Mechanism of the CuII-catalyzed benzylic oxygenation of (aryl)(heteroaryl)methanes with oxygen

Article abstract of DOI:10.1039/c5sc03530a

A mechanistic study of the copper-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes was performed. Initial reaction rates were measured making use of in situ IR reaction monitoring and a kinetic analysis of the reaction was executed. The reaction proved to be first order in oxygen concentration. For substrate and acid concentration, saturation kinetics due to O₂ mass transfer limitation were observed. The occurrence of mass transfer limitation was further confirmed by examining the effect of the stirring rate on the initial reaction rate. Interestingly, the effect of the concentration of the catalyst on the rate shows that higher loadings result in a maximal initial rate, followed initially by a steady decrease and subsequently a rate plateau when the concentration is increased further. Mass transfer limitation and increased concentration of dinuclear catalytically active species rationalizes this hitherto unprecedented rate behavior. Continuous-wave and pulsed electron paramagnetic resonance methods were used to characterize the catalytic species present in the solution during the reaction and confirmed the presence of both mono- and dinuclear copper species. Analysis of a diverse substrate scope points towards imine-enamine tautomerization as a crucial process in the oxidation reaction. DFT calculations of these equilibrium constants (pK_eq) provided us with a qualitative tool to predict whether or not a substrate is viable for oxidation under the reaction conditions developed.

Full text of DOI:10.1039/c5sc03530a

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ARTICLE
II
Mechanism of the Cu -Catalyzed Benzylic Oxygenation of
(
Aryl)(heteroaryl)methanes with Oxygen
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
b
a
Hans Sterckx , Johan De Houwer , Carl Mensch , Ignacio Caretti , Kourosch Abbaspour Tehrani ,
Wouter A. Herrebout , Sabine Van Doorslaer , Bert U.W. Maes*
a
b
a
DOI: 10.1039/x0xx00000x
A mechanistic study of the copper-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes was performed.
Initial reaction rates were measured making use of in-situ IR reaction monitoring and a kinetic analysis of the reaction was
executed. The reaction proved to be first order in oxygen concentration. For substrate and acid concentration, saturation
www.rsc.org/
2
kinetics due to O mass transfer limitation were observed. The occurrence of mass transfer limitation was further
confirmed by examining the effect of the stirring rate on the initial reaction rate. Interestingly, the effect of the
concentration of the catalyst on the rate shows that higher loadings result in a maximal initial rate, followed initially by a
steady decrease and subsequently a rate plateau when the concentration is increased further. Mass transfer limitation and
increased concentration of dinuclear catalytically active species rationalizes this hitherto unprecedented rate behavior.
Continuous-wave and pulsed electron paramagnetic resonance methods were used to characterize the catalytic species
present in the solution during the reaction and confirmed the presence of both mono- and dinuclear copper species.
Analysis of a diverse substrate scope points towards imine-enamine tautomerization as a crucial process in the oxidation
reaction. DFT calculations of these equilibrium constants (pKeq) provided us with a qualitative tool to predict whether or
not a substrate is viable for oxidation under the reaction conditions developed.
and iron with molecular oxygen as the terminal oxidant are of
special interest. After all, these metals are abundant, feature a
low toxicity, and oxygen is the most sustainable oxidant on
Introduction
Two decades ago benzylic oxidation reactions made use of
unsustainable oxidants such as potassium permanganate or
chromium acid derivatives. This produced vast quantities of
8
earth. There is a great number of important articles available
on the structure and reactivity of various Cu- and, to a lesser
9
1
II
III
degree, Fe-complexes with molecular oxygen.
The
hazardous waste. While Mn and Cr are present as trace
VI
elements in the human body as essential nutrients, Cr is a
VII
stoichiometric study of these complexes provides a simplified
mimic of the active site of several important metalloproteins
(for instance: tyrosinase, dopamine β-monooxygenase,
galactose oxidase or cytochrome P450) and are therefore
easier to study. These complexes are usually very well defined
known carcinogen and exposure to Mn
can lead to
2
manganism’, a central nervous system disorder. Nowadays
‘
these classical oxidants are mostly shunned and a major shift
has taken place towards less toxic and sustainable oxidants like
I
and are formed by reaction of a reduced metal center (Cu and
II
Fe ) with O
peroxides or molecular oxygen preferably in combination with
3
cheap transition-metal catalyst. Recently substantial
2
to form the reactive intermediate, which reacts
a
directly with the substrate. Alternatively, they can also be
II
formed by using metals in a higher oxidation state (Cu and
progress has been made in the development of preparative
base metal-catalyzed aerobic oxidation reactions of benzylic
III
Fe ) in combination with H
4
alcohols. The direct benzylic methylene oxygenation is
2
O
2
. A stabilizing nitrogen-
5
however far less studied. Notable examples using peroxides
containing ligand (bidentate or higher) is a prerequisite for
these systems to be stable enough to be studied. Furthermore
the ligand provides a mimic of the polypeptide chain around
the metal center and can be used to tune the reactivity of the
complex.
as the terminal oxidant on active methylenes are reported by
the groups of Bolm, Punniyamurthy, Chen and Sasson using
II
respectively FeCl , a Cu Salen-H , a Mn(OAc) ·4H O complex
3
4
2
2
6
,7
and CuCl as the catalyst. Methylene oxidations using copper
2
In comparison to the reports describing well characterized
model complexes in stoichiometric reactions, preparative
protocols for oxygenation of active methylenes involving in
situ formed copper and iron catalysts with oxygen as the
1
0,11
stoichiometric oxidant are still limited.
In 2012 our group
published a communication describing a synthetic protocol for
the copper- and iron-catalyzed oxidation of the methylene
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group of aryl(di)azinylmethanes with acetic acid as promoter proceed. Besides, the acidity of the methylene protons is also
1
1a
(Scheme 1).
important since 2-methylpyridine (10) could not be oxidized.
Further support that a combination of these two factors is
necessary was gathered by performing experiments on a
selected set of substrates (Table 1). When the acidity of the
methylene in 10 is increased by introducing an electron-
withdrawing group, either on the pyridine ring or on the
Scheme 1 Oxidation of model substrate 2-benzylpyridine (1) to 2-benzoylpyridine (2) methylene group, the substrate can be oxidized again as
under the standard reaction conditions
exemplified by methyl 2-(pyridin-2-yl)acetate (14) and 6-
methylnicotinonitrile (12). A control experiment with methyl 2-
phenylacetate (16) proves that the imine moiety is still
necessary and that activation by the methyl ester alone is not
sufficient for this reaction to proceed. To test whether this
oxidation protocol can also be used beyond azine type systems
Several groups have made creative use of these reaction
conditions and some extended them to other substrate
systems. Kappe successfully translated our protocol into an
efficient flow process allowing scale up and continuous
12
production. By slightly modifying our disclosed reaction
conditions Touré achieved selective oxidation of C-H bonds in
drug candidates and APIs delivering drug metabolites. The
oxidation protocol could also be applied to oxygenate carbons
alpha to a tertiary amine and therefore mimic or complement
it was applied to azoles; 2-benzyl-1-methyl-1H-imidazole (18
)
and 1,2-dimethylimidazole (20). The phenyl-activating group
appears to still be a necessary structural element since we
were only able to oxygenate the former substrate, similarly to
what has been observed for 10. Other 2-benzylazoles can also
be used, as shown by the oxidation of 2-benzylbenzoxazole
1
3
cytochrome P450. Very recently Zhuo and Lei disclosed a
similar oxidation protocol in which ethyl chloroacetate was
(
22) and 2-benzylbenzothiazole (24), further underlining the
1
4
used as a promoter instead of acetic acid. A final interesting
and notable example of an extension towards other
functionalizations is the copper-catalyzed α-methylenation of
general applicability of the oxidation method.
Imine-enamine tautomerization: Computational study
1
5
benzylpyridines using DMA as a one-carbon source. When
Na was used as an oxidant instead of O2, chemoselective
The structural features of substrates suitable for oxidation
under our protocol (vide supra) indicated that the mechanism
of the oxidation seems to revolve around an (initial) imine-
enamine tautomerization. The imine-enamine tautomerization
can be thermodynamically quantified by an equilibrium
constant Keq (Figure 1). To gain more insight in these
tautomerizations, the pKeq values for the different
experimentally tested substrates were calculated using density
functional theory (DFT, Table 1).
2 2 8
S O
methylation occurred over oxygenation of the methylene.
Although there are several publications describing preparative
2
methylene oxidation protocols based on copper or iron and O ,
no detailed mechanistic studies (involving kinetics) have been
performed yet to support the proposed catalytic cycles. As
copper and iron salts easily form polynuclear species, the
nature of the catalyst in these reactions remains also
unknown. To allow further developments in this field,
knowledge of the catalytically active species and the catalytic
cycle is crucial. In this paper we disclose the results of
mechanistic studies on the oxidation of 2-benzylpyridine under
copper catalysis with oxygen as oxidant as model system
H
N
pKeq = 11.5
N
DMSO, 25 °C
pKeq = 11.0
(Scheme 1), leading to an insight into the actual reaction
N
DMSO, 25 °C
HN
mechanism of this intriguing transformation. DMSO was
chosen as the solvent for this mechanistic study to avoid Figure 1 Imine-enamine equilibrium of 2- and 4-benzylpyridine
solubility problems considering the large ranges of
First, the geometries of the different conformations of both
concentrations of the different reaction components that had
to be used.
the imine- and the enamine-form were optimized at the
B3PW91/aug-cc-pVDZ level of theory. Due to the rather large
dipole moment of the molecules and the difference in dipole
moment of the imine and the respective enamine tautomer
Results and discussion
(Table S5), the self-consistent reaction field (scrf) model was
Substrate scope: Structural requirements
used to account for solvent-solute interactions with DMSO. In
a second phase, the most stable imine and respective enamine
conformer were used to calculate the Gibbs free energy (ΔG°)
and the desired equilibrium constant Keq (See supporting
information for more details). All calculations were performed
using the Gaussian09 program. In Table 1 the results of these
calculations for the different experimentally tested benzylic
systems are summarized. These calculated values do not have
The previously developed reaction conditions (Scheme 1)
allowed to oxidize 2- (
1) and 4-benzylpyridine (
6), while no
oxidation of 3-benzylpyridine (
4) and diphenylmethane (8)
1
1a
occurred. From this was concluded that the oxidation is not
a directed reaction since coordination of the metal catalyst to
the nitrogen in 4-benzylpyridine would bring the metal too far
away from the benzylic position to promote an intramolecular
reaction. Instead, these observations point to an imine-
enamine tautomerization as a prerequisite for the reaction to
2
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a direct absolute meaning but can be compared relatively Table 1 Calculated pKeq values and Cu-catalyzed oxidation reaction for structurally
different substrates.
between different substrates.
Benzylpyridines (
respectively, which is up to 9 orders of magnitude lower than
-benzylpyridine ( ), with a pKeq value of 20.4. This is because
1 and 6) have a pKeq value of 11.5 and 11.0,
a
Entry
Substrate
Product
pKeq
Yield (%)
3
4
in 3-benzylpyridine stabilization by an enamine tautomeric
form is not possible, as is also the case for diphenylmethane
d
1
11.5
92
(
8
). Furthermore, without the second aromatic ring attached
to the methylene center the pKeq rises with about 4 orders of
magnitude, as exemplified by 2-methylpyridine 10).
(
d
2
3
4
5
6
7
8
9
20.4
11.0
21.7
15.9
13.0
6.2
0
Introducing an electron withdrawing group either on the
pyridine or on the methylene moiety results in a higher
equilibrium constant (12 and 14). Although a keto-enol
tautomerization can be drawn for the methylester
functionality of methyl 2-phenylacetate (16) it still provides a
relatively high pKeq value (18.8) (See Table S4 for more details
on the tautomerization equilibria).
d
89
Interestingly, from Table 1, a clear correlation exists between
the calculated pKeq values and whether oxidation occurs or not
for each substrate. Only the substrates with a sufficiently low
pKeq or high Keq value are reactive enough to be oxidized.
Empirically, based on Table 1 and the pKeq values calculated
for substrates previously published, one can deduce the
maximum pKeq value for the reaction to proceed under our
standard reaction conditions to be around 15.
d
0
d
0
Homolytical benzylic C-H bond dissociation energies (BDE) of
the molecules in Table 1 were also calculated (see Table S6). If
a correlation exists this would be an indication for a
mechanism in which the active catalyst abstracts a hydrogen
b
27 (60)
atom from the substrate before quenching with O
no correlation could be found since the bond dissociation
energies of diphenylmethane ( ), 2-, 3-, and 4-benzylpyridine
, and ) are similar while there is a major difference in
2
. However,
c
23 (83)
8
(
1,
4
6
their reactivity in our oxidation protocol. DFT calculations thus
provide an interesting qualitative tool to predict whether or
not a substrate will be viable for oxygenation under our
reaction conditions and strongly suggest that the oxidation
reaction proceeds via the enamine tautomer as the reactive
species.
18.8
13.9
19.0
9.1
0
b
34 (85)
1
1
1
0
1
2
0
98
99
8.1
a
Substrate (0.5 mmol), CuI (10 mol %) AcOH (1 eq.), DMSO (1 mL), O
2
b
c
balloon), 100 °C, 24 h. at 120 °C. in n-BuOAc (1 mL) with addition of
(
d
molecular sieves.
reference 11a.
Compound reported in our communication, see
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Kinetic experiments
exclusively via pathway 1a/1b the first step (1a) should be rate
determining to account for a benzylic oxidation in to ketone
which is not influenced by a radical scavenger, while the
1
In the oxidation reaction of
1
,
small amounts of
2
phenyl(pyridin-2-yl)methanol (3) were observed besides the
1
desired 2-benzoylpyridine (
1a
oxidation of alcohol 3 (pathway 1b) to the same product is
2
).
This raised the question
) proceeds via
significantly accelerated by its addition. Contradictorily, a
comparison between the initial rate of oxidation of and
whether formation of the 2-benzoylpyridine (
2
1
3,
phenyl(pyridin-2-yl)methanol (
pathway 1a/1b) or via
benzylpyridine (
3
) as an intermediate (Figure 2,
shows that the oxidation of the latter is in fact slower than the
oxidation of the former. On the other hand, if the second step
a
pathway directly from 2-
1
) (Figure 2, pathway 2), in which case the
(pathway 1b) would be rate determining, one expects a build-
alcohol is merely a formed side product.
up of alcohol in the reaction mixture. This is not the case since
only small amounts are present during the reaction course
(
vide supra). These contradictions imply that an indirect
pathway 1a/1b can be excluded and our reaction proceeds via
a direct pathway 2 with the formation of as side compound.
3
In addition to the kinetic experiments using TEMPO we also
tried to isolate TEMPO-adducts to find out whether stable
1
8
radical species were formed during the reaction. No such
adducts could be observed via LC-MS analysis. When using 1,1-
diphenylethylene as an alternative radical scavenger the
oxidation reaction was also not inhibited and
1 was fully
converted into ketone
quantitatively recovered.
2
and 1,1-diphenylethylene was
Next to these liquid radical
1
9a
Figure 2 Two possible reaction pathways in the oxidation of
1
scavengers activated carbon was used as a solid scavenger.
Also in this case no inhibition could be detected (Figure
As β-hydride elimination of copper alkoxide complexes is
known but rare, we first tested whether alcohol could be
oxidized under our reaction conditions. When the optimal
reaction conditions were applied (Scheme 2), ketone was
isolated in 77 % yield with 12 % recovery of
1
9b
3
S27). These results suggest that no stable organic radical
species are formed in solution during the course of this
reaction. This is also supported by EPR analysis (vide infra).
1
6
2
3.
Scheme 2 Copper-catalyzed oxidation reaction of 3 under standard conditions
Scheme 3 Benzylic radical clock reaction
To gain more insight we performed a kinetic study using in-situ Considering that TEMPO, 1,1-diphenylethylene and activated
IR monitoring. The concentration of ketone
was monitored carbon are bimolecular probes and oxygen is also a radical
over time (CO stretch frequency) and the initial reaction rate trap, we synthesized a substrate which can act as an
was determined. Both the oxidation of and
(Figure 3) were intramolecular probe for benzylic radical. 2-(2-
2
1
3
a
followed in function of time. For each of these transformations Allylbenzyl)pyridine (26) was selected for this purpose. While
the results were compared to a similar reaction where 1 benzylic radical clocks are known to be relatively slow due to
equivalent
of
tetramethylpiperidinyloxyl (TEMPO) was added to the reaction unimolecular rate constant (k = 3 x 10 s ) is still a factor of 10
the
radical
scavenger
2,2,6,6- the inherent stability of the benzylic radical, the reported
2
-1
7
-5
-1
mixture. Figure 3 (left) shows that the presence of TEMPO has faster than our overall maximum reaction rate (2 x 10 M.s )
19c
2
, starting (vide infra). (2-Allylphenyl)(pyridin-2-yl)methanone (27) was
almost no influence on the formation of ketone
from 1. However, the oxidation of alcohol
3
is significantly formed and no ring closed products due to radical cyclization
accelerated in the presence of the radical scavenger (Figure 3, could be detected in the reaction mixture (Scheme 3).
right). Stahl already reported that smooth oxidation of Formation of 27 further supports that a free benzylic radical is
alcohols can be achieved by the use of a radical catalyst, such not involved in our reaction protocol.
as TEMPO, in combination with a copper catalyst and oxygen
as the stoichiometric oxidant, which accounts for these
1
7
observations.
Assuming that the reaction proceeds
4
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Figure 3 Effect of TEMPO on the rate of the oxidation reaction of 1 and 3
It is important to determine whether mass-transfer effects are reaction approaches zeroth order for the acid and
1
2
in play since O is a gaseous reagent. The effect of the stirring concentrations. This saturation behavior with vmax at
0
2
-1
on the initial reaction rate was examined at 0.2 M of catalyst approximately 1.2 mM.min is due to the occurrence of O2
Figure 4). It was found that up until 550 rpm there is a first mass transfer limitation conditions as was the case for the
(
2
0
order relation of the stirring rate on the initial rate of the stirring experiments (vide supra). The measured data points
reaction. At higher stirring rates the v becomes independent. are in accordance with hyperbolic functions (see supporting
i
From this we can conclude that at a certain reaction rate (vmax
)
information for derivations). An alternative explanation for the
the uptake of O becomes rate limiting. From the stirring rate saturation behavior might be the formation of a pre-
2
experiment we see that the value of v is approximately 1.2 equilibrium between substrate, AcOH and catalyst before rate
max
-
1
17b
mM.min . Under our standard reaction conditions we work at determining oxygenation.
a stirring rate of 700 rpm and thus no mass-transfer effects are excluded. After all, when the concentration of these three
This scenario, however, can be
in play.
components was raised simultaneously, thereby keeping their
respective ratios constant, the initial rate again showed the
same vmax value (Figure S16).
The dependence of the reaction rate on the catalyst
concentration follows a more complex pattern. At very low
catalyst concentrations the rate increases very fast in a
-1
hyperbolic fashion. At a rate of 1.2 mM.min it also reaches a
maximum and after that the reaction rate becomes invariant
of the catalyst concentration. The value of this maximum is
determined by the O mass transfer limitation and corresponds
2
to the vmax that was observed for [AcOH] and [1]. However,
when the catalyst loading is further increased, the reaction
rate diminishes significantly (Figure 5, lower left) to finally
settle at a constant rate independent of the catalyst
concentration. As the occurrence of mass transfer limitation
Figure 4 Effect of the stirring rate on the initial reaction rate
-1
would result in a hyperbolic curve approaching 1.2 mM.min
partial pressure as vmax, the significant drop in initial rate cannot be explained
2
A first order dependence was found for the O
(
Figure 5, upper right, solid line). Since this first order relation by the occurrence of mass transfer limitation and another
might also derive from the observed mass transfer limitation factor has to be taken into account. Other examples of non-
effects we also examined the influence of the O
partial linear dependence on [Catalyst] for aerobic oxidations have
pressure at a very low catalyst concentration (6.25 mM versus previously been reported by the groups of Stahl and
2
1
7b,21
5
0 mM) to make sure that no mass transfer limitation is in Sheldon.
play. In this instance again a first order relation was found existence of dinuclear Cu-species. Trapping the active catalyst
dashed line). From this we can conclude that the observed in a dinuclear species can inhibit the reaction since adding
We attribute the continuous drop in rate to the
(
first order relation derives directly from the involvement of O
in or before the rate determining step.
2
more catalyst will only result in the formation of more dimer
via a second order process in [Catalyst]. The non-zero reaction
For the substrate (
concentration saturation kinetics are seen. A quasi linear (first considering that these dinuclear species are also catalytically
order) dependence is observed when less than 1 equivalent active (rate constant k ), however substantially less reactive
0.5 M) of acetic acid or
is used (Figure 5, upper left and than the mononuclear species (rate constant k ) (k > k ). This
lower right). When higher concentrations are used the is interesting as usually non-reactive dinuclear complexes are
1
) as well as for the acetic acid rate at very high catalyst loadings can only be explained by
d
(
1
m
m
d
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CuI (x mol%)
AcOH (1 eq.)
O
considered. A rate law (equation 1) was derived (see
supporting information) which takes into account reactive di-
N
N
O
2
2
2
DMSO
24 h, 100 ºC
nuclear complexes but no mass transfer limitation. A very
good fit could be obtained for the data points before and after
mass transfer limitation (dashed line). Between a copper
1
2
10 mol% CuI (0.05 M): 92 % (0 % 1)
00 mol% CuI (0.5 M): 55 % (42 % 1)
1
concentration from 25 mM to 125 mM (triangles) where O
2
Scheme 4 Control experiments with (super) stoichiometric amounts of catalyst
diffusion is at play the simulated rate is much higher than the
measured data points as expected.
To exclude the possibility of any catalyst degradation the
reaction was monitored with in-situ IR and, after the reaction
ꢎ
ꢀ
ꢁꢂꢃ ꢆ ꢈ ꢁꢊꢋꢃ ꢌ ꢆ ꢈ ꢁꢊꢋꢃ
was complete, another batch of substrate (1) was added. The
ꢇ
ꢉ
ꢍ ꢎ
ꢅ
ꢒꢒꢒꢒꢒꢒꢒꢓ1ꢔ
ꢎ
ꢀ
ꢄ
ꢈ ꢌ ꢈ ꢁꢊꢋꢃ ꢌ ꢈ ꢁCuꢃ
second reaction proceeded with no significant loss in reaction
rate (See Figure S21). Work-up of this reaction mixture
ꢏ
ꢐ
ꢑ
To support the catalytic activity at very high catalyst loading an provided ketone
2 in 92% yield with no starting material
experiment was performed with a stoichiometric catalyst remaining. From this we conclude that no significant
loading. Significant conversion and a moderate yield was seen degradation of the catalyst to inactive (dimeric) species is
after 24 hours (Scheme 4) which is in accordance with the occurring.
kinetic measurements. No significant side reactions take place
at high catalyst loading as the reaction gave a good mass
balance (> 90 %).
Figure 5 Dependence of the copper-catalyzed oxidation of 2-benzylpyridine (1) on [1] (upper left), O
initial reaction rate. The dashed curve for the [CuI] (lower left) is a fit of the following equation: d[2]/dt = (c
points for the [AcOH] and [1] respectively fit to the following equations: d[2]/dt = c [AcOH]/(c [AcOH] + c ) and d[2]/dt = c
mol %), AcOH (1 eq.), O (balloon), DMSO (10 mL), 100 °C.
2
partial pressure (upper right), [Cu] (lower left) and [AcOH] (lower right) on the
2
2
1
[Cu] + c
2
[Cu])/(c
3
[Cu] + c [Cu] + c
4
5
) to the datapoints (ꢀ). The data
1
2
3
1
[1]/(c
2
[1] + c ). Reaction conditions: 1 (5 mmol), CuI (10
3
2
II 11a
Cu ).
Structure of the catalytic species: An EPR-study
2
As we are working under O atmosphere in the
presence of acetic acid, the active catalytic species is likely to
II
contain a Cu center and the reaction therefore involves initial
In order to identify the copper species present during the
reaction, continuous-wave (CW) and pulsed EPR experiments
were performed on the oxidation reaction of the model
oxidation when salts at lower oxidation state are used as
2
precatalyst (equation 2).
4
2
3
substrate
1 shown in Scheme 1. In the initial screening of
catalysts it was shown that the reaction worked well for most
0
1
4
1
2
I
copper sources, irrespective of the oxidation state (Cu , Cu , ꢊꢋꢉꢕ
ꢕ
ꢎꢕ
ꢌ
ꢖ ꢌ ꢗ ꢒ→ꢒꢊꢋ ꢌꢒ ꢗ ꢖꢒꢒꢒꢒꢒꢒꢓ2ꢔ
ꢎ
ꢎ
6
| J. Name., 2012, 00, 1-3
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ARTICLE
I
The oxidation of Cu in the presence of pyridine to hydroxide- 0.34 cm and characteristic EPR spectra. Figure S2 shows the
-1
30
2
5
bridged polynuclear complexes has been well-documented.
temperature dependence of one of the high-field signals of
The situation in our case is different: since we are able to start this contribution, from which the exchange coupling J can be
-1
II
from a Cu source. This would require the use of H
2 2
O in stead determined (J = -274 cm ), in agreement with what was earlier
-1
of O to end up with the same reactive species. Possible anions reported for Cu (OAc) (H O) , namely J = -269 cm in frozen
2 4 2 2
2
II
for the Cu species are iodide, acetate and hydroxide. The acid solution. In the EPR spectra of the mixture without
31
I
latter is a result from the oxidation of Cu while the former two addition of acetic acid (Table 2, entry 1), no such dinuclear
are deliberately added to the reaction. Since no ligand is added copper complex could be found, in accordance with the
it is likely that DMSO will ligate (S- or O-ligation) to the copper absence of bridging ligands.
2
6
center to stabilize it in solution. Alternatively the substrate
) or reaction product ( ) can also act as a ligand. The
intermediate reacting with O
with the methylene carbon (Figure 10,
(
1
2
II
3
2
likely contains a Cu -C(sp ) bond
and B’). As stated
B
above this bond can be formed through initial tautomerization
of substrate followed by reaction with copper species.
However, since the equilibrium of this tautomerization is
highly shifted towards the imine tautomer we expect the
concentration of this intermediate to be very low during the
course of the reaction.
II
CuII(DMSO) (OAc)2
2
II
[
Cu (DMSO)
n
]X
2
[Cu (DMSO)
n
(1)
2
]Y
2
I
II
III
Figure 6 Experimental (cyan) and simulated (black) CW-EPR spectra of the
reaction mixture with 0.05 M CuI and 0.5 M 2-benzylpyridine ( ), 0.5 M acetic
acid and DMSO heated to 100 °C under O for 5 min, 10 min, 1 h and 4 h. The
1
II
II
II
II
Cu (OAc)
2
-
(1)
2
Cu (OAc)
2
(1)
2
(2)
(1)Cu (OAc)
4
Cu (1)
2
IV
V
VI
spectra were recorded at 100 K with a microwave power of 0.47 mW and a
microwave frequency of 9.73 GHz. (A) The spectrum of species III, obtained by
subtraction of the spectra obtained after 5 and 10 minutes is shown at the
bottom with its corresponding simulated spectrum. (B) Zoom on the low-field
components revealing the time-dependent evolution of the different species.
The experimental spectra are normalized for comparison.
-
X = HO , I
-
-
-
Y = HO , I , AcO
n = 2, 3, 4
Chart 1 Mono- and dinuclear copper species present in the reaction
Next, EPR measurements were done on reaction mixtures.
Figure 6A shows the EPR spectra observed after heating a
reaction mixture for 5 min, 10 min, 1 h and 4 h. The field area
Firstly, control CW-EPR measurements at 100 K were
performed on a solution of 0.05 M CuI in DMSO heated to 100
o
2
C during 10 minutes under O atmosphere (Figure S1(a)). The
II
II
Cu complex observed (species I) (Table 2, entry 1) has g and
specific for mononuclear Cu complexes is shown for the
spectra recorded at 100 K. None of the EPR spectra showed
signals typical of organic radicals. Instead, a clear evolution of
II
mononuclear Cu complexes is observed in function of the
copper hyperfine values that are similar to those reported
earlier for CuBr
2 2
.2H O in DMSO and is in accordance with the
II
complexation of Cu with DMSO ligands.
27
The same
reaction time, with different species contributing to the
spectra, as is best visible in the low-field range (Figure 6B). At
short reaction times (5 and 10 min), the EPR spectra revealed
two species, labeled III and IV, with the contribution of III
decreasing over time. After 1 h, only component IV is left and
II as the reaction progresses, a contribution of a new species V
starts to emerge. The EPR parameters of species IV are slightly
II changing with time (species IV’), which may be related to
changes in the direct neighborhood of the complex. The EPR
spectrum of species III can be obtained by a weighted
subtraction of the spectra recorded after 5 and 10 minutes
experiment was performed, but now in the presence of 0.5 M
AcOH (Figure S1(b)); copper (II) acetate is known to exist
mainly in a dinuclear form Cu
2 4
(OAc) in acetic acid and other
solvents, with only a small amount of mononuclear Cu(OAc)
2
2
8
II
complex present. Both types of Cu species (monomeric and
multimeric) can be distinguished by EPR. Indeed, two Cu
mononuclear complexes (species I’ and II) are detected (Table
2, entry 2, Fig. S1(b)), together with high-field signals from Cu
dimers (Fig. S2). Species I’ has parameters similar to those of
the complex observed without acetic acid and can be assigned
to the same complex. The small shifts in the parameters are
induced by the change in the dielectric constant of the
mixture. Species II features EPR parameters similar to those
(bottom spectrum in Figure 6A). In the high-field region, clearly
resolved hyperfine couplings are visible that can be
satisfactorily simulated considering the interaction of the
2
9
2 2
observed earlier for Cu(OAc) .2H O in different solvents.
1
4
unpaired electron with the copper nucleus and with two
N
With regard to the dinuclear species, the strong
antiferromagnetic coupling within the pair of copper ions in
surrounding nuclei. The hyperfine coupling of the latter
interaction (40 MHz) is similar to that obtained for the
2 4
Cu (OAc) generally results in a triplet state that lies
-1
hyperfine value of pyridine coordinated via nitrogen in Cu(py)
4
approximately 250-300 cm (=|J|) above the singlet state,
with typical zero-field splitting (D) for the triplet of the order of
3
2
complexes. Given that species III is observed at an early stage
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Journal Name
1
ꢜ
1
of the reaction it can be ascribed to an initial complexation of
ꢘꢙꢚꢛ
∝
ꢒꢒꢒꢒꢒꢒꢒꢒꢒꢒꢓ3ꢔ
1
3
the copper ion with two 2-benzylpyridine (
1
) molecules,
ꢝꢞꢟ⁄ꢠꢡ
ꢒ
1
ꢌ
-
Cu(DMSO) ]Y (Figure 6), where n= 2, 3 or 4 and Y = OH, I
-
[
n
(
1)
2
2
-
or OAc. Moreover, when the same reaction is carried out in
toluene instead of DMSO, the CW-EPR signal after 5 minutes
This is larger in absolute value than the one found for the
copper acetate dimer, agreeing with the earlier observation
reaction (Figure S12) shows only species with
g and A
that addition of pyridine to copper carboxylates yields
31
dinuclear Cu (O CR) py complex with increased |J| value.
2 2 4 2
parameters similar to species IV (see Table S3), without
contribution from DMSO-related species III. The EPR
parameters of species IV are very close to those reported for a
Furthermore, slight changes in the position of EPR peaks are
observed, indicative of a change in the D values of the triplet
state. The changes in J and D prove the presence of dinuclear
powder of Cu(O
2 3 2
CCPh ) .2py and for a frozen solution of
3
3,34
CaCu(OAc) .6H O in pyridine.
4
2
Addition of pyridine to
copper species with ligation of 2-benzylpyridine (
accordance with Cu (OAc) (species VI).
1), in
dinuclear copper carboxylates has been shown to yield
dinuclear complexes in equilibrium with mononuclear species
2
4 2
(1)
3
of the form Cu(O CR) py . The structure of IV can therefore
1
2
2
2
be assigned to Cu(OAc)2(1)2 (Figure 6). This is further
supported by the decrease of gz and increase of |Az|
compared to complex I and II, which is expected if more N-
II
bases are ligated to the Cu than in the former case. The
pulsed EPR analysis also confirmed the involvement of 2-
benzylpyridine (
supporting information). The influence of acetic acid on the N-
coordination of is neglible (Figure S13 and S14).
1) ligation in the mononuclear species IV (see
1
Furthermore, it has been reported that substitution of one N
by one C in copper (II) porphyrins significantly lowers the gz
value and increases |A | to values significantly different from
x,y
3
5
those observed for species III and IV. Hence, ligand to
catalyst coordination through a Cu-C bond can be discarded in
species III and IV.
Additionally, EPR signals in agreement with dinuclear copper
species could be found in the reaction mixture at all times Figure 7 Temperature evolution of the EPR intensity of one of the high-field EPR
signals typical for copper dimers (
benzylpyridine ( ) 0.5 M, 0.05 M CuI, 0.5 M acetic acid and DMSO heated to 100
C under O for 1 h. The red curve shows the fit using equation 3. The inset
ꢀ) formed in the reaction mixture: 2-
during the reaction. Figure 7 shows a temperature analysis of
one of the high-field EPR signals from copper dimers displayed
in the inset. The EPR intensity variation can be fit using the
Bleaney-Bower equation (equation 3), yielding a value for the
1
°
2
shows the high-field EPR signal used for the evaluation. The spectra were
recorded using a microwave frequency of 9.73 GHz and a microwave power of
0.047 mW.
-1 36
exchange coupling J of -306 cm .
8
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ARTICLE
II
Table 2 Principal g and copper hyperfine values of the mononuclear Cu complexes in the different reaction mixtures heated to 100 C
o
Entry
[CuI]
M)
Heating
time
g
x
g
y
g
z
|A
(MHz)
15
45
x
|
|A
y
|
z
|A |
(
±0.002
±0.002
±0.001
(MHz)
±15
55
(MHz)
±5
±
1
2
CuI/DMSO
0.05
0.05
10’
10’
I
2.082
2.087
2.405
385
CuI/DMSO/AcOH
I’
II
2.081
2.080
2.070
2.062
2.070
2.062
2.063
2.083
2.080
2.070
2.063
2.070
2.063
2.063
2.403
2.374
2.333
2.286
2.333
2.286
2.285
26
30
25
35
25
35
30
25
26
25
35
25
35
30
375
430
440
510
440
510
510
a)
3
4
CuI/DMSO/AcOH/(1)
CuI/DMSO/AcOH/(1)
0.05
0.05
5’
III
IV
a)
10’
III
IV
IV
5
6
CuI/DMSO/AcOH/(1)
CuI/DMSO/AcOH/(1)
0.05
0.05
1 h
4 h
IV’
V
2.063
2.067
2.066
2.072
2.062
2.075
2.063
2.067
2.066
2.072
2.063
2.072
2.290
2.262
2.286
2.330
2.285
2.334
30
35
35
25
35
25
30
35
35
25
35
25
505
560
510
450
510
455
7
8
CuI/DMSO/AcOH/(1)
CuI/DMSO/AcOH/(1)
0.25
0.25
10’
4 h
IV
b)
III
IV
b)
III
a)
The relative contributions of the different species to the experimental spectra are given in the supplementary material. For the simulation of the
1
4
contribution of species III in reaction mixture with starting concentration [CuI] = 0.05 M, the interaction with two N nuclei with a isotropic hyperfine
b)
14
coupling of 40±5 MHz had to be taken into account, The N hyperfine interaction was not resolved due to the increased linewidth, but was considered
in the simulation.
Interestingly, mononuclear complexes III and IV are also found presence of a type-V species (see supplementary material,
in the EPR spectra of the reaction mixture using a higher Figures S6-S7) supporting our hypothesis. The trend in the EPR
copper concentration of 0.25 M (Figure S5). However, here the parameters suggests a higher number of nitrogen ligands in
contribution of species III dominates the EPR spectrum even the case of species V than for species III and IV, suggesting an
after 4 h of reaction (Table 2, entries 7 and 8, spectrum not extra ligation of
shown), while it disappears within the first hour in the reaction y ligated to two other nitrogen ligands
mixture with a 0.05 M copper concentration (Figure 6B, Table In order to check the influence of the measurement
, entries 3-6). This can be rationalized when considering that temperature on the occurrence of the different copper
the Cu(OAc) ( )2 complex (IV) is readily formed for high species, CW-EPR experiments were performed at different
2 to a copper ion that is already
3
.
7
1
2
1
2
II
II
[1
]/[Cu ] and [AcOH]/[Cu ] ratios, as is the case for our temperatures. Figures 8 and 9 show the room-temperature
standard reaction conditions. However, when the copper CW-EPR spectra of the copper-catalyzed oxidation of 2-
concentration is increased, the relative amount of acetate per benzylpyridine ( ) with starting concentrations of 0.05 M and
copper is lower and mononuclear copper complexes involving 0.25 M CuI, respectively, recorded on aliquots of the reaction
1
-
-
1
and/or DMSO with I or HO as anions, instead of
1
and mixture taken at different times in the reaction. Again, none of
the spectra show contributions of organic radicals, confirming
acetate may be formed at higher relative quantities.
Complex V is only resolved in the EPR spectra of the reaction the low-temperature EPR results and the kinetic experiments
mixture with low copper content after a longer (4 h) reaction using radical scavengers. In line with the low-temperature EPR
II
]/[Cu ] ratio can (Figure 6, Figure S5), a significant variation of the EPR
time (Table 2, entry 6, Figure 6B). Since the [
2
already be significant at this stage of the reaction, the ligation spectrum can be seen during the course of the reaction
of to the copper complex becomes competitive. In the involving a lower copper loading due to contributions of
reaction with high copper content, the [ ] may be too small for species III and IV (Figure 8), whereas a negligible variation is
2
2
the complex to be formed. Unfortunately, the copper amount seen when a higher amount of copper is used (Figure 9) (see
was too high at this stage of the reaction for both mixtures to also detailed comparison in supporting information, Figures
allow for pulsed EPR analyses to verify this possibility (too fast S8-S9). Comparison of the latter spectra with the EPR
electronic relaxations). However, CW-EPR spectra recorded of spectrum of the solution without substrate 1 (bottom Figure 9)
II
revealed the suggests a strong contribution of Cu complexes that are
a reference mixture of CuI, AcOH and ketone
2
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Journal Name
related to species I and II. This is surprising, since no due to spectral broadening effects as reported earlier by
3
8
II
contributions of these species were observed in the spectra at others for dinuclear copper acetate species. Large Cu
00 K (Figure S5). This indicates that the equilibrium of concentrations are required to be able to observe the typical
1
reaction (4) shifts to the right as temperature decreases.
EPR features stemming from dinuclear copper species at room
temperature (Figure S11, signals indicated with arrows). The
amount of dinuclear species is clearly increasing during the
reaction time. Furthermore, the signal change at a later stage
of the experiment (see for instance the appearance of a peak
ꢢꢢ
ꢢꢢ
ꢁ
Y = OH, I, OAc
ꢊꢋ ꢓꢣꢤꢥꢖꢔ ꢃꢧ ꢌ 2ꢓꢨꢔ
ꢁꢊꢋ ꢓꢣꢤꢥꢖꢔ ꢓꢨꢔ ꢃꢧ ꢒꢒꢒꢒꢒꢒꢒꢒꢓ4ꢔ
ꢦ ꢎ ꢎ
ꢦ
ꢎ
-
-
-
II
A high [
1
]/[Cu ] ratio evidently also pushes the equilibrium to around 480 mT) is indicative of variation in the types of
the right, explaining why the contribution of species III and IV dinuclear complexes that are formed under these
can still be seen and I and II are less dominant in the room- circumstances. This points to a variation in the axial ligands L
temperature spectra of the reaction mixture at lower CuI of Cu (OAc) L ;
1, 2 or solvent molecules. Further proof for
2
4 2
II
concentration (Figure 8).
these acetate bridged dinuclear Cu species was obtained
using infrared spectroscopy. When working at increasing
concentrations of added CuI, new peaks started to arise in the
infrared spectrum of the reaction mixture. By deconvolution of
the overall IR spectrum a new IR spectrum could be obtained.
The resulting spectrum matches with that of Cu(OAc) ·2H O in
2
2
DMSO which is known to exist as a dinuclear species and a
II
reported dinuclear acetate bridged Cu complex (See Figure
3
9
S23-S24). Furthermore, increasing amounts of CuI cause a
decrease in the concentration of free AcOH in the reaction
mixture. This can be monitored by following the decrease in
-1
area of the C=O bond vibration of AcOH (around 1718 cm ). At
the same time an increase in intensity is observed for the
-1
vibration appearing at 1623 cm (See Figure S25-S26). The
lowering of the wavenumber of AcOH can be rationalized by
its complexation, bridging two copper centers, hereby
weakening it’s C=O bond.
Figure 8 Room-temperature X-band CW-EPR spectra of the copper-catalyzed oxidation
of 1 with 0.05 M CuI recorded in function of time. The spectra are recorded with a
microwave power of 0.047 mW and a microwave frequency of 9.73 GHz.
Catalytic cycle
Based on all the insight gathered a catalytic cycle is proposed
in Figure 10. Aerobic oxidation of the added CuI brings the
catalyst to the active +II oxidation state (complexes
initial acid-catalyzed imine-enamine tautomerization,
characterized by the equilibrium constant Keq transforms the
substrate into the enamine tautomer . Nucleophilic attack
of on an electrophilic Cu center (monomer IV or dimer VI
produces a C-Cu bond (
for the tautomerization. Although adding an acid does not
change the equilibrium between and , it will lower the
activation energy, thereby increasing the rate by which
enamine is replenished. All these steps are reversible and in
I-IV). An
1
A
II
A
)
II
B
or B’). Acetic acid acts as a catalyst
1
A
A
rapid equilibrium characterized by their respective equilibrium
constants. Their relative concentrations depend on the initial
reaction conditions (the ratios between all the reaction
components: Substrate, Catalyst, Acid and Solvent). In the next
Figure 9 Room-temperature X-band CW-EPR spectra of the copper-catalyzed oxidation
of 1 with 0.25 M CuI in function of time. At the bottom, the corresponding spectrum of
the reaction mixture without the substrate 1 is shown. The spectra are recorded with a
microwave power of 0.047 mW and a microwave frequency of 9.73 GHz.
II
step the Cu center that is bound to the substrate molecule
III
to a highly reactive Cu -superoxide
will be oxidized by O
2
4
0,41
species (
rate determining step and it is herein that lies the difference in
reaction rate for mononuclear (k ) versus dinuclear (k
catalyst species (k > k ). The superoxide species will quickly
rearrange via a radical pathway with an electron transfer to
C
or C’).
The oxidation of B/B’ is thought to be the
Although clear evidence of the presence of dinuclear species in
the reaction mixture with 0.05 M CuI (Table 2, entries 3-6) and
the CuI/DMSO/AcOH system (Table 2, entry 2) is found at low
temperatures (Figure S2, Figure 7), no signals due to dimers
are observed in the EPR spectra at room temperature (Figure
S10). This is not due to the absence of the dimers, but is simply
m
d
)
m
d
II
the catalyst producing the Cu organoperoxide
D or D’.
Heterolytic dissociation of these organoperoxides by
1
0 | J. Name., 2012, 00, 1-3
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deprotonation of the remaining benzylic proton produces the Alcohol
reaction product and recovers the catalyst with a hydroxide study of the mechanism of its formation was not possible.
rather than an acetate bound (
converted back to IV and VI by anion exchange with acetate, hydride elimination (Scheme 2).
3 is formed in such small quantities so that an in-depth
2
4
2
E
or E’).
E and E’ can be Alcohol 3 can be transformed into 2 by copper-catalyzed β-
1
6
4
3
hereby producing one equivalent of water.
The amount of O required to make one molecule of ketone
2
Conclusions
was determined by performing gas uptake experiments. It was
found that when using CuI (10 mol %) as the catalyst the
This research has provided deeper insight into the mechanism
II
of Cu -catalyzed aerobic oxygenations. Although the
2
O :Substrate stoichiometry is ∼1 (see supporting information).
These results confirm that in accordance with our mechanistic
proposal for each molecule of product one molecule of water
is formed and that no extra oxygen is required to oxidize the
catalyst during the catalytic cycle.
mechanism of Cu-catalyzed aerobic alcohol oxidation has been
thoroughly studied, kinetic studies on the corresponding
methylene oxidation are unprecedented. Only reactions on
stoichiometric Cu-complexes with oxygen have been reported.
In this study we have shown that the substrates are activated
via an initial acid catalyzed imine-enamine tautomerization.
DFT calculations can be used as useful method to predict the
equilibrium constant (Keq) and can act as a tool to qualitatively
For our proposed catalytic cycle a kinetic isotope effect is
expected even though C-H/D bond cleavage is not included in
the rate-determining step. As the C-H bond cleavage (via imine
-
enamine tautomerization) is reversible and its k-1 is much
faster than the k of the RDS (oxygenation), the observed KIE is
the equilibrium isotope effect. When comparing the initial
rates of the reaction on using AcOH with that of -d using
AcOD-d a KIE value of 4.28 was found (Figure S19). As an
2
predict whether or not a substrate can be oxidized. Alcohol
3
4
4
was excluded as an intermediate in this reaction and is a side
product presumably generated by the homolytical breaking of
1
1
2
4
the O-O bond in the hydroperoxide formed from complex
D/D’
additional experiment we tested if deuterium could be build-in
via tautomerization under our reaction conditions. When
via protonation. Kinetic studies revealed O mass transfer
2
limitation effects limiting the turnover of the reaction at high
concentrations of substrate and acetic acid. A complex kinetic
behavior was observed when increasing the catalyst loading.
At intermediate loadings mass transfer is again occurring
resulting in a maximum rate. The continued decrease of the
reaction rate at higher concentrations of catalyst however
can’t be explained by the occurrence of mass transfer alone.
When using transition metal catalysis in combination with
mixing 2-benzylpyridine with d
4
-AcOD in deuterated DMSO in
the singlet of the benzylic
the absence of catalyst and O
2
1
protons started to disappear in H-NMR and a broad triplet
resulting from -d started to appear further supporting the
imine-enamine tautomerization (See SI Figure S20). In
1
1
contrast, diphenylmethane (
same manner as expected.
8) could not be deuterated in the
The EPR experiments (Table 2) indicate that the catalyst
resting state is species IV with even at low [Catalyst] a
significant contribution of dinuclear species VI. When the
(
acetate) bridging ligands dinuclear species need to be
considered. Although these are usually considered to be
related to catalyst deactivation this study shows this is not
necessarily the case as they explain the further reduction in
rate observed at a higher concentration than at which the
mass transfer determined vmax occurs. The formation of a
dinuclear catalytically active species which is less reactive than
the mononuclear catalyst explains the non-zero reaction rate
at increased concentration of added catalyst. Such behavior is
to the best of our knowledge unprecedented in literature. In
addition to these kinetic experiments we performed an in-
depth EPR-study to characterize the catalytic species present
in the reaction. These measurements confirmed the presence
[
Catalyst] is increased the equilibrium is significantly shifted
towards the dinuclear species VI. Because the equilibrium
between the imine ( ) and enamine ( ) tautomers is highly
shifted towards the imine ( ) the concentration of species
1
A
1
B
and B’ is expected to be very low which explains why these
species were never directly observed by EPR measurements.
The reason why the dinuclear species oxidize slower than the
mononuclear is unclear. The simplest explanation is the
increased steric bulk of the catalyst (4 bridging acetates).
II
However it is also possible that the second Cu in C’ reacts with
III
the formed Cu -superoxide species producing a less reactive
II
of both different mono- and dinuclear Cu -species. The results
dioxygen bridged species.
presented in this paper can directly be used in the mechanistic
study of other active methylene oxygenations where the
methylene moiety is activated by a tautomerization step.
Formation of side product
intermediate or D’ producing a hydroperoxide that can
undergo a Fenton like Cu -catalyzed homolytical cleavage of
the O-O bond yielding alcohol and a hydroxyl radical. This
3 can occur via protonation of
D
I
3
4
5
radical is known to be very reactive and thus very short-lived.
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ARTICLE
O
O
cat. AcOH
N
N
2
2
N
2
NH
K
eq
1
A
CuII(OAc)L
Cu (AcO)
II
CuIIL
3 2
2
O
O
O
CuII(OAc)L
CuII(AcO)
OH
CuII
O
3
L
2
OH
E'
H
N
E
AcOH
AcOH
H
N
D
H
2
O
H
2
O
D'
CuII(OAc)
L
2
L= (1)
2
I
II
III
CuII(OAc)
2
L
2
CuII
2
(OAc)
4
L
2
K
6
K
5
K
1
K
2
IV
2L
VI
O
O
CuIII(OAc)L2
O
N
CuIII(AcO) CuIIL
3 2
k3
k4
O
A
A
N
CuII(AcO) CuIIL
3 2
II
AcOH
AcOH
Cu (AcO)L
C
2
C'
RDS
RDS
N
N
k
m
O
2
B
B'
k
d
O
2
Figure 10 Mechanistic proposal for the aerobic Cu-catalyzed oxidation of 1 into 2.
5
(a) Y.-F. Wang, F.-L. Zhang, S. Chiba, Synthesis 2012, 44,
1
4
526-1534. (b) B. Orlińska, Tetrahedron Lett. 2010, 51, 4100-
102. (c) N. Komiya, T. Naota, Y. Oda, S. I. Murahashi, J Mol
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This work was supported by the Research Foundation Flanders
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3
6
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(
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