Aerobic intramolecular carbon-hydrogen bond oxidation promoted by Cu(i) complexes

Article abstract of DOI:10.1039/d0dt03198d

The oxidation of C-H bonds by copper centres in enzymes with molecular oxygen takes place in nature under ambient conditions. Herein we report a similar transformation in which under ambient pressure and temperature (1 atm, 25 °C) the complex TpMsCu(THF)

Full text of DOI:10.1039/d0dt03198d

View Article Online
View Journal
Dalton
Transactions
An international journal of inorganic chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Alvarez, F.
Molina, M. R. Fructos, J. Urbano, E. Alvarez González, M. Sodupe, A. Lledós and P. J. Perez, Dalton Trans.,
2020, DOI: 10.1039/D0DT03198D.
Volume 46
Number 10
14 March 2017
Pages 3073-3412
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Dalton
Transactions
An international journal of inorganic chemistry
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
rsc.li/dalton
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 0306-0012
COMMUNICATION
Douglas W. Stephen et al.
shall the Royal Society of Chemistry be held responsible for any errors
N-Heterocyclic carbene stabilized parent sulfenyl, selenenyl,
and tellurenyl cations (XH+, X = S, Se, Te)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/dalton

Please do not adjust margins
Page 1 of 10
Dalton Transactions
View Article Online
DOI: 10.1039/D0DT03198D
PAPER
Aerobic Intramolecular Carbon-Hydrogen Bond Oxidation
Promoted by Cu(I) Complexes
Received 00th January 20xx,
Accepted 00th January 20xx
María Álvarez,a Francisco Molina,a Manuel R. Fructos,a Juan Urbano,b Eleuterio Álvarez,c Mariona
Sodupe,d Agustí Lledós,*d and Pedro J. Pérez*a
DOI: 10.1039/x0xx00000x
The oxidation of C-H bonds by copper centres at enzymes with molecular oxygen takes place in nature at ambient
conditions. Herein we report a similar transformation in which under ambient pressure and temperature (1 atm, 25 °C) the
complex TpMsCu(THF) (TpMs = hydrotris(3-mesityl-pyrazol-1-yl)borate) undergoes the intramolecular oxidation of an alkylic
C-H bond with O2, leading to the formation of a trinuclear compound where alkoxy and hydroxyl ligands are bonded to the
copper centres, as inferred from X-ray studies. The presence of adventitious Cu(0) derived from partial decomposition of
the initial TpMsCu(THF) facilitates the formation of such trinuclear compound. DFT studies support the reaction taking place
through a Cu(III) alkoxy-hydroxyl copper intermediate.
bonds of the ancillary ligand (usually
a bis-, tris- or
tetracoordinated, N-donor ligand) as a model for biological
systems have been achieved.6 These transformations occur
Introduction
Copper enzymes are ubiquitous in Nature, mainly involved in
oxidation processes with O2 as the oxygen source.1 In the
context of carbon-hydrogen bond oxidations, oxygenases are
responsible for the hydroxylation of highly inert
hydrocarbons,2 as it is the case of methane monooxygenases
(MMOs), responsible for the conversion of methane into
methanol in methanotrophic bacteria.3 Particulate MMO is a
copper-containing enzyme for which the nuclearity of the
active site involved in O2 activation has been the subject of
controversy for the last decade. A very recent report has
concluded4 that despite the closeness of two copper units, it is
a monocopper site the one that is able to catalyse methane
oxidation. From this perspective, work carried out in the last
decades with mononuclear copper complexes toward O2
activation regain more interest,5 particularly in the context of
subsequent C-H bond oxidations. Outstanding advances in this
area such as the intramolecular oxidation (Scheme 1) of Csp3-H
Scheme 1 The intramolecular C-H bond oxidation with Cu(I) complexes.
through the generation of end-on copper(II)-superoxide
complexes LCuII(O2•),7 some of them being detected or
isolated, from the reaction of a Cu(I) complex with O2, which
can take place within several pathways.8,9,10,11,12
a.Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC CIQSO-Centro de
Investigación en Química Sostenible and Departamento de Química, Universidad
de Huelva, 21007-Huelva (Spain).
In view of the importance of these studies relative to the
development of biomimetic catalytic systems, we have
focused in the aerobic oxidation of the complex TpMsCu(THF)
b.Departamento de Química, Universidad de Huelva, 21007-Huelva (Spain).
c. Instituto de Investigaciones Químicas, Centro de Investigaciones Isla de la Cartuja,
Avda Américo Vespucio 49,41092 Sevilla (Spain)
(
1-THF) (TpMs = hydrotris(3-mesityl-pyrazol-1-yl)borate) and
d.Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola
del Vallès, Barcelona (Spain).
found that the hydroxylation of a Csp3 bond of the mesityl
fragment takes place under very mild conditions. DFT studies
and experimental evidences allow proposing the implication of
a Cu(II)-Cu(I) dinuclear intermediate.
E-mail: agusti@klingon.uab.es.
†
Electronic Supplementary Information (ESI) available: All procedures and
characterization data for new compounds, additional computational data and
Cartesian coordinates and energies of the optimized structures. See
DOI:10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Dalton Transactions
Page 2 of 10
ARTICLE
Journal Name
which is close to that expected for three unpaired electrons.
This is at variance with the above complexes described by
Pierpont,17 which displayed eff = 1.82 MB, but similar to the
View Article Online
DOI: 10.1039/D0DT03198D
Results and Discussion
Reaction of TpxCu cores with molecular dioxygen
trinuclear
copper
complex
[Cu3(m-
triethanolaniline)
We first investigated the reaction of Tolman’s complex
TpMsCu(THF)13
(1-THF) with O2 in tetrahydrofuran at room
methoxybenzoato)4(H2TEA)2]19 (TEA
=
described by Ferreti, also containing two O-bridges between
each couple of Cu ions, and with eff = 3.4 MB.
temperature. When this complex was dissolved in an O2-
saturated solvent, the initially colourless solution smoothly
became greenish with time, leading to the formation of green
crystals within 24h at that temperature. The formation of this
crystalline material result is independent of the solvent, since
acetone, toluene or dichloromethane solutions led to the
same outcome, albeit at variable time. The product was
completely insoluble in organic solvents, precluding the use of
NMR techniques. The IR spectra showed an absorption
centered at 3652 cm-1, in the typical region for v(O-H).
Elemental analysis was consistent with the formulation
(TpMs)2(O2)2Cu3, indicating a significant deviation from the
initial 1:1 TpMs:Cu stoichiometry. Fortunately, the crystalline
material formed, in all the above solvents, was suitable for X-
ray studies,14 allowing the determination of the solid structure
of the molecules of this new complex 2a. It contains three
copper centres with two different environments (Scheme 2).
On one hand, the central copper CuC is connected to four
oxygen donors, in a square-planar fashion. On the other, the
lateral copper CuL ions are five coordinate, bonded to the
three N donors of the TpMs ligand, in a 3 mode, as well as to
two oxygen donors, shared with CuC, in a square-pyramidal
environment. One of the oxygen atoms corresponds to a
hydroxyl group (which generate that band in the IR spectrum)
and the other one to an alkoxy group derived from the
oxidation of one of the Csp3-H bonds of the mesityl ring in the
ancillary ligand. The reaction has been carried out up to a scale
of 0.35 g (0.05 mmol) of 1-THF, leading to the isolation of
0.158 g of 2a.(1.1 x 10-4 mmol). Assuming that molecules of 1a
are required for the formation of 2a, the isolated yield is 68%.
Ligand hydroxylation with copper complexes leading to
alkoxy (or aryloxy)-hydroxy derivatives is a well-known process
for dinuclear compounds. Seminal work by Karlin15 in 1982
showed the oxidation of an aryl C-H bond and the formation of
a hydroxyl ligand, and several related examples were further
reported.16 These transformations occurs through the
activation of the dioxygen molecule by a Cu2 core, at variance
with our system, which cannot accommodate an O2 molecule
between two TpMsCu units due to the steric hindrance of the
Ms substituents (see below), thus occurring by a mononuclear
O2 activation, similar to that reported by Kitajima and
Solomon,7a,b

Scheme 2 The trinuclear complex 2a and its molecular structure (H
atoms omitted for clarity).
The formation of 2a from TpMsCu(THF) and O2 requires
partial decomposition of the initial copper complex at some
extent to provide the third copper centre. Since ligand
degradation can proceed at the B-H group,20 we also prepared
the boron-substituted MeTpMs ligand,21 for which the
corresponding Me-TpMsCu(THF) complex could not be isolated.
Thus, we synthetized the new complexes TpMsCu(NCPh) (1a
)
and Me- TpMsCu(NCPh) (1b), only differing in the substitution
at boron. When these complexes were submitted to the
conditions which provided 2a from 1-THF, green crystalline
materials were isolated in both cases, corresponding to the
trinuclear complexes 2a and 2b (Scheme 3). The latter has also
been characterized by X-ray studies (see ESI for X-ray
characterization).14 It is worth noting the different in the yields
observed: 2a was isolated in 71% yield, showing that the THF
or nitrile ligands in the starting materials do not influence the
reaction, whereas 2b was separated in only 25% yield (0.2 g
reaction scale)
The structure of complex 2a is similar to that reported by

Pierpont for [Cu{TpCum,MeCu( -OMe)2}2]17 albeit using a rather
distinct synthesis route, excluding O2/C-H bond activation
processes. Two of the CuL-Npyr distances are very close
(2.013(4) and 2.026(4) Å) whereas the third one is significantly
longer (2.369(4) Å). The CuL– CuC distances of 3.007(7) Å
surpasses that of the sum of van der Waals radii18 for two Cu
(2.40 Å), discarding any Cu-Cu bonding interaction. It is also
worth mentioning that the measurement of the magnetic
moment eff (Evans balance, see SI) led to a value of 3.3 MB,
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 10
Dalton Transactions
Journal Name
ARTICLE
starting Cu(I) complexes including the trapped freVeiepwyArrtaiczleoOlen.linIet
is worth mentioning that at varianceDwOIi:t1h0.1o0t3h9e/Dr0DsyTs0t3e1m98sD,
where H2O2 is proposed to form from O2 activation,9c en route
to the copper hydroperoxide, in our case the reaction of
TpMsCu(L) (L = THF, NCPh) with H2O2 does not induce the
formation of 2a
.
Since two TpMsCu units and a third “naked” Cu ion form the
trinuclear compounds, we reasoned that the latter could come
from some metallic copper formed from the partial
decomposition of the starting materials. Thus, we carried out
twin experiments with TpMsCu(L) (L = THF or NCPh) and O2 in
THF or acetone, in the absence or presence of added metallic
copper. The results were the same in all cases: those
experiments having added metallic copper showed the
formation of 2a at a higher rate, which could be visually
observed (Figure 1.1). Unfortunately, the exact yields could
not be calculated since excess of metallic copper could not be
completely separated from crystalline material. In any case, we
believe that these experiments demonstrate the involvement
of metallic copper in the formation of the trinuclear complex
Scheme 3 Synthesis of the complexes 2a and 2b from nitrile adducts
1a,b).
2a
.
Monitoring of the reaction by UV-Vis has provided valuable
NMR monitoring of the consumption of 1a only showed the information. Fig. 1 shows the variation with time of such
disappearance of its resonances, as well as the formation of spectra for the experiments carried out with and without
minor amounts (ca. 5-10%) of the new complex added metallic copper, under the same conditions of initial
TpMsCu(HpyrMs
)
(3a
,
HpyrMs
=
3-mesitylpyrazole), Cu(I) concentration (0.035 M) and at room temperature (no
demonstrating the availability of free pyrazole from partial reaction is observed at temperatures lower than 0 °C). A band
degradation of the initial copper complex. This compound has centred at ca. 675 nm increases with time until 24 h, then
been independently synthetized and characterized, including decreasing when microcrystalline material of 2a comes out of
X-ray studies (see SI).[14] Since the only difference between the solution. We assume from this observation that this band
both reactants 1a and 1b[14] is the group attached at boron (H corresponds to 2a, consistently with the low absorbance
or Me), we believe that the observed distinct reactivity must values. Since solutions of isolated 2a were not available due to
be related to the different reducing power of both moieties,22 its insolubility in most organic solvents, TD-DFT calculations
which must be responsible of the partial decomposition of the were performed to confirm that assignment. Only the
Fig. 1 (1)(a) Formation of 2a from TpMsCu(THF) and O2 at room temperature after 12 h. (b) Same experiment in the presence of metallic copper (Cu(0)
powder) added. (2) UV-Vis monitoring of the reaction of complex TpMsCu(THF) (0.025 M) and O2 at room temperature (a,b): no metallic copper (Cu(0))
added. (c,d) metallic copper (Cu(0)) added. (3) Comparison for absorbance values at 675 nm
.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Dalton Transactions
Page 4 of 10
ARTICLE
Journal Name
trimetallic complex (and not mononuclear or dinuclear ones) Karlin and others.9b However this does not seem to be the case
View Article Online
displays the most intense band in this region. In particular, the since at this stage Cu(0), either adDvOenI:t1i0ti.1o0u3s9/Db0yDTp03a1r9t8iaDl
simulated spectrum (see ESI) shows a band at ca. 620 nm that decomposition of the starting material or externally added,
corresponds to Cu d → Cu d transitions. A similar behaviour would promote the reduction of two units of such
was found for the experiment containing added metallic intermediate leading to the formation of 2a. DFT calculations
copper, albeit the absorbance increased with a twenty-fold will give the complete energy landscape of the reaction and
factor (maximum of ca. 0.3 vs 0.015, see Fig. 1), We interpret identify the key intermediates.
this observation as a proof of the need of metallic copper for
the formation of 2a
.
From 1-THF to intermediate
TpMsCuI(THF) (
-THF) can easily dissociate the THF ligand
Reactivity of TpxCu(I) complexes with O2: mechanistic aspects (ΔGTHF = 14.0 kcal mol-1) to generate species
that will
Trinuclear complexes 2a and 2b contain two oxygen atoms coordinate the O2 molecule in O2. The hydroxylation reaction
bonded to the lateral copper centres, which could correspond that leads to starts with a Cu(I) complex with a singlet spin
C: C-H bond oxidation.
1
1
1
-
C
to the initial O2 molecule, albeit we have no experimental state and a O2 molecule with a triplet spin state. We have only
evidence to support it. On the other hand, experimental considered mononuclear copper species along the reaction
evidences point out the key role of Cu(0) in their formation, pathway, discarding dinuclear species. It is evident from the
although no intermediate along the reaction pathway from 1- optimized structure of
1 (Fig. 2, top) that the mesityl wings in
THF to 2a has been isolated. On these bases, DFT calculations the TpMs ligand preclude the formation of such species.
have been performed to provide additional information Attempts to stabilize by DFT calculations a TpMs2Cu2 unit were
toward the understanding of this transformation and to unsuccessful. This is in agreement with the previous
identify potential intermediates (see ESI for calculations observation of mononuclear O2 activation by bulky TpxCu
details).
cores.7a,b
Three different electronic scenarios have been considered for
this reaction: triplet (T), open-shell singlet (OSS) and closed-
shell single (CSS). Fig. 3 depicts the Gibbs energy profile in THF
Mechanistic considerations
From Itoh’s work12 and our experimental evidences,
a
plausible reaction pathway, depicted in Scheme 4, can be for the most favourable pathway for the reaction (triplet
proposed. Initially, a TpMsCuII(O2•) superoxide (
) would form state). Transition state structures connecting the different
A
from TpMsCuI(THF) and O2, which could be either end-on or species of this profile are gathered in Fig. 4. The exploration of
side-on. Subsequent hydrogen atom abstraction process (HAT) the potential energy surface (PES) has been performed with
takes place generating a hydroperoxide and a carbon-centred the TPSSh functional, including dispersion corrections (TPSSh-
radical at the alkyl substituent of the mesityl ring (
intermediate, the O-O cleavage would lead to the formation of ESI). Gibbs energy profiles for the open- and closed-shell
C-O and Cu-O bonds in intermediate , which could be either a singlet energy surfaces explored can be found at the ESI. It
B). From this D3), with a SMD continuum description of the THF solvent (see
C
Cu(II) or Cu(III) species, both bearing alkoxy and hydroxyl must be pointed out that most of the intermediates and
ligands bonded to the metal centre. Interestingly, this transition states have very similar geometries and energies in
intermediate could evolve toward a Cu-oxyl and hydroxyl
radical, and/or originate Fenton chemistry as proposed by
Fig. 2 Optimized structures of the TpMsCu core (
1) and
intermediate C in Scheme 4 (left) and their space filling
pictures (right). C-H bonded hydrogen atoms have been
omitted in the optimized geometries.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Scheme 4 Plausible reaction pathway toward the formation of complex
2a.
Please do not adjust margins

Please do not adjust margins
Page 5 of 10
Dalton Transactions
Journal Name
ARTICLE
for our system (25.5 kcal mol-1) compared to the Itoh’s one
) yields the copper(II) (21.8 kcal mol ) could be related with the stronger C-H bond in
1-
O2, which lies 4.8 kcal mol-1 below our system (methyl vs. benzyl C-H bonds).24
the T and OSS potential energy surfaces.
Coordination of O2 to the TpMsCu core (
View Article Online
DOI: 10.1039/D0DT03198D
-1
1
side-on superoxo complex
the separated reactants (Fig. 3). Triplet is the ground state of In I-OOH the unpaired electron at the organic moiety is spread
1-O2 the ope(CO)n-shell-singlet and closed-shell-singlet over the carbon atom that has transferred the hydrogen and
structures lying 10.0 and 12.7 kcal mol-1 above the triplet the two oxygen atoms. The O-O distance has notably
complex, respectively. It should be noted that all attempts to elongated in the hydroperoxo ligand (from 1.31 Å in O2 to
characterize an end-on isomer in our system reverted to the 1.46 Å in OOH) favouring the splitting into the O and OH
,
1
-
1
-
side-on conformation, at variance to Itoh’s system, bearing a fragments. At this point the reaction can follow two different
different N-tridentate ligand (N-[2-“2-pyridyl)ethyl]-1,5- pathways (A and B, Fig. 3) depending on which one of the two
diazacyclooctane), for which calculations12 found the existence fragments binds to the copper and carbon centres. In pathway
of two Cu(II)-superoxide isomers, end-on and side-on, with A after the O-OH bond breaking (TSCO, Fig. 4) the OH group
very similar energies (end-on 0.6 kcal mol-1 more stable than binds the copper centre and the O atom binds the radical
side-on). Furthermore, side-on coordination of the superoxo carbon centre. In this way the O-OH scission leads directly to
ligand were disclosed independently by Kitajima and Solomon, the final product C. However, before the O-O scission the OOH
including X-ray analysis, in copper-superoxo complexes bearing group must rotate (TSrot) to achieve the right conformation for
highly hindered hydrotris(pyrazolyl)borate ligands.7a,b Those the rupture to take place. In pathway B the CH2 group is
ligands contained bulky alkyl groups at the pyrazolyl rings (tBu, hydroxylated and
a copper(II) oxyl is formed (I-COH).
iPr, Ad), at variance with the aromatic rings in 1a,b. Previous Abstraction of the hydrogen atom of the hydroxyl group by the
studies from our laboratory showed23 significant differences in copper(II) oxyl group (TSOHO) generates the same intermediate
the redox properties of the copper centre derived from such
C than pathway A. In both pathways the highest point in the
those substitutions. For example, the Epa (mv) of TpCyCu(CO) energy profile corresponds to the O-OH bond breaking step
(Cy, cyclohexyl) was recorded as 515 whereas that of (Fig. 3). However, the transition state in pathway A (TSCO) is 4.5
TpMsCu(CO) was 603. A difference in the (CO) was also found: kcal mol-1 lower than that in pathway B (TSCOH), pointing out

2064 and 2079 for TpCy and TpMs, respectively. We believe that that pathway A is favoured, as found for the Itoh’s system.10c
these electronic differences may affect the nature of the spin Very similar results are obtained for the reaction in the open-
and the reactivity.
shell singlet state; i.e., TSCO-
OSS is found at 24.1 kcal mol-1, 4.7
ΔGTHF
30
27.6
TSCOH
23.1
20.7
20.1
TSrot
TSCO
18.6
18.5
20
10
TSCH
I-OOH
I-OOH_rot
pathway A
triplet A
triplet B
pathway B
0.0
0
1 + O2
-4.8
1-O2
-10.2
-10
-20
-30
TSOHO
-15.2
I-COH
-19.3
C-T
-26.9
C-CSS
Fig. 3 DFT-computed (TPSSh-D3/BS2) Gibbs energy profile for the reaction of
1 with O2 in tetrahydrofuran in the triplet state. Relative ΔG
values are given in kcal mol-1 and are reported with respect to separated
1
and O2.
kcal mol-1 below TSCOH-OSS (28.8 kcal mol-1). Noticeably, the
The 1-O2 complex has one unpaired electron at the copper reaction in the closed-shell singlet state features a significantly
centre and another one distributed between the two oxygen higher barrier (34.1 kcal mol-1), which corresponds to the
atoms of the superoxide unit and is capable to abstract a abstraction of a C-H proton by the peroxo ligand (TSCH-CSS),
hydrogen atom from the closest methyl substituent of one entailing the concomitant O-O bond breaking and formation of
mesityl ring in the next step. The hydrogen atom abstraction copper-oxo and alcohol groups (see Supporting Information).
takes places through the transition state TSCH with a barrier of Optimization of the hydroperoxide intermediate I-OOH in the
25.5 kcal mol-1 and leads to the copper(II) hydroperoxo closed-shell singlet state, starting from the triplet geometry,
intermediate I-OOH. The somewhat higher calculated barrier gives intermediate I-COH-CSS with a copper(III)-oxo/C-OH
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Dalton Transactions
Page 6 of 10
ARTICLE
Journal Name
nature, at 1.9 kcal mol-1. We have explored this alternative supplemented with the Grimme’s dispersion correction D3,
View Article Online
route to enter into the Cu(III) region, by locating the crossing with the extended basis set basis-II (BDSO2,I: 1s0e.1e03S9I/)D. 0TDhTi0s311908%D
point (minimum energy crossing point, MECP) between the exchange functional accurately reproduces the relative
triplet and singlet surfaces that connects both intermediates. energies of spin states of first-row transition metal complexes
This MECP is found at 31.0 kcal mol-1, much higher than TSrot and predicts the reactivity of Cu(III).26 However, in order to be
and TSCO in the triplet surface. Therefore, this alternative route fully confident about the correct electronic ground state of
to reach
C
can be discarded.
intermediate C, we performed single point electronic energy
Fig. 4 Optimized geometries of the transition states in the Gibbs energy profile of Fig. 3. Distances in Å.
As a conclusion of this mechanistic investigation, pathway A in calculations, using
a set of functionals, on TPSSh/BS1
the triplet PES appears as a feasible mechanism for the optimized geometries of C-CSS and C-T with a more extended
formation of the mononuclear alkoxy-hydroxyl intermediate
C.
basis-III (BS3, see SI). Furthermore, we have performed
calculations with the highly correlated coupled cluster single
and double excitations, and perturbatively estimated triple
Nature of intermediate
C: A Cu(II) or Cu(III) centre?
In the triplet state, intermediate
C
can be described as a Cu(II) excitations, [CCSD(T)], within a domain-based local pair natural
centre with an additional unpaired electron delocalized over orbital (DLPNO) formulation, at the TPSSH-D3/BS1 optimized
the two oxygen atoms. An alternative description of this geometries of C-CSS and C-T. This approach has already been
intermediate is obtained in the closed-shell singlet state: a used as a benchmark to estimate singlet-triplet gaps in copper
formally Cu(III) centre with an hydroxyl ligand. Optimization of complexes.27
C
in the CSS state gives a structure notably more stable than The hydroxylation reaction analysed in the precedent section
the triplet (
CSS, 7.6 kcal mol-1 below C-T). Indeed, in the OSS implies computing three different oxidation states of copper (I,
PES TSOHO leads directly to this structure. The structural II, and III) and two different spin states (singlet and triplet).
features of the singlet and triplet isomers of are similar. The Table S1 (in SI) collects the relative energies of Cu(I) ( + O2
C-
C
1
main difference is found in the Cu-N distance with the nitrogen triplet), Cu(II) (C-T) and Cu(III) (C-CSS) as well as the singlet-
atom above the plane defined by the two N and two O atoms. triplet Cu(II)/Cu(III) energy gap computed with the different
This distance is considerably longer in the singlet structure methods. Most accurate DLPNO-CCSD(T) calculations agree
than in the triplet one (2.40 vs. 2.27 Å), in agreement with a with a Cu(III)-singlet character of intermediate
square-planar favoured coordination for a Cu(III)-d8 centre. about 20 kcal mol-1 more stable than the Cu(II)-triplet isomer
Conversely, all the other Cu-N and Cu-O bond distances are and 40 kcal mol-1 below the reactants (
+ O2 triplet). Taking
C, which is
1
shorter in the singlet species.
the DLPNO-CCSD(T) values as a reference, the data collected in
The characterization of the hydroxylation product
C
as a Cu(III) Table S1 highlight the difficulties of DFT functionals to describe
species contrasts with the description of a similar product in in a balanced way such situations. Anyway, and despite
the Itoh’s system as Cu(II) complex with a triplet ground significant changes in the relative energies, DLPNO-CCSD(T)
state.12c Accurate calculation of the energy splitting between and all the functionals, with the exception of M11, agree in
low-spin and high-spin states of copper compounds in assigning a singlet ground state to
different oxidation states is difficult due to its strong functional mol-1 more stable than the Cu(II) triplet isomer. Thus, it can be
dependence.25 All the energies reported herein have been safely assumed that the mononuclear species
resulting from
is a Cu(III)-alkoxy-hydroxyl intermediate.
C, between 5 and 20 kcal
C
obtained with the hybrid meta-GGA TPSSh functional the hydroxylation of
1
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 7 of 10
Dalton Transactions
Journal Name
In the next section we will address how this intermediate quality of collected data for the new compound
ARTICLE
5
precludes a
View Article Online
DOI: 10.1039/D0DT03198D
evolves toward the final, experimentally characterized complete structural description, its connectivity agrees with
trinuclear complex 2a that depicted in Scheme 5. We believe that the formation of
.
5
demonstrate the participation of the dinuclear intermediate in
to 2a: Comproportionation and role of the pathway leading to the trinuclear compounds described
above. The low yield (ca. 13%) can be explained as the result of
From intermediate
Cu(0).
C
As evidenced by the optimized structures of
1 and C (Fig. 2), the presence of the Me-B bonded to boron and a more
the steric hindrance of the TpMsCu core precludes its sterically protected copper centre, the decomposition route
interaction with the Cu(III) intermediate ensuing reduction, as producing Cu(0) (probably colloidal copper) and free pyrazole
it happened in the Itoh’s system:12c only a Cu(0) atom can being less favourable. Experiments carried out using
4, O2 and
approach efficiently toward that end. We have placed a Cu(0)
atom in the vicinity of the oxygen atoms of
C and optimized
the bimetallic system in the doublet spin state. Optimization
leads to the complex C-Cu, depicted in Fig. 5. According to spin
density values (Fig. 5), a comproportionation reaction, in which
the Cu(III)/Cu(0) centres become Cu(II)/Cu(I), occurs upon
formation of the bimetallic species.
The spin density over the initial Cu(0) radical almost vanishes,
and is transferred to the initial Cu(III) centre. Some spin
density is also delocalized over the two oxygen atoms. The
redox process results in a huge stabilization of the system: the
bimetallic Cu(II)-Cu(I) complex lies 81.3 kcal mol-1 below the
separated Cu(III) (C) and Cu(0) atom (ΔGTHF). Optimization of C-
Cu in the quartet spin states gives one structure that is 42.3
Scheme 5 Formation of dinuclear complex 5.
added metallic copper and free pyrazole/pyrazolate were not
successful. Refined structural details of the complex, as well as
of its electronic structure, have been obtained by means of a
DFT optimization (Fig. 6, see also SI).
In 5 both copper centres are not equivalent. One has a square-
pyramidal arrangement of ligands, with five positions occupied
by the three nitrogen atoms of the Me-TpMe2-biphen, the oxygen
bonded to the activated methylene and a bridging pyrazolate
ligand, coming from the partial decomposition of the starting
complex. The spin density in this centre (0.58) agrees with a
Cu(II) formulation. The second copper centre displays a
Fig. 5 Optimized structures of the TpMsCu core
1 and intermediate
C in Scheme 4 (left) and their space filling pictures (right). C-H
bonded hydrogen atoms have been omitted in the optimized
geometries.
kcal mol-1 above the doublet. Thus, the doublet is the ground
state of C-Cu
.
We have no experimental evidences for that bimetallic
complex intermediate when employing 1-THF or 1a,b as
reactants, all having 3-mesitylpyrazolyl groups. We reasoned
that to block the incorporation of the third copper centre to
the binuclear intermediate, a more sterically hindered ligand
should be employed. Thus, we designed and synthetized the
Fig. 6 Optimized structure of
orange) and Mulliken atomic spin populations (in blue).
5 showing its spin-density map (in
novel, bulkier Me-TpMe2-biphen ligand with
a
biphenyl
substituent at the pyrazolyl ring, increasing the steric
hindrance of the ancillary ligand when coordinated at the
tetrahedral coordination. It is bonded to four ligands: the
bridging pyrazole, two pyrazoles and the oxygen. There is no
spin density in this copper centre, as expected for a Cu(I) ion.
copper centre in complex
4 (Scheme 5; see SI for
characterization). This compound was reacted with O2
following the above protocols. A very slow transformation
took place, and after two weeks standing at room
temperature, some crystalline material deposited. X-ray
studies were performed with those crystals: although the
From the optimized structure of
5 it is apparent that in this
case further interaction with a third copper centre is avoided
by the biphenyl groups. Thus, by using a very bulky ligand the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Dalton Transactions
Page 8 of 10
ARTICLE
comproportionation process that yields the trimetallic complex submitting complex TpMsCu(L) (TpMs
has been stopped at the binuclear complex.
With the TpMs ligand, the coordination of another
Journal Name
=
hydrotris(3-
View Article Online
DOI: 10.1039/D0DT03198D
mononuclear Cu(III) complex
C to C-Cu is possible, forming in
this way the trimetallic species 2a. We have optimized the
structure of 2a both in the doublet (D) and quartet (Q) spin
states. Computed structural parameters are very similar and
agree with the X-ray determined ones (see SI). Analysis of the
electronic structure of 2a shows that its formation entails
another internal redox process, in which the Cu(I) atom of C-
Cu becomes formally a Cu(II) and the Cu(III) of the incoming
C
also becomes a Cu(II). Both the doublet and quartet optimized
structures of 2a have three equivalent copper (II) centres, with
one unpaired electron each. The only difference between 2a-D
and 2a-Q is that in 2a-Q the three unpaired electrons have spin
alpha, whereas in 2a-D the unpaired electron of the central
copper has a beta spin. Gibbs energy values at the TPSSh-
D3/BS3 level of theory indicate that the 2a-D is the most stable
one, in contrast to the ferromagnetic behaviour observed
experimentally. It should be noted, however, that the
computed energy difference between 2a-D and 2a-Q is very
small, (1.2 kcal mol-1), and that packing effects in the solid may
also influence the relative stability between these two almost
degenerate spin states. There is a huge thermodynamic driving
force directing the formation of the trimetallic copper(II)
complex. The ΔG in THF for the formation of 2a from two
Scheme 6 The reaction pathway from mononuclear CuI complexes to
the trinuclear CuII compounds involving CuIII and Cu(0).
molecules of
C
and a copper atom is -148.4 kcal mol-1.
Accordingly, the copper(III)-alkoxy-hydroxyl intermediate is
trapped as a trinuclear Cu(II) species.
mesitylpyrazolyl)borate) to 1 atm of O2 at room temperature.
A copper(III)-alkoxy-hydroxy moiety has been trapped upon
spontaneous reaction with metallic copper derived from
decomposition of , leading to a trinuclear complex which has
been characterized by X-ray studies. Computational studies
have identified the crucial role of Cu(0) as a promotor of
comproportionation reactions with Cu(III) species and support
a dinuclear Cu(II)-Cu(I) species as intermediate on the pathway
towards 2a. These studies provide another view of C-H bond
oxidation by copper centres under biological reaction
conditions of pressure and temperature
Global mechanistic proposal
Based on experimental and computational data, Scheme 6
contains the global picture for the conversion of mononuclear
copper(I) complexes bearing trispyrazolylborate-type ligands
into trinuclear complexes 2a,b after exposure to dioxygen
atmosphere at room temperature. The interaction of the
TpMsCu core with O2 yields the Cu(II) side-on superoxo
evolves into a hydroperoxo intermediate upon a HAT
process. At this stage O-O cleavage takes place with
concomitant formation of the alkoxy-hydroxy intermediate
which reacts with Cu(0) en route to the dinuclear intermediate
. The latter contains two copper ions in +1 and +2 oxidation
states, and serves as 1e- source for another molecule of
generating the trinuclear complex possessing three Cu(II) ions.
It is of note that intermediate , which could originate a Cu-
A which
B
C,
Conflicts of interest
There are no conflicts to declare.
D
C
,
C
oxyl and a hydroxyl radical, reacts in turn with Cu(0),
precluding Fenton chemistry at variance with other reported
systems. We cannot rule out the possible exchange of the OH
ligand with adventitious water.
Acknowledgements
Support for this work was provided by the MINECO (CTQ2017-
82893-C2-1-R CTQ2017-87889-P and CTQ2017-89132-P) and
P.O. FEDER 2014-2020, UHU-1260216. MA thanks Ministerio
de Economía
fellowship.
y Competitividad for an FPI predoctoral
Conclusions
Dioxygen splitting and C-H bond oxidation with concomitant
formation of alkoxy and hydroxyl groups are observed upon
Notes and references
.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 9 of 10
Dalton Transactions
View Article Online
DOI: 10.1039/D0DT03198D
PAPER
I. Solomon, K. D. Karlin, Angew. Chem. Int. Ed., 2019,
58, 17572–17576.
1
(a) E. I. Solomon, D. E. Heppner, E. M. Johnston, J. W.
Ginsbach, J. Cirera, M. Qayyum, M. T. Kieber-Emmons,
C. H. Kjaergaard, R. G. Hadt and L. Tian, Chem. Rev.
2014, 114, 3659–3853; (b) G. M. Yee, W. B. Tolman,
Transition Metal Complexes and the Activation of
Dioxygen. In Sustaining Life on Planet Earth:
Metalloenzymes Mastering Dioxygen and Other Chewy
Gases chapter 5, pp 131-204 (2014).
(a) J. P. Klinman, Chem. Rev. 1996, 96, 2541–2562; (b)
E. I. Solomon, U. M. Sundaram, T. E. Machonkin, Chem.
Rev., 1996, 96, 2563–2606; (c) M. Fontecave, J.-L.
Pierre, Coord. Chem. Rev., 1998, 170, 125–140.
(a) V. C. C. Wang, S. Maji, P. P.-Y. Chen, H.-K. Lee, S. S.-
F. Yu, S. I. Chan, Chem. Rev., 2017, 117, 8574–8621; (b)
T. J. Lawton, A. C. Rosenzweig, Curr. Op. Chem. Biol.,
2016, 35, 142–149.
O. M. Ross, F. MacMillan, J. Wang, A. Nisthal, T. J.
Lawton, B. D. Olafson, S. L. Mayo, A. Rosenzweig, B.
Hoffman, Science, 2019, 364, 566–570.
(a) C. E. Elwell, N. L. Gagnon, B. D. Neisen, D. Dhar, A. D.
Spaeth, G. M. Yee, W. B. Tolman, Chem. Rev., 2017,
117, 2059–2107; (b) R. Tramell, K. Rajabimoghadam, I.
Garcia-Bosch, Chem. Rev., 2019, 119, 2954–3031.
D. A. Quist, D. E. Diaz, J. L. Liu, K. D. Karlin, J. Biol. Inorg.
Chem., 2017, 22, 253–288.
(a) K. Fujisawa, M. Tanaka, Y. Moro-Oka, N. A Kitajima,
J. Am. Chem. Soc., 1994, 116, 12079–12080; (b) P.
Chen, D. E. Root, C. Campochiaro, K. Fujisawa, E. I.
Solomon, J. Am. Chem. Soc., 2003, 125, 466–474; (c) C.
Wꢀrtele, E. Gaoutchenova, K. Harms, M. C.;
Holthausen, J. Sundermeyer, S. Schindler, Angew.
Chem., Int. Ed., 2006, 45, 3867–3869; (d) D. J. E.
Spencer, N. W. Aboelella, A. M. Reynolds, P. L. Holland,
W. B. Tolman, J. Am. Chem. Soc., 2002, 124, 2108–
2109. (e) K. Fujisawa, T. Ono, Y. Ishikawa, N. Amir, Y.
Miyashita, K.-I. Okamoto, N. Lenhert, Inorg. Chem.
2006, 45, 1698-1713.
10
(a) Y. Y. See, A. T. Herrmann, Y. Aihara, P. S. Baran, J.
Am. Chem. Soc., 2015, 137, 13776–13779; (b) R.
Trammell, Y. Y. See, A. T. Herrmann, N. Xie, D. E. Díaz,
M. A. Siegler, P. S. Baran, I. Garcia-Bosch, J. Org. Chem.,
2017, 82, 7887–7904.
S. Kim, J. W. Ginsbach, J. Y. Lee, R. L. Peterson, J. J. Liu,
M. A. Siegler, A. A. Sarjeant, E. I. Solomon, K. D. Karlin,
J. Am. Chem. Soc., 2015, 137, 2867–2874.
11
12
2
3
(a) S. Itoh, Acc. Chem. Res., 2015, 48, 2066–2074; (b) T.
Tano, Y. Okubo, A. Kunishita, M. Kubo, H. Sugimoto, N.
Fujieda, T. Ogura, S. Itoh, Inorg. Chem., 2013, 52
,
10431–10437; (c) A. Kunishita, M. Z. Ertem, Y. Okubo, T.
Tano, H. Sugimoto, K. Ohkubo, N. Fujieda, S. Fukuzumi,
C. J. Cramer, S. Itoh, Inorg. Chem., 2012, 51, 9465–
9480; (d) A. Kunishita, M. Kubo, H. Sugimoto, T. Ogura,
4
5
K. Sato, T. Takui, S. Itoh, J. Am. Chem. Soc., 2009, 131
2788–2789.
,
13
14
J. L. Schneider, S. M. Carrier, C. E. Ruggiero, V. G. Young Jr.,
W. B. Tolman, J. Am. Chem. Soc. 1998, 120, 11408 – 11418.
CCDC 1998194 (1a), 1998192 (1b), 1998369 (2a),
1998208 (2b), 1998370 (3a) 1998191 (3b), contain the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre
6
7
15
16
K. D. Karlin, Y. Gultneh, J. P. Hutchinson, J. Am. Chem.
Soc. 1982, 104, 5240-5242.
(a) E. A. Lewis, W. B. Tolman, Chem. Rev. 2004, 104
,
1047-1076; (b) S. Mahapatra, J. A. Halfen, E. C.
Wilkinson, L. Que, Jr., W. B. Tolman, J. Am. Chem. Soc.
1994, 116, 9785-9786.
17
M. Ruf, C. G. Pierpont, Angew. Chem. Int. Ed., 1998, 37
1736–1739.
,
18
19
A. Bondi, J. Phys. Chem., 1964, 68, 441–451.
A. Ozarowski, C. J. Calzado, R. J. Sharma, S. Kumar, J.
Jezierska, C. Angeli, F. Spizzo, V. Ferretti, Inorg. Chem.,
2015, 54, 11916–11934.
J. L. Kisko, T. Hascall, G. Parkin, J. Am. Chem. Soc. 1998, 120,
10561-10562.
R. Dias, X. Wang, Polyhedron 2004, 23, 2533-2536.
M. Smith, Organic Synthesis, 4th ed. Academic Press, 2016.
M. A. Mairena, J. Urbano, J. Carbajo, J. J. Maraver, E.
Álvarez, M. M. Díaz‐Requejo, P. J. Pérez, Inorg. Chem. 2007,
46, 7428-7435.
8
9
J. J. Liu, D. E. Diaz, D. A. Quist, K. D. Karlin, Isr. J. Chem.,
2016, 56, 738 – 755.
(a) D. Maiti, D.-H. Lee, K. Gaoutchenova, C. Würtele, M.
C. Holthausen, A. A. N. Sarjeant, J. Sundermeyer, S.
20
21
22
23
Schindler, K. D. Karlin, Angew. Chem. Int. Ed., 2008, 47
,
82–85; (b) M. Bhadra, J. Y. C. Lee, R. E. Cowley, S. Kim,
M. A. Siegler, E. I. Solomon, K. D. Karlin, J. Am. Chem.
Soc., 2018, 140, 9042–9045; (c) D. E. Diaz, D. A. Quist,
A. E. Herzog, A. W. Schaefer, I. Kipouros, M. Bhadra, E.
Please do not adjust margins

Please do not adjust margins
Dalton Transactions
Page 10 of 10
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/D0DT03198D
24
25
Y.-R. Luo, Comprehensive Handbook of Chemical Bond
Energies, CRC Press, Boca Ratón, 2007.
(a) B. F. Gherman, C. J. Cramer, Coord. Chem. Rev.,
2009, 253, 723–753; (b) B. Dereli, M. A. Ortuño, C. J.
Cramer, ChemPhysChem, 2018, 19, 959–966.
J. Cirera, M. Via-Nadal, E. Ruiz, Organometallics, 2015,
34, 1294–1300.
26
27
M. Mandal, C. E. Elwell, C. J. Bouchey, T. J. Zerk, W. B.
Tolman, C. J. Cramer, J. Am. Chem. Soc., 2019, 141
17236–17244.
,
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins