Directed Hydroxylation of sp2 and sp3 C-H Bonds Using Stoichiometric Amounts of Cu and H2O2

Article abstract of DOI:10.1021/acs.inorgchem.9b00901

The use of copper for C-H bond functionalization, compared to other metals, is relatively unexplored. Herein, we report a synthetic protocol for the regioselective hydroxylation of sp² and sp³ C-H bonds using a directing group, stoichiometric amounts of Cu and H₂O₂. A wide array of aromatic ketones and aldehydes are oxidized in the carbonyl γ-position with remarkable yields. We also expanded this methodology to hydroxylate the β-position of alkylic ketones. Spectroscopic characterization, kinetics, and density functional theory calculations point toward the involvement of a mononuclear LCu^II(OOH) species, which oxidizes the aromatic sp² C-H bonds via a concerted heterolytic O-O bond cleavage with concomitant electrophilic attack on the arene system.

Full text of DOI:10.1021/acs.inorgchem.9b00901

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Directed Hydroxylation of sp2 and sp3 C−H Bonds Using
Stoichiometric Amounts of Cu and H2O2
Rachel Trammell,† Lorenzo D’Amore,‡ Alexandra Cordova,† Pavel Polunin,† Nan Xie,†
Maxime A. Siegler,∥ Paola Belanzoni,⊥,# Marcel Swart,*,‡,§ and Isaac Garcia-Bosch*,†
†Department of Chemistry, Southern Methodist University, Dallas, Texas 75275, United States
‡
̀
University of Girona, Campus Montilivi (Ciencies), IQCC, 17004 Girona, Spain
§ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
∥Johns Hopkins University, Baltimore, Maryland 21218, United States
⊥
̀
Dipartimento di Chimica, Biologia e Biotecnologie, Universita degli Studi di Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy
#Consortium for Computational Molecular and Materials Sciences (CMS)2, Via Elce di Sotto 8, 06123 Perugia, Italy
S
* Supporting Information
ABSTRACT: The use of copper for C−H bond functionalization, compared to other
metals, is relatively unexplored. Herein, we report a synthetic protocol for the
regioselective hydroxylation of sp2 and sp3 C−H bonds using a directing group,
stoichiometric amounts of Cu and H2O2. A wide array of aromatic ketones and
aldehydes are oxidized in the carbonyl γ-position with remarkable yields. We also
expanded this methodology to hydroxylate the β-position of alkylic ketones.
Spectroscopic characterization, kinetics, and density functional theory calculations
point toward the involvement of a mononuclear LCuII(OOH) species, which oxidizes
the aromatic sp2 C−H bonds via a concerted heterolytic O−O bond cleavage with
concomitant electrophilic attack on the arene system.
this knowledge to carry out the functionalization of a wide
array of substrates containing sp2 and sp3 C−H bonds (Figure
1B).
1. INTRODUCTION
Synthetic methods that use 3d metals to carry out
regioselective C−H hydroxylations are scarce.1 One of the
main challenges of this approach is to overcome the tendency
of these metals to generate radical species, which usually lead
to unselective C−H oxidations and functional group
degradation.2 Metalloenzymes have evolved to bypass these
issues by developing active centers that can regulate the redox
reactivity of the metal−O2 intermediates and to control the
substrate spatial orientation for site selectivity.3,4 Que, Costas,
and White have shown that non-heme Fe complexes catalyze
the regioselective hydroxylation of complex organic molecules
with H2O2 via formation of Fe−oxo intermediates.5−7 On the
other hand, our research group has recently reported that
analogous Cu catalysts react with H2O2 to generate unselective
hydroxyl radicals (Fenton-like chemistry).8 The use of
directing groups (DGs) is an elegant method for circum-
venting regioselectivity issues in organic synthesis.9 We have
recently studied the mechanism by which Cu promotes the
intramolecular γ sp3 C−H hydroxylation of steroidal imino-
o-Acylphenols are commonly found in several bioactive
natural products and drugs and are widely used as building
blocks in the synthesis of pharmaceuticals and oxygen-
containing heterocycles.15 A classic approach for the synthesis
of o-acylphenols is a two-step procedure that entails acylation
of the phenols followed by Fries rearrangement’ however, this
method is not selective, and the substrate scope is limited.16
A
very attractive synthetic route is the direct regioselective
hydroxylation of arylketones. Catalytic amounts of precious
metals (Pd, Rh, and Ru) have been used for this purpose, but
their reactivity often relies on harsh reaction conditions and
the use of expensive hypervalent iodine oxidants [i.e.,
PhI(CF3CO2)3].17−19 The Yu research lab showed that Cu
can promote intramolecular ortho hydroxylation of phenyl-
amides at high temperatures by using excess amounts of a
metal source and adding external oxazoline ligands and various
additives.19 Very recently, Uchiyama reported the directed
ortho hydroxylation of N,N-diisopropylamides by deprotona-
tion using excess amounts of a cuprate base followed by
pyridine substrates,10 a reaction first developed by Schoneck-
̈
er11−13 and later optimized by Baran14 (Figure 1A). On the
basis of our findings, we were able to redesign the reaction
conditions to use cheaper reagents with shorter reaction times
under milder conditions.10 In this work, we take advantage of
Received: March 28, 2019
© XXXX American Chemical Society
A
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Figure 1. Cu-directed hydroxylation of sp2 and sp3 C−H bonds.
20
t
oxidation with BuOOH. Inspired by our findings on Cu-
directed hydroxylation of sp3 C−H bonds using H2O2 as an
oxidant (see Figure 1A), we decided to determine if a similar
methodology could be used for the synthesis of o-acylphenols
under mild conditions.
The study of the oxidative properties of LCu/O2 species has
led to a better understanding of the reactivity of Cu-dependent
monooxygenase enzymes.21−24 For several examples, the
formation of a metastable LCu/O2 intermediate is followed
by the intramolecular oxidation of the ligand scaffold, including
ligand hydroxylation,25,26 sulfoxidation,27 and N-dealkyla-
tion.28 In selected examples, Cu complexes have been used
to promote the intermolecular oxidation of external sub-
strates,29 with a focus on mimicking the tyrosinase-like ortho
hydroxylation of phenolates, including stoichiometric30−32 and
catalytic transformations.33,34 Despite the rich reactivity of Cu/
O2 species in the synthetic inorganic literature, their use in
synthetic organic chemistry has been restricted to a handful of
examples.23 Among these, it is worth mentioning Lumb’s
reports on Cu-catalyzed aerobic functionalization of phe-
Figure 2. (A) Optimization of the reaction conditions for the
hydroxylation of L1. (B) Gram scale oxidation of S1 using the
optimized CuI/H2O2 conditions. See the Supporting Information.
experimental details). The Cu-promoted oxidation of L1 was
optimized under various reaction conditions (Figure 2A). One-
pot mixing of equimolar amounts of L1 and [CuI(CH3CN)4]-
(PF6) in acetone followed by addition of 5 equiv of H2O2
produced the hydroxylation product P1 in excellent yields
(Figure 2A, entry 3). The use of various Cu sources was tested
(Figure 2A, entries 14−18) with [CuI(CH3CN)4](PF6)
reaching the highest yields (≤85%). Acetone was found to
be the best solvent, followed by THF, CH2Cl2, and CH3CN
(Figure 2A, entries 3 and 9−11). We also analyzed the use of
O2 as an oxidant. We observed that an increase in the reaction
temperature from −20 to 50 °C (Figure 2A, entries 5−8)
afforded higher yields (from 7% to 46%). A similar effect was
observed in the oxidation of sp3 steroidal systems and was
attributed to the formation of H2O2 via reduction of O2 by CuI
(i.e., formation of CuII and superoxide) and subsequent
oxidation of the solvent, which is favored at high temper-
atures.10 The efficiency of other oxidants such as cumyl
nols.35−37 Reglier pioneered the field of Cu-directed oxidation
́
of C−H bonds,38,39 an approach that inspired the work of
11−13
̈
Schonecker
on steroid sp3 hydroxylation. Using a similar
methodology, Schindler has also shown that bidentate amines
can direct the hydroxylation of sp2 and sp3 C−H bonds
employing CuI and O2 with modest oxidation yields (<50%).40
On the basis of these precedents, we report the Cu-directed
hydroxylation of sp2 and sp3 C−H bonds in which
unprecedented regioselectivity and a deeper mechanistic
understanding of the reaction mechanism are achieved (Figure
1B).
2. RESULTS AND DISCUSSION
2.1. Synthesis and Oxidation of Imino-Pyridine
Substrates. Condensation of benzophenone, S1, with 2-
picolylamine led to the formation of the substrate−ligand
system L1 (Figure 2A; see also the Supporting Information for
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hydroperoxide (CumOOH) and tert-butyl hydroperoxide
(tBuOOH) was also studied (Figure 2A, entries 12 and 13,
respectively), but only H2O2 produced the oxidation product
P1. Noticeably, when other first-row transition metal sources
were used (e.g., MnII, FeII, and NiII), P1 was not formed and
only starting material was recovered (Figure 2A, entries 19−
21). We performed the oxidation of L1 on a gram scale using
the optimized conditions (1 equiv of CuI and 5 equiv of
H2O2), which afforded the hydroxylation product, P1, in 71%
yield (Figure 2B; note that a 64% overall yield includes the
installation of the directing group).
With the most suitable oxidation conditions in hand, we
explored the hydroxylation of the substrate−ligand systems
derived from the condensation of 2-picolylamine with various
benzophenones, acetophenones, and benzaldehydes (Figure
3A). For all of these systems, we obtained the oxidation
products derived from the γ-hydroxylation of the sp2 C−H
bond (P1−P13) with moderate to excellent yields (30−85%).
Substrates in which the oxidation can occur at multiple sites
(e.g., 2-acetonaphthone can be oxidized at the β sp3 position or
two different γ sp2 positions) were also tested. Oxidation of 2-
acetonaphthone occurred selectively at position 1 of the
naphthyl ring with remarkable yields (P14, 84%). Similarly, the
oxidation of the imino-pyridine substrate derived from 1-
acetonaphthone led to the sp2 hydroxylation product (P15,
33%). We also aimed to verify that our oxidation conditions
did not generate overoxidation products. To do so, we
synthesized the imino-pyridine system derived from P1 and
subjected it to oxidation with CuI and H2O2, which led to
recovery of P1 (P16, 0%) and differed from other Cu/O2
systems in which intramolecular hydroxylation of phenol
substituents was observed.41
A new set of sp3 C−H bond-containing systems were also
oxidized using CuI and H2O2 (Figure 3B). The substrate−
ligand system derived from dicyclohexyl ketone was selectively
oxidized at the β position in high yields (P17, 70%). This
selectivity differs from previous findings in which the sp3 C−H
hydroxylation occurred at the γ position. Like in previous
reports, the systems derived from dehydro-epi-androsterone
and R-camphor were selectively oxidized at the γ site (P20 and
P21).10−14 The β selectivity was also observed by the oxidation
of the asymmetric system derived from cyclohexyl phenyl
ketone (P18, 55%). More importantly, our methodology
allowed synthesis of the β-hydroxylation product of 2-
adamantanone with remarkable yields (P19, 70%), which is
inaccessible using classic silyl enol ether/peroxyacid oxidations
and other base-triggered oxidation reactions.42−45 Our
methodology also resulted in the γ sp2 hydroxylation of cyclic
ketones such as 2-methyl-1-tetralone with good yields (Figure
3C, P22, 54%). Interestingly, this regioselectivity differs from
the reactivity observed by Schoenebeck and co-workers, in
which a combination of Cu2O, a strong base, and O2 led to the
oxidation of the β-sp3 C−H bond (P23, 92%).42
2.2. Synthesis of Copper Complexes. With the
substrate−ligand systems in hand, we synthesized and
characterized cuprous complexes in which one or two ligand
scaffolds are bound to the metal ion (Figure 4A; see also the
Figure 3. (A) γ-Hydroxylation of sp2 C−H bonds. (B) β- and γ-
hydroxylation of sp3 C−H. (C) Divergent regioselectivity: γ-sp2
hydroxylation described this work (DG, 2-picolylamine) vs β-sp3
hydroxylation reported by Schoenebeck.42 All reactions were
performed with 40 mM LX using 5 equiv of 30% H2O2 (2.5 equiv
for sp2 C−H hydroxylation) for 30 min at room temperature in
acetone. See the Supporting Information for further details.
Figure 4. (A) Synthesis of CuI substrate−ligand complexes. (B) X-ray
diffraction analyses of the systems derived from benzaldehyde (left)
and 1-acetophenone (right). See the Supporting Information for
further details.
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Figure 5. (A) Proposed reaction mechanism for the Cu-directed sp2 C−H hydroxylation with H2O2. (B) (i) UV−vis and EPR characterization of
the reaction intermediates formed upon addition of H2O2 (20 equiv) to the [(L1)CuI(CH3CN)]+ complex (0.5 mM) in acetone at −20 °C (note
that the EPR shows mixtures of intermediates and only the main contributor is indicated; the g⊥, g∥, and A∥ values can be found in the Supporting
Information; also see the Supporting Information for CuII signal quantification). (ii) Evolution of the absorbance at 380 nm of the reaction (top)
and analysis of the hydroxylation yields over time (bottom). (iii) Kinetic analysis of the reaction by varying [CuI]0 and [H2O2]0, KIE analysis, and a
Hammett plot (see the text and Supporting Information for details).
Supporting Information). X-ray diffraction analysis of the
isolated substrate−ligand Cu complexes provided structural
information about the site of hydroxylation (Figure 4B; see
also the Supporting Information). For example, analysis of the
CuI system derived from 2-acetophenone (L15) showed that
the γ sp2 C−H position that will undergo oxidation (Coxid.) is
the closest to the Cu ion, with the CH3 site pointed away from
the CuN3 T-shaped core.
spectra in Figure 5B, i). We independently synthesized and
characterized the CuII-bound hydroxylation product (ligand
derived from P1), and its UV−vis spectrum overlaps with the
species formed in the LCuI/H2O2 reaction (see the Supporting
Information). Fitting of the absorbance at 380 nm (Figure 5B,
ii, top) suggested a three-step reaction in which the initial LCuI
is quickly transformed to the LCuII(OOH) complex (0−5 s),
which evolves to generate two forms of the hydroxylation
product [(L-O)CuII(OH2) from 5 to 200 s and (L-O)CuII
from 200 to 3000 s]. The same species are observed by EPR,
during which, upon addition of H2O2 to LCuI, three distinctive
mononuclear CuII complexes are consecutively formed (Figure
5B, i, inset). We confirmed that the hydroxylation of the
substrate occurred at short reaction times (from 5 to 200 s
after addition of H2O2) by analyzing the hydroxylation yields
at different reaction times (Figure 5B, ii, bottom).
Kinetic analysis at different Cu and H2O2 concentrations
indicated that the hydroxylation rate is first-order in [LCuI]0
and zero-order in [H2O2]0, which suggested that the
intramolecular hydroxylation is not a one-step bimolecular
process between LCuI and H2O2 and that the decay of the
putative LCuII(OOH) intermediate occurs in the r.d.s. (Figure
5B, iii). The kinetic isotope effect (KIE) of the reaction was
obtained by comparing the reaction rates of the benzophe-
none-derived ligand system L1 with the benzophenone-d10
analogue L7 (Figure 5B, iii; see also the Supporting
Information). The KIE value (∼0.83) indicates that during
the r.d.s. the C−H bond that is oxidized undergoes sp2 to sp3
hybridization, which is consistent with an electrophilic attack
of the LCuII(OOH) on the arene substrate.47
2.3. Mechanistic Studies. With the isolated complexes
[(LX)CuI(CH3CN)]+, we studied the mechanism by which
the Cu-directed sp2 hydroxylation takes place (Figure 5). In
our previous study, we proposed that the reaction between
LCuI and O2 generated LCuII and superoxide that, upon
oxidation of the solvent, formed H2O2.10 Subsequent reaction
of LCuII and H2O2 would produce a mononuclear
LCuII(OOH) intermediate before the rate-determining step
(r.d.s.). We found that the same LCuII(OOH) species could
also be formed by addition of H2O2 to the LCuI or LCuII
complexes.46 For the benzophenone-derived CuI complexes
described herein, we suggest a similar hydroxylation pathway
(Figure 5A). The reaction between LCuI and H2O2 was
followed by ultraviolet visible (UV−vis) and electron para-
magnetic resonance (EPR) (Figure 5B, i). Addition of H2O2
(20 equiv) to a 0.5 mM acetone solution of [(L1)-
CuI(CH3CN)]+ at −20 °C (orange spectrum) generated a
species with spectral features characteristic of LCuII(OOH)
complexes (green spectrum, λmax = 380−400 nm, ε = 2000
M−1 cm−1).46 Decomposition of the metastable LCuII(OOH)
produced two mononuclear CuII species in a stepwise manner
(λmax ∼ 380 nm), which we assign as CuII compounds in which
the γ sp2 C−H bond has been oxidized (purple and blue
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We also obtained the reaction rates of CuI substrate−ligand
systems derived from 4-substituted benzophenones (X = MeO,
Me, F, Cl, or Br). The hydroxylation rates were found to be
independent of the substituent (kobs vs σ+ , Hammett plot, in
p
Figure 5B, iii), which might appear to contradict the proposed
direct electrophilic attack of the LCuII(OOH) on the aromatic
system, because this reaction would be accelerated for
electron-donating systems.48 However, the possibility that
the introduction of electron-donating or electron-withdrawing
subtituents into the substrate−ligand structure might also
affect the electrophilicity of the LCuII(OOH) cores should be
considered: for example, the use of the 4-MeO substituent will
produce a substrate more reactive toward electrophilic attack
but will also lead to a more electron-rich LCuII(OOH) species,
and hence less electrophilic (see Figure 6B), compensating for
the substrate substituent effect.
To substantiate this mechanistic hypothesis, we measured
the redox potentials of the benzophenone-derived Cu
complexes (Figure 6). We found that the complex derived
from benzophenone [(L1)CuI(CH3CN)]+ was reversibly
oxidized in CH3CN at −0.07 V versus ferrocene/ferrocenium
(Fc0/+). For the systems containing electron-donating groups,
the CuI/CuII redox couple shifted to lower redox potentials
(−0.11 V for 4-Me and −0.16 V for 4-MeO), while for the
systems with electron-withdrawing substituents, the redox
potentials were found at higher potentials (0.00 V for 4-F and
0.02 V for 4-Cl and 4-Br).
Overall, substitution of position 4 of the substrate−ligand
phenyl substituent led to a change in the redox potentials of
almost 0.2 V, with the 4-MeO system having the lowest redox
potential and the 4-Br system having the highest, which we
believe corroborates our hypothesis about the electrophilicity
of the putative LCuII(OOH) reactive intermediates [i.e., 4-
MeO substrate more prone to electrophilic attack but
LCuII(OOH) less electrophilic].
2.4. Computational Studies. Density functional theory
(DFT) calculations were carried out to improve our under-
standing of the mechanism by which the putative mononuclear
LCuII(OOH) promotes intramolecular hydroxylation (Figure
7). Our calculations (including solvent and scalar relativistic
corrections) at S12g/TZ2P//BP86-D3/TDZP showed that
the end-on CuII−hydroperoxide intermediate (RC) undergoes
heterolytic O−O cleavage with concomitant electrophilic
attack of the phenyl substituent.49 We found that the resulting
Wheland-like intermediate50 (INT1) isomerized to a Cu
complex in which the H at the γ-carbon is transferred to the δ
aromatic position (INT2).51 This hydrogen shift could then
trigger the deprotonation of the organic fragment by the CuII−
OH core (TS3) to generate H2O and recover the aromaticity
of the ring (PC).
On the basis of these results, O−O bond cleavage is the
reaction step that requires more energy. This agrees with our
kinetic measurements [i.e., first-order dependence of [Cu]0,
zero-order dependence of [H2O2]0, and KIE (vide supra)] and
spectroscopic characterizations, all of which suggested that the
O−O bond cleavage, coupled with electrophilic attack, is rate-
limiting. We also carried out the same calculations for the 4-
substituted systems 4-MeO and 4-Br. We computed that the
energetics of the rate-determining step for 4-MeO and 4-Br
were very similar to the values found for the 4-H system (15.8
kcal/mol for 4-H, 16.2 kcal/mol for 4-MeO, and 14.6 kcal/mol
for 4-Br). These findings (∼1 kcal/mol difference between the
4-substituted systems) are in agreement with the kinetic data
Figure 6. (A) Cyclic voltammetry measurements for the family of
benzophenone-derived CuI complexes. (B) Effects on the reactivity of
the putative LCuII(OOH) species.
described above in which similar reaction rates were observed
for all of the 4-substituted benzophenone−ligand complexes.
2.5. Mechanistic Considerations. Copper(I) complexes
react with O2 to generate fleeting mononuclear Cu/O2 species
that are difficult to trap due to their tendency to react with
other LCuI equivalents and form more stable Cu2O2 cores.21,52
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that these ligand scaffolds are more likely oxidized via
formation of mononuclear Cu/O2 intermediates (Figure 8B).10
Our mechanistic findings supported the idea that H2O2 is
the active oxidant in these intramolecular hydroxylations.10 We
proposed that the reaction between LCuI and O2 generated
LCuII and free superoxide, which was reduced to H2O2 via
solvent oxidation. The resulting LCuII would then react with
H2O2 to produce a mononuclear LCuII(OOH) intermediate
before ligand hydroxylation. We found that this LCuII(OOH)
species could also be generated by adding H2O2 to LCuI,
which would form sequentially LCuII(OH) and LCuII(OOH).
Alternatively, we observed that the LCuII(OOH) could also be
formed by addition of H2O2 to the corresponding LCuII
complex in a presence of a base. On the basis of mechanistic
evidence, we suggested that the mononuclear LCuII(OOH)
complex underwent homolytic O−O bond cleavage to
generate a hydroxyl radical, which would abstract a H atom
from the γ sp3 C−H bond of the ligand scaffold before C−O
bond formation (Figure 8B). The mechanistic studies of sp2
hydroxylation presented herein also support the formation of
LCuII(OOH) intermediates. However, the reaction pathway
for sp2 C−H hydroxylation seems to entail a concerted C−O
bond formation with heterolytic O−O bond cleavage as the
rate-determining step of the reaction rather than homolytic
cleavage.
As we have shown, the LCuII(OOH) complex is formed by
addition of H2O2 to the copper(I) complex (see Figure 5B).
We also tested if LCuII(OOH) could be generated by adding
H2O2 to a solution of LCuII and NMe4OH (see the Supporting
Information). Interestingly, we observe that the UV−vis
changes and the rate of hydroxylation for L1 with CuII,
H2O2, and hydroxide were identical to those found in the
oxidation of L1 with CuI and H2O2 [note that the use of
NMe4OH also led to higher reaction yields in the oxidation of
L1 with CuII(NO3) (see entry 25 in Figure 2)]. We also
carried out the oxidation of L7 (deuterated version of L1) in
the presence of CuII, H2O2, and HO−, and the rates of
hydroxylation were also similar to those calculated in CuI/
H2O2, leading to an inverse kinetic isotope effect [KIE = 0.89
(see the Supporting Information)]. These findings suggest that
under both oxidation conditions (CuI/H2O2 or CuII/H2O2/
HO−) the same reaction intermediates are formed.
It is worth mentioning that the formation of dinuclear
Cu2O2 species under the reaction conditions presented here
cannot be ruled out. However, the fact that the CuI complexes
do not generate Cu2O2 cores at low temperatures upon
reacting with O2 suggests that these species are not involved in
the oxidation of the ligand scaffold. The first-order dependence
on [LCuI]0 and zero-order dependence on [H2O2]0, the
observed inverse kinetic isotope effect, and the spectroscopic
characterization of the reaction intermediates point toward the
involvement of a mononuclear species as the active
hydroxylating agent. The formation of a Cu2O2 species after
the rate-determining step and before C−H oxidation would
not lead to a kinetic isotope effect (KIE = 1). The generation
of a Cu2O2 core before the rate-determining step could also
show a first-order dependence on [LCuI]0 and a zero-order
dependence on [H2O2]0, but if that were the case, the putative
Figure 7. DFT calculations on the Cu-directed hydroxylation of sp2
C−H bonds.
Because of this, the reactivity of Cu2O2 species has been
studied in detail, and it has been established that end-on
dicopper(II)−peroxide intermediates are normally nucleo-
philic oxidants while side-on dicopper(II)−peroxide complexes
and dicopper(III) bis-μ-oxo compounds are considered
electrophilic oxidants.32,53,54 On the other hand, mononuclear
Cu/O2 complexes are scarce and the study of their reactivity
has been restricted to a few selected systems.55−58
Several research groups have reported that both mono-
nuclear and dinuclear Cu/O2 species can perform intra-
molecular C−H hydroxylations (Figure 8A). For example,
Karlin and co-workers observed that a Cu complex bearing a
superbasic tetradentate ligand (Figure 8A, i) could undergo
intramolecular sp3 C−H hydroxylation via formation of a
putative mononuclear LCuII−oxyl species.25 The same
research group also found that an LCuII(OOH) complex
promoted the intramolecular sp2 hydroxylation of a tmpa-
derived tetradentate scaffold and showed that the correspond-
ing L2Cu2O2 adduct did not undergo intramolecular ligand
oxidation (Figure 8A, ii).59 Itoh and co-workers were able to
generate and characterize a unique CuII−superoxide complex
that underwent intramolecular C−H hydroxylation via H atom
abstraction of the supporting tridentate ligand (Figure 8A,
38
iii).26,60 Reglier, Schindler,40,61 and Tolman48 have reported
́
that for some bidentate and tridentate ligands, these intra-
molecular hydroxylations entail the formation of Cu2O2 cores
because N2 and N3 scaffolds usually favor their formation52
[note that both Schindler and Tolman observed the formation
of L2CuIII2(O2−)2 cores before ligand hydroxylation]. On the
basis of reaction yields, a similar mechanistic scenario was
Cu2O2 species would accumulate before ligand oxidation
(r.d.s.) and would be observed spectroscopically [CuII (O2
)
2−
2
̈
and CuIII2(O2−)2 intermediates are EPR silent, and their UV−
vis features are very intense and characteristic]. However, the
possible involvement of dinuclear species was computed, and
hypothesized by Schonecker and co-workers for the intra-
molecular hydroxylation of sp3 C−H bonds in steroid-derived
bidentate ligands.11−13 However, we have recently proposed
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Figure 8. (A) Copper complexes that undergo intramolecular C−H hydroxylation via formation of mononuclear or dinuclear Cu/O2 species. (B)
Proposed reaction mechanisms for the intramolecular γ-hydroxylation of C−H bonds discussed herein.
we found that the activation energy for the intramolecular sp2
C−H hydroxylation is slightly lower than that found for the
LCuII(OOH) intermediate (see the Supporting Information).
Our calculations also indicate that the generation of the
L2 Cu2O2 cores from LCuI I(OOH) is exergonic
group to promote the hydroxylation of different substrate sites
(β vs γ vs δ) and to generate a wide variety of Cun/O2 species
(mononuclear and dinuclear) that will lead to a better
understanding of the reactivity of Cu-dependent monoox-
ygenases.
[2LCuII(OOH) ↔ L2CuII (O22−) + H2O2 (ΔG ∼ −7 kcal/
2
mol)], but the fact the reactions are carried out under excess
amounts of H2O2 might favor the formation of the
mononuclear LCuII(OOH) species, a behavior that has also
been observed in the Cu-catalyzed hydroxylation of benzene
by dicopper species with H2O2.62
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b00901.
3. CONCLUSIONS AND FUTURE PERSPECTIVES
Experimental details, including substrate−ligand syn-
thesis and oxidation, complex synthesis and character-
ization, kinetic analysis, spectroscopic characterization,
and DFT calculations (PDF)
In summary, we report here a synthetic protocol for the
functionalization of ketones (and aldehydes) based on the use
of directing groups (easily installed and removed), Cu, and
H2O2, which resulted in hydroxylation products with
remarkable yields and unprecedented selectivity (i.e., β-
hydroxylation of sp3 systems and selective hydroxylation in
unsymmetric ketones). Close examination of the overall
reaction mechanism led us to propose an LCuII(OOH)
species as a key reaction intermediate, which has also been
invoked in some Cu-containing metalloenzymes (e.g., lytic
polysaccharide monooxygenases).63 Inspired by these findings,
our lab is now focused on rationally modifying the directing
Accession Codes
CCDC 1880982−1880987 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
G
DOI: 10.1021/acs.inorgchem.9b00901
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Inorganic Chemistry
Article
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: marcel.swart@udg.edu.
*E-mail: igarciabosch@smu.edu.
ORCID
Lorenzo D’Amore: 0000-0003-2245-1956
Paola Belanzoni: 0000-0002-1286-9294
Marcel Swart: 0000-0002-8174-8488
Isaac Garcia-Bosch: 0000-0002-6871-3029
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank the Robert A. Welch Foundation, the
National Institutes of Health (Grant R15GM128078 to I.G.-
B.), MINECO (CTQ2017-87392-P), UdG (IFUdG2016
fellowship to L.D.), and FEDER (UNGI10-4E-801 to M.S.)
for financial support, CSUC for extensive computer time, and
SMU for financial support and facilities. The authors thank Dr.
Vogel and Dr. Wise (SMU) for help with EPR and Dr. Baran
for providing ligand systems L20 and L21 and for helpful
advice.
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