Solid-state chemistry at an isolated copper(I) center with O2

Full text of DOI:10.1002/anie.200902691

Angewandte
Chemie
DOI: 10.1002/anie.200902691
Dioxygen Activation
Solid-State Chemistry at an Isolated Copper(I) Center with O2**
Grꢀgory Thiabaud, Geoffroy Guillemot, Isabelle Schmitz-Afonso, Benoit Colasson, and
Olivia Reinaud*
The controlled oxygenation of organic compounds at room
temperature by O2 remains a challenge of the most impor-
tance.[1] In that context, metalloenzymes are fascinating
natural factories that perform regio- and stereoselective
oxygenation of organic substrates.[2,3] Among these, copper
monooxygenases such as PHM (peptidylglycine a-hydroxy-
lating monooxygenase),[4] DbH (dopamine b-hydroxylase),[5]
and TbH (tyramine b-hydroxylase)[6] catalyze a two-electron
oxidation process corresponding to the insertion of an oxygen
has provided evidence that a mononuclear CuI center can
ꢀ
activate O2 for breaking a C H bond. Herein, we report a
study related to a system of the same family of calixarene-
based ligands, but with a tris(2-pyridylmethyl)amine (tmpa)
cap[16,17] in place of the tren unit.
Two different cuprous complexes based on the cal-
ix[6]tmpa ligand[16] (Scheme 1) have been synthesized and
isolated. Complex 1 was isolated from a THF/CH2Cl2 mixture
ꢀ
atom into a C H bond with O2 and two electrons provided by
ascorbate, thus releasing water. Quercetinase, in contrast,
catalyzes a four-electron oxidation process with the oxygen-
ation–decarbonylation of quercetine.[7] For these enzymes, it
has been demonstrated that the reactive chamber contains a
single copper center. In the case of monooxygenases,
however, a second copper center is present approximately
10 ꢀ away, which allows sequential transfer of electrons from
ascorbate to the catalytic site. In analogy to the well-known
cytochrome P450 chemistry, it has been long proposed[8] that
two electrons are required to activate O2 at a copper center,
leading to the hypothesis that CuIIOOH (or more recently
suggested CuO) was the reactive species in copper mono-
oxygenases.[9,10] Relatively recently, however, a series of
studies, either biochemical,[11,5] chemical,[12] or theoretical,[13]
have suggested that CuIIOOC, corresponding to an only one-
electron-reduced O2 species, might well be the reactive
ꢀ
species responsible for the C H bond breaking process in
these enzymes. More recently, while exploring the properties
of a copper center isolated in the tris(aminoethyl)amine
(tren) cap[14] of our calix[6]arene-based model compounds,[15]
we discovered that the CuI complex reacts with O2 to produce
a species that leads to the oxygenation of the ligand, in which
the insertion of one and two oxygen atoms was detected.[14c] In
view of the geometrical constraints of the system, this study
Scheme 1. Guest ligand binding in solution and solid-state O2 reaction
at the CuI center embedded in the calix[6]tmpa ligand.
containing equimolar amounts of calix[6]tmpa and [Cu-
(MeCN)4]PF6. Complex 2 was obtained from the reaction of
CuOTf (Tf = trifluoromethanesulfonyl) with the ligand in
toluene. Both complexes were characterized by 1H NMR
spectroscopy (Figure 1). The spectra displayed signatures
depicting C3v symmetry for the calixarene cone and tmpa cap.
Complex 1 showed an extra resonance at d = ꢀ1.02 ppm,
which attested to the presence of a guest ligand (MeCNin)
derived from the synthetic procedure. Such a high-field-
shifted resonance indicates inclusion of the ligand into the
aromatic core provided by the calixarene macrocycle. Its
binding to the metal center, in the absence of free acetonitrile
(MeCNout), emphasizes the very high affinity of this guest for
the cuprous host. Adding a few extra molar equivalents of
MeCN to the CDCl3 solution of the complex did not change
the NMR profile; however, saturation transfer experiments
showed that MeCNout and MeCNin were in exchange.
[*] G. Thiabaud, Dr. G. Guillemot, Dr. B. Colasson, Prof. O. Reinaud
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxico-
logiques
Universitꢀ Paris Descartes (Paris 5), CNRS UMR 8601
45 rue des Saints-Pꢁres, 75006 Paris (France)
Fax: (+33)1-4286-8387
E-mail: olivia.reinaud@parisdescartes.fr
Homepage: http://www.biomedicale.univ-paris5.fr/umr8601/
-Chimie-Bioinorganique-.html
Dr. I. Schmitz-Afonso
ICSN-CNRS, Laboratoire de Spectromꢀtrie de Masse
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
[**] This research was supported by CNRS and Agence National pour la
Recherche (Calixzyme Project ANR-05-BLAN-0003).
Complex 2 displayed a slightly different profile with
broader peaks, which are attributable to a more flexible
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902691.
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Figure 2. a,b) Infrared spectra of 2 before and after exposure to air:
a) nCO band of the CO adduct of cuprous complex 2 before (dashed
line) and after (solid line) exposure to O2 in the solid state (the
samples were dissolved in CH2Cl2 into which CO was bubbled);
Figure 1. 1H NMR spectra (CDCl3, 250 MHz, 300 K) of complexes
1 (bottom) and 2 (top).
=
b) vibration frequency shift in the C O region of 2: before oxida-
tion (solid line), after oxidation under 16O2 (dashed line), after oxida-
tion under 18O2 (dotted line). c) ESI-MS spectrum of [D2(H2)2]-2
exposed as a solid to atmospheric dioxygen for 9 days.
conformation owing to the lack of guest ligand. The chemical
shifts of the protons belonging to the tmpa cap were also more
downfield, which indicates a slightly more Lewis acidic metal
center. Addition of MeCN to complex 2 led to the appearance
of the MeCNin peak together with a change of the calixarene
signature, which became identical to that of complex 1. More
interestingly, when CO was bubbled into a solution of
complex 2 in CDCl3 free of MeCN, a change of the NMR
signature and an IR stretch at 2103 cmꢀ1 were observed,
attesting to the coordination of CO to the cuprous center. The
presence of one molar equivalent of MeCN completely
inhibited CO binding. The value of the stretching vibration
(12 cmꢀ1 higher than that reported for the non-calixarene
based tmpa cuprous analogue) indicates a moderately elec-
[M+Cu+MeCN+14], respectively (confirmed by MS–MS).
The ratio of these + 14 products relative to the intact material
confirmed the approximate 40% conversion. When solid
complex 2 was submitted to an atmosphere of 18O2, incre-
ments of 2 mass units were observed by ESI-MS for both
products ([M+Cu+16] and [M+Cu+MeCN+16]), relative to
the complex treated in air or with 16O2. The isotope pattern
was, in each case, consistent with the insertion of one O atom
and the removal of two H atoms, and no appreciable trace of
[M+Cu+O] compound. IR spectroscopic analyses of the
oxygenated products revealed a new stretching band at
1738 cmꢀ1 that was shifted to 1708 cmꢀ1 for the complex
18
ꢀ1
tron-rich
center,
similar
to
those
in
[Cu-
treated with 18O2 (calculated value: n( OC) = 1692 cm ).
~
(calix[6]trisimidazole)(CO)]+ complexes (2092–2102 cmꢀ1),
but significantly less than that in [Cu(calix[6]tren)(CO)]+
(2075 cmꢀ1).
Altogether, these data indicate the formation of a new C O
=
bond by a sequence of oxygenation/dehydrogenation (+
Oꢀ2H) of a CH2 moiety belonging to the calix[6]tmpa ligand.
Considering that the value of the CO stretch fits very well
with the formation of an ester function, we suspected the site
of attack by dioxygen to be one of the methylene linkages that
seal the calixarene core to the tmpa cap. To confirm this
proposal through isotope labeling, the hexadeuterated ligand
[D6]calix[6]tmpa was synthesized, for which all three CH2
groups were replaced by CD2 (Scheme 2). The corresponding
cuprous triflate complex indeed led, after reaction in air in the
solid state, to oxygenated products with mass increments of
+ 16ꢀ4 (instead of + 16ꢀ2 for the protiated complex), which
Neither complex 1 nor complex 2 showed any reactivity
toward dioxygen in CDCl3, CD2Cl2, or CD3CN for more than
a week, as checked by proton NMR spectroscopy. In the solid
state, however, they behaved very differently. Solid complex 1
was stable in air for months. In contrast, we discovered that
complex 2, although remaining colorless and EPR silent, had
undergone structural changes after 8 h of exposure to air.
Indeed, bubbling CO into a solution of the air-exposed (in the
solid state) complex 2 in CH2Cl2 led to the appearance of a
new nCO absorption band shifted 17 cmꢀ1 to higher energy
relative to that exhibited by the complex kept in the glove box
(Figure 2). 1H NMR analyses of the solid sample dissolved in
CDCl3 revealed a change of the initial C3v signature into a
more complicated one with a number of additional resonan-
ces. Addition of a few molar equivalents of CH3CN to the
NMR tube led to the appearance of two high-field-shifted
resonances: one at d = ꢀ1.02 ppm that corresponds to the
intact complex with MeCNin bound to the cuprous ion, the
other at d = ꢀ0.97 ppm attesting to the formation of a new
cuprous species that remained capable of binding MeCN
inside the calixarene cavity. Integration of the peaks showed a
conversion of approximately 40%. Finally, ESI-MS analyses
showed two new sets of peaks, one at m/z 1417.7 and the other
Scheme 2. Possible pathways for the oxygenation of complex 2 in the
at
1457.8
corresponding
to
[M+Cu+14]
and
solid state.
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demonstrates that the oxygen atom insertion into the ligand is
associated with the removal of two deuterium atoms.
A possible mechanism (Scheme 2) relies on the intra-
ꢀ
molecular two-electron oxidation of the proximal C H bond
Very interesting results stemmed from competitive oxy-
genation of both ligands. Indeed, a special sample of complex
2 was synthesized with an approximately 1:1 mixture of
protiated and hexadeuterated ligands and then left in air as a
finely ground colorless solid. Samples were analyzed by ESI-
MS to evaluate the kinetic isotope effect (KIE) possibly
associated with the oxygenation process. The kinetic data did
not show an exponential increase of the oxygenated product
as expected for a pseudo-first-order process. Rather, it
exhibited a parabolic dependence over time, thus providing
evidence of diffusion-controlled processes for both com-
pounds (Fickꢁs law). However, the hexadeuterated compound
[D6]-2 reacted much more slowly than the protiated one (KIE
extrapolated at the origin = 6.4(1.0)). Assuming that the
oxygenation process follows a mixed kinetic law leading to a
masked KIE, we synthesized a ligand combining two CH2
arms with one CD2 arm to obtain the intramolecular KIE. The
CuI complex [D2(H2)2]-2 based on this ligand was then treated
with O2 in the solid state at room temperature. The ESI-MS
pattern of the corresponding oxygenated complex is shown in
Figure 2. From these data, an estimated intramolecular KIE
of 21 was obtained.[18] Such a high value denotes a nonclassical
KIE and possible hydrogen tunneling.[19] Accordingly, meas-
urements at 277 and 313 K also led to high KIE values, 29 and
15, respectively. An Arrhenius plot indicated a difference of
the apparent activation energies DEa = 14 kJmolꢀ1 exceeding
by the mononuclear [CuO2]+ center (either through a radical
pathway or through direct hydride abstraction),[13b] followed
by the fast intramolecular evolution of the resulting alkylhy-
droperoxide[24] toward the formation of the keto product with
release of H2O.[25] Kinetics have indicated that C H bond
ꢀ
cleavage is a relatively fast process, hence suggesting that the
[CuO2]+ intermediate is quite reactive.
In conclusion, this study describes a unique case of
oxygenation in the solid state of an organic moiety (a CH2
group) by O2 mediated by a single CuI center. The reaction is
chemo- and regioselective, giving a keto product. This
selectivity attests to a metal-centered four-electron oxidation
reaction, a process that has been scarcely reported with other
model complexes.[26] The reaction displays a nonclassical
intrinsic KIE value of 21 at room temperature, which is by far
the highest value ever recorded for a monocopper reactive
center.j19] Interestingly, in the natural systems DbH and PHM,
unusually high KIE values have also been reported (10.9 at
358C and 10.6 at 378C, respectively, values that might actually
be underestimated),[5] thereby suggesting tunneling as well.[27]
It is also important to note that in the herein reported
reaction, CuI activates O2 but remains in the same oxidation
state in the final product, which is, to our knowledge, the first
case of its kind. It shows that if the oxidation were to be not
directed toward the ligand itself but toward an exogenous
substrate, it could act catalytically. Finally, this case study
unambiguously shows that O2 interaction at an isolated CuI
ꢀ
ꢀ
the zero point energy difference of the C H and C D bonds
(ca. 5 kJmolꢀ1) and a ratio of the preexponential factors AH/
AD = 0.06, which is lower than the normal value of 0.6.[20]
Considering that 1) the reaction occurs in the solid state,
2) the presence of MeCNin completely inhibits the oxidative
process, 3) when a mixture of ligand and complex 2 was
subjected to O2 in the solid state, the ESI-MS analyses
revealed that only the Cu complex had incorporated an O
atom, with no trace of oxygenated free ligand, 4) no CuII is
accumulated upon reaction of 2 with O2, and 5) a single
oxygenated product is detected at a temperature up to
408C,[21] we deduce that the oxidation is a metal-centered
process and does not involve radical diffusion chemistry. We
thus propose the transient formation of a mononuclear
[CuO2]+ adduct (presumed to be a CuII superoxide com-
plex)[22] as a first intermediate in the course of the oxidative
process, although we have not been able to detect any
intermediate. In solution, the equilibrium leading to its
formation remains largely displaced in favor of the starting
material, which is in agreement with literature data related to
classical tmpa-based copper chemistry.[23] In the solid state,
which facilitates the contact of CuI with O2, it reacts with the
close CH2 group of the ligand leading, ultimately, to a four-
ꢀ
ion can give rise to a species reactive enough to break a C H
bond, at least in substrates activated by a heteroatom or a
p system in the a position. Most importantly, it also shows
that a single CuI center in interaction with O2 can mediate an
even-electron transfer process without the assistance of a
redox cofactor, which is a key point for the development of a
catalytic process devoted to the oxidation of organic sub-
strates. We are actively working on the design of new
experiments and new complexes to identify the detailed
mechanism and direct the oxidizing power of the system
toward guest substrates.
Received: May 20, 2009
Published online: September 1, 2009
Keywords: calixarenes · copper · dioxygen activation ·
kinetic isotope effects · oxygenation
.
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=
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=
electron-withdrawing effect of the newly formed C O moiety
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Communications
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[21] When the solid complex 2 was left in air at 608C and 1008C for
several days, a small amount of a dioxygenated product was
detected by ESI-MS at M+28.
[22] K. D. Karlin, N. Wei, B. Jung, S. Kaderli, P. Niklaus, A. D.
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[24] CuIIOOH are now well known species, whereas CuIOOH has not
yet been spectroscopically characterized, although it has been
proposed as transient species in a few instances: W. Ghattas, M.
Giorgi, Y. Mekmouche, T. Tanaka, A. Rockenbauer, M. Rꢄglier,
Y. Hitomi, J. Simaan, Inorg. Chem. 2008, 47, 4627 – 4638, and
references therein. See also references [12b] and [14c].
[25] Attempts to find evidence for the formation of D2O were
unsuccessful. However, the fact that, in solution, the CuI
complexes (either 1 or 2) underwent fast oxidation into CuII
upon the addition of H2O2 supports the proposed release of
water in the solid state rather than the formation of H2O2.
Indeed, when H2O2 (a few molar equivalents) was added to a
solution containing complex 1 or 2, oxidation of CuI to CuII was
quickly observed and was associated with the formation of a few
percent of the alcohol derivative [M+16], but no keto product.
When the cupric aqua complex itself {[Cu(calix[6]tmpa)-
(H2O)]2+} was treated with 10 molar equivalents of H2O2 in the
presence of Et3N (2 equiv), the corresponding hydroxo–CuII
complex {[Cu(calix[6]tmpa)(OH)]+} was produced with, again,
only a trace of the M+16 product and no keto derivative. In
contrast, however, when the dicationic cupric complex was
treated with KO2 (3 equiv) and crown ether ([18]crown-6), both
M+14 and M+16 products (ca. 10% and 5%, respectively) were
detected.
[15] O. Reinaud, Y. Le Mest, I. Jabin in Calixarenes Enter The
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2006, chap. 13.
[16] For the synthesis and first complexation studies for the
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[18] See the Supporting Information for the calculation methods.
=
[26] Examples of CH2 oxidations to C O mediated by Cu/O2 are
rare. For dinuclear complexes, see: a) J. A. Halfen, V. G.
Young, Jr., W. B. Tolman, J. Am. Chem. Soc. 1996, 118, 10920 –
10921; b) H. R. Lucas, L. Li, A. A. Narducci Sarjeant, M. A.
Vance, E. I. Solomon, K. D. Karlin, J. Am. Chem. Soc. 2009, 131,
3230 – 3245. For a mononuclear complex, see Ref. [14c].
[19] Hydrogen tunneling has been previously evidenced with dinu-
II
=
clear M2O2 complexes for intramolecular oxidations: a) M Co :
[27] Hydrogen tunneling has also been reported for Fe enzymes such
as TauD, lipoxygenase, and methane monooxygenase; see: a) A.
Kohen, J. P. Klinman, Acc. Chem. Res. 1998, 31, 397 – 404; b) J. P.
Klinman, Biochim. Biophys. Acta Bioenerg. 2006, 1757, 981 –
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Chem. Soc. 2008, 130, 17632 – 17633.
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6980; b) M CuIII: E. A. Lewis, W. B. Tolman, Chem. Rev. 2004,
=
104, 1047 – 1176. Only one example of a high KIE (19.2 at
ꢀ408C) has been reported for monocopper species (an CuII–
alkylperoxide): c) A. Kunishita, H. Ishimaru, S. Nakashima, T.
Ogura, S. Itoh, J. Am. Chem. Soc. 2008, 130, 4244 – 4245;
Hydrogen tunneling has also been evidenced with some
biomimetic monoiron–oxo species, either porphyrinic: d) Z.
Pan, J. H. Horner, M. Newcomb, J. Am. Chem. Soc. 2008, 130,
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