The Baeyer-Villiger oxidation versus aromatic ring hydroxylation: Competing organic peracid oxidation mechanisms explored by multivariate modelling of designed multi-response experiments

Article abstract of DOI:10.1002/poc.3462

Peroxy acids can be used as the terminal oxidant for the Baeyer-Villiger oxidation of acetophenones and for direct ring hydroxylation of methoxy-substituted benzenes. An oxidative system involving 3-chloroperbenzoic acid (mCPBA) and 2,6-dimethoxyacetophenone as model substrate was investigated by means of statistical experimental design, multivariate modelling and response surface methodology. The outcome of the organic peracid oxidation experiments was portrayed by a multi-response matrix consisting of the yields of three different compounds; 2,6-dimethoxyphenyl acetate, 1-(4-hydroxy-2,6-dimethoxy-phenyl)ethanone and 3-hydroxy-2,6-dimethoxy-phenyl acetate. The optimized reaction protocol was utilized to investigate a series of various substituted acetophenones. The overall investigation revealed that both the molecular structure of the acetophenone substrate and the experimental conditions exhibited a substantial impact on whether the oxidation reaction follows the oxygen insertion or direct ring hydroxylation mechanism. An improved protocol for the direct ring hydroxylation was also obtained from the experimental and modelling described herein.

Full text of DOI:10.1002/poc.3462

Research article
Received: 27 February 2015,
Revised: 03 April 2015,
Accepted: 04 May 2015,
Published online in Wiley Online Library: 15 June 2015
(wileyonlinelibrary.com) DOI: 10.1002/poc.3462
The Baeyer-Villiger oxidation versus aromatic
ring hydroxylation: competing organic peracid
oxidation mechanisms explored by multivariate
modelling of designed multi-response
experiments
a
b
Cristian Gambarotti and Hans-René Bjørsvik *
Peroxy acids can be used as the terminal oxidant for the Baeyer–Villiger oxidation of acetophenones and for direct ring
hydroxylation of methoxy-substituted benzenes. An oxidative system involving 3-chloroperbenzoic acid (mCPBA) and
2
,6-dimethoxyacetophenone as model substrate was investigated by means of statistical experimental design, multivariate
modelling and response surface methodology. The outcome of the organic peracid oxidation experiments was portrayed
by a multi-response matrix consisting of the yields of three different compounds; 2,6-dimethoxyphenyl acetate, 1-(4-hy-
droxy-2,6-dimethoxy-phenyl)ethanone and 3-hydroxy-2,6-dimethoxy-phenyl acetate. The optimized reaction protocol was
utilized to investigate a series of various substituted acetophenones. The overall investigation revealed that both the mole-
cular structure of the acetophenone substrate and the experimental conditions exhibited a substantial impact on whether the
oxidation reaction follows the oxygen insertion or direct ring hydroxylation mechanism. An improved protocol for the direct
ring hydroxylation was also obtained from the experimental and modelling described herein. Copyright © 2015 John Wiley &
Sons, Ltd.
Keywords: aromatic ring hydroxylation; Baeyer–Villiger oxidation; multivariate regression; oxidation mechanisms; response surface
methodology; statistical experimental design
[
12]
0
CoQ )
that is an essential building block in the synthesis of ubiqui-
INTRODUCTION
n
nones (also known as coenzyme Q , n=1,…, 12, and mitoquinones),
and the synthetic analogue idebenone.
Direct hydroxylation of the benzene ring, step (iv) of Scheme 1,
can be of pronounced importance from an industrial point of view
when focusing process efficacy, process economy and environmen-
tal issues, because an operating alternative encompassing the steps
(i–iii) of Scheme 1 that involves a Friedel–Crafts acylation,
Baeyer–Villiger oxidation and an ester hydrolysis. The Baeyer–
Villiger oxidation with a successive Fries rearrangement is a path-
way frequently utilized for the purpose to introducing a hydroxyl
[
1]
[13]
Phenol derivatives are valuable industrial chemicals used for
the synthesis of advanced pharmaceutical intermediates and
[
2]
active pharmaceutical ingredients, for the production of agro-
[3]
[4]
chemicals, flavouring and fragrances, monomers for poly-
[5]
[6]
mers, various antioxidants and numerous of other fine
chemical applications and commodity chemicals as well.
Industrial synthesis of phenol is based on the Hock process,
[14]
a
[8]
[15]
[
7]
[16]
which involves autoxidation of cumene. Phenol derivatives
can be prepared by means of the Baeyer–Villiger oxidation
[
8]
with a subsequent ester hydrolysis. Access to various phenol
derivatives have also been revealed by direct hydroxylation, by
group in the ortho-position to an acetyl group. The resulting ortho-
acetylphenols can serve as versatile building blocks and have been
[
9]
[17]
peracid oxidation of the aromatic ring and palladium catalysed
used in the synthesis of carbazomycin G and H
and
[10]
[18]
C–H oxygenation.
carbazoquinocin C, for the synthesis of natural products and bio-
logical activity compounds and in the synthesis of precursors of
[19]
Previously, one of our research assignments pertained direct hy-
droxylation of the benzene ring with the objective to produce the
corresponding phenol and their derivatives. The research activity in-
cluded (1) preparation of methoxy-substituted phenols by oxidation
of the corresponding benzenes in one synthetic step, path (iv) of
*
Correspondence to: Hans-René Bjørsvik, Department of Chemistry, University
of Bergen, Allégaten 41, N-5007 Bergen, Norway.
E-mail: Hans.Bjorsvik@kj.uib.no
[1,4]
Scheme 1, and (2) synthesis of 2-methoxy-3-methyl- benzo-qui-
none 6 by means of a two-step telescoped process, where the phe-
nol was generated in the first step (not isolated), whereupon the
phenolic hydroxyl group was further oxidized by a second oxidant
a C. Gambarotti
Department of Chemistry, Materials and Chemical Engineering, Politecnico di
Milano, Piazza Leonardo da Vinci 32, I-20133, Milan, Italy
[11]
to induce the formation of the resultant quinone derivate. This
latter process was afterward adapted for the synthesis of the 2,3-
dimethoxy-5-methylcyclohexa-2,5-diene-1,4-dione (also known as
b H.-R. Bjørsvik
Department of Chemistry, University of Bergen, Allégaten 41, N-5007, Bergen,
Norway
J. Phys. Org. Chem. 2015, 28 619–628
Copyright © 2015 John Wiley & Sons, Ltd.

C. GAMBAROTTI AND H.-R. BJØRSVIK
Scheme 1. Two synthetic pathways (i)–(iii) or (iv) that are both leading to 2,4-dimethoxy-3-methylphenol 5 starting from 1,3-dimethoxy-2-
methylbenzene 1. Another pathways (iv) and (v) that are also starting from 1,3-dimethoxy-2-methylbenzene 1 that proceed via 2,4-dimethoxy-3-
methylphenol 5 as an intermediate to obtain 2-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione 6 as target molecule
[
20]
anti-tubulin agents. However, the same phenolic precursor can be
easily prepared in one step from the appropriate substituted toluene
by direct hydroxylation of the aromatic ring.
Clara, CA, USA) gas chromatograph (GC) system equipped with
a 30 m × 0.250 mm HP-5MS GC column and an Agilent 5973 mass
selective detector (MSD). All the reaction products were known
and were thus identified by comparison with literature data.
Furthermore, the desired product 9 (new compound) was
1
EXPERIMENTAL
anyhow isolated and characterized by GC-MS, H nuclear mag-
13
netic resonance (NMR) and C NMR, for which the recorded
spectra are included in the supporting information file. The
quantification was conducted by means of an internal standard
method. The internal standard (100 mg of 1,4-dinitrobenzene)
was added to the reaction mixture from the start of the reaction.
A Bruker AV 400 (Billerica, MA, USA) NMR instrument equipped
with a 5 mm multinuclear probe with a reverse detection was
Computing and software
An in-house developed function library (by H. R. B.) for MATLAB
(MathWorks, Natick, MA, USA) was used for the multivariate re-
gression and for the productions of the iso-contour projections
of the response surfaces and other line graphics. This library
was used under the MATLAB program version 7.11.0.584
[
19]
1
13
(R2010b), 64-bit (maci64), Date: 16 August 2010
that was
used to record H-NMR spectra (at 400 MHz) and C NMR
spectra (at 100 MHz).
run with OS X, Version 10.8.3 (12D78) as the operating system.
The in-house developed function library has earlier been
benchmarked versus various commercial softwares such as SAS
General experimental procedure that was used for the ex-
perimental design
(Institute Inc., Cary, NC, USA). Regression and model assessments
were also conducted by means of the SAS software version 9.4
for Windows.
2,6-Dimethoxyacetophenone (1 mmol, 180 mg) was transferred
to a round-bottom flask (25 mL) and dissolved in acetonitrile
(
(
5 mL). Then para-toluenesulfonic acid monohydrate (pTSA)
quantity as stated in the experimental design table), meta-
Materials and equipment
2
,6-Dimethoxyacetophenone (assay 98%), meta-chloroper-
chloroperbenzoic acid (mCPBA, quantity as reported in the
experimental design table) and the internal standard 1,4-
dinitrobenzene (0.73 mmol) were added to the round-bottom
flask. The resulting reaction mixture was heated under contin-
uous vigorous stirring at the temperature as given in the ex-
perimental design table. During the first hour of the
reaction, samples (0.100 mL) were withdrawn from the reac-
tion mixture every 15 min, filtered through a pad silica gel
(1 cm height in a Pasteur pipette) using acetone (3 mL) as
solvent and analysed on a GC-MS.
benzoic acid (mCPBA, technical grade ≈70%), para-toluene-
sulfonic acid monohydrate (purum ≥98%), 1,4-dinitrobenzene
®
(assay 98%), acetonitrile (CHROMASOLV [Sigma-Aldrich, St.
Louis, MO, USA] gradient grade, for high-performance liquid
chromatography, ≥99.9%) and propionitrile (purum, ≥99%) were
purchased from commercial sources and used without further
purification.
Gas chromatography–mass spectrometry (GC-MS) spectra
were recorded with an Agilent 6890 (Agilent Technologies, Sta.
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Copyright © 2015 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2015, 28 619–628

COMPETING ORGANIC PERACID OXIDATION MECHANISMS
Optimized experimental procedure
hydroxylation of the benzene ring as previously described in an
[
9]
account from our laboratory, a mechanism that we believe in-
2
,6-Dimethoxy-acetophenone 7 (1 mmol, 180 mg) was trans-
+
volves a direct HO transfer from peracid [R–C(=O)OOH] to the
ferred to a round-bottom flask (25 mL) and dissolved with aceto-
nitrile (5 mL). Then Amberlite IR120 (Sigma-Aldrich; acid form,
benzene ring of the acetophenone (see pathway ① of Scheme 2)
[
8]
and (2) the well-known Baeyer–Villiger oxidation that involves
an oxygen insertion between the acetyl group and the benzene
ring of the acetophenone, a reaction sequence that involves the
2
00 mg), mCPBA (1.75 mmol) and the internal standard 1,4-
dinitrobenzene (0.73 mmol) were added. The resulting reaction
mixture was heated under continuous vigorous stirring at re-
flux temperature (80 °C). A sample (0.100 mL) was withdrawn
at reaction times of 30 and 45 min, filtered over silica gel
[
21]
Criegee intermediate (see pathway ② of Scheme 2).
[
9,11]
At the outset of our previous studies,
we followed the pro-
[
22]
cedure reported in the literature (Scheme 1, (i)–(iii)). Together
with our target molecule 5, we observed in addition a side prod-
uct 4 (<10%). This surprising result, we could only explained by
the operation of both of the two distinct mechanisms outlined in
Scheme 2. This result spurred us to investigate the possibility to
(1 cm height in a Pasteur pipette) using acetone (3 mL) as sol-
vent and analysed on a GC-MS. All the identified compounds
were compared with authentic samples. The reaction pro-
duced 1-(3-hydroxy-2,6-dimethoxyphenyl)ethan-1-one 9 in a
yield of 73.5% and 2,6-dimethoxyphenyl acetate 8 in a yield
of ≈3.5%. Work-up: In order to isolate the phenolic product
perform
a
one step direct hydroxylation with 2,6-
dimethoxytoluene 1 as substrate to achieve target molecule 5.
In the present study, we wanted to explore in depth this oxi-
dative system involving peracid with acetophenones as sub-
strate to discern whether it was achievable to control the
direction of the oxidation process to either follow pathway ①
9, the post reaction mixture was diluted by adding water
(20 mL), adjusting the pH ≈ 12 by drop-wise addition of 10%
NaOH, followed by extracting the side-products (8) with di-
chloromethane (3 × 10 mL). The basic aqueous layer was acidi-
fied by adding few drops of conc. HCl (pH < 2), followed by
extraction using dichloromethane (3 × 10 mL). The solvent
was removed under reduced pressure to obtain the com-
pound 9 in an isolated yield of 65–70% as a yellowish sticky
solid.
1
H NMR of 9 (400 MHz, CDCl ): δ 2.52 (s, 3 H, CH ), 3.77 (s, 3 H,
3
3
CH ), 3.81 (s, 3 H, CH ), 5.32 (s, 1 H, OH), 6.59 (d, J = 8.8 Hz, 1 H,
3
3
CH), 6.92 (d, J = 8.8 Hz, 1 H, CH) ppm.
13
C NMR of 9 (100 MHz, CDCl ): δ 32.3, 56.3, 62.9, 107.7, 116.3,
3
1
25.5, 143.0, 143.8, 150.0 and 201.8 ppm.
RESULTS AND DISCUSSION
Scheme 3. Direct hydroxylation of the benzene ring versus the Baeyer–
Villiger oxidation. Procedure: 2,6-dimethoxyacetophenone (1.0 mmol)
was dissolved in CH CN (5.0 mL) followed by adding pTSA (0.20 mmol)
3
Oxidation of acetophenones – two pathways
When an acetophenone is treated with a peracid (e.g. mCPBA),
two distinct oxidation mechanisms can take place: (1) the direct
and mCPBA (1.0 mmol). The reaction mixture was then leaved under stir-
ring for 1 h at 80 °C (reflux)
Scheme 2. Proposed mechanisms for the ① direct hydroxylation of the benzene ring using peracid (mCPBA) and ② the well-established reaction
mechanism for the Baeyer–Villiger oxygen insertion between the actyl group and the benzene ring
J. Phys. Org. Chem. 2015, 28 619–628
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C. GAMBAROTTI AND H.-R. BJØRSVIK
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COMPETING ORGANIC PERACID OXIDATION MECHANISMS
or ② (Scheme 2) solely by tuning the experimental variables
explored. The outcome of these initial trials revealed a lower
selectivity and some product degradation when the acetic acid
and hydrogen peroxide were used as the oxidative system,
which probably is due to the high concentration of the acetic
acid (used as solvent) with a large excess of hydrogen peroxide
necessary to promote the formation of the peracetic acid. Moreover,
the large surplus of hydrogen peroxide may cause subsequent
oxidations (over oxidation) of the formed phenolic or ester
products.
(experimental condition controlled) or if the favoured mechanistic
pathway barely was controlled by the electronic effects (and
eventually steric, bulkiness effects) of the substituents on the
acetophenone substrate. Introductory screening experiments
were performed with 2,6-dimethoxyacetophenone 7 as a model
substrate, Scheme 3.
Introductory experiments
Three different products were formed during the oxidation of
7: 2,6-dimethoxy-phenyl acetate 8, 1-(4-hydroxy-2,6-dimethoxy-
phenyl) ethanone 9 and 3-hydroxy-2,6-dimethoxyphenyl acetate
At the outset of this investigation, both in situ generated peracid
using acetic acid with hydrogen peroxide and mCPBA were
10 (Scheme 3). At the first glance, this primary result was some-
what disappointing as a rather low selectivity was demonstrated.
However, from the past experience, we know that fine-tuning of
the experimental variables enables one to improve the selecti-
vity of any synthetic reaction. Propelled by this fact, we decided
to undertake a methodical investigation of the oxidative condi-
tions involving mCPBA by means of a statistical experimental de-
[
23]
sign
and multivariate regression using the multiple linear
[
24]
[25]
regression
and by means of the MATLAB software.
method as implemented in the SAS software
[
26]
Statistical experimental design
Four different measured responses were explored, namely,
y = the %-yield of 2,6-dimethoxyphenyl acetate 8, y = the %-
8
9
yield of 1-(4-hydroxy-2,6-dimethoxyphenyl)-ethanone 9, y10 = the
-yield of 3-hydroxy-2,6-dimethoxyphenyl acetate 10 and
y = the %-decomposition, that is y = 100–ynot conv. – y – y – y
10
%
8
9
and present a complete mass balance for each single experiment
of Table 1.
k
A full factorial 2 design D with k = 3 experimental variables
(
x , x and x ), each explored at two distinct experimental levels,
1 2 3
denoted as xk,L = ꢀ1 and xk,H = +1 (the actual numerical values
are provided in the footnote a of Table 1). In addition, c = 3
experiments were placed in the centre of the experimental
Table 2. Estimated parameter values for the models, Eqn (2)
for the responses y , y , y and y
8
9
10
a
Coefficient
Model parameters (model at t = 30 min)
y
8
y
9
y
10
y
β0
β1
β2
β3
3.2909
1.4125
1.0125
1.7125
0.8625
0.9625
0.7625
0.6125
0.977
22.9455
16.4500
ꢀ0.1250
ꢀ2.2750
ꢀ0.7250
ꢀ3.7750
ꢀ3.7500
ꢀ3.8500
0.940
4.6273
5.4500
0.3250
1.1500
0.3250
1.1500
ꢀ0.6250
ꢀ0.6250
0.902
6.2727
8.6250
7.1250
2.8750
7.1250
2.8750
2.8750
2.8750
0.912
β12
β13
β23
β
1
23
2
R
RMSEP
RSD
0.387
0.428
3.843
4.249
1.623
1.794
3.841
4.247
a
Responses: yield of y
= 1-(3-hydroxy-2,6-dimethoxyphenyl)ethanone 9
and yield of y10 = 3-hydroxy-2,6-dimethoxyphenyl acetate
0. y = %-decomposition in total. RMSEP, root mean
8
= 2,6-dimethoxyphenyl acetate 8,
yield of y
9
Figure 1. Progress of each single experiment in four responses (y
8 9
, y ,
y10 and y) of the experimental design of Table 1. Samples were with-
1
drawn from the reaction mixtures at 15, 30, 45 and 60 min and repre-
sented as a line graph for each experiment
squared error of prediction; RSD, relative standard deviation,
J. Phys. Org. Chem. 2015, 28 619–628
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C. GAMBAROTTI AND H.-R. BJØRSVIK
domain, which ultimately provides a design matrix D constituted
As a first stage data analysis of the determined response values,
a series of line graphs showing the course of reaction (time versus
yield) were produced (Fig. 1). Each of the identified compounds 8,
9, 10 and the decomposition are represented as separate plots,
from which it is evident that the reaction time should be kept
within a range of 15–30 min in order to achieve high outcomes
of 8 and 9. Prolonged reaction time results in concerted oxidation
k
3
by 2 + c = 2 + 3 = 11 experiments, summarized in Table 1. The ex-
periments were performed in a random order from which samples
were withdrawn during the course of the reaction, namely, at
t = 15, 30, 45 and 60 min. The samples were analysed by using a
GC with 1,4-dinitrobenzene as an internal standard. The measured
responses are tabulated adjacent to the design matrix in Table 1.
Figure 2. Iso-contour projections of the response surfaces (yield) for the Baeyer–Villiger oxidation [2,6-dimethoxyphenyl acetate 8], the direct ring hy-
droxylation [1-(3-hydroxy-2,6-dimethoxyphenyl)ethanone 9], concurrent hydroxylation and oxidation [3-hydroxy-2,6-dimethoxyphenyl acetate 10], and
product decomposition. The figure is composed of four subplot collections (at reaction time t ∈[15, 30, 45, 60] min), where each subplot collection are
composed of a 4×5 matrix of 2D iso-contour maps. Each of the 2D plots displays the reaction temperature (x
oxidant mCPBA (x ) as ordinate. The location of the 2D plot in the horizontal direction (the outer frame) views the experimental variable quantity of
pTSA (x ) at five discrete experimental levels. Each of the rows shows thus a graphical representation of an empirical model derived with a basis in
1
) as the abscissa and the quantity of the
2
3
the experimental design in Table 1. Each row of 2D plots embodies the response (the iso-contour lines) – the %-yield of the Bayer–Villiger oxidation
product (the first row from the bottom of the figure), the %-yield of the product from the direct hydroxylation, the %-yield of product of concurrent
hydroxylation and Bayer–Villiger oxidation and finally the %-degradation products (that is converted substrate – the sum of the outcome of the three
distinct oxidation/hydroxylation products)
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COMPETING ORGANIC PERACID OXIDATION MECHANISMS
of the acetyl group, direct ring hydroxylation and decomposition
processes. Moreover, the ring hydroxylation appears to take place
at a higher rate than the Baeyer–Villiger oxidation.
predicts only a small degree (≈10%) of decomposition under
these conditions.
Even though the model for the direct ring hydroxylation also
The second stage of the data analysis involved a multivariate
correlation of the model matrix M (Eqn (1)) with the four
3
predicts high yields at high levels of the acid catalyst pTSA (x ),
it is beneficial to keep the quantity of the pTSA at a lower level,
because this suppresses the formation of the other oxidation
products as well as the decomposition reaction.
responses y
8
, y
9
, y10 and y (Eqns (2) and (3)).
M ¼ ½1 D x1x2 x1x3 x2x3 x1x2x3ꢁ
(1)
(2)
In an attempt to further improve the optimized direct hydro-
xylation reaction described previously, we thought that a solid-
[
27]
y ¼ Mb; y∈½y; y ; y ; y ꢁ
supported strong acidic catalyst such as Amberlite IR120
8
9
10
À
Á
ꢀ
1
T
T
could replace the dissolved acid catalyst pTSA. We assumed that
this interchange could contribute to defeat the degradation of
the acidic labile phenol. In fact, when Amberlite IR120 was uti-
lized in the place of pTSA, almost no degradation took place.
Moreover, the absence of strong acid in the reaction medium
avoided the product decomposition during the work-up. In fact,
the removal of the solvent by evaporation results in an increa-
sing concentration of the pTSA, which accelerate the degrada-
tion rate of the phenolic products. Thus, this finding is a direct
improvement of our previous protocol for the preparation of
b ¼ M M M y
y ¼ fðx1; x2; x3Þ ¼ β þ β x1 þ β x2 þ β x3 þ β x1x2þ
J
0
1
2
3
12
β x1x3 þ β x2x3 þ β x1x2x3; J ¼ 8; 9; 10; decomp:
13
23
123
(3)
È
À
ÁÉ
1
zi ꢀ zi;L þ ꢂ zi;H ꢀ zi;L
2
xi ¼
È
À
ÁÉ ;
i ¼ 1; …; 3
(4)
1
2
zi;H ꢀ zi;L þ ꢂ zi;H ꢀ zi;L
[
9]
activated phenols via direct hydroxylation method.
In order to facilitate the calculation of the regression coeffi-
cients (β ) of the empirical mathematical model (Eqn (3)), the ex-
perimental variables x , …, x were scaled according to Eqn (4),
where x is the experimental variable i = 1, …, 3 provided in
scaled units. z is the experimental variable, with variable i = 1,
, 3 given in the real unit. zi,L and zi,H denote the selected low
Figure 3 displays the results of experiments where various
quantities of the acidic resin were used. The best outcome was
achieved when an acidic resin loading versus substrate
k
1
3
i
(acetophenone) corresponding to 200 mg: 1 mmol was utilized.
i
Moreover, the reaction rate was also substantially improved to-
wards the hydroxylated product, proving higher selectivity and
yield. The Baeyer-Villiger oxidation product was only observed
in minor quantities (<5%). The major part of the by-product
…
and high experimental values in the real unit for each experi-
mental variable, with variable i = 1, …, 3 (footnote a of Table 1).
The estimated numerical values of the regression coefficients
for the model describing the response surface at time t = 30 min
are listed in Table 2.
Interpretation of the empirical models
The four empirical models Eqn (3) with the adjacent model pa-
rameters listed in Table 2 were used to produce the iso-contour
projection maps of the response surfaces, where the contour
lines express the yield-%. Figure 2 shows the iso-contour maps
at reaction time t = 15, 30, 45 and 60 min, respectively.
The iso-contour projection maps of the response surfaces
(Fig. 2) can clearly contribute answers to the major questions
we stated at the outset of this investigation. The model can ex-
plain the course of the Baeyer–Villiger oxidation, predict the
most beneficial conditions at a short reaction time, t = 30 min
Figure 3. The effect of various loadings of the solid acid catalyst
Amberlite IR120 submitting the 2,6-dimethoxy-acetophenone 7 for the
mCPBA oxidative conditions
(
which confirms the observations of the the raw data plot of
Fig. 1). By using high experimental levels (+1) of all of the expe-
rimental variables x , …, x , a maximum outcome of ≈15% can
1
3
be achieved of the Baeyer–Villiger oxidation product. However,
at such reaction conditions, the degradation proceeds to an
extent of >40%. The two other oxidative processes, the direct
ring hydroxylation and the concurrent direct ring hydroxylation
and Baeyer–Villiger oxidation occurs to an extent of 12–15%
each. Even though at a low selectivity, the Baeyer–Villiger oxida-
tion product can be prepared with the presented method.
An improved selectivity and outcome can be attained for the
direct ring hydroxylation of the acetophenone. At short reaction
time (t = 30 min), the direct ring hydroxylation is promoted by
high level (+1) of x and x while keeping the experimental level
1
2
of x (the quantity of the acid catalyst pTSA) at a low to moderate
3
level (ꢀ1 to 0). Under such conditions, the model predicts a yield
of >70% and low quantities of the other oxidation products,
namely, <1 and ≈10%, respectively. Moreover, the model
Figure 4. Investigation of the oxidation procedure by using recycled
Amberlite IR120 resin. Five times use of the same resin provides a mean
yield of 66.8% of the product 8
J. Phys. Org. Chem. 2015, 28 619–628
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C. GAMBAROTTI AND H.-R. BJØRSVIK
Table 3. The substitution patterns influence on the peracid oxidation – directing direct hydroxylation mechanism or the Baeyer–
Villiger oxidation mechanism
#
Substrates
#
R
Products
/Yield
#
#/Yield
1
2
3
4
5
6
7
11
12
13
14
15
16
17
ꢀH
11a
3%
nd
nd
nd
37%
14%
ꢀNO
ꢀCN
ꢀF
2
12a
13a
14a
15a
16a
ꢀOCH
3
ꢀCH
3
ꢀOH
17a >99%
18b 31%
8
9
1
18
19
20
–
18a
19a
20a
6%
–
–
38%
1%
19b 4%
0
20b 10%
11
12
13
14
21
22
23
24
–
–
–
–
21a
22a
23a
24a
45%
41%
7%
–
–
–
–
40%
1
5
25
–
25a
45%
–
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Copyright © 2015 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2015, 28 619–628

COMPETING ORGANIC PERACID OXIDATION MECHANISMS
meta-chloro benzoic acid, that is the reduction product from
mCPBA, precipitate during the cooling of the post-reaction mix-
ture, which further simplified the work-up procedure.
The acid catalyst resin was easily recycled by filtering off from
the warm post-reaction mixture. The isolated resin was washed
with acetonitrile and re-used without further purification, regen-
eration procedures or addition of more fresh resin. We repeated
the reaction five times (that is four recycles of the resin). The
achieved results showed only a small variance providing a yield
of desired product in the range 65-69%, see Fig. 4.
ring drives the oxidation towards the most activated carbocyclic
carbon. When there is the concomitant activating effect of the
two groups in the meta position to each other, the oxidation
shows high selectivity on the respective activated carbocyclic
carbon, achieving mostly the corresponding phenol or Baeyer–
Villiger product. Nevertheless, by means of a fine-tuning of the
experimental variables, we are able to maximize the yields of
the corresponding phenol or Baeyer–Villiger products when
the two mechanisms are in a competition.
CONCLUSIONS
The influence of the substitution pattern
We have investigated the selectivity of the peracid oxidation of
substituted acetophenones. Depending on the nature of the
substituents of the acetophenone, the direct aromatic ring
hydroxylation can compete with the Baeyer–Villiger oxygen
insertion. By means of multivariate modelling of designed expe-
riments with 2,6-dimethoxy-acetophenone as model substrate,
we could establish predictive empirical models from which it
was possible to device the favoured oxidation pathway by fine-
tuning the settings of the various experimental variables. Then,
the protocol that provided the highest yield of the correspond-
ing phenol was used to investigate a library of various
acetophenones with the goal to explore the electronic effect of
the substituents depending on their relative positions on the ar-
omatic ring. We revealed that both the molecular structure of the
substrate and the experimental conditions demonstrated a con-
siderable impact on whether the oxidation reaction follows the
oxygen insertion or the direct ring hydroxylation mechanism,
particularly the synergic activation by strong electron donating
group can drive the selectivity of oxygen attack. Besides reveal-
ing the various mechanistic issues, we revealed an improved
protocol for the direct aromatic ring hydroxylation.
The kinetics of the Baeyer–Villiger oxidation of acetophenones
[
28]
has previously been studied.
Studies have shown that elec-
tron donating groups in conjugated positions have two contra-
dictory effects on the reaction rate. Because of the activating
effect, the lower electrophilicity of the carbonyl group ought to
lower the reaction rate, but the activation results in an increased
basicity of the carbonyl oxygen, which once protonated in-
creases the electrophilicity of the carbonyl carbon promoting
the peracid addition. This second effect slightly prevails and
[
29]
speeds up the overall mechanism.
A question which then
arises is the following: what happens when there are more sub-
stituents on the aromatic ring and how varies the selectivity rel-
ative to the various groups position? We have tried to shed some
light on this issue by exploring the electronic effects of the sub-
stituents by treating series of acetophenones 11–25 of Table 3,
using the optimized oxidation protocol (as developed with
acetophenone 7 using Amberlite IR 120 as the acid catalyst).
The three deactivated acetophenones 12–14 were not oxi-
dized using the conditions developed herein. Acetophenone
11 and acetonaphthone 23 provided, as expected, only small
quantities of the Baeyer–Villiger product. The phenolic derivative
p-hydroxyacetophenone 17 and 22 showed different selectivity:
the first one was completely converted to the corresponding
benzoquinone 17a, whereas the second one provided only the
corresponding Baeyer–Villiger derivative. We believe that in the
case of the acetophenone 17, the formation of the quinone
could be ascribed to a fast oxidation by mCPBA of the acetic es-
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
Acknowledgements
[11]
ter intermediates.
Economic support from the Department of Chemistry at
University of Bergen and the Department of Chemistry,
Materials and Chemical Engineering at Politecnico di Milano
are gratefully acknowledged. H.R.B. acknowledges the Faculty
of Mathematics and Natural Sciences at University of Bergen
for funding to a sabbatical leave in 2013 where the project
disclosed herein was completed.
The activated acetyl position of 2,4-dimethoxyacetophenone
9 directed the reaction versus a Baeyer–Villiger mechanism;
1
however, the activating effect of the methoxy groups in posi-
tions 2 and 4 towards the carbocyclic atom in the 4-position
made the reaction product reactive, and small amounts of the
corresponding hydroxylated product were recovered. The con-
comitant electro donating effect on the same carbon atom is
not present in 2,5-dimethoxy acetophenone 24 and 3,4-methy-
lene-dioxyaceto-phenone 25, which only provided the Baeyer–
Villiger oxidation product. On the other hand, because of the
strong activation of the aromatic carbon, 3,4,5-trimethoxy-
acetophenone 18 and 3,5-dimethoxy-acetophenone 20 pro-
vided the corresponding phenols as the major products, which
is similar to the results obtained with our model substrate 2,6-
dimethoxy-acetophenone 7. The model interpretation from the
previous discussion taken together with the results achieved
during the scope of the reaction investigation, it comes clear that
the Baeyer–Villiger and direct ring hydroxylation mechanisms
can compete depending both on the experimental conditions
and on the effects of the aromatic ring substituents. It is evident
that the presence of electron donating groups on the aromatic
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2
SUPPORTING INFORMATION
[
[
1
Additional supporting information may be found in the online
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