A competing, dual mechanism for catalytic direct benzene hydroxylation from combined experimental-DFT studies

Article abstract of DOI:10.1039/c7sc02898a

A dual mechanism for direct benzene catalytic hydroxylation is described. Experimental studies and DFT calculations have provided a mechanistic explanation for the acid-free, Tp^xCu-catalyzed hydroxylation of benzene with hydrogen peroxide (Tp^x = hydrotrispyrazolylborate ligand). In contrast with other catalytic systems that promote this transformation through Fenton-like pathways, this system operates through a copper-oxyl intermediate that may interact with the arene ring following two different, competitive routes: (a) electrophilic aromatic substitution, with the copper-oxyl species acting as the formal electrophile, and (b) the so-called rebound mechanism, in which the hydrogen is abstracted by the Cu-O moiety prior to the C-O bond formation. Both pathways contribute to the global transformation albeit to different extents, the electrophilic substitution route seeming to be largely favoured.

Full text of DOI:10.1039/c7sc02898a

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A competing, dual mechanism for the catalytic direct benzene
hydroxylation from combined experimental-DFT studies
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
,c
,b
,a
Laia Vilella, Ana Conde, David Balcells,* M. Mar Díaz-Requejo,* Agustí Lledós,* and Pedro
DOI: 10.1039/x0xx00000x
,b
J. Pérez.*
www.rsc.org/
A dual mechanism for the direct benzene catalytic hydroxylation is described. Experimental studies and DTF calculations
x
have provided a mechanistic explanation for the acid-free, Tp Cu-catalyzed hydroxylation of benzene with hydrogen
x
peroxide (Tp = hydrotrispyrazolylborate ligand). In contrast with other catalytic systems that promote this transformation
through Fenton-like pathways, this system operates through a copper-oxyl intermediate that may interact with the arene
ring following two different, competitive routes: (a) the electrophilic aromatic substitution, with the copper-oxyl species
acting as the formal electrophile, and (b) the so-called rebound mechanism, in which the hydrogen is abstracted by the Cu-
O moiety prior to the C-O bond formation. Both pathways contribute to the global transformation albeit at different
extent, the electrophilic substitution route seeming largely favoured.
from a practical point of view is that of the direct benzene
Introduction
hydroxylation toward phenol, for which a number of systems
1
Phenol is a raw material for a large number of chemicals and
it is prepared at the industrial scale by means of the so-called
2
cumene process. It consists in a three step overall procedure
in which benzene and propylene are converted first into
cumene, which is further oxidized into cumyl hydroperoxide en
route to acid-induced decomposition into acetone and phenol
(Scheme 1). The instability of the peroxide intermediate as
well as the formation of stoichiometric, low-valued acetone
are the major drawbacks of this process. One of the most
interesting transformations yet to be efficiently developed
3
have been reported. Several oxidants have been employed,
4
5
such as molecular oxygen, dinitrogen oxide and hydrogen
peroxide, the latter being, by far, the most employed in the
6
plethora of contributions described toward that end.
Unfortunately, most of them are yet far from being practical
from an industrial point of view.
7
We have previously reported a copper-based catalyst
8
containing a trispyrazolylborate type ligand that induced the
hydroxylation of benzene with high selectivity toward phenol
2 2
(Scheme 2), with H O as the oxidant and in the absence of
acids. Further work from our laboratories also showed the
3
catalytic capabilities of this system to oxidize the Csp -H bonds
of alkanes as well as to promote their oxidative
9
dehydrogenation (Scheme 2). We are interested in the study
of the mechanisms of these transformations, given our
experience with the somewhat related carbene (from
1
0
11
diazocompounds)
and nitrene (from iminoiodonanes)
transfer reactions from coinage metal-based catalysts. Those
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Journal Name
7
M=X moieties (X = carbene or nitrene, Scheme 3) are well In our preliminary communication, the catalytic conversion of
established as intermediates in those functionalization benzene into phenol with hydrogen peroxide as oxidant was
9
processes. In our alkane oxidation catalytic system, the described to proceed in the presence of complexes of type
x
presence of [Tp Cu=O] species was also proposed, based on Tp Cu(NCMe) (Scheme 2) and in the absence of acids. For
x
*,Br
experimental data and theoretical calculations. The latter instance, Tp Cu(NCMe) provided 92% of selectivity into
showed that the electronic structure of this species is closer to phenol and 8% in benzoquinone, with sulfolane as an additive
•
a Cu(II)-O oxyl configuration, with radical character on (82% in phenol without sulfolane: the use of sulfolane
oxygen, than to a closed-shell Cu(III)=O oxo. On the other decreases overoxidation of phenol upon protection through
hand, the arene oxidation reaction with hydrogen peroxide is hydrogen bond formation) for 25-30% conversion of benzene
well-known to proceed through the so-called Fenton at 80 °C. Once we had established the viability of these copper-
1
2
chemistry, where the role of the metal center stands on the based complexes for the target reaction, we focused on the
generation of radical species that trigger the C-H oxidation study of the mechanism of this transformation. We first
reaction. The generation of hydroxyl radicals (•OH) capable of collected information regarding the possible generation of
oxidizing the arene ring has been known since the last •OH radicals in the reaction mixture containing the
1
3
x
century, and is still subject of studies. For instance, a recent Tp Cu(NCMe) catalyst, following Fenton chemistry. One typical
1
4
contribution by Karlin, Fukuzumi and co-worker has shown
2
+
the ability of [Cu(tmpa)] (tmpa = tris(2-pyridylmethyl)amine)
to induce the direct hydroxylation of benzene by means of
Table 1. Effect of additives in the reaction of benzene and H
Tp* Cu(NCMe) as the catalyst.
2
O
2
using
,Br
a
2 2 2
generating free HO • radicals from H O , that interact with the
arene. Herein we report a mechanistic study on the benzene
x
hydroxylation reaction with Tp Cu(NCMe) as the catalyst to
verify whether this transformation occurs via a Fenton-like
b,c
b,d
Entry
1
Additive
None
% Conversion
8.5
PhOH:BQ:Ph-X
6%:2.5%:0
(70:30:0)
2
CCl
4
9
6%:2.5%:0.5%
67:28:5)
(
e
3
CBrCl
3
8.5
6.8%:1.3%:0.4%
80:15:5)
, 1 mmol; H
CN; 0.5 mL of radical
trap. Values determined by GC using cycloheptanone as internal
(
a
Reaction conditions: catalyst, 0.01 mmol; C
6
H
6
2 2
O , 1.5
mmol; temp = 80 °C; time = 4h; 2.5 mL of CH
3
b
c
d
standard. As percentage of initial benzene consumed. Yields and ratio
of products. o-Br-phenol is also detected in ca. 8 % from oxidation of
e
the bromobenzene formed. (see ESI, Figs. S2 and S3).
observation in these reactions is the formation of bis-aryl
13
derivatives, derived from homocoupling of aryl radicals. In
pathway or through Cu-oxyl species en route to oxygen
transfer to benzene. Experimental and theoretical data
presented in this work has allowed not only proposing the
latter, but also the unprecedented feature of the co-existence
of two competing pathways from that Cu-oxyl intermediate:
our case, we have not detected, by GC studies with the
reaction mixtures, any biaryl compound when using benzene
or toluene as substrates (Scheme 4a).
A previous report by Marusawa, Tezuka and co-workers
17
demonstrated that the distribution of cresols derived from
1
5
an electrophilic aromatic substitution pathway and the so-
1
6
called rebound route, where a hydrogen atom transfer takes
place, the former being more favored in the overall
transformation.
photolytically generated •OH radicals and toluene was 71:9:20
9
for o:m:p-isomers, respectively. We have previously reported
x
that the oxidation of toluene with Tp Cu(NCMe) yielded a ratio
of 61:0:39 (accounting the benzoquinone derivatives from
their respective cresol precursors, Scheme 4b), a somewhat
distinct ratio from that based on the involvement of •OH
radicals.
Results and Discussion
x
Benzene oxidation induced by Tp Cu(NCMe): experimental
data to evaluate Fenton-like pathways
2
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A third piece of information comes from competition methylphenol (BHT) was excluded since they were also
experiments with protio- and deutero-benzenes (Scheme 4c), oxidized under the reaction conditions, due to the presence of
from which a relatively low kinetic isotopic effect k
be obtained as 1.12 0.01. The k /k overoxidation reaction of The use of Oxone®, an oxidant based on KHSO
a mixture of phenol-H and phenol-D has also been similar result in the reaction of benzene and such reactant in
determined as 0.98 0.01, thus the above value is not the presence of catalytic amounts of Tp Cu(NCMe) (Scheme
H D
/k could aromatic or aliphatic C-H bonds.
±
H
D
5
, has led to a
6
6
*,Br
±
influenced by the subsequent oxidation reaction. For Fenton- 4d). It is generally accepted that no radicals are involved in
type hydroxylations, KIE values of ca. 1.7 are frequently such oxidation, with a metalloxo intermediate being usually
1
8
20
reported.
proposed as intermediate.
In an effort to check the involvement of radical species, a Effect of substituents in the benzene ring in the oxidation
series of experiments were run in the presence of a radical reactions
trap. As it is shown in Table 1, the experiment in the absence We have also carried out a series of experiments with several
of such additives gave 8.5% of benzene conversion with ca. substituted benzenes bearing electron-withdrawing or electron-
2
7
0% selectivity toward phenol. The presence of CCl
4
or CBrCl
3
donating groups, to assess their effect on the Csp -H bond oxidation
x
did not affect such results, since both benzene conversions reaction catalyzed by Tp Cu(NCMe) complexes, with hydrogen
and phenol selectivity were found within a narrow interval in peroxide as the oxidant. When R-C were employed as
6 5
H
all cases. However, within the total amount of oxygenated substrates, mixtures of products were obtained (Table 2), in most
products, a ca. 5% of chloro- or bromobenzene were formed, cases consisting of the three X-substituted phenols (in different
referred to 95% of phenol and benzoquinone (entries 2 and 3 ratio) as well as the ortho-substituted benzoquinone. With toluene,
•
19
in Table 1) suggesting the formation of the C
6
H
5
radical at as previously shown (Scheme 4b), the product derived from the
oxidation of the methyl group was also observed. The study was
any stage of the catalytic process (blank experiments in the
*,Br
absence of catalyst did not show such amounts of performed with two copper complexes as catalysts, Tp Cu(NCMe)
Br3
halobenzenes). In the cyclohexane oxidation with these and Tp Cu(NCMe). Table 2 displays the values of the yields of each
9
catalysts, we found nearly complete trapping of the product, from which a general trend is extracted: arenes with
corresponding cyclohexyl radical (97% of the products). From electron donating groups as substituents are more prone to react
this difference, it seems that the main path in the benzene than those bearing electron withdrawing groups. We have
hydroxylation reaction is not that based on the generation of employed those values of reactivity to build Hammett-like plots
phenyl radicals, albeit their presence in the reaction mixture (Figure 1), albeit data do not correspond to competition
must be explained when proposing a mechanistic picture. The experiments, that due to the very low conversions observed (<5%),
use of radical inhibitors such as TEMPO or 2,6-di-tert-butyl-4- do not provide good quality data toward such purpose. Thus, the
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H
/P corresponds to the yields of all hydroxylation products vs
Journal Name
ratio P
that of benzene, in what we consider an estimation of the relative The nuclearity of the active species
reactivity of the whole arene. The ρ values obtained from fitting The activation of dioxygen by copper complexes bearing
x
,
Br
Br3
22
were -0.75 and -1.1 for Tp* Cu(NCMe) and Tp Cu(NCMe), trispyrazolylborate ligand has been extensively studied. Kitajima
2
3
respectively. With the above restrictions in mind, we interpret the and co-workers pioneered this area, showing that two copper
negative value as the consequence of an electrophilic intermediate centers were involved in the activation of O . In a previous report
with a certain positive charge that is respectively stabilised or from these laboratories we also found that a series of Tp Cu
destabilised with donor or acceptor groups in the benzene ring. complexes reacted with dioxygen and carbon dioxide in
2
x
a
2
1
Visser, Nam and co-workers have described negative ρ values for consecutive sequence leading to dinuclear carbonato-bridged
the aromatic hydroxylation reaction where and oxo-iron complexes. Thus, we wondered about a possible implication of
2
4
intermediate is involved. Although they found a much larger effect
of the substituents (ρ = -3.9), we believe that our data (that are not
obtained from pure competition experiments from substrates), in
conjunction with the other pieces of information, points toward
Table 2. Effect of substituents in the benzene ring in the oxidation
,
Br
Br3
a
reactions using Tp* Cu(NCMe) and Tp Cu(NCMe) as catalysts.
b,c
b
b
b
b
R
Conversion
P1%
P2%
P3%
P4%
NMe
2
22%
73
-
7%
-
27
-
OMe
9.5%
14%
72
18.6
20.6
38
2.4
d
Me
31.2
38
23.2
Cl
5.9%
4.8%
1.4%
3%
-
24
-
CO
2
Me
27.5
8.5
19
31
41.5
39.1
53
CF
3
52.4
28
-
NO
2
-
b,c
b
b
b
b
R
NMe
Conversion
31.5%
9.33%
12.5%
6.03%
1.96%
1.2%
P1%
P2%
P3%
P4%
2
48
-
52
-
OMe
61
12.3
-
16
10.7
d
Me
22.7
29
17.8
32
34.5
Cl
-
39
-
CO
2
Me
18
36
60.5
41
46
CF
3
9.8
15
29.7
44
-
NO
2
0.9%
-
a
Reaction conditions: catalyst, 0.01 mmol; substrate 1 mmol; H
2
O
2
, 1.5
b
mmol; temp = 80 ⁰C; time = 4h; 3 mL of CH
3
CN. Values determined by GC
c
using cycloheptanone as internal standard. As percentage of initial
d
benzene consumed. Benzaldehyde is also detected in ca. 25 % from
oxidation of the toluene, for both catalysts.
fitting in the aromatic electrophilic substitution mechanism, where
a copper-oxyl species would act as electrophile attacking the
nucleophile arene ring
4
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dinuclear intermediates in the aromatic hydroxylation reactions In view of this dichotomy between two possible paths arisen from
described in this contribution, in spite of being performed with experimental data, we decided to study this reaction from a
hydrogen peroxide, and not with molecular oxygen. A series of theoretical point of view, as shown in the next section.
catalytic experiments of benzene oxidation were run varying the
*,Br
concentration of the catalyst (Tp Cu(NCMe)) from 1.66 mM to
.66 mM. As shown in Figure 2, a linear dependence was observed,
Computational Studies: Electrophilic aromatic substitution on
benzene
6
assessing a first-order dependence in catalyst concentration. In With the aim of providing a better understanding of the benzene
-1
addition, TOF values of 2.4 h were found for the experiments oxidation process and rationalizing the experimental observations,
carried out with 3.33 mM and 6.66 mM in catalyst. The observance
of this TOF value independent of the concentration of catalyst
supports the proposal of a mononuclear species as the catalytically
relevant in this process.
a computational study of the reaction mechanism was performed at
the Density Functional Theory (DFT) level (see ESI for details). We
have first computed the interaction of benzene and the copper-oxyl
*,Br
•
species Tp Cu-O , the reaction pathway shown in Figure 3. Once
the oxyl is formed from the catalyst and hydrogen peroxide, which
The mechanism of the benzene hydroxylation reaction from
-1 9
is exoergic by -3.6 kcal mol , the first step, T-I1 → T-I2, involves
the addition of the substrate to the oxyl ligand. This reaction takes
place in the triplet state, which is the ground state of the copper-
2
5,26
oxyl species.
In the transition state, T-TS1 (Figure 3), the oxyl
binds to benzene (Table 3), d(C···O) = 1.89 Å (3.39 and 1.40 Å in T-I1
and T-I2, respectively), and remains bound to the metal centre,
d(Cu-O) = 1.80 Å (1.81 Å in T-I1 and T-I2, respectively). The
relaxation of T-TS1 by means of IRC calculations connected this
transition state to intermediates T-I1 (reactant) and T-I2 (product).
In T-I1, benzene is associated to the oxyl through a weak hydrogen
bond; d(CH···O) = 2.58 Å. Due to the entropy penalty, this
intermediate is almost isoenergetic with the starting reactants. In T-
I2, the substrate appears bound to copper through the oxyl. This
2
7
species can be described as a Wheland intermediate due to its
zwitterionic nature, with the copper-oxyl and benzene fragments
negatively and positively charged, respectively; q = q(C H ) = –
6
6
*,Br
q(Tp CuO) = 0.29. In line with this, electron density is transferred
*,Br
6 6
from the C H fragment to Tp CuO as the system evolves from T-
experimental data
I1 (q = 0.00) to T-TS1 (q = 0.18). This charge redistribution and the
nature of T-I2 are consistent with an electrophilic aromatic
substitution (EAS) mechanism, in which the aromatic ring acts as
Based on the above data, any mechanistic interpretation for the
x
Tp Cu-catalyzed hydroxylation of benzene and its derivatives should
account with the following: (a) the lack of formation of •OH or
the nucleophile. The loss of aromaticity is reflected on the Cipso
-
2 2
other H O -derived free radicals; (b) the involvement of copper-oxyl
C
ortho distance, which elongates from 1.39 Å (T-I1) to 1.50 Å (T-I2).
species; (c) the formation of intermediates that resemble the
electrophilic aromatic substitution mechanism (based on the effect
of the substituents) and (d) the presence of phenyl radical (albeit at
a very low extent). Scheme 5 shows a plausible general picture in
agreement with the above requirements. The interaction of the
-1
The formation of T-I2 is endoergic, ꢀG = 1.6 kcal mol , and involves
a significant energy barrier, ꢀG = 20.2 kcal mol
‡
-1
.
The data given in Table 4 reflect the spin density redistribution
along the triplet state stage of the reaction pathway. In the initial
addition step, the evolution of the local spin densities from T-I1
x
x
•
Tp Cu core with H
2 2
O leads to the Tp Cu-O species, that was found
x
(
ρ(O) = 1.11, ρ(C
6
H
6
6 6
) = 0.00) to T-I2 (ρ(O) = 0.14, ρ(C H ) = 0.95)
to be more feasible than hydroperoxo Tp Cu-OOH or superoxo
x
2
9
shows that one of the π electrons of benzene pairs with the single
electron on oxygen (oxyl) yielding the C-O bond. The spin density
plot of the addition transition state, T-TS1 (Figure 4), shows the
pairing of α and β electron densities along the incipient C•••O
bond. The metal centre does not participate in this electron
rearrangement, as shown by the high but invariant values of ρ(Cu)
2
Tp Cu(η -O ) alternatives. Such copper-oxyl intermediate may
react with benzene throughout the so-called rebound route in
which a hydrogen atom is abstracted from benzene, two radical
species being originated. These short-lived radicals collapse upon
forming a C-O bond leading to phenol. This path would explain the
observance of small amounts of halobenzenes when the reaction is
*,Br
on T-I1, T-TS1 and T-I2. A similar role is played by the Tp ligand,
carried out in the presence of CCl
4 3
or CBrCl . The second path
which has low but also invariant
ρ
values, consistent with a redox-
corresponds to an electrophilic substitution, the copper-oxyl
intermediate, electrophilic in nature, attacking the arene ring with innocent behaviour.
the concomitant formation of a Wheland-intermediate, from which
phenol is finally delivered.
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Journal Name
calculations revealed that these species are higher in energy in the
-1
singlet (47.9, closed-shell, and 53.7, open-shell, kcal mol for S-I2)
-1
and triplet (57.9, open-shell, kcal mol for T-I3) states.
The comparison of MECP1 to T-I2 revealed two interesting features
in the former geometry; i.e. the C-O bond is shorter, 1.30 Å (1.40 Å
in T-I2), and the H bound to the ipso C is shifted towards the ortho
C, d(C-H) = 1.19 and 1.83 Å (1.10 and 2.10 Å in T-I2). The flow of
electron density along this spin crossover process takes place from
the organic fragment to the metal complex, q = q(C
6
H
6
) = –
*,Br
q(Tp CuO) = 0.29 (T-I2) and 0.74 (S-I3), which is consistent with an
Figure 4. Spin density plot of T-TS1 (left) and T-TS3 (right), both
2
8
EAS mechanism. MECP1 lies at a rather high energy level, 30.6 kcal
plotted at isovalue = 0.001. Color code: blue (α), green (β).
-1
mol above reactants. This energy may be lowered by factors not
considered in this model due to their complexity, including
tunneling and explicit solvation of the H transferred. Further, the
The generation of phenol from T-I2 (Figure 3) requires transferring
the hydrogen atom from the ipso carbon to oxygen. Despite low conversions observed experimentally in the oxidation of
benzene are consistent with high-energy reaction pathways.
numerous attempts, no transition state could be located for this
The optimization of MECP1 yielded T-I2 in the triplet state and S-I3
process. In contrast, the re-optimization of T-I2 in the singlet state
yielded cyclohexadienone as oxidation product. This suggested that in the singlet (Figure 3). In S-I3, 1,3-cyclohexadienone is formed and
1
triplet to singlet spin-crossover, which is needed to recover the coordinated to copper in a η -O fashion, d(Cu-O) = 2.06 and d(C-O)
Cu(I) catalyst in its ground state, may play a key role by triggering = 1.23 Å (Table 4). Triplet-to-singlet spin crossover is strongly
-1
the oxidation of the substrate. The minimum energy crossing point exoergic, with S-I3 lying 30.4 kcal mol below reactants (Figure 3).
MECP) associated with this process, MECP1 (Figure 3), was Cyclohexadienone decoordination and isomerization to phenol
(
-1
optimized. This point of the potential energy surface has the make the overall reaction exoergic by 44.1 kcal mol . The keto-enol
distinct property of having the same energy in the singlet and triplet tautomerization taking place in the last step has been well
2
9
states. The full optimization of MECP1 in the triplet and singlet characterized experimentally as an extremely fast and exoergic
states yielded intermediates T-I2 and S-I3, respectively. Single point process in polar solvents.
6
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It is noteworthy to mention that we also explored the activity of
superoxo (Figure S14) and hydroperoxo species (Figure S15) in the
benzene oxidation. The barriers associated to benzene oxidation by
-
1
Table 5. Energies, in kcal mol , and selected bond distances, in Å, for MECP1
in the EAS pathway with para-substituted Ph-X.
-1
the superoxo (32.8 and 41.4 kcal mol ) and hydroperoxo (47.3 kcal
-1
X
ꢀGMECP1
Cu-O
1.95
1.98
1.94
1.94
1.93
1.92
C
ipso-O
C
ipso-H
C
ortho-H
2.05
1.93
2.18
2.19
2.19
1.45
C
ipso-Cortho
C
ortho-O
2.38
2.41
1.91
1.86
1.83
2.42
mol ) species are all higher than that of the oxyl species (30.6 kcal
a
-1
-NMe
2
18.8
21.1
1.35
1.32
1.41
1.41
1.42
1.29
1.12
1.15
1.09
1.09
1.09
1.28
1.49
mol ; Figure 3). These results suggest that the superoxo and
b
-
OMe
1.48
hydroperoxo complexes are less reactive in the C−H oxidaꢀon of
-
Me
Cl
CF
27.4
29.2
33.4
31.6
1.47
-
1.47
-
3
1.47
-
NO
2
1.46
Table 3. Selected bond distances, in Å, for the species involved in the EAS
pathway.
a
-1 b
1
mol .
7.3 (ortho) and 19.6 (meta) kcal mol ; 21.0 (ortho) and 22.8 (meta) kcal
-1
Species
T-I1
Cu-O
1.81
1.80
1.81
1.97
2.06
C
ipso-O
C
ipso-H
C
ortho-H
2.14
2.15
2.10
1.83
1.09
C
ipso-Cortho
C
ortho-O
4.47
2.56
2.38
2.40
2.36
two-spin-state nature of the reaction pathway found in this system.
The observation of this trend in both the experiments and the
calculations support the EAS as the mechanism operating in this
reaction.
3.39
1.89
1.40
1.30
1.23
1.08
1.08
1.10
1.19
2.11
1.39
T-TS1
T-I2
1.42
1.50
MECP1
S-I3
1.47
1.51
The structure of MECP1 also depends strongly on the nature of the
2 2
substituent X (Table 5). With X = NO , OMe and NMe , the spin
crossover triggers the same chemical transformations observed for
a
Table 4 involved in the EAS pathway.
benzene (Figure 3), i.e. H migration from the ipso to the ortho C
b
Species
T-I1
| q |
0.00
0.18
0.29
0.74
ρ(Cu)
0.79
0.78
0.81
0.00
ρ(O)
ρ(C
6
H
6
)
ρ(Tp*,Br)
0.10
3
yielding 1,3-cyclohexadienone. In contrast, with X = Me, Cl and CF ,
1.11
0.78
0.14
0.00
0.00
0.36
0.95
0.00
the oxygen atom adds to the ortho C yielding benzene oxide, which
T-TS1
T-I2
0.08
31
is another tautomer of phenol , (Figure S22); e.g. with X = CF ,
3
0.10
d(Cipso-O) = 1.42 Å and d(Cortho-O) = 1.83 Å. Nonetheless, these
S-I3
0.00
a
benzene oxides are much less stable than their 1,3-
q and ρ are not given for MECP1 due to different values in the singlet and
triplet states. Absolute values of the local charges of the C H (> 0) and
6 6
-1
b
cyclohexadienone isomers, by ca. 30 kcal mol , and it is well-known
*
,Br
*,Br
32
CuOTp (< 0) fragments; q(C
H
6 6
) = -q(CuOTp ).
from the literature that they rapidly isomerize to phenols through
dienone intermediates. Thus, for the sake of comparison, the
3
energies of the S-I3 intermediate with X = Me, Cl and CF (see ESI)
correspond to the ketone form. The Wheland-type intermediate
benzene, which is in agreement with similar systems previously
3
0
•
found for benzene, T-I2, is also formed with all substituted Ph-X
reported. In this regard, the potential role of OOH radicals in
6 5
substrates. The local charges and spin densities on the C H X
yielding active copper-hydroperoxo species was excluded.
fragment (Table S1) show its radical-cation nature, with values
ranging from 0.26 to 0.30 (q) and from 0.93 to 0.97 (ρ). Likewise
benzene, the formation of T-I2 is moderately endoergic for most X
substituents, as shown by the Gibbs energy of this intermediate
Electrophilic aromatic substitution on the substituted benzenes
The EAS mechanism was fully recomputed for the para- substituted
3 2 2
benzenes, Ph-X (X = CF , NO , Cl, Me, OMe, NMe ). The energy
2
relative to reactants, GT-I2. Only X = NO yield GT-I2 < 0, -3.8 kcal
profiles (see ESI) showed that the most demanding step is the
-1
mol
.
triplet-to-singlet spin crossover, as in the case of benzene (T-I2 →
MECP1 → S-I3), except for -NMe
2
. The energy barrier associated
The Oxygen rebound on benzene route
with the MECP (Table 5), ꢀGMECP1, is very sensitive to the nature of
-1
The radical oxyl character of the Cu-O moiety in T-1 (ρ(O) = 1.11,
Table 4) suggests that benzene may also be oxidized through a
the substituent, ranging from a minimum of 18.8 kcal mol (X =
-
1
NMe
2
) to a maximum of 33.4 kcal mol (X = CF
3
). Further, for X =
3
3
rebound mechanism initiated by H abstraction. The calculations
showed that the oxyl abstracts one H from benzene by following a
single-step pathway in the triplet state, T-1 → T-TS2 → T-4 (Figure
OMe and NMe
2
, we also computed the EAS mechanism for the
ortho and meta positions. In both cases, the ortho gave the lowest-
energy MECP1, though with a very small difference compared to
the meta and para, in line with the composition of the product
mixtures observed experimentally. These results also showed that
the relative orientation of the electrophile does not have a
significant impact on the mechanism.
5
). C-H cleavage in the transition state T-TS2 (d(Cipso···H) = 1.32 Å,
d(O···H) = 1.14 Å; Table 6) yields a phenyl fragment, C , which is
weakly bound to a hydroxo complex, [Tp Cu(OH)], in intermediate
T-I4 (d(O-H) = 0.95 Å). The C fragment in T-I4 is well-defined as a
neutral phenyl radical by its local charge, q(C ) = -0.01, and spin
density, ρ(C ) = 1.00 (Table 7). The values of ρ(O) and ρ(C ) in
6 5
H
*,Br
6 5
H
6 5
H
The apparent trend is that the reaction is accelerated by electron-
-1
H
5
6 5
H
donating groups (ꢀGMECP1 < 28 kcal mol with X = Me, OMe and
NMe ) and slowed down by electron-releasing groups (ꢀG > 28
6
T-TS2, 0.62 and 0.56, respectively, show the homolytic nature of the
C-H cleavage, with a single electron being transferred from the
phenyl ring to the oxyl. Conversely, ρ values for copper and the
2
MECP1
-1
2 3
kcal mol with X = Cl, NO and CF ). Interestingly, this signature
feature of the EAS mechanism is preserved despite of the unusual
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ARTICLE
Journal Name
*,Br
Tp ligand are almost invariant, thus showing their spectator role step undermines the possibility of having free diffusing radicals at
-1
in this reaction. The ꢀG for H abstraction, 15.1 kcal mol , suggests concentrations allowing for the formation of homocoupling
that the phenyl radical is thermally accessible, in line with the Ph-Cl products, which are not observed in the experiments. This step is
and Ph-Br products observed experimentally in the presence of more endoergic than the addition of benzene to the Cu-oxyl moiety
-1
halogenation reagents. Nonetheless, the endoergic nature of this in the EAS mechanism (ꢀG = 3.3 kcal mol ; Figure 3). In contrast,
‡
-1
the energy barrier, ꢀG = 16.8 kcal mol , is significantly lower than
‡
-1
that of the addition (ꢀG = 21.9 kcal mol ).
Table 6. Selected bond distances, in Å, for the species involved in the
rebound pathway.
Hydrogen abstraction is followed by the rebound of the phenyl
radical to the hydroxo ligand, T-I4 → T-TS3 → T-I5 (Figure 5). In the
transition state, the cleavage of the Cu-O bond, 1.91 Å (1.81 Å in T-
I4; Table 6), is counterbalanced by the formation of the Cipso-O
bond, 1.79 Å (4.39 Å in T-I4). The full optimization of T-TS3 towards
the products side yields intermediate T-I5, where the phenyl ring
appears hydroxylated (d(Cipso-O) = 1.37 Å). Interestingly, the spin
density distribution does not change to any significant extent in this
reaction, with one unpaired electron located on copper and the
Species Cu-O
C
ipso-H
O-H
2.58
1.14
C
ipso-O
Cu-Cortho
4.13
Cu-Cmeta
5.12
T-I1
T-TS2
T-I4
1.81
1.81
1.81
1.91
3.14
2.87
3.90
1.08
1.32
4.09
2.30
1.91
1.92
1.91
3.39
2.46
4.39
1.79
1.37
1.38
1.35
4.04
5.38
0.95
0.96
0.95
0.96
0.95
6.56
2.44
2.03
1.98
2.36
6.67
3.33
2.95
2.99
2.49
T-TS3
T-I5
MECP2
S-I6
other located on the C
ρ(C ) = 0.91 (Table 7 and Figure 5). The oxygen rebound step is
endoergic and involves the highest energy barrier of the
6 5
H fragment, e.g., in T-TS3, ρ(Cu) = 0.83 and
Table 7. Selected local charges (q) and spin densities (ρ), in a.u., for the
6 5
H
a
species involved in the rebound pathway.
-1
q(Cu)
0.79
q(O)
mechanism, with T-I5 and T-TS3 standing 6.4 and 34.1 kcal mol
Species
T-I1
q(C
6
H
5
)
ρ(Cu)
ρ(O)
ρ(C
6
H
5
)
ρ(Tp*,Br)
above reactants, respectively. The rebound mechanism is thus less
favourable than the EAS, in which the most energy-demanding step,
1.111
0.00
0.79
1.11
0.00
0.10
T-TS2
T-I4
0.80
0.83
0.83
1.00
0.00
0.62
0.09
0.17
0.03
0.00
0.56
1.00
0.91
0.90
0.00
0.80
0.83
0.83
1.00
0.00
0.62
0.09
0.17
0.03
0.00
0.56
1.00
0.91
0.90
0.00
0.09
0.08
0.08
0.07
0.00
-1
the triplet-to-single spin crossover, involves an MECP 30.6 kcal mol
above reactants (MECP1; Figure 3).
T-TS3
T-I5
The intermediate yielded by the rebound step, T-I5 (Figure 5),
showed an unexpected structural feature, i.e. the hydroxylated
phenyl ring does not appear coordinated to the metal as a neutral
phenol molecule. Instead, it coordinates as a formally anionic ligand
S-I6
a
q and ρ are not given for MECP1 due to different values in the singlet
and triplet states.
8
| J. Name., 2012, 00, 1-3
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Plea sC eh de om ni oc ta al dS j uc si et nm c ae rgins
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DOI: 10.1039/C7SC02898A
ARTICLE
through a single Cu-Cortho covalent bond (d = 2.03 Å), in which
copper has a formal oxidation state of +2. This suggests that,
likewise the EAS mechanism (Figure 3), the reaction can only be
completed by spin crossover to the singlet state. The MECP found
Conclusions
Two competitive pathways have been found for the benzene
and substituted benzenes) hydroxylation reaction, with an
(
unprecedented dual behavior of a copper-oxyl intermediate.
Using hydrogen peroxide as oxidant, in the absence of acids,
-1
for this process, MECP2, lies 9.3 kcal mol above reactants (Figure
). When the structure of MECP2 is fully optimized in the singlet
5
state, the system evolves towards the products side of the reaction
-
1
Table 8. Energies, in kcal mol , and selected bond distances, in Å, for T-
TS3 in the rebound pathway with Ph-X.
by yielding intermediate S-I6. The formation of this species is
-
1
2
exoergic by 37.9 kcal mol . In S-I6, phenol is formed and η -
X
ꢀGT-TS3
38.6
34.9
36.3
31.1
29.8
20.8
Cu-O
1.92
1.92
1.92
1.91
1.90
1.88
C
ipso-H
O-H
0.96
0.96
0.96
0.96
0.96
0.96
C
ipso-O
Cu-Cortho
2.39
Cu-Cmeta
3.30
coordinated to the metal through the Cortho=Cmeta moiety (d(Cu-C) =
-
NMe
2
2.30
2.31
2.31
2.29
2.31
2.31
1.79
1.78
1.79
1.77
1.79
1.82
2.36 and 2.49 Å). The exoergic dissociation of S-I6 yields phenol and
-
OMe
-Me
2.39
3.31
recovers the catalyst.
2.41
3.32
-
Cl
CF
-NO
2.57
3.48
Oxygen rebound on the substituted benzenes
-
3
2.63
3.51
The rebound pathway was recalculated for all substituted Ph-X
2
2.63
3.77
3 2 2
substrates (X = CF , NO , Cl, Me, OMe, NMe (see profiles in ESI).
x
x
and using Tp Cu (Tp = hydrotrispyrazolylborate) as the
catalyst, experimental evidences have allowed first discarding
Fenton-like mechanisms and later proposed the plausible
competition between an electrophilic aromatic substitution
pathway with the alternative rebound (hydrogen abstraction)
route. Both pathways involve a common copper-oxyl species
The reaction pathway has the same essential features observed
with benzene, i.e. H-abstraction yields a neutral phenyl radical,
which undergoes rebound followed by triplet-to-singlet spin
crossover. The bond distances (Table 8) and local spin densities
(Table S2) found for the key transition state, T-TS3, show the
x
•
rebound of the phenyl radical to the hydroxyl through Cipso
,
,
of type Tp Cu-O . Based on the theoretical calculations, the
EAS mechanism proposed in this work is not the conventional
accompanied by the binding of Cortho to copper; e.g., for X = NMe
2
d(Cipso-O) = 1.79 Å and d(Cu-Cortho) = 2.39 Å, ρ(O) = 0.18 and ρ one, since it requires spin crossover after the addition step.
X) = 0.91. Nonetheless, it follows the expected trend of being
6 4
(C H
As for benzene, the rebound T-TS3 barrier involves the highest accelerated by electron-donating groups and decelerated with
electron-releasing groups, which is in line with the Hammett
energy barrier (ꢀGT-TS3) with all X substituents. Interestingly, the
dependence of this barrier on the donor/acceptor nature of X
plots derived experimentally. In contrast, the rebound
mechanism follows the opposite trend, although it accounts
follows a trend opposite to that observed in the EAS mechanism;
6 5
for the formation of halobenzenes derived from the C H •
i.e., the reaction is accelerated by electron-releasing groups and
slowed down by electron-donating groups. Whereas the T-TS2 H-
abstraction barrier is almost unaffected by the nature of X (Figure
radical intermediate. In the rebound mechanism, this radical is
generated in the initial H abstraction step, which is reversible
and faster than the addition step in the EAS mechanism. The
observance of two competitive pathways and the dual
behavior of the Cu-oxyl species may serve for future design of
novel catalysts toward the direct functionalization of benzene
into phenol.
-
1
S2), the value of ꢀGT-TS3 ranges from a minimum of 20.8 kcal mol
-1
2 2
with X = NO to a maximum of 38.6 kcal mol with X = NMe . This
trend is consistent with the electron density flow observed in the
critical rebound step. For X = H, the largest variations on the local
charges are given by q(C H ), which evolves from -0.01 (T-I4) to -
6
5
0
.20 (T-TS3) and -0.37 (T-I5), and by q(O), which evolves from -1.10
T-I4) to -0.94 (T-TS3) and -0.74 (T-I5). These charges show an Acknowledgements
electrophilic attack of the phenyl ring to the hydroxyl. Further, the
most electron-releasing groups of the series, X = CF and NO , yield
barriers that are lower than those observed for the EAS mechanism.
(
We thank MINECO for Grants CTQ2014-52769-C3-1-R and
CTQ2014-54071-P and COST Action CARISMA CM1205. D.B.
acknowledges the support from the Norwegian Research
Council through the Centre of Excellence for Theoretical and
Computational Chemistry (CTCC; grant No. 179568/V30), the
3
2
With X = NO , the observation of radical species should be
2
hampered by fast rebound, which, in this case, involves a low
-1
barrier of 20.8 kcal mol . We note that the yields obtained with X = Norwegian Metacenter for Computational Science (NOTUR;
CF and NO (Figure 1) are somewhat lower than those expected grant nn4654k) and the EU Research Executive Agency for a
3
2
from the calculated rebound barriers which do not agree with the Marie Curie Fellowship (grant CompuWOC/618303).
Hammett equations derived experimentally (Figure 1). This suggests
that the reaction either follows a different mechanism or generates
Notes and references
radical species from intermediate T-I4 (Figure 5) giving rise to
undesired homo-coupling by-products and detrimental side
rd
reactions hampering the access to T-TS3. Further, the accuracy of
the DFT calculations may not be high enough in these two particular
cases.
1
K. Weissermel and H. J. Arpe, Industrial Organic Chemistry, 3
ed., John Wiley & Sons, 2008
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ARTICLE
Journal Name
2
3
(a) R. Molinari and T. Poeria, Asia-Pac. J. Chem. Eng., 2010, 5,
91-206; (b) R. J. Schmidt, Appl. Catal., A, 2005, 280, 89-103.
(a) S. Ito, A. Kunai, H. Okada and K. Sasaki, J. Org. Chem., 1988,
3, 296-300; (b) S. Goto, Y.-J. Seo, Y. Mukai and T. Tagawa, J.
8232; (b) 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, L. Tian, Chem. Rev., 2014, 114, 3659-
1
3
853; (c) I. Kong, M. Wang, F. Zhang, M. Xu, Y. Li, Org. Lett.,
2016, 18, 6124-6127
6 (a) K. B. Cho, H. Hirao, S. Shaik, W. Nam, Chem. Soc. Rev., 2016,
5, 1197-1210; (b) J. C. Schoneboom, S. Cohen, H. Lin, S. Shaik,
W. Thiel, J. Am. Chem. Soc., 2004, 126, 4017-4034
5
Mol. Catal. A: Chem., 1997, 120, 149-154; (c) U. Schuchardt, A.
T. Cruz, C. H. Collins and L. C. Passoni, Stud. Surf. Sci. Catal.,
.
1
4
1994, 82, 551-559.
.
4
(a) S. Niwa, M. Eswaramoorthy, J. Nair, A. Raj, N. Itoh, H. Shoji,
T. Namba and F. Mizukami, Science, 2002, 295, 105-107; (b) M.
Tani, T. Sakamato, S. Mita, S. Sakaguchi and Y. Ishii, Angew.
1
1
1
7 H. Marusawa, K. Ichikawa, N. Narita, H. Murakami, K. Ito and T.
Tezuka, Bioorg. Med. Chem,. 2002, 10, 2283−2290.
8 R. Augusti, A. O. Dias, L. L. Rocha and R. M. Lago, J. Phys. Chem.
A, 1998, 102, 10723-10727.
9 For radical trapping with these halomethanes see: (a) J.-P.
Mahy, G. Bedy, P. Battioni, D. Mansuy, New J. Chem., 1989, 13,
Chem. Int. Ed., 2005, 44, 2586-2588
.
5
6
V. N. Parnon, G. I. Panov, A. Uriarte and A. S. Noskov, Catal.
Today, 2005, 100, 115-131.
(a) Y. Morimoto, S. Bunno, N. Fujieda, H. Sugimoto and S. Itoh, J.
Am. Chem. Soc., 2015, 137, 5867-5870; (b) O. Shoji, T.
Kunimatsu, N. Kawakami and Y. Watanabe, Angew. Chem., Int.
Ed., 2013, 52, 6606−6610; (c) X. Chen, J. Zhang, X. Fu, M.
Antonietti and X. Wang, J. Am. Chem. Soc., 2009, 131, 11658-
6
51−657; (b) K.-B. Cho, X. Wu, Y.-M. Lee, Y.-H. Kwon, S. Shaik
and W. Nam, J. Am. Chem. Soc., 2012, 133, 20222−20225
0 T. W.-S. Chow, Y. Liu and C.-M. Che, Chem Commun., 2011, 47,
1204−11206.
1 S. P. De Visser, K. Oh, A.-R. Han, W. Nam, Inorg. Chem., 2007,
6, 4632– 4641.
.
2
2
2
2
1
1
2
1659; (d) Y. Leng, H. Ge, C. Zhou and J. Wang. Chem. Eng.,
008, 145, 335-339; (e) Y. Tang and J. Zhang. Transition Met.
4
2 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.
3 (a) N. Kitajima, T. Koda, Y. Iwata, Y. Moro-oka, J. Am. Chem. Soc.
Chem., 2006, 31, 299-305; (f) N. I. Rudakova, M. V. Klyuev, Y. G.
Erykalov and D. N. Ramazanov. Russ. J. Gen. Chem., 2006, 76,
1
407-1409; (g) P. M. Reis, J. A. L. Silva, J. J. R. Frausto da Silva
and A. J. L. Pombeiro, J. Mol. Catal. A Chem., 2004, 224, 189-
95; (h) T. K. Si, K. Chowdhury, M. Mukherjee, D. C. Bera and R.
1990, 112, 8833-8839; (b) N. Kitajima, T. Koda, S. Hashimoto, T.
Kitakawa, Y. Moro-oka, J. Am. Chem. Soc. 1991, 113, 5664-5671.
4 M. A. Mairena, J. Urbano, J. Carbajo, J. J. Maraver, E. Álvarez, M.
M. Díaz-Requejo, P. J. Pérez, P. J. Inorg. Chem. 2007, 46, 7428-
1
2
2
Bhattacharyya, J. Mol. Cat. A: Chem., 2004, 219, 241-247; (i) F.-
S. Xiao, J. Sun, X. Meng, R. Yu, H. Yuan, D. Jiang, S. Qiu and R. Xu,
Appl. Catal. A Gen., 2001, 207, 267-271; (j) D. Bianchi, R.
Bortolo, R. Tassinari, M. Ricci and R. Vignola, Angew. Chem. Int.
Ed., 2000, 39, 4321-4323.
7435.
5 (a) M. Lundberg, M. R. A. Blomberg and P. E. M. Siegbahn, Inorg.
Chem., 2004, 43, 264−274; (b) P. E. M. Siegbahn and R. H.
Crabtree, J. Am. Chem. Soc., 1999, 121, 117−127; (c) N. Gagnon
and W. B. Tolman, Acc. Chem. Res., 2015, 48, 2126-2131; (d) C.
E. Elwell, N. L. Gagnon, B. D. Neisen, D. Dhar, A. D. Spaeth, G. M.
Yee and W. B. Tolman, Chem. Rev., 2017, 117, 2059-2107.
7
8
A. Conde, M. M. Díaz-Requejo, P. J. Pérez, Chem. Commun.,
2011, 47, 8154−8156.
(a) S. Trofimenko in Scorpionates, The Coordination Chemistry
of Polypyrazolylborate Ligands; Imperial College Press: London, 26 (a) S. M. Huber, M. Z. Ertem, F. Aquilante, L. Gagliardi, W. D.
1
999; (b) C. Pettinari in Scorpionates II: Chelating Borate
Tolman and C. J. Cramer, Chem. Eur. J., 2009, 15, 4886-4895; (b)
S. Kim, J. Ståhlberg, M. Sandgren, R. S. Paton and G. T.
Beckham, Proc. Nat. Acad. Sci. 2014, 111, 149-154; (c) E. A.
Span, D. L. M. Suess, M. C. Deller, R. D. Britt and M. A. Marletta,
ACS Chem. Biol., 2017, 12, 1095-1103.
Ligands; Imperial College Press; River Edge NJ 2008. (c) C.
Pettinari, R. Pettinari and F. Marchetti, Adv. Organomet. Chem.
2016, 66, 175-260.
9
1
A. Conde, L. Vilella, D. Balcells, M. M Díaz-Requejo, A. Lledós
27 (a) A. Cornelis and P. Laszlo, Synthesis, 1985, 909-918; (b) S.
Sugden and H. Wilkins, J. Chem. Soc., 1929, 1291-1298; (c) P.
Laszlo, Acc. Chem. Res., 1986, 19, 121-127.
and P. J. Pérez, J. Am. Chem. Soc., 2013, 135, 3887−3896
0 (a) A. Pereira, Y. Champouret, C. Martin, E. ÁLvarez, M. Etienne,
T. R. Belderrain and P. J. Pérez, Chem. Eur. J., 2015, 21, 9769-
2
8 C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34,
33-639.
9 (a) K. Lammertsma and B. V. Prasad, J. Am. Chem. Soc., 1994,
6
9
775. (b) A. A. C Braga, F. Maseras, J. Urbano, A. Caballero, M.
M. Díaz-Requejo and P. J. Pérez, Organometallics, 2006, 25,
292-5300.
2
1
1
16, 642-650; (b) A. Lledós and J. Bertran, Tetrahedron Lett.,
981, 22, 775-778; (c) O. N. Ventura, A. Lledós, R. Bonaccorsi, J.
5
1
1 L. Maestre, W. M. C. Sameera, M. M. Díaz-Requejo, F. Maseras
and P. J. Pérez, J. Am. Chem. Soc., 2013, 135, 1338-1348.
2 (a) A. E. Shilov and G. B. Shul’pin, Chem. Rev., 1997, 97, 2879-
Bertran and J. Tomasi, Theor. Chim. Acta, 1987, 72, 175-195; (d)
L. Rodríguez-Santiago, O. Vendrell, I. Tejero, M. Sodupe and J.
Bertran, Chem. Phys. Lett., 2001, 334, 112-118; (e) L. Bellarosa,
J. Díez, J. Gimeno, A. Lledós, F. J. Suárez, G. Ujaque and C.
Vicent, Chem. Eur. J., 2012, 18, 7749-7765.
1
2
932; (b) S. Ito, A. Mitarai, K. Hikino, M. Hirama and K. Sasaki, J.
Org. Chem., 1992, 57, 6937-6941
3 C. Walling and R. A. Johnson, J. Am. Chem. Soc., 1975, 97,
63−367
4 M. Yamada, K. D. Karlin and S. Fukuzumi, Chem. Sci., 2016, 7,
856-2863
.
1
1
1
3
0 (a) A. Crespo, M. A. Martí, A. E. Roitberg, L. M. Amzel and D. A.
Estrin, J. Am. Chem. Soc., 2006, 128, 12817-12828; (b) K.
Yoshizawa, N. Kihara, T. Kamachi and Y. Shiota, Inorg. Chem.,
3
.
2
.
2006, 45, 3034-3041. ꢀ
31 D. Jerina, J. Daly, B. Witkop, P. Zaltzman-Nirenberg and S.
5 (a) A. Kunishita J. D. Scanlon, H. Ishimaru, K. Honda, T. Ogura,
M. Suzuki, C. J. Cramer, S. Itoh, Inorg. Chem., 2008, 47, 8222-
Udenfriend. Arch. Biochem. Biophys., 1968, 128, 176-183.
1
0 | J. Name., 2012, 00, 1-3
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2 N. T. Nashed, J. M. Sayer and D. M. Jerina, J. Am. Chem. Soc.,
993, 115, 1723-1730.
1
33 D. Balcells, C. Raynaud, R. H. Crabtree and O. Eisenstein, Chem.
Commun., 2008, 744-746.
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