Mechanism of alkene, alkane, and alcohol oxidation with H2O2 by an in situ prepared MnII/pyridine-2-carboxylic acid catalyst

Article abstract of DOI:10.1021/acscatal.6b00320

The oxidation of alkenes, alkanes, and alcohols with H₂O₂ is catalyzed efficiently using an in situ prepared catalyst comprised of a Mn^II salt and pyridine-2-carboxylic acid (PCA) together with a ketone in a wide range of solvents. The mechanism by which these reactions proceed is elucidated, with a particular focus on the role played by each reaction component: i.e., ketone, PCA, Mn^II salt, solvent, etc. It is shown that the equilibrium between the ketone cocatalysts, in particular butanedione, and H₂O₂ is central to the catalytic activity observed and that a gem-hydroxyl-hydroperoxy species is responsible for generating the active form of the manganese catalyst. Furthermore, the oxidation of the ketone to a carboxylic acid is shown to antecede the onset of substrate conversion. Indeed, addition of acetic acid either prior to or after addition of H₂O₂ eliminates a lag period observed at low catalyst loading. Carboxylic acids are shown to affect both the activity of the catalyst and the formation of the gem-hydroxyl-hydroperoxy species. The molecular nature of the catalyst itself is explored through the effect of variation of Mn^II and PCA concentration, with the data indicating that a Mn^II:PCA ratio of 1:2 is necessary for activity. A remarkable feature of the catalytic system is that the apparent order in substrate is 0, indicating that the formation of highly reactive manganese species is rate limiting.

Full text of DOI:10.1021/acscatal.6b00320

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Article
Mechanism of alkene, alkane and alcohol oxidation with H2O2
by an in situ prepared MnII/ pyridine-2-carboxylic acid catalyst
Pattama Saisaha, Jia Jia Dong, Tim Geert Meinds, Johannes W de Boer,
Ronald Hage, Francesco Mecozzi, Johann B Kasper, and Wesley R. Browne
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00320 • Publication Date (Web): 18 Apr 2016
Downloaded from http://pubs.acs.org on April 22, 2016
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Mechanism of Alkene, Alkane and Alcohol Oxidation with
H2O2 by an in situ prepared MnII/ Pyridine-2-Carboxylic Acid
Catalyst
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Pattama Saisaha,a Jia Jia Dong,a Tim G. Meinds,a Johannes W. de Boer,b Ronald Hage,b Francesco
Mecozzi,a Johann B. Kasper,a Wesley R. Browne a,*
aMolecular Inorganic Chemistry, Stratingh Institute for Chemistry, Faculty of Mathematics and Natural Sciences,
University of Groningen, Nijenborgh 4, 9747 AG, The Netherlands.
bCatexel Ltd, BioPartner Center Leiden, Galileiweg 8, 2333 BD Leiden, The Netherlands.
ABSTRACT: The oxidation of alkenes, alkanes and alcohols with H2O2 is catalyzed efficiently using an in situ prepared
catalyst comprising of a MnII salt and pyridine-2-carboxylic acid (PCA) together with a ketone in a wide range of solvents.
The mechanism by which these reactions proceed is elucidated, with a particular focus on the role played by each reac-
tion component, i.e. ketone, PCA, MnII salt, solvent etc. It is shown that the equilibrium between the ketone co-catalysts,
in particular butanedione, and H2O2 is central to the catalytic activity observed and that a gem-hydroxyl-hydroperoxy
species is responsible for generating the active form of the manganese catalyst. Furthermore the oxidation of the ketone
to a carboxylic acid is shown to antecede the onset of substrate conversion. Indeed addition of acetic acid either prior to
or after addition of H2O2 eliminates a lag-period observed at low catalyst loading. Carboxylic acids are shown to affect
both the activity of the catalyst and the formation of the gem-hydroxyl-hydroperoxy species. The molecular nature of the
catalyst itself is explored through the effect of variation of MnII and PCA concentration, with the data indicating that a
MnII:PCA ratio of 1:2 is necessary for activity. A remarkable feature of the catalytic system is that the apparent order in
substrate is zero indicating that the formation of highly reactive manganese species is rate limiting.
KEYWORDS. manganese, oxidation, catalysis, Raman spectroscopy, epoxidation.
Introduction
Catalytic systems for the oxidation of alkenes to epoxides or
cis-diols and for C-H and alcohol oxidation, based on 1st row
transition metals, continue to attract substantial attention,1 not
least those systems that use the atom economic and environ-
mentally friendly terminal oxidants O2 and H2O2. Manganese2
and iron3 based catalysts, due to negligible toxicity and envi-
ronmental impact, have seen rapid progress in terms of cost
and reactivity. The development of new ligand systems to
control reactivity and selectivity has focused most notably on
polyalkyl amine/pyridyl frameworks, e.g., the 1,4,7-
triazacylononane4 and pyridyl-amine based ligand families
(e.g., TPA, TPEN, TPTN).5
Figure 1. Ligands discussed in the text and conversion of
pyridyl-amine based ligands to pyridine-2-carboxylic acid
Over the last two decades, manganese complexes of the
(PCA) under oxidizing conditions.9
,10
pyridyl-amine based ligand families (Figure 1) have been
,
applied to a wide range of oxidative transformations.6 7 Alt-
Later mechanistic studies by our group revealed that during
the lag period pyridyl-amine ligands, such as TPEN, and its
aminal precursors, underwent oxidative degradation to pyri-
dine-2-carboxylic acid (PCA)
(Figure 1).10 It was, in fact, the PCA formed through ligand
degradation, together with manganese and a ketone that was
responsible for the catalytic activity and selectivity observed.
Indeed, where PCA was used in place of the more complex
ligands, the efficiency with respect to H2O2 became essentially
hough, many of these complexes showed good activity in the
epoxidation of alkenes, they presented severe limitations in
regard to application. Most critically, 8-10 equiv. of H2O2
w.r.t. substrate were required. This inefficiency was due to
extensive H2O2 disproportionation during a lag period that
preceded the oxidation of organic substrates.8 Furthermore,
these catalyst systems were active only in ketone based sol-
vents such as acetone, which presents additional risks in oxi-
dations with H2O2.
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complete with elimination of the wasteful disproportionation
of H2O2.
The catalytic system based on MnII/PCA that was discov-
ered through these mechanistic studies still presented the dis-
advantage that ketone solvents were necessary for activity to
be observed.10 Subsequently, it was found that ketones such as
acetone and CF3COCH3 could be used as co-solvents,11 and in
particular, that butanedione12 could be used sub-
stoichiometrically. In addition, with sub-stoichiometric bu-
tanedione the reaction times were reduced dramatically from
several hours to several minutes, in comparison to reactions
carried out in acetone. Furthermore, the use of a ketone sub-
stoichiometrically enabled the application of this system in a
wide range of polar protic and aprotic solvents, e.g., ethanol
and acetonitrile (Scheme 1).
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Scheme 2. Equilibrium between butanedione/H2O2 and 3-
hydroperoxy-3-hydroxybutanone.
Furthermore, initial mechanistic studies established12 that
the ketones, i.e. acetone, butanedione, undergo oxidation to
yield carboxylic acids also; i.e. acetic acid in the case of bu-
tanedione and acetone. Notably, however, the deliberate addi-
tion of acetic acid did not affect the conversion and selectivity
of the reaction,12 and the in situ formation of peracetic acid
was excluded. These observations raise questions regarding
the role, if any, of the acetic acid formed during the reaction
and indeed the effect of carboxylic acids on the reaction in a
general sense.
In this contribution, the mechanism by which MnII/PCA in
combination with butanedione and a base engages in the cata-
lyzed oxidation of alkenes, alkanes and alcohols with H2O2 is
explored. The high activity and low catalyst loadings required
and the absence of spectroscopic signals assignable to manga-
nese species involved in this system (e.g., by EPR or UV/Vis
spectroscopy)12 means that direct identification of the ‘active
species’ or even the catalyst in its resting state is impractical.14
Nevertheless, insight into the role of each reaction component
can be gained through reaction progress monitoring, from
which a global mechanistic understanding of the reaction
emerges. The aim is not to propose a microkinetic description
of the catalytic system but instead to rationalize the empirical
observations made with regard to all reaction components and
hence to establish the understanding needed to facilitate rapid
optimization of reaction conditions.
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Results
Although the MnII/PCA catalyst system shows a broad sub-
strate scope, including alkene, alcohol and alkane oxidation,
alkenes undergo oxidation preferentially. Furthermore, it is
expected that a common active oxidant is responsible for all
three transformations. Hence, cyclooctene, styrene, 1-
phenyethanol and 3-vinyl-benzaldehyde were chose as repre-
sentative substrates with which to probe the mechanism of the
reaction. The conversion of substrate, the formation of prod-
ucts and the changes of butanedione and H2O2 concentration
were determined by monitoring changes in characteristic Ra-
man bands relating to each component over time (see for ex-
ample in Figure 2).12
Scheme 1. Oxidation of alkenes, alkanes and alcohols using
an in situ prepared MnII/PCA catalyst system.11,12
The preparation of catalysts in situ from readily available
components is advantageous as it circumvents the need for
prior ligand and catalyst synthesis. The in situ formed catalyst
system based on PCA, a MnII salt and a base (e.g., NaOH,
NaOAc, etc.), together with a ketone, either as solvent or co-
solvent, enabled high turnover numbers (>300,000) and turno-
ver frequencies (40 s-1) to be achieved in the epoxidation and
cis-dihydroxylation of alkenes11,12 and in alcohol and C-H
bond oxidation13 with H2O2. The system provides good to
excellent multigram conversions and yields, as well as a broad
functional group tolerance.
Despite that the catalyst system is prepared in situ, it was
apparent that the mechanism by which it works is complex.
From UV/Vis absorption, 13C NMR and Raman spectroscopy
it was apparent that the ketone forms a gem-hydroxy-
hydroperoxy species (Scheme 2), which is essential to the
generation of the active (oxidizing) form of the catalyst.12
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clooctene). As noted earlier12 addition of acetic acid (0.2
equiv. w.r.t substrate) to the reaction either before or after
addition of H2O2 did not affect conversion or yield significant-
ly.12 13C NMR spectroscopy confirmed that, in the case of
butanedione, acetic acid forms prior to the end of the lag peri-
od. However, addition of acetic acid (0.2 equiv. w.r.t sub-
strate) before H2O2 results in an immediate reaction upon
addition of H2O2 (i.e. the lag period was eliminated). Similar-
ly, when acetic acid was added after addition of H2O2, conver-
sion started immediately also. Notably, however, the reaction
rate (at maximum TOF) was the same regardless of whether
acetic acid was added or not (Figure 3). Indeed addition of
acetic acid after the onset of substrate oxidation has no effect
on the reaction rate (i.e. neither on the rate of oxidation of the
alkene nor butanedione itself). These data confirm that acetic
acid is essential to the onset of catalytic activity and its for-
mation in situ from butanedione is an autocatalytic reaction
that is manifested in a lag time followed by the rapid onset of
catalytic activity. Furthermore, oxidation of butanedione con-
tinues at an essentially constant rate concomitant with oxida-
tion of the substrate, e.g., cyclooctene (vide infra, ).
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Figure 2. Reaction progress monitoring of styrene oxidation
by Raman spectroscopy (ex 785 nm). Selected characteristic
bands and changes observed during oxidation are indicated.
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At low concentrations of MnII (e.g., 0.05 mM) a lag period
follows addition of H2O2, after which substrate oxidation is
observed (Figure 3). The duration of the lag period is depend-
ent [MnII] (vide infra). By contrast, the absorbance band at
max 417 nm (vide infra) and carbonyl stretching band of bu-
tanedione (Figure 2) decrease within a few seconds of addition
of H2O2. The lag period observed is, therefore, not due to a
delay in the formation of 3-hydroxy-3-hydroperoxy-butanone
(Scheme 2). Furthermore the lag period shows little sensitivity
to substrate (e.g. diethylfumarate, cyclooctene).15 Hence, a
second slower process occurs prior to the onset of catalytic
oxidation of substrates; possibly the oxidation of the ketone to
the corresponding carboxylic acid.
Figure 4. Change in [cyclooctene] over time during oxida-
tion in ethanol and in acetonitrile without and with addition
of acetic acid (0.1 M) prior to addition of H2O2. Conditions:
0.5 M cyclooctene, 0.75 M H2O2, 0.25 M 1,2-dichlorobenzene
(internal reference), 0.25
M
butanedione, 0.05 mM
Mn(ClO4)2, 2.5 mM PCA, 5 mM NaOAc, at 15 oC.
Figure 3. Change in [cyclooctene] over time in acetonitrile
under the conditions stated in Scheme 1, without (green) and
with addition of acetic acid (0.1 M) before (red) and after
(black) addition of H2O2. Points of addition are indicated by
arrows. Conditions: 0.5 M cyclooctene, 0.75 M H2O2, 0.25 M
1,2-dichlorobenzene (internal reference), 0.25 M butanedi-
one, 0.05 mM Mn(ClO4)2, 2.5 mM PCA, 5 mM NaOAc, at 15
oC.
Effect of acetic acid on reaction progress
A notable feature of the MnII/PCA system is that oxidation
of the ketone (e.g., -oxidation of acetone and butanedione) is
observed in addition to oxidation of the substrate (e.g., cy-
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Figure 5. Change in [cyclooctene] over time in C2H5OH and
in C2H5OD, without and with acetic acid (0.1 M) added prior
to addition of H2O2 and D2O2, respectively. Conditions: 0.5 M
cyclooctene, 0.75 M (H/D)2O2, 0.25 M 1,2-dichlorobenzene
(internal reference), 0.25
M
butanedione, 0.05 mM
Mn(ClO4)2, 2.5 mM PCA, 5 mM NaOAc, at 15 oC.
The MnII/PCA catalyzed oxidation of cyclooctene with
H2O2 and butanedione, proceeds in both the polar aprotic sol-
vent, acetonitrile, and the polar protic solvent, ethanol (Figure
4). The reaction rate is solvent dependent, however, as for
acetonitrile, the lag time observed in ethanol is eliminated also
by the addition of acetic acid. Raman and UV/Vis absorption
spectroscopy confirm that the decrease in reaction rate in
ethanol is not due to an effect of solvent on the extent of for-
mation of the 3-hydroxy-3-hydroperoxybutanone (Scheme 2)
and indeed equilibrium is reached within several seconds in
both solvents.
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The reaction does not show a solvent kinetic isotope effect
(i.e. KIE = 1 is observed) in ethanol, i.e. the use of
CH2CH3OD, CH3CO2D and D2O2 in D2O has no effect on
reaction rate with and without acetic acid (Figure 5). Further-
more, both the lag time and reaction rate in acetonitrile shows
relatively little sensitivity to temperature with only a doubling
o
in reaction rate between 0 and 45 C. The origin of the minor
dependence on temperature is due in small part to the rapid
prior equilibrium between butanedione and H2O2, which is
shifted to the left as temperature is increased, thereby decreas-
ing the concentration of the perhydrate. The lag phase ob-
served in the absence of acetic acid is, however, reduced as the
temperatures increases.
Figure 6. Conversion (after 1 and 4 h) of cyclooctene using
standard conditions (upper) in acetonitrile and (lower) in
ethanol w.r.t. the pKa of various acids (0.1 M) added prior to
addition of H2O2. Conditions: 0.5 M cyclooctene, 0.75 M
H2O2, 0.25 M 1,2-dichlorobenzene (internal reference), 0.25
M butanedione, 0.05 mM Mn(ClO4)2, 2.5 mM PCA, 5 mM
NaOAc, at 15 oC.
These data raise questions regarding the role, if any, of ace-
tic acid during the reaction and indeed the effect of carboxylic
acids on the reaction in a general sense.
Effect of carboxylic acids on the oxidation of cyclooctene
Perchloric acid and a series of carboxylic acids, covering a
pKa range from -10 to 4.76,16 were added under standard reac-
tion conditions both in acetonitrile and in ethanol (Figure 6).17
Except with trichloroacetic acid and with perchloric acid, the
same maximum conversion was reached typically within 4 h
(Table S1). The lack of substrate conversion in the presence of
trichloroacetic acid or perchloric acid can be ascribed to their
pKa. These are the only acids in the series for which their pKa
With all other carboxylic acids examined, the progress of
the reactions over time (Figure 7) shows a dependence on the
acid added. In addition to those acids that prevent oxidation of
cyclooctene completely (i.e. with a pKa lower than PCA, e.g.,
CCl3CO2H), the presence of acids with pKas in the range 1.69-
3.45, (e.g. CH2ClCO2H) leads to a considerable reduction in
reaction rate. For acids with pKa’s > 3.5, the lag period that
follows addition of H2O2 was eliminated, although the reaction
rate was not affected. In the case of salicylic acid, the decrease
in reaction rate is likely to be due to competition with PCA for
binding to MnII, thereby reducing the effective concentration
of the catalyst. Thus it is apparent that the pKa of the acid
present determines its effect on the reaction with acids with a
pKa < 0.7 inhibiting the reaction completely, those with a pKa
< 3.5 retard the reaction and those with a pKa > 3.5 only elim-
inate the lag period.
-
is lower than that of PCA {pKa1 = 1.07 (CO2H/CO2 ) and pKa2
= 5.25 (PyH+/Py)},18 and hence are expected to protonate PCA
and thereby inhibit formation of the catalyst by reducing the
effective concentration of PCA (vide infra).
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to that observed with and without acetic acid. In the case of
chloroacetic acid the decrease was biphasic with a moderately
rapid phase (over 3 min) and a subsequent slower phase, while
for trichloroacetic acid only a slow (exponential) decrease in
absorbance was observed. Importantly in both cases a con-
comitant appearance of the Raman bands of 3-hydroxy-3-
hydroxyperoxy-butanone was observed. Hence the decrease in
reaction rate in the former case and absence of reactivity in the
latter case, are not due to the absence of 3-hydroxy-3-
hydroperoxybutanone. Furthermore, the consumption of H2O2
in each case corresponded to the extent of alkene conversion,
excluding the occurrence of H2O2 disproportionation. In both
cases, however, the butanedione and the 3-hydroxy-3-
hydroxyperoxy-butanone are both consumed over the course
of the reaction. An additional signal observed at 117 ppm by
13C NMR spectroscopy after the reaction is consistent with
loss of butanedione due to aldol condensations. Hence the lack
of conversion in the case with CCl3CO2H is most likely due to
a reduction in the effective concentration of PCA through
protonation (vide supra).
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Figure 7. Conversion of cyclooctene in acetonitrile under
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conditions shown in Figure 6 without added acid, with acetic
acid (0.1 M), with CH2ClCO2H (0.1 M), and with CCl3CO2H
(0.1 M).
It should be noted that almost full conversion of diethyl-
fumarate is observed earlier using CF3COCH3 (10 vol%) as
ketone in acetonitrile, whereas conversion was not observed
with CF3COCF3 or CCl3COCCl3.11 The differences in behavior
cannot be ascribed to differences in the extent to which a 3-
hydroperoxy-3-hydroxy species forms. Instead it is more like-
ly that the lack of reactivity in the latter cases is due to the fact
that oxidation of CF3COCF3 and of CCl3COCCl3 will lead to
the formation of CF3CO2H and CCl3CO2H, respectively. In
contrast, with CF3COCH3, oxidation will likely produce acetic
acid and not CF3CO2H. Since trihaloacetic acids inhibit the
reaction completely (vide supra) then their formation can
rationalize the lack of conversion observed.
The effect of several of the acids on the equilibrium be-
tween butanedione and H2O2 was examined by UV/Vis ab-
sorption and Raman spectroscopy. The intense near-UV ab-
sorption band of butanedione (Figure 8), together with the
Raman band at 640 and 702 cm-1 of 3-hydroperoxy-3-
hydroxybutanone (Figure 2), allows for in-line monitoring the
concentration of both species. Only acetic acid gives behavior
comparable with that observed in the absence of added acid,
i.e. a sudden decrease in absorbance and concomitant increase
in the Raman band at 850 cm-1 due to formation of 3-hydroxy-
3-hydroperoxybutanone. The reaction in the presence of acetic
acid does not show a lag time after addition of H2O2 (vide
supra) and maximum conversion is reached within 5 min
(Figure 7), which is concomitant with the partial recovery of
the absorbance and Raman bands of butanedione (Figure 8).
Hence, the equilibrium between butanedione and H2O2 and its
adduct is unaffected by the presence of acetic acid.
Dependence of reaction on [MnII]
The lag time and reaction rate showed a dependence on
[MnII] in the oxidation of cyclooctene (Figure S1), 3-
vinylbenzaldehyde (Figure 9) and styrene. Decreasing [MnII]
resulted in a lengthening of the duration of the lag time and a
reduction in the rate of substrate oxidation (M s-1). In all cases,
however, after the lag period, the rate of substrate oxidation
increases to a maximum rapidly and then proceeds at that rate
until conversion ceases. In the presence of 0.2 equiv. of acetic
acid w.r.t. substrate, the reaction commences immediately
upon addition of H2O2, however, the maximum rate of sub-
strate oxidation is the same as without acid. The maximum
conversion reached at higher [MnII] was found to be essential-
ly constant. The dependence of the maximum rate of oxidation
of substrate on [MnII] confirms that the manganese catalyst
formed is involved at the rate determining step of the reaction.
For all substrates the turnover frequency once the reaction had
reached a maximum rate of substrate oxidation (i.e. the linear
part of the graphs) was relatively independent of catalyst con-
centration (ranging from 15 to 30 s-1), indicative of a 1st order
dependence on [MnII]. Notably, with a [MnII] > 0.5 mM, the
maximum conversion reached decreases substantially, in part
due to the low [PCA] to [MnII] ratio (vide infra).
Figure 8. Change in absorbance of butanedione at 450 nm19
after addition of H2O2 with various acids in the oxidation of
cyclooctene; for conditions see Figure 6.
The effect of addition of H2O2 on the UV/Vis absorption
spectrum of the reaction mixture with butanedione in the pres-
ence of chloroacetic acid or trichloroacetic acid was different
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Figure 9. Conversion of 3-vinylbenzaldehyde (0.5 M) during
Figure 10. Dependence of change in concentration of styrene
oxidation in acetonitrile with 0.01 (light blue), 0.025 (blue),
0.05 (red), and 0.5 mM (black) Mn(ClO4)2. Conditions: 0.5 M
cyclooctene, 0.75 M H2O2, 0.25 M 1,2-dichlorobenzene (in-
ternal reference), 0.25 M butanedione, 2.5 mM PCA, 5 mM
NaOAc, at 15 oC. H2O2 was made at t = 1 min.
over time on [PCA] with (upper) 0.05 and (lower) 0.5 mM
MnII(ClO4)2, with an initial concentration of 0.5 M styrene, 5
mM NaOAc, 0.25 M butanedione, and 0.1 M acetic acid in
acetonitrile. A single addition of H2O2 (to a final concentra-
tion of 0.75 M) was made at the time indicated.
Dependence of reaction on [pyridine-2-carboxylic acid]
In the absence of acetic acid a lag time is observed also
(Figure 11), the duration of which increases, together with a
decrease in reaction rate (at highest TOF), as the [PCA] is
decreased. The increase in the duration of the lag-time is con-
sistent with a model in which the same catalyst is responsible
for oxidation of butanedione to acetic acid as well as for al-
kene oxidation.
Both the reaction rate and maximum conversion are de-
pendent on [PCA] (Figure 10), however, this dependence is
linked to [MnII] also. With 0.5 mM MnII the reaction rate
decreases as [PCA] is decreased and below a [PCA]:[MnII] of
1:1, negligible conversion of substrate and also of H2O2 is
observed (Figure 10, lower). Above a 1:1 ratio the reaction
rate increases sharply with increasing [PCA]. A more complex
situation arises with a [MnII] of 0.05 mM (Figure 10, upper).
The rate of oxidation increases moderately with [PCA] and
then decreases with a large excess of PCA w.r.t. MnII. The
most pronounced effect of variation in [PCA] is on the maxi-
mum conversion achieved, with conversion increasing with
[PCA]. The time over which conversion is observed appears to
be dependent on [PCA] also. PCA was shown earlier to even-
tually undergo oxidation to the corresponding N-oxide under
reaction conditions, which together with the absence of con-
version when the corresponding N-oxide was used in place of
PCA,10 indicates that PCA oxidation may be an important
deactivation channel.
These data confirm that the reaction rate is dependent on
[PCA], i.e. that PCA is involved before or at the rate determin-
ing step of the reaction. Furthermore, the inhibition seen at
high [PCA] and the loss of activity observed at low [PCA]
support the conclusion that PCA acts as a ligand in the active
catalyst.
Figure 11. Conversion of cyclooctene over time for various
[PCA] (2.5 mM (black), 1.25 mM (red), 0.5 mM (green), 0.25
mM (blue) and 0.125 mM (light blue)). With 0.5 M cy-
clooctene, 5 mM NaOAc, 0.25 M butanedione, 0.25 M 1,2-
dichlorobenzene (internal reference), 0.05 mM MnII(ClO4)2
in acetonitrile. A single addition of 1.5 equiv. of H2O2 was
made at t = 2 min.
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Dependence of reaction on [substrate]
In early studies it was noted that the reaction appeared to
show a zero-order dependence on substrate concentration (in
the case of alkenes), which was taken advantage of to achieve
full conversion simply by lowering substrate concentration
and holding the concentration of all other reaction components
constant.12 The success of this approach is apparent from
Figure 12. With 0.2 M styrene, full conversion is achieved
whereas with 1.0 M styrene only 60% conversion is observed.
Notably, neither the reaction rate nor (in the absence of acetic
acid, Figure S2) the duration of the lag-time show sensitivity
to substrate concentration, in the case of styrene, cyclooctene
and sec-phenyl ethanol (Figure S3). These data confirm that
the reaction is zero order with respect to substrate under the
conditions employed.
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Figure 13. Conversion of styrene over time with 0.125 and
0.500 M butanedione; with 2.5 mM PCA, 5 mM NaOAc, 0.5
M cyclooctene, 0.25 M 1,2-dichlorobenzene (internal refer-
ence), 0.05 mM MnII(ClO4)2 in acetonitrile. A single addition
of 1.5 equiv. of H2O2 was made at the time indicated.
In addition to the near complete decrease in the carbonyl
stretching band of butanedione upon addition of H2O2, the loss
in conjugation by formation of 3-hydroxy-3-hydroperoxy-
butanone, results a concomitant loss of the absorbance of
butanedione at 417 nm (Figure 14). Importantly, since 3-
hydroperoxy-3-hydroxybutanone forms within several seconds
after addition of H2O2, the lag phase cannot be due to a delay
in its formation (vide supra). Furthermore, the absorbance of
butanedione does not recover further after 30 min and the
amount of butanedione consumed is approximately linearly
dependent on the amount of H2O2 added, and hence the extent
of oxidation and the time taken for this to occur is dependent
primarily on the amount of H2O2 added. The oxidation of
butanedione proceeds at a constant rate over the course of the
reaction analogous to the oxidation of substrates (e.g. styrene,
Figure S4).
Figure 12. Conversion (change in concentration) over time,
of styrene, with an initial concentration of 0.2 M and 1.0 M;
2.5 mM PCA, 5 mM NaOAc, 0.25 M butanedione, 0.05 mM
MnII(ClO4)2 and 0.2 M acetic acid in acetonitrile. A single
addition of H2O2 (to a final concentration of 0.75 M) was
made at t = 0 s.
Dependence of reaction on [butanedione] and [H2O2]
The reaction rate is strongly dependent on the concentration
of butanedione with a 4 fold decrease in concentration result-
ing in a 10 fold decrease in reaction rate (Figure 13), confirm-
ing that butanedione is involved at or before the rate determin-
ing step of the reaction. Notably, in the absence of added
acetic acid, the lag time observed is dependent on [butanedi-
one] also; decreasing with increasing concentration (Figure
S4). This later observation is expected since the decomposi-
tion of butanedione to acetic acid occurs prior to the onset of
substrate oxidation (vide supra).
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Figure 15. Conversion of cyclooctene over time for various
equivalents of H2O2 (0.25 to 1.5 w.r.t cyclooctene). With 2.5
mM PCA, 5 mM NaOAc, 0.25 M butanedione, 0.25 M 1,2-
dichlorobenzene (internal reference), 0.05 mM MnII(ClO4)2
in acetonitrile. A single addition of H2O2 was made at the t =
4 min.
In most cases the reaction proceeds at an essential constant
rate (i.e. rate of oxidation of substrate) for a defined period
after which substrate conversion ceases. If the initial concen-
tration of substrate is greater than the maximum amount that
can undergo oxidation before the reaction ceases then conver-
sion will be incomplete. In the case of substrates such as sty-
rene the cessation of catalytic activity is due to the loss of
butanedione and H2O2 and addition of both butanedione and
H2O2 results in a further oxidation. Importantly, there is no
evidence for oxidation of the PCA to 2-carboxy-pyridine-N-
oxide. For less reactive substrates, in particular diethylmaleate,
although some conversion is observed initially, the reaction
ceases with only a minor amount of H2O2 and butanedione
consumed even after 30 min. Subsequent addition of styrene
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Figure 14. (a) Change in absorbance of butanedione at 417
nm over time after addition of H2O2 at t = 0 min (0.125 to
0.875 M; 0.25, 0.50, 0.75, 1.00, 1.25, 1.35, and 1.50 eq. w.r.t.
cyclooctene); 0.05 mM MnII(ClO4)2, 0.5 M cyclooctene, 5 mM
NaOAc, 0.25 M butanedione, 2.5 mM PCA in acetonitrile. (b)
Dependence of butanedione consumed on amount of H2O2
added.
1
does not result in conversion (Figure S7). H NMR analysis
shows complete conversion of PCA to 2-carboxy-pyridine-N-
oxide. Notably, with a 1:1 mixture of styrene and diethylmale-
ate conversion of styrene proceeds as expected, confirming
that neither diethylmaleate nor its oxidation product meso-
tartrate inhibit the catalyst.
The reaction rate is unaffected by the initial concentration of
H2O2 where [H2O2] > [butanedione] (Figure 15) and the con-
version increases linearly with increase in [H2O2] (Figure S5).
The lag phase observed prior the onset of oxidation of cy-
clooctene, however, was absent for [H2O2]:[butanedione] < 2
and above 2 it increased with the initial concentration of H2O2.
These data can be rationalised by considering that the reaction
requires the formation of acetic acid by oxidation of butanedi-
one. As the [H2O2] is increased the [butanedione] decreases
(Figure 14b) due to formation of 3-hydroxy-3-
Discussion
A first step in elucidating the mechanism by which the cata-
lyzed oxidation of organic substrates with MnII/PCA lies in
examination of its substrate scope and product distributions.
Indeed, several observations of mechanistic relevance can be
gleaned from the substrate scope.12 Most notably the lack of
retention of configuration in the epoxidation of cis- and trans-
2-heptene, with a 75% yield of a 2:1 mixture of cis- and trans-
2-heptene oxide from cis-2-heptene.12 Similarly, a 1:5 mixture
of cis- and trans-2-heptene epoxide was obtained from trans-2-
heptene. These data indicated that the epoxidation of alkenes
is a stepwise reaction in which an intermediate is formed that
allows free rotation around the C-C bond of the epoxide. Simi-
lar results were obtained with cis- and trans-methylstyrene and
stilbene. By contrast, examination of the product distribution
of cis- and trans-alkenes showed that cis-dihydroxylation
occurred only, i.e. it is a concerted reaction.11,12 The absence of
allylic oxidation, e.g., with cyclohexene, indicates that the lack
of retention of configuration is not due to radical oxidation
pathways.20 Nevertheless, it is still possible that these two
transformations go through a common intermediate. Moreo-
ver, the high activity for both the epoxidation of electron rich
alkenes and cis-dihydroxylation of electron deficient alkenes
and low activity for α,β-unsaturated alkenes, indicates that the
catalyst operates electrophilically in the case of epoxidation
and nucleophilically in the case of syn-dihydroxylation.
hydroperoxybutanone.
Hence,
although
3-hydroxy-3-
hydroperoxybutanone is the species responsible for generating
the active oxidant (manganese species), the rate of this process
requires acetic acid which is formed only by oxidation of
butanedione – which is scarcely available at high [H2O2].
Overall, these data confirm that the lack of a significant de-
pendence of reaction rate on [H2O2] is due to a prior rapid
equilibrium (Scheme 2).
From a mechanistic perspective, the most striking observa-
tion for this system is the equilibrium between butanedione
and H2O2 with 3-hydroperoxy-3-hydroxybutanone (Scheme 2).
It was shown earlier12 that this equilibrium is established rap-
idly (< 10 s) and that the formation of this hydroxyl-peroxy
species is essential in order to achieve catalytic activity. In the
present study it is shown that the oxidation of butanedione is
catalyzed by the MnII/PCA catalyst and that the acetic acid
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formed through this reaction is key to achieving a significant
butanedione is low and the 3-hydroperoxy-3-hydroxybutanone
rate of oxidation (Scheme 3). The role of acetic acid (or indeed
any carboxylic acid) in the reaction is intriguing since alt-
hough its presence is essential for catalytic activity to be ob-
served, the reaction rate is essentially unaffected by variation
in its concentration. Furthermore, acetic acid does not affect,
significantly, the equilibrium between butanedione/H2O2 and
3-hydroperoxy-3-hydroxybutanone (Scheme 2). The absence
of an effect of adding acid once substrate conversion has
commenced indicates that the acid is responsible primarily for
formation of the active form of the catalytic species but its role
as a proton donor in the reaction between the perhydrate and
the catalyst cannot be excluded.
itself is likely to be relatively unreactive towards oxidation.
Hence, although some butanedione is initially oxidized to
acetic acid, it is only towards the end of the reaction, where
[H2O2] < [butanedione], that it is present at sufficient concen-
trations to compete with substrates such as alkenes. That this
is the case is supported by the fact that a rapid oxidation of
butanedione would reduce the effective concentration of 3-
hydroxy-3-hydroperoxy-butanone, and thereby the reaction
rate would decrease; which is not observed.
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The equilibrium between butanedione/H2O2 and 3-
hydroperoxy-3-hydroxybutanone together with the zero order
dependence of reaction rate on [H2O2] and the non-zero order
dependence on [butanedione] indicates that the rate determin-
ing step in the reaction is the formation of the active oxidizing
species by reaction of 3-hydroperoxy-3-hydroxybutanone with
the manganese catalyst. Once formed this species reacts with
substrates at a rate much faster than the rate of its formation
and hence reaction shows a zero order dependence on all sub-
strates (Figure S8). Notably, however, the oxidation of sub-
strates competes with oxidation of butanedione, and hence the
extent of conversion observed for a particular substrate is
dependent on the ease with which it undergoes oxidation rela-
tive to butanedione.
The dependence of the reaction rate on both [MnII] and
[PCA] is non-zero order, which together for the necessity that
the ratio of PCA:MnII > 2: 1, indicates that the catalyst is a
Mn-PCA complex. The characterization of the active form
catalyst is challenging and indeed it is not practical to deter-
mine the structure of the resting state of the catalyst at the low
concentrations of catalyst used in the reaction. It is notable,
however, that EPR spectra of the reaction mixtures were fea-
tureless (perpendicular mode, at 77 K), which suggests the
absence of octahedral mononuclear MnII complexes.21 Hence
multinuclear MnII and mononuclear MnIII are possible candi-
dates for the oxidation state of the resting state. The essentially
1st order dependence of the reaction rate on the concentration
of manganese indicates that a mononuclear catalyst is in-
volved.
Scheme 3 Proposed mechanism for the oxidation of alkenes
under the present system based on data from kinetic analyses
and orders of the reaction.
Conclusions
A combination of reaction monitoring by Raman and
UV/Vis absorption spectroscopy has enabled a detailed picture
of the mechanisms involved in the manganese catalyzed oxi-
dation of alkenes with H2O2. Overall, it is apparent that an
attempt to reveal the nature of the active oxidizing species
through kinetic analyses is limited by the interdependence of
reaction components, not least the MnII and PCA. Neverthe-
less it is clear that a prior rapid equilibrium (i.e. butanedi-
one/H2O2  3-hydroxy-3-hydroperoxybutanone) is followed
by the reaction of 3-hydroxy-3-hydroperoxybutanone with the
reduced form of the catalyst to yield an active oxidizing spe-
cies. This latter step is rate limiting and hence the substrate
does not influence the overall reaction rate. The nature of both
the reduced and oxidized form of the Mn/PCA catalyst can be
speculated on. The absence of a 6-line EPR signal (character-
istic of mononuclear MnII) and the high the essentially 1st
order dependence on [MnII] are consistent with a mononuclear
MnIII resting state and a reasonable hypotheses, in our view, is
that the reaction between 3-hydroxy-3-hydroperoxybutanone
and a MnIII(PCA)2 complex yields a highly reactive species,
e.g., [(PCA)2MnV(=O)(OH)] (Scheme 3).
A notable feature of the reaction is that conversion stops af-
ter a certain period for all reactions, with the time dependent
on catalyst concentration, in particular the relative concentra-
tion of MnII and PCA. The lack of activity observed, even in
the presence of acetic acid, when the concentration of PCA is
less than that of MnII, indicates that the limited time over
which conversion is observed is due to oxidation of the PCA
to its corresponding N-oxide. Furthermore, the effect of other
carboxylic reactions on reaction rate is consistent with the
reduction in the effect concentration of PCA (i.e. through
protonation).
In a wider context, the data reported here highlights that,
although the catalytic system is relatively simple in terms of
composition, the intricate relations between individual com-
ponents in the reaction and the multiple effects each compo-
nent can have on the system as a whole complex. Understand-
ing the complex interactions will certainly be key to expand-
ing the systems scope and utility in synthesis. In the present
contribution the interactions and reactions leading to the rate
The decomposition of butanedione to acetic acid is cata-
lyzed by MnII/PCA and indeed in the absence of MnII, oxida-
tion is not observed even over several hours. However, in
order for oxidation to proceed acetic acid needs to be present
which presents an interesting mechanistic conundrum. The
oxidation of butanedione by the catalyst therefore can compete
with alkene oxidation. However, for most of the reaction, i.e.
while [H2O2] > [butanedione], the absolute concentration of
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determining step have been explored. In future studies we will
attempt to look beyond the rate determining step to elucidate
the molecular nature of the manganese catalyst itself.
Supporting Information. Additional graphs showing sub-
strate conversion over time. This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental section
AUTHOR INFORMATION
All reagents are of commercial grade and used as received
unless stated otherwise. Hydrogen peroxide was used as re-
ceived (ACROS chemicals) as a 50 wt. % solution in water;
note that the grade of H2O2 employed can affect the outcome
of the reaction, as some sources are stabilized using seques-
Corresponding Author
* w.r.browne@rug.nl
9
Funding Sources
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trants. D2O2 was obtained from Icon isotopes. H NMR (400.0
Financial support from the European Research Council
(ERC-2011-StG-279549, WRB), Catchbio (WRB) the Ministry
of Economic affairs. (Gravity program 024.001.035, WRB) is
acknowledged.
MHz) and 13C NMR (100.59 MHz) spectra were recorded on a
1
Varian Avance 400. Chemical shifts22 are relative to H NMR
CDCl3 (7.26 ppm), CD3CN (1.94 ppm) and 13C NMR CDCl3
(77 ppm), CD3CN (118 ppm).
ACKNOWLEDGMENT
Caution. The drying or concentration of solutions that po-
tentially contain H2O2 should be avoided. Prior to drying or
concentrating, the presence of H2O2 should be tested for using
peroxide test strips followed by neutralization on solid Na-
HSO3 or another suitable reducing agent. When working with
H2O2, suitable protective safeguards should be in place at all
times due to the risk of explosion.
COST action CM1003 “Biological oxidation reactions – mech-
anism and design of new catalyst” is acknowledged for dis-
cussion.
REFERENCES
Caution. Butanedione has been linked with lung disease
upon prolonged exposure to its vapors. It should be handled in
a properly ventilated fumehood and exposure to vapors should
be avoided.23
Typical procedure for catalytic oxidations described in
Scheme 1
(1)
(a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547. (b) Lane, B. S.; Burgess, K.
Chem. Rev. 2003, 103, 2457-2474. (c) Bryliakov, K. P.; Talsi, E. P.
Coord. Chem. Rev. 2014, 276, 73-96. (d) Sun, C. L.; Li, B. J.; Shi, Z.
J. Chem. Rev. 2011, 111, 1293-1314.
The substrate (1 mmol) was added to a solution containing
Mn(ClO4)2.6H2O and PCA in acetonitrile to give a final con-
centration of the substrate of 0.5 M. NaOAc (aq. 0.6 M) and
butanedione (0.5 mmol) were added to give a final volume of
2 ml. The solution was stirred in an ice/water bath before
addition of H2O2 (50 wt. %). Conversion was verified 1H NMR
by dilution of a part of the reaction mixture in CD3CN. Prod-
uct isolation involved addition of brine (10 ml) and extraction
with dichloromethane. The combined organic layers were
washed with brine and dried over Na2SO4 (anh.), filtered, and
the dichloromethane was removed in vacuo. 1,2-
Dichlorobenzene, which has a negligible effect on the reac-
(2)
(a) Signorella, S.; Hureau, C.; Coord. Chem. Rev. 2012,
256, 1229-1245. (b) Saisaha, P.; de Boer, J. W.; Browne, W. R.
Chem. Soc. Rev. 2013, 42, 2059-2074. (c) Sibbons, K. F.; Shastri K.;
Watkinson, M. Dalton Trans. 2006, 645-661.
(3)
(a) Enthaler, S.; Junge K.; Beller, M. Angew. Chem., Int.
Ed. 2008, 47, 3317–3321. (b) Gelalcha, F. G. Adv. Synth. Catal.
2014, 356, 261-299.
(4)
Wieghardt, K.; Bossek, U.; Nuber, B.; Weiss, J.;
Bonvoisin, J.; Corbella, M.; Vitols, S. E.; Girerd, J. J. J. Am. Chem.
Soc. 1988, 110, 7398-7411.
1
tion, was employed as internal standard for Raman and H
(5)
(a) Toftlund, H.; Yde-Andersen, S. Acta Chem. Scand.
NMR spectroscopy. Reaction monitoring with Raman spec-
troscopy focused primarily on the intensity of the C=C and
C=O stretching bands between 1550-1800 cm-1 (e.g., at 1650
cm-1 for cyclooctene, and 1724 cm-1 for butanedione) and
between 600-900 cm-1 relating to the C=C and C=O bending
modes (682 cm-1 for butanedione, 701 cm-1 for cyclooctene),
and the O-O stretching mode of H2O2 at 870 cm-1. UV/Vis
absorption spectroscopy were recorded in 1 or 10 mm path-
length cuvettes on a AnalytikJena Specord 600. Raman spectra
at 785 nm were recorded using a Perkin Elmer Raman Station
and at 532 nm using a custom made Raman spectrometer; a
532 nm DPSS laser (25 mW, Cobolt Lasers) was fiber coupled
to a low cost Raman probe (inphotonics) and the collected
scattering feed into a Shamrock163 spectrograph (500 nm
blaze, 1200 l/mm grating, Andor Technology) and dispersed
onto a Newton EMCCD (Andor Tehcnology) operated in
conventional CCD mode.
Ser. 1981, 35A, 575-585. (b) Chen, K.; Que, Jr., L. Chem. Commun.
1999, 1375-1376. (c) Kim, J.; Harrison, R. G.; Kim, C.; Que, Jr., L. J.
Am. Chem. Soc. 1996, 118, 4373-4379. (d) Lim, M. H.; Rohde, J.-U.;
Stubna, A. Bukowski, M. R.; Costas, M.; Ho, R. Y. N.; Munck, E.;
Nam, W.; Que, Jr., L. Proc. Natl. Acad. Sci. USA 2003, 100, 3665-
3670. (e) Roelfes, G.; Lubben, M.; Leppard, S. W.; Schudde, E. P.;
Hermant, R. M.; Hage, R.; Wilkinson, E. C.; Que, Jr., L.; Feringa,
B. L. J. Mol. Cat. A: Chem. 1997, 117, 223-227.
(6) (a) Murphy, A.; Dubois, G.; Stack, T. D. P. J. Am. Chem.
Soc., 2003, 125, 5250-5251. (b) Murphy, A., Pace, A.; Stack, T. D. P.
Org. Lett. 2004, 6, 3119-3122; Garcia-Bosch, I.; Ribas, X.; Costas,
M. Adv. Synth. Catal. 2009, 351, 348-352. (c) Wu, M.; Wang, B.;
Wang, S.; Xia, C.; Sun, W. Org. Lett. 2009, 11, 3622-3625. (d)
Wang, B.; Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem.–Eur. J.
2012, 18, 6750-6753. (e) Garcia-Bosch, I.; Gomez, L.; Polo, A.;
Ribas, X.; Costas, M. Adv. Synth. Catal. 2012, 354, 65-70. (f) Lya-
kin, O. Y.; Ottenbacher, R. V.; Bryliakov, K. P.; Talsi, E. P. ACS
Catal. 2012, 2, 1196-1202. (g) Ottenbacher, R. V.; Bryliakov, K. P.;
Talsi, E. P. Adv. Synth. Catal. 2011, 353, 885-889.
ASSOCIATED CONTENT
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(23) More, S. S.; Vartak A. P.; Vince, R. Chem. Res. Toxicol.
2012, 25, 2083-2091.
(7)
(a) Brinksma, J. Rispens, M. T. Hage, R. Feringa, B. L.
Inorg. Chim. Acta 2002, 337, 75–82. (b) Brinksma, J.; Hage, R.;
Kerschner, J.; Feringa B. L. Chem. Commun. 2000, 537-538.
(8)
Brinksma, J.; Hage, R.; Kerschner, J.; Feringa, B. L.
Chem. Commun. 2000, 537-538.
10
11
12
13
14
15
16
17
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19
20
21
22
23
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25
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27
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57
58
59
60
(9) (a) Groni, S.; Dorlet, P.; Blain, G.; Bourcier, S.; Guillot R.;
Anxolabehere-Mallart, E. Inorg. Chem., 2008, 47, 31663172. (b)
Grau, M.; Kyriacou, A.; Cabedo Martinez, F.; de Wispelaere, I.
M.; White, A. J. P.; Britovsek, G. J. P. Dalton Trans. 2014, 43,
17108-17119.
(10)
Pijper, D.; Saisaha, P.; de Boer, J. W.; Hoen, R.; Smit,
C.; Meetsma, A.; Hage, R.; van Summeren, R. P.; Alsters, P. L.;
Feringa, B. L.; Browne, W.R. Dalton Trans. 2010, 39, 10375-10381.
(11)
(a) Saisaha, P.; Pijper, D.; de Boer, J. W.; Hoen, R.; van
Summeren, R. P.; Alsters, P. L.; Hage, R.; Feringa B. L.; Browne,
W. R. Org. Biomol. Chem. 2010, 8, 4444. (b) Browne, W. R.;
Alsters, P. L.; van Summeren, R. P.; Ijpeij, E.; de Boer, J. W.;
Saisaha, P.; Pijper D.; Feringa, B. L. PCT Int. Appl., 2011, WO
2011104333.
(12)
Dong, J.; Saisaha, P.; Meinds, T. G.; Alsters, P. L.; Ijpeij,
E. G.; van Summeren, R. P.; Mao, B.; Fana
̃
nás-Mastral, M.; de
Boer, J. W.; Hage, R.; Feringa B. L.; Browne, W. R. ACS Catal.
2012, 2, 1087.
(13) Dong, J.; Unjaroen, D.; Mecozzi, F.; Harvey, E. C.;
Saisaha, P.; Pijper, D.; de Boer, J. W.; Alsters, P.; Feringa, B. L.;
Browne, W. R. ChemSusChem 2013, 6, 1774–1778.
(14) The range of [MnII] that can be used in the reaction is
between from 0.01-0.25 mM. At higher concentrations reactivity
is reduced substantially, indicating the formation of non-
catalytically active manganese species.
(15) The reaction rate observed with phenylethanol as sub-
strate is lower than for alkenes (see SI Figure S3), however, this
is most likely to be due to solvent effects considering the differ-
ences in rate of alkene oxidation in acetonitrile and in ethanol.
(16)
It should be noted that the pKa values are determined
in water. These values can differ substantially in acetonitrile and
to a lesser extent in ethanol. However, an excess of water w.r.t.
acid is added to the reaction both through the addition of
NaOAc and upon addition of H2O2.
(17) The reaction mixture contains a considerable amount of
water (> 100 mol% w.r.t. substrate) due to its presence in the
H2O2 added and hence the maximum acidity is limited by the
pKa of water (c.f. levelling effect).
(18)
384.
Connors, K. A.; Lipari, J. M. J. Pharm. Sci. 1976, 65, 379-
(19) The absorbance at 450 nm is plot as under these condi-
tions the absorbance at the maximum 417 nm is greater than 2.
(20) Zhang, W.; Lee N. H.; Jacobsen, E. N. J. Am. Chem. Soc.
1994, 116, 425.
(21)
It should be noted, however, that although EPR spec-
troscopy shows that MnII at 0.05 mM shows the expected 6-line
signal, under reaction conditions before addition of H2O2 no EPR
signals were observed at room temperature indicating that mon-
onuclear MnII is not present in significant amounts. See ref. 12
for details.
(22) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb,
H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I.
Organomet. 2010, 29, 2176-2179.
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