Mechanistic Insights into the ortho-Defluorination-Hydroxylation of 2-Halophenolates Promoted by a Bis(μ-oxo)dicopper(III) Complex

Article abstract of DOI:10.1021/acs.inorgchem.0c02246

C-F bonds are one of the most inert functionalities. Nevertheless, some [Cu2O2]2+ species are able to defluorinate-hydroxylate ortho-fluorophenolates in a chemoselective manner over other ortho-halophenolates. Albeit it is known that such reactivity is promoted by an electrophilic attack of a [Cu2O2]2+ core over the arene ring, the crucial details of the mechanism that explain the chemo- and regioselectivity of the reaction remain unknown, and it has not being determined either if CuII2(η2:η2-O2) or CuIII2(μ-O)2 species are responsible for the initial attack on the arene. Herein, we present a combined theoretical and experimental mechanistic study to unravel the origin of the chemoselectivity of the ortho-defluorination-hydroxylation of 2-halophenolates by the [Cu2(O)2(DBED)2]2+ complex (DBED = N,N′-di-tert-butylethylenediamine). Our results show that the equilibria between (side-on)peroxo (P) and bis(μ-oxo) (O) isomers plays a key role in the mechanism, with the latter being the reactive species. Furthermore, on the basis of quantum-mechanical calculations, we were able to rationalize the chemoselective preference of the [Cu2(O)2(DBED)2]2+ catalyst for the C-F activation over C-Cl and C-H activations.

Full text of DOI:10.1021/acs.inorgchem.0c02246

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Mechanistic Insights into the ortho-Defluorination-Hydroxylation of
2‑Halophenolates Promoted by a Bis(μ-oxo)dicopper(III) Complex
‡
‡
́
́
Pau Besalu-Sala, Carla Magallon, Miquel Costas,* Anna Company,* and Josep M. Luis*
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ABSTRACT: C−F bonds are one of the most inert functionalities. Nevertheless, some
[Cu2O2]2+ species are able to defluorinate-hydroxylate ortho-fluorophenolates in a
chemoselective manner over other ortho-halophenolates. Albeit it is known that such
reactivity is promoted by an electrophilic attack of a [Cu2O2]2+ core over the arene ring, the
crucial details of the mechanism that explain the chemo- and regioselectivity of the reaction
remain unknown, and it has not being determined either if CuII (η2:η2-O2) or CuIII2(μ-O)2
2
species are responsible for the initial attack on the arene. Herein, we present a combined
theoretical and experimental mechanistic study to unravel the origin of the chemoselectivity
of the ortho-defluorination-hydroxylation of 2-halophenolates by the [Cu2(O)2(DBED)2]2+
complex (DBED = N,N′-di-tert-butylethylenediamine). Our results show that the equilibria
between (side-on)peroxo (P) and bis(μ-oxo) (O) isomers plays a key role in the
mechanism, with the latter being the reactive species. Furthermore, on the basis of quantum-
mechanical calculations, we were able to rationalize the chemoselective preference of the
[Cu2(O)2(DBED)2]2+ catalyst for the C−F activation over C−Cl and C−H activations.
the corresponding chatecols.6−8 On the contrary, tyrosinase,
which catalyzes the ortho-hydroxylation of phenols, cannot
ortho-defluorinate-hydroxylate 2-fluorophenols.9,10 Indeed, 2-
fluorophenols inhibit the catalytic activity of tyrosinase. The
active species of this enzyme consists of a (η2:η2-peroxo)-
dicopper(II) species (P), which is able to hydroxylate phenols
through an electrophilic aromatic substitution. Some of us have
shown that bioinspired systems such as [CuIII2(μ-O)2(m-
XYLMeAN)]2+ and [Cu2(μ−η2:η2-O2)(DBED)2]2+ (Figure 1)
elicit the hydroxylation-defluorination of 2-fluorophenolates to
give the corresponding catechols (XYL = meta-xylyl-
N,N,N′,N′,N′′-pentamethyldipropylenetriamine; DBED =
N,N′-di-tert-butylethylenediamine).11 In contrast, other
model systems such as [Cu2(μ−η2:η2-O2)(LPy2Bz)2]2+ are
unable to cleave the C−F bond. Although the peroxo (P)
species is the most stable isomer of both [Cu2(μ−η2:η2-
O2)(DBED)2]2+ and [Cu2(μ−η2:η2-O2)(LPy2Bz)2]2+, the for-
mer is in equilibrium with the bis(μ-oxo)dicopper(III) (O)
isomer. This led us to consider that the latter isomer is the
active species in the defluorination of 2-fluorophenols (Figure
1).12−14
INTRODUCTION
■
The high electronegativity of fluorine strongly polarizes and
shortens C−F bonds, reinforcing the ionic component of the
chemical bond. As a consequence, the C−F bond has the
largest C−X (X = F, Cl, Br, I) dissociation energy (up to 130
kcal·mol−1).1 Thus, C−F is considered the most inert organic
functionality, which confers a high thermal stability to the
fluorinated organic compounds. On the one hand, because of
the increment of the lipophilicity caused by the fluorination,
fluorinated drugs present larger in vivo residence times than
their nonfluorinated counterparts.2,3 Therefore, fluorinated
compounds are of great interest in medicinal chemistry and
agrochemistry.2 In addition, fluorinated compounds are also
currently in the spotlight, since their metabolization is very
difficult due to the aforementioned high stability, which
triggers their bioaccumulation and environmental persistence.
This scenario pops up a dilemma, since we are facing two sides
of the same coin. The particular properties of fluorinated
organic molecules make them interesting for medicinal
chemistry or agrochemistry. However, they are also responsible
for their bioaccumulation and biomagnification.4,5 Therefore,
finding strategies to promote the activation and subsequent
transformation of C−F bonds into more reactive function-
alities is the key to facilitate the degradation of the fluorinated
organic molecules.
Received: July 28, 2020
In nature, aliphatic and aromatic fluorinated compounds can
be enzymatically functionalized. In particular, the defluorina-
tion of aromatics occurs in cytochrome P450, chloroperox-
idase, and flavin adenine dinucleotide (FAD)-containing
phenol hydroxylases, which can convert 2-fluorophenols into
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COMPUTATIONAL DETAILS
■
The computationally aided modeling of [Cu2O2]2+-based
compounds for the defluorination-hydroxylation of fluorophe-
nols has been exploited in the past decade, yet it is not an easy
task.22−25 Because of the high number of electrons that must
be correlated, multireference methods have not been
extensively used to study [Cu2O2]2+ reactivity. Density
functional theory (DFT) arises as a powerful alternative to
study these compounds due to its good accuracy/cost
balance.26,27 However, some important considerations must
be taken into account. In particular, and of high interest for the
current manuscript, is that an unequivocal characterization of
[Cu2O2]2+ isomerization equilibria is certainly quite difficult to
achieve by DFT means.26,28,29 Whereas (end-on)peroxo/(side-
on)peroxo isomerization equilibria is usually well-described by
hybrid functionals, (side-on)peroxo/bis(μ-oxo) (P/O) equi-
libria presented by 1 is better described by pure functionals.30
Hybrid functionals tend to understabilize bis(μ-oxo) species,
the magnitude of the understabilization being proportional to
the amount of exact exchange introduced in the functional
definition. Therefore, we performed the DFT calculations
using a pure functional. Nevertheless, the DFT results of the
P/O equilibria, which have a key relevance in the present
manuscript, were improved with the domain-based local pair
natural orbital coupled cluster method (DLPNO-CCSD(T))
calculations, which produce more reliable predictions than
DFT.31−34
DFT electronic structure calculations were performed with
the Gaussian 09 software package35 using the spin-unrestricted
UM06-L36 density functional. For the geometric optimizations
the molecular orbitals were spanned into the Pople-type 6-
311G(d) basis set37,38 (Method A). Singlet (both open and
closed shell) and triplet spin symmetries were explored,
reporting always the most stable one. The nature of the
stationary points was determined by analytical frequency
calculations. To compute subsequent Gibbs free energy
corrections, the temperature was set up at 183.15 K to
simulate the experimental conditions. Furthermore, the
connection between the transition state (TS) and intermedi-
ates was unambiguously established by intrinsic reaction path
calculations (IRCs),39 using the local quadratic approximation
to determine the prediction step.40 All DFT energy values were
systematically improved by evaluating the electronic structures
of the optimized geometries using the Dunning’s correlation
consistent triple-ζ basis set cc-pVTZ, suppressing the functions
with higher angular momentum only for the Cu atoms (cc-
pVTZ-g)41,42 and introducing solvation (acetone) effects
through the universal solvation model (SMD) (Method B).43
Spin contamination was removed if necessary by using the
following expressions26,44,45
Figure 1. Three Cu2O2-based species. Green tick marks indicate that
defluorination-hydroxylation products are obtained, whereas the red
cross indicates the opposite.
In the case of [CuIII2(μ-O)2(m-XYLMeAN)]2+ only the O
isomer is observed,15 further supporting the idea that this
isomer is the only one competent to perform the
defluorination reaction.11 Of relevance to these observations,
high-valent iron-oxo and iron-manganese species have also
shown analogous reactivity.16−20 In addition, de Visser and co-
workers showed that a μ-nitrido diiron phthalocyanine
complex is able to activate and hydroxylate the C−F bonds
of hexafluorobenzene derivatives.21
In this work, theory and experiments are combined to
determine the details of the mechanism of the selective ortho-
hydroxylation−defluorination of 2-fluorophenolates with
[Cu2O2(DBED)2]2+ (1), a compound first described by
Stack and co-workers.12,13 Specifically, our study was directed
to address the following questions; to unravel which is the
actual defluorination-oxygenation agent, either the P or O
species, (1P and 1°, Figure 2). Both isomers have been
Figure 2. Schematic representation of the two studied isomers of
[Cu2O2(DBED)2]2+ (1): the (η2:η2-peroxo)dicopper(II) species (1P,
left) and the bis(μ-oxo)dicopper(III) species (1°, right).
ES − aE(S+1)
Espin−corr
=
(1)
experimentally detected for this system: The P isomer is
generated upon reaction of the copper(I) precursor with O2,
while the O compound is experimentally detected upon
coordination of a phenolic substrate to P. A second aspect to
clarify is the origin of the selective oxygenation at the ortho C−
F over the ortho C−H position in the reaction with 2-
fluorophenols, despite the former being devised as more
electron poor than the latter. Finally, the study aimed at
explaining the reason for C−Cl bonds, weaker than C−F
bonds, remaining unreactive.
1 − a
2
⟨SS ⟩ − S·(S + 1)
a =
⟨S(S+1)2⟩ − S·(S + 1)
(2)
where ES and E(S+1) are the broken-symmetry DFT energies for
the S and S+1 spin states, respectively, obtained at UM06-L/
cc-pVTZ-g ∼ SMD level of theory. ⟨Ss2⟩ and ⟨S(s+1)2⟩ are the
expectation values of the square total spin momentum
obtained at the same level of theory for the S and S+1 spin
states, respectively. And Espin‑corr is the spin-corrected DFT
B
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Figure 3. Schematic representation of the ortho-defluorination-hydroxylation reaction mechanism (Path A) and the competing ortho-hydroxylation
reaction mechanism (Path B). The proton source in the final steps is HClO4 (0.5 M). In Path A, the source of the electrons of the last step is given
by an external reducing agent (ascorbate or Zn powder)11 or, in its absence, by an intermolecular decomposition of a second Cu2O2 complex.
Figure 4. (A) Relative stability (kcal·mol−1) of 1P/1° and 2P/2° computed at the DLPNO-CCSD(T)/cc-pVTZ ∼ SMD//M06-L/6−331G(d)
level. (B) Reactive 2° conformers for 2-fluorophenolate and 2,6-difluorophenolate (apical coordination) and 6-chloro-2-fluorophenolate (basal
coordination).
electronic energy. In this manner, the a parameter takes into
account the amount of spin contamination on the S state due
to the S+1 state.
of the ortho-defluorination-hydroxylation mechanism of 2-
fluorophenolate and 2,6-difluorophenolate promoted by 1
(Figure 3).
Furthermore, we investigated the chemo-selectivity that 1
exhibits on the C−F bond activation over C−H or C−Cl bond
activations for 2-fluorophenolate and 2-chloro-6-fluoropheno-
late. Therefore, a total of five different possible reaction paths
were studied (Figure 5).
The proposed mechanism of ortho-defluorination-hydrox-
ylation of 2-fluorophenolate compounds performed by 1
presents two principal steps (Figure 3). The first main step
is the electrophilic attack of the [Cu2O2]2+ core to the aromatic
ring, which implies the pyramidalization of the attacked
carbon. This C−X activation can occur at each of the two
phenolate ortho positions, giving two possible reaction paths,
Path A or Path B, which will be indicated using either A or B
subscripts in the name of the intermediates and TSs. The
second main step is given by the rearomatization of the
substrate that leads to the catechol product either by the
transfer of the halogen to one of the metals (Path A, ortho-
defluorination-hydroxylation reaction) or through the proton
abstraction by the remaining oxygen atom of the core (Path B,
ortho-hydroxylation). Path A has some important differences
ORCA 4.1.0 software package46 was used for the domain-
local pair natural orbitals coupled cluster with singles, doubles,
and perturbative triples, DLPNO-CCSD(T), single-point
energy calculations, together with the cc-pVTZ basis set
(and cc-pVTZ as auxiliary basis) and SMD solvent corrections.
Tight PNO cutoffs were set for the transformation of the
orbitals into the DLPNOs. A tight self-consistent field (SCF)
criterion was set for the convergence of the SCF and the
coupled cluster (CC) iterations.
The values of T1 diagnostic of all DLPNO-CCSD
calculations were always lower than 0.024, indicating that
most of the correlation energy is captured by the DLPNO-
CCSD(T) method. Therefore, there is no evidence of
requiring multireferential calculations to obtain a good
description of the studied species.
RESULTS AND DISCUSSION
■
To address the questions described at the end of the
Introduction, we performed a detailed computational study
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with respect to the mechanism of defluorination-hydroxylation
of hexafluorobenzene catalyzed by a μ-nitrido diiron
phthalocyanine complex. In the latter case a ketone
intermediate is formed after a 1,2-fluoride shift, and only one
transition metal is involved in the C−F activation.21 However,
in both defluorination-hydroxylation mechanisms the rear-
omatization of the ring plays a key role.
have the proper symmetry to form an apical bond. Therefore,
combination of the dz of the Cu(III) and one lone pair of the
2
halogen leads to a nonbonding covalent interaction. However,
there exists a noncovalent attractive interaction between the
halogen and the Cu(III), as it can be seen in attractive
interaction isosurfaces generated by the NCIPLOT47,48
program based on the real-space analysis of the reduced
density gradient (see Figure 6 and the Supporting
Information).
Along with the aforementioned Cu−X interaction, the C−X
bond is slightly elongated (from 1.35 to 1.38 Å). This key
attractive interaction does not exist for the attack at position 6
of 2-fluorophenolate, because the proton obviously does not
have a lone pair to interact with the Cu(III). Therefore, for the
competing C−H ortho-hydroxylation reaction intermediate 3H
does not exist.
1 is formed in situ by the reaction of [CuI(DBED)-
(CH3CN)]1+ and atmospheric oxygen.11 Although the most
stable isomer is the species 1P, this compound may be in
equilibrium with its bis(μ-oxo)dicopper(III) isomer, 1°. The
first requirement to elucidate the reaction mechanism is to
determine which is the actual reactive species, 1P or 1°.
Spectroscopic monitoring of the reaction of 1P with
fluorophenolates (vide infra) reveals that it proceeds via an
initial phenolate binding to one of the copper atoms.
Consequently, using 2-fluorophenolate as a model substrate,
we computed the relative Gibbs energies of P and O isomers
either without (1P/1°) or with (2P/2°) 2-fluorophenolate
coordinated to the complex at the DLPNO-CCSD(T)/cc-
pVTZ ∼ SMD//M06-L/6−331G(d) level of theory. In the
absence of substrate, the 1P species is 4.1 kcal·mol−1 more
stable than 1°. However, upon substrate coordination, this
behavior is reversed, and 2° becomes 3.6 kcal·mol−1 more
stable than 2P (Figure 4A). These results are in line with those
previously described by Stack and co-workers, indicating that
conversion to the O isomer occurs when P coordinates to a
phenolic substrate.12
For all substrates, the next step of the reaction is an
electrophilic attack of the [Cu2O2]2+ core to the aromatic ring.
This attack is ruled by the electrophilic character of the Cu,
and therefore it is particularly favored in the bis(μ-oxo)-
dicopper(III) 2° isomer compared to the (η2:η2-peroxo)-
dicopper(II) 2P species (see Supporting Information for
details). The highest occupied molecular orbital (HOMO) of
the intermediate 3 is mainly located over the arene, which
agrees with its nucleophilic character, while the lowest
unoccupied molecular orbital (LUMO) is an antibonding
orbital mainly placed on the [Cu2O2]2+ core, which agrees with
its electrophilic character (Figure 7). In the transition state of
this step, which corresponds to the rate-determining step (rds)
of the reaction, the C−X (TS1A) or C−H (TS1B) bond is
elongated, while the C−O distance is shortened, and the
attacked carbon of the aromatic ring is pyramidalized. The
apical attack of the [Cu2O2]2+ on the arene cannot be
explained only with the participation of the HOMO and
LUMO, and, for instance, the apical attack to the 2,6-
difluorophenolate requires the participation of the HOMO−2
and LUMO+2 orbitals (Figure 7).
To confirm the electrophilic nature of the attack of the
Cu2O2 over the aromatic ring, a Hammett plot was
experimentally determined (Figure 8). Compound 1P was
generated at −80 °C in Me-THF (THF = tetrahydrofuran)
upon reaction of the copper(I) precursor [Cu(DBED)-
(CH3CN)]+ with O2. This process was monitored by UV−
vis spectroscopy. Once 1P was fully formed, the temperature
was lowered to −110 °C, and the appropriate amount of
sodium 2-fluoro-4-Y-phenolate (Y = Cl, F, H, CH3) was added.
This resulted in the formation of the corresponding 2° species,
in which the bis(μ-oxo) core is bound to the phenolate. The
experimental characterization of 2° was solely done by
comparison of the UV−vis spectra with those of analogous
species previously generated for m-XYLMeAN systems11 and
taking into account that analogous species have been
experimentally detected for the DBED system with 2-tert-
butyl-4-Y-phenolates.12 Decay of the UV−vis spectroscopic
features of 2° showed a first-order kinetics and could be
adjusted to a single exponential function. The decay rate (k)
was dependent on the nature of the para-substituent Y. Thus,
plotting the logarithm of the decay rate (k) as a function of the
Hammett parameter of the para-substituent (σp) resulted in a
linear correlation with a negative slope (ρ = −3.5, Figure 8)
indicative of an electrophilic attack over the aromatic ring,
which agrees with the proposed mechanism based on
Thus, the DLPNO-CCSD(T) single-point calculations agree
with the experimental observation that, when the Cu2O2
species is generated by reaction of the copper(I) precursor
[CuI(DBED)(CH3CN)]+ with O2, the main isomer is 1P.
However, upon addition of the phenolic substrate in the
reaction mixture, the equilibrium is shifted toward 2°.
Therefore, we placed the focus of our study on the 2° species,
although both 2° and 2P isomers were considered as possible
active species of the reaction mechanism.
It is worth highlighting that, for all fluorophenolate
substrates studied, both apical and basal coordination motifs
(with respect to the N2CuO2 plane) were explored and that, in
all cases, the former was the most stable. However, for the
particular case of the attack over the position 6 of 6-chloro-2-
fluorophenolate (Figure 5), we were only able to find the
Figure 5. Five possible attacks studied in this manuscript over 2-
fluorophenolate, 2,6-difluorophenolate, and 6-chloro-2-fluoropheno-
late.
transition state corresponding to the electrophilic attack for the
isomer presenting basal coordination (Figure 4B). In this case,
the activation barrier corresponding to the C−F activation, the
reaction observed experimentally, is smaller than the barrier
associated with a hypothetical C−Cl cleavage, which therefore
is irrelevant.
The first step of the reaction corresponds to a noncovalent
attractive interaction between the reactive halogen (F or Cl)
with the less coordinatively saturated Cu, giving intermediate
3. Within crystal field theory, for a square-planar Cu(III)
2
2
center, all d orbitals are occupied but the dx −y , which does not
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Figure 6. Two different views of the noncovalent attractive interaction isosurfaces generated by NCIPLOT for the 3FF intermediate.
Figure 8. Experimental Hammett plot.
theoretical calculations. The calculated free-energy profile of
the different mechanisms studied is shown in Figure 9.
The intermediates 4A (Figure 9) of Path A contain a
dearomatized ring presenting one nearly sp3 carbon bound to
both the reactive oxygen from the [Cu2O2]2+ core and the
halogen. This halogen (either Cl or F) is strongly interacting
with the closest Cu. For the attack at position 6 of 2-
fluorophenolate (Path B), the intermediate 4B is generated
(Figure 9). This intermediate presents also one nearly sp3
carbon, but in this case, it is bound to the reactive oxygen from
the [Cu2O2]2+ core and one proton. The main difference of 4B
with respect to 4A is that the proton cannot interact with the
Cu(III), ultimately determining the reactivity of 4B. Neither 4A
nor 4B are stable intermediates and quickly rearomatize and
evolve to the final product. For Path A, such a product (5A) is
obtained through a halogen transfer from the aromatic ring to
the metal. Because of the inclusion of the entropic and thermal
corrections, the Gibbs energy barriers of the halogen transfers
are close to zero or even negative, indicating that this step is a
barrierless process. Interestingly, for the attack at the chlorine
position of 2-chloro-6-fluorophenolate, the intermediate 4A
does not exist, and TS1A evolves directly to products in a
Figure 7. Molecular orbital energy diagram of the six frontier orbitals
of 2F. Copper complex simplified for clarity.
E
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Figure 9. Calculated free-energy profiles at the UM06-L/cc-pVTZ-g ∼ SMD//UM06-L/6-311G(d) level of theory for 2-fluorophenolate (top),
2,6-difluorophenolate, and 6-chloro-2-fluorophenolate (bottom) substrates. Gibbs free energies (G, in kcal·mol−1) are relative to 2°.
concerted asynchronous manner (confirmed by IRC calcu-
lations).
[Cu2O2]2+ core forming an OH group. In the transition state of
this step (TS2B) the substrate rearomatizes. To do so, the
nearly sp3 carbon formed in the previous step has to become
sp2 again, releasing the proton. This proton is very close in
space to the remaining O of the [Cu2O2]2+ core to which it
ultimately will be transferred (Figure 9, top). The formation of
the final product 5B is highly exergonic (i.e., ΔG = −60.9 kcal·
mol−1).
For the alternative ortho C−H oxygenation, the mechanism
homologous to Path A would lead to a Cu−H species, which
has not been experimentally detected. Computationally, for 2-
fluorophenolate, the formation of the copper hydride is
endergonic by 15 kcal·mol−1. Instead, the Path B mechanism
leads to a kinetically and thermodynamically favorable pathway
for the ortho-hydroxylation of the 2-halophenolates. This path
differs from Path A at intermediate 4B, which suffers a quasi-
barrierless proton transfer to the remaining oxygen of the
The computed energy barriers (ΔG‡) determined by TS1,
from lowest to highest, are 9.3 kcal·mol−1 for the C−F
activation of 2-chloro-6-fluorophenolate, 11.7 kcal·mol−1 for
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the C−F activation of 2,6-difluorophenolate, 14.5 kcal·mol−1
for the C−F activation of 2-fluorophenolate, 15.5 kcal·mol−1
for the C−H activation of 2-fluorophenolate, and 15.6 kcal·
mol−1 for the C−Cl activation of 2-chloro-6-fluorophenolate.
These DFT barriers are in full agreement with observed
chemoselectivities. The attack on fluoride instead of chloride in
2-chloro-6-fluorophenolate is 6.3 kcal·mol−1 more favorable,
which is in concordance with the fact that experimentally only
the ortho-defluorination is observed.11 For case of 2-
fluorophenolate substrate, for which both Path A and Path B
are possible, the attack on C−F (Path A) is 1 kcal·mol−1 more
favored compared with the attack on C−H (Path B), again in
reasonable agreement with the fact that both products are
obtained, although the ortho-defluorination is the major
reaction (18:1 C−F vs C−H oxygenation, 38% total yield).
The precision of the computed reaction barriers was
checked by experimentally measuring the decay rate of 2°
formed in the reaction of 1P with sodium 2,6-difluorophenolate
at different temperatures via an Eyring plot analysis (see
Supporting Information for details). The experimentally
targeted TS1A. Although O2 is not properly located to react
with the aromatic ring, we also performed a second linear
transit calculation, where the O2 approached the C of the C−F
bond.
However, in this relaxed scan the energy rises ∼40 kcal·
mol−1 without finding a structure similar to that of TS1A.
These two linear transit calculations further suggest that only
bis(μ-oxo) isomers are able to perform the C−F activation,
and then 2P should evolve to 2° in order to perform the
electrophilic attack.
Our results also give theoretical insight about why some
49
compounds such as [CuIII2(O)2(m-XYLMeAN)]2+
and
[CuII (O2)(DBED)2]2+ (1) are able to perform ortho-
2
defluorination-hydroxylations, whereas [CuII (O2)(LPy2Bz)2]2+,
2
which has been previously reported by Itoh,14 does not show
this chemistry. Our computations suggest that ortho-defluori-
nation-hydroxylation reactions can only be performed by O
isomers, which is the most stable species of [CuIII2(O)2(m-
XYLMeAN)]2+ and 2. On the contrary, the P isomer, which is
the only populated stable isomer of [CuII (O2)(LPy2Bz)2]2+, is
2
derived ΔG‡ is 11.8 0.6 kcal·mol−1, which is in excellent
unable to activate the C−F bonds of the aromatic rings. These
computational results are in full concordance with the known
reactivity of tyrosinase; 2-fluorophenolates are known inhib-
itors of oxytyrosinase, which has been spectroscopically
characterized as a pure P species. The corresponding O
isomer has never been detected and is computed to be at least
23 kcal·mol−1 higher in energy.29
exp
agreement with the aforementioned computed ΔG‡ = 11.7
calc
kcal·mol−1. Indeed, the difference between the experimental
and theoretical ΔG‡ is far lower than the DFT or experimental
errors.
Once the reactivity for the bis(μ-oxo) catalyst was
understood, we computationally analyzed whether the η2:η2-
peroxospecies could present the same reactivity. We performed
linear transit calculations starting from 2P and explored the
electrophilic attacks from both oxygens to the aromatic ring at
UM06-L/6-311G(d) level.
CONCLUSIONS
■
In this manuscript we have explored the reaction mechanism of
the ortho-dehalogenation-hydroxylation of 2-fluorophenolates
by combining computational methods and experiments. By
using high-level DLPNO-CCSD(T) calculations we have
reproduced the experimental description of [Cu2O2-
(DBED)2]2+ (1), for which there is an equilibrium between
P and O isomers, shifted toward O upon substrate
coordination. Our coupled cluster and DFT calculations
revealed that O is the real executor of the ortho-
defluorination-hydroxylation, as it was previously suggested.11
This fact explains why Cu2O2 complexes for which only the P
isomer is stable are unable to perform defluorination-
hydroxylation reactions, and it also suggests a plausible reason
why tyrosinase is inhibited by 2-fluorophenols.
The energy profiles presented in Figure 10 were obtained
performing relaxed potential energy surface (PES) scan
The full reaction mechanism was determined for three
substrates (2-fluorophenolate, 2,6-difluorophenolate, and 2-
chloro-6-fluorophenolate) exploring attacks of the Cu2O2 core
at the 2 and 6 positions. Thus, we took into account also the
possibility of having a competing hydroxylation over a C−H
bond (Path B). In all cases, the attack of one oxygen of the
[Cu2O2]2+ core over the arene was the rate-determining step,
while the second step was barrierless or quasi-barrierless. This
result reproduces the experimental observation of the
phenolate-Cu2O2 adduct as the last spectroscopically detect-
able intermediate.
Figure 10. Schematic representation of linear transit calculations
starting from 2P using C−O1 (green) and C−O2 (red) distances as
reaction coordinate. DBED ligand omitted for clarity.
calculations with respect to Csp2−O distances. Both linear
transits were targeting a transition state equivalent to TS1A. At
this level of theory, species 2P is 7.0 kcal·mol−1 higher in
energy than 2°, preserving the DLPNO-CCSD(T) trends.
In the first linear transit calculation, the O1 approaches the
C of the C−F bond. At the beginning of the relaxed scan the
electronic energy increases ∼10 kcal·mol−1. However, at the
O1−C bond distance of 2.27 Å, there is a significant drop in
energy corresponding to the isomerization from distorted 2P to
2°. As discussed above, 2° may evolve until reaching the
The electrophilic character of the rate-determining step was
elucidated by means of an experimental Hammett plot.
Analysis of the frontier molecular orbitals for the substrates
further confirm the electrophilic nature of the reaction.
An Eyring plot experiment for 2-fluorophenolate as substrate
showed full agreement with calculations (ΔG‡ = 11.8 kcal·
exp
mol−1; ΔG‡ = 11.7 kcal·mol−1). The experimental chemo-
calc
selectivity was rationalized on the basis of relative activation
energy differences between C−F, C−H, and C−Cl activations.
G
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Article
In all cases, the ortho C−F bond is kinetically preferred over
the other possible ortho bond (either C−Cl or C−H)
explaining the observed chemoselectivity for the [Cu2(O)2-
(DBED)2]2+ catalyst.
cowrote the manuscript. All authors contributed to the analysis
of the results, and they all gave approval to the final version of
the manuscript. P.B.-S. and C.M. contributed equally to this
work.
The identification of the O isomer as the active species and
the rationalization of the chemoselectivity that [Cu2O2]2+
species present over specific substrates may facilitate the
design of more efficient systems, eventually catalytic, and may
also broaden their scope of applications.50−53 Because of the
bioinspired nature of such catalysts, they can be understood as
simplified (bio)models, and therefore their relatively easy study
and understanding is also helpful to acquire greater knowledge
on the behavior of bigger systems such as the ubiquitous
copper-based metalloproteins.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported with funds from the Spanish
government MICINN (PGC2018-098212-B-C22 to J.M.L.,
PGC2018-101737-B-I00 to M.C., CTQ2016-77989-P to A.C.)
and the Generalitat de Catalunya (2017SGR39 to J.M.L., 2017
SGR 00264 and ICREA Academia to M.C. and A.C.). We
thank the Spanish Government for the predoctoral grant to
P.B.-S. (FPU17/02058). We are also grateful for the
computational time financed by the Consorci de Serveis
Universitaris de Catalunya.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c02246.
■
sı
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AUTHOR INFORMATION
Corresponding Authors
■
Miquel Costas − Institut de Química Computacional i Catàlisi
and Departament de Química, Universitat de Girona, 17003
Girona, Catalonia, Spain; orcid.org/0000-0001-6326-
8299; Email: miquel.costas@udg.edu
Anna Company − Institut de Química Computacional i
Catàlisi and Departament de Química, Universitat de
Girona, 17003 Girona, Catalonia, Spain; orcid.org/
0000-0003-4845-4418; Email: anna.company@udg.edu
Josep M. Luis − Institut de Química Computacional i Catàlisi
and Departament de Química, Universitat de Girona, 17003
Girona, Catalonia, Spain; orcid.org/0000-0002-2880-
8680; Email: josepm.luis@udg.edu
Authors
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Catàlisi and Departament de Química, Universitat de
Girona, 17003 Girona, Catalonia, Spain; orcid.org/
0000-0002-0955-9762
́
Carla Magallon − Institut de Química Computacional i
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Girona, 17003 Girona, Catalonia, Spain; orcid.org/
0000-0001-6425-5238
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.0c02246
Author Contributions
‡P.B.-S. performed all the calculations, C.M. carried out all the
experiments, and both wrote the first draft of the manuscript.
M.C., A.C., and J.M.L. designed and supervised the project and
H
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