilized phenoxyl
radical (B, Scheme 1) formed in approximately 37% yield.
Other products identified in this reaction of 1 and 4-MeO-2,6-
tBu2-phenol are the 2,6-tBu2-benzoquinone (A, ca. 22%
yield) and the aryl hydroperoxide (C). More importantly, a
crystalline, green copper complex was also isolated in
approximately 80% yield; the product is the alkoxide
C. Würtele, Prof. Dr. S. Schindler
Institut für Anorganische und Analytische Chemie
Justus-Liebig-Universität Gießen
Heinrich-Buff-Ring 58, 35392 Gießen (Germany)
Prof. Dr. M. C. Holthausen
Institut für Anorganische und Analytische Chemie
Johann Wolfgang Goethe-Universität Frankfurt
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
[+] Current addresses:
Department of Chemistry and Research Institute of Physics and
Chemistry (RINPAC), Chonbuk National University
Jeonju 561-756 (Korea)
[**] We are grateful to the NIH (K.D.K., GM28962) and Deutsche
Forschungsgemeinschaft (J.S., S.S., and M.C.H.) for research
support.
complex
[CuII(TMG3trenOꢀ)]B(C6F5)4
(3;
ESI-MS:
m/z 518.19, [CuII(TMG3trenOꢀ)]+). Its X-ray structure[10]
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
reveals that hydroxylation of a ligand methyl group has
82
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Angew. Chem. Int. Ed. 2008, 47, 82 –85

Angewandte
Chemie
Superoxo complex 1 also reacts with other phenols to give
oxidation products similar to those seen for 2 (Scheme 1).[2a]
As determined by low-temperature reactions and subsequent
warming and workup, 2,6-tBu2-phenol and 2,4,6-tBu3-phenol
produce benzoquinone A (Scheme 1, 33 and 35%, respec-
tively). With 18O2-labeled 1, approximately 65% 18O-atom
incorporation into A occurs for the reaction of 1 and 2,4,6-
tBu3-phenol. With 2,4-tBu2-phenol, the typical[13] oxidative
coupling product 4,4’,6,6’-tBu4-2,2’-biphenol (10%) is
observed. Reaction of 3,5-tBu2-catechol with 1 leads to the
corresponding benzoquinone (20%, Scheme 1).[9]
In fact, all of the reactions of 1 with these other phenols
also lead to substantial yields (65% or more)[9] of ligand-
hydroxylated copper(II) alkoxide [CuII(TMG3trenOꢀ)]+ (3),
as determined by comparison of authentic 3 (see above) ESI-
MS and EPR spectroscopic signatures of the dark green
crystalline solids obtained. As we concluded for the chemistry
of 2 with phenols,[2a] the products observed with 1 (Scheme 1)
can be explained by initial phenol-substrate H-atom abstrac-
tion and subsequent addition of the superoxo complex to the
ArOC species. We suggest that alkoxide complex 3 arises from
the course of reaction {CuII(O2Cꢀ)} + ArOH!{CuII-
(OOHꢀ)} + ArOC, wherein a highly reactive cupric hydro-
peroxo species is produced in close proximity to the
TMG3tren N-methyl group.
Scheme 1. Reactivity of 1 with exogenous phenolic substrates. Dark
circles represent 18O.
occurred, with the result that the cupric ion is now coordi-
nated by the inserted O atom of the alkoxide (Figure 1).[11]
With an 18O2 source used in the generation of 1 and
subsequent addition of 4-MeO-2,6-tBu2-phenol, GC-MS
To further test this hypothesis, we used a H-atom donor
that might not itself react further. Reaction of 1 with
TEMPO-H (Scheme 2) at ꢀ808C or below (i.e. to ꢀ1208C)
in MeTHF over one hour produces a dark green solution. This
process leads to disappearance of the characteristic bands
ascribed to 1 (447, 680, 780 nm; Figure 2a),[8b] while a new
absorption at approximately 350 nm (sh) appears. The
presence of an isosbestic point suggests that 1 directly
converts to the new complex formulated as hydroperoxo
complex [CuII(TMG3tren)(OOHꢀ)]+ (4, Scheme 2). Support
for this supposition comes from EPR spectroscopy. During
Figure 1. X-ray structure of [CuII(TMG3trenOꢀ)]B(C6F5)4 (3) with near
trigonal-bipyramidal copper-ion coordination. Selected bond lengths [Š]
and angles [8]: Cu1–O1’ 1.972(5), Cu1–N2 2.091(2), Cu1–(N1,N3,N4)
2.053–2.117; O1’-Cu1-N2 170.01(16).
reveals 18O incorporation into A and C (68% and 85%,
respectively). For product cupric complex 3, the ESI-MS
positive ion parent peak (which shows the expected 63,65Cu
isotope pattern) shifts to m/z 520.27 (99% incorporation),
thus indicating that [CuII(TMG3tren18Oꢀ)]+ has formed; the
alkoxide O atom is derived from dioxygen.[9]
The observed oxidative reactivity of [CuII(TMG3tren)-
(O2Cꢀ)]+ (1) is similar to the CuM-centered action at the PHM
active site (CuM has His2Met coordination), in which oxygen-
ꢀ
ation of a prohormone peptide substrate C H group adjacent
to an amide nitrogen atom occurs.[1c] Furthermore, our cupric
alkoxide complex 3 mimics the “product complex” discussed
for both PHM and DbM,[1c] which is formed in the enzyme in
the step just prior to product release. When 1 is warmed from
ꢀ808C to room temperature, O2 is released, giving the
cuprous compound [CuI(TMG3tren)]+.[12] Thus, the cupric
superoxo complex itself is not capable of the observed
hydroxylation reaction. As described above, reaction of 1
with a phenol is required.
Scheme 2. Varying pathways to produce hydroxylated product 3.
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83

Communications
(see above), we carried out the reaction of iodosylbenzene
with the cuprous complex [CuI(TMG3tren)]+.[12] PhIO and its
analogues have been extensively employed as oxo-transfer
reagents to generate high-valent metal oxo complexes
through reactions with reduced species (i.e. PhIO + [Mn+
-
(ligand)]![Mn+2 (O )(ligand)] + PhI; M = heme, non-heme
Fe, Mn, etc.).[14] Interestingly, [CuI(TMG3tren)]+ [12] also
produces alkoxo species 3 in near quantitative yields upon
reaction with PhIO (Scheme 2).[9,15] This observation suggests
the possibility that a high-valent Cu oxo (or perhaps a
Cu(OIPh) species)[16] forms during the hydroxylation reac-
tion.
2ꢀ
=
In summary, we have described a novel example of a
copper–dioxygen adduct that undergoes a reaction reminis-
cent of certain copper monooxygenases, that is, O-atom
transfer from a dioxygen-derived species to the N-methyl
group of the ligand in [CuII(TMG3tren)(O2Cꢀ)]+ (1). The
hydroxylated product has been captured as the alkoxide
complex [CuII(TMG3trenOꢀ)]+ (3). The CuII(O2Cꢀ) moiety in 1
is not able to effect this reaction, but when a hydrogen-atom
donor (i.e. a phenol or TEMPO-H) is added, the hydroxyl-
ation reaction occurs.
A
hydroperoxo complex [CuII-
(TMG3tren)(OOHꢀ)]+ (4) is thus implicated as the active
species formed by such a reaction,[11] as further supported by
the observation that ligand hydroxylation occurs when [CuII-
(TMG3tren)]2+ (5) is subjected to basic hydrogen peroxide.
Thus, while these [CuII(ligand)(O2Cꢀ)]+ complexes (1 and
2) can effect phenolic H-atom abstractions and subsequent
phenol oxidation or oxygenation, a copper(II) hydroperoxo
complex (but not an analogue with an end-on superoxo
Figure 2. a) UV/Vis and b) EPR spectroscopic monitoring of the reac-
tion of [CuII(TMG3tren)(O2Cꢀ)]+ (1) with TEMPO-H. In (a), the starting
spectrum is green and the final spectrum is dark blue; in (b), the
starting spectrum is pink and the final spectrum in light green.
ꢀ
the UV/Vis monitoring at ꢀ808C, aliquots of the solution
were transferred to EPR sample tubes and immediately
frozen at 77 K. The EPR spectra thus obtained (as a function
of time) confirm the increasing intensity of the signal arising
from TEMPOC as the reaction progresses (Figure 2b). Com-
parison of EPR instensity to authentic TEMPOC suggests the
reaction yield to be approximately 90%. Using ESI-MS or
EPR spectroscopy to characterize reaction solutions from
which the TEMPOC product has been separated by extrac-
tion,[9] the formation of [CuII(TMG3trenOꢀ)]+ (3, Scheme 2)
was confirmed by comparison of data to the crystallograph-
ically characterized 3 (see above). The results thus strongly
support the view that a hydroperoxo complex derived from 1
forms and is active in the hydroxylation of the N-methyl
ligand.
More support comes from the finding that the same
chemistry occurs by treating a copper(II) analogue with
hydrogen peroxide (Scheme 2). The complex [CuII-
(TMG3tren)]2+ (5) was synthesized as the bis-perchlorate
salt and isolated after reaction of CuII(ClO4)2·6H2O with the
ligand TMG3tren in acetonitrile. Addition of a small excess of
H2O2/Et3N to a greenish-blue acetonitrile solution of 5 at
ꢀ408C rapidly leads to a dark green product solution, which,
after workup, was confirmed to be authentic 3. The formation
of 18O-labeled 3 (as determined by ESI-MS) when H218O2 was
employed in this reaction[9] further implicates formation of a
CuII(OOHꢀ) species that leads to the hydroxylation.
ligand) can effect C H activation, that is, O2-derived hydrox-
ylation of a methyl group. As we have suggested in reports
concerning the chemistry of mono- and dinuclear copper(II)
hydroperoxo complexes,[2b,c,17] the true oxidant may be the
(CuII)nOOH moiety or a species derived from it, such as a
high-valent copper oxo moiety (see above).[1e,3] This possibil-
ity is hinted at but is certainly not proven by the results of
reactions using PhIO. Additional experimental and theoret-
ical research is required to provide deeper insights into the
dioxygen activation chemistry described.
Received: September 23, 2007
Published online: November 16, 2007
ꢀ
Keywords: C H activation · copper · hydroxylation · oxo ligands ·
.
superoxide ligands
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