Carboxylic acids from methyl aryl ketones by means of a new composite aerobic oxidation process

Article abstract of DOI:10.1016/S0040-4039(02)00929-2

A new aerobic oxidation method for conversion of methyl aryl ketones to the corresponding benzoic acids is presented. The method is cheap and environmentally friendly, which also makes it suitable for large scale industrial use. The method affords a yield of >75% with an almost 100% selectivity. Experiments have shown that the process operates following two mechanistic pathways, namely by base-catalysed autoxidation and by single electron transfer processes.

Full text of DOI:10.1016/S0040-4039(02)00929-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4985–4987
Carboxylic acids from methyl aryl ketones by means of a new
composite aerobic oxidation process
Hans-Rene´ Bjørsvik,* Lucia Liguori, Raquel Rodr´ıguez Gonza´lez and Jose´ Angel Vedia Merinero
Department of Chemistry, University of Bergen, Alle´gaten 41, N-5007 Bergen, Norway
Received 18 February 2002; revised 3 May 2002; accepted 13 May 2002
Abstract—A new aerobic oxidation method for conversion of methyl aryl ketones to the corresponding benzoic acids is presented.
The method is cheap and environmentally friendly, which also makes it suitable for large scale industrial use. The method affords
a yield of >75% with an almost 100% selectivity. Experiments have shown that the process operates following two mechanistic
pathways, namely by base-catalysed autoxidation and by single electron transfer processes. © 2002 Elsevier Science Ltd. All rights
reserved.
The lignosulfonate oxidation process for the production
of vanillin1 also produces several side-products such as
1-(4-hydroxy-3-methoxyphenyl)-ethanone (acetovanil-
lone), vanillic acid, para-hydroxy benzaldehyde, and
more. Acetovanillone serves as an industrial feedstock
for 3,4-dimethoxybenzoic acid (veratric acid), which is
an important intermediate for the synthesis of several
pharmaceutical chemicals such as mebeverine,2 vesnari-
none,3 and itopride.4 A current industrial process to
veratric acid that is based on acetovanillone is shown in
Scheme 1.
tiated a project with the goal to look for more green
and environmentally benign selective processes for vera-
tric acid. Recently, we reported a method based on the
alkaline nitrobenzene lignin oxidation method for the
oxidation of methyl aryl ketones.6 Even though this
method afforded both high yields and demonstrated
good selectivity for the corresponding aromatic car-
boxylic acid, the method was encumbered with a draw-
back since the oxidant, 1,3-dinitrobenzene, was
required in stoichiometric quantities.
In this context, we have, in an endeavour to develop the
stoichiometric 1,3-dinitrobenzene oxidation method
into a catalytic process, discovered a complex com-
posite oxidation process, that is partly catalytic in
1,3-dinitrobenzene and partly proceeds as a base-
catalysed autoxidation (Scheme 2).
The oxidation step of this process is based on the
haloform reaction with NaOCl. However, this process
suffers a serious drawback from an environmental
point of view, since 1 equiv. of chloroform is produced
for each molecule of target compound. Moreover, chlo-
rinated aromatic side-products may also be formed
during this process.5
We have discovered that one of the crucial points for
the new oxidation method is the production of the
enolate anion from the methyl aryl ketone. When the
enolate anion is formed, the oxidation takes place by
means of single electron transfer (SET) processes as we
have reported earlier for the method using 1,3-dini-
trobenzene as stoichiometric oxidant.6 The SET pro-
cesses and the oxygen atom transfer are illustrated in
pathway (a) of Scheme 2. In our attempts to develop
this process into a catalytic process using oxygen as the
terminal oxidant, we discovered that by using only 5%
(w/w) of 1,3-dinitrobenzene with concomitant bubbling
of molecular oxygen through the reaction mixture, a
high yield (>75%) of benzoic acid was obtained when
acetophenone was used as a model compound.
Due to the continuing demand for more environmen-
tally friendly industrial production processes we ini-
Scheme 1.
* Corresponding author. Tel.: +47 55 58 34 52; fax: +47 55 58 94 90;
e-mail: hans.bjorsvik@kj.uib.no
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00929-2

4986
H.-R. Bjørs6ik et al. / Tetrahedron Letters 43 (2002) 4985–4987
(HMPA) and dimethylformamide (DMF), respectively.
Moreover, the process using HMPA as reaction
medium also needs a very long reaction time, which is
a drawback from an industrial point of view.
When our new oxidation process was performed with-
out the presence of the mediator, 1,3-dinitrobenzene
(entry c6, Table 1), a surprisingly high yield of benzoic
acid (58.2%) was produced. Hence, the base-catalysed
autoxidation, pathway (c) of Scheme 1, is a substantial
contributor to the overall picture. An experiment per-
formed without bubbling oxygen (entry c7, Table 1),
but with the catalytic quantity of 1,3-dinitrobenzene
present, afforded, as expected, less than 8% of benzoic
acid ascribed to the participation of 1,3-dinitrobenzene
as stoichiometric oxidant.6 The results of these experi-
ments reveal a significant catalytic effect of 1,3-dini-
trobenzene. The total outcome of the combined process,
including pathways (a), (b), and (c) of Scheme 2, gives
a high yield with an excellent selectivity (entry c4).
Scheme 2.
The outcome of the oxidation process was, however,
very dependent on the reaction temperature as well as
the quantity of base (experiments c1–4, Table 1). A
maximum yield of 75.2% (entry c4) was obtained when
acetophenone was oxidised.
When the oxidation method was applied to the oxida-
tion of acetoveratrone, the industrial feedstock for vera-
tric acid (Scheme 3), an excellent yield and selectivity
(78 and 100%, respectively) were achieved.
The reaction conditions and the solvent (tert-BuOH)
may easily be implemented in a full scale industrial
plant, however, the base tert-BuOK is expensive and
preferably should be substituted with a cheaper one.
When attempts were made to carry through the oxida-
tion by using water as solvent and sodium hydroxide as
base (entry c5), the reaction failed. This is in contrast
to the stoichiometric method which can be performed
successfully under such conditions.6
O
CH3
O
OH
Base-catalysed aerobic oxidation of acetophenone into
benzoic acid is described in the old literature.7 Later
reports by Wallace et al.8 and Petric et al.9 describe such
processes affording high yields. However, these pro-
cesses also suffer from ‘environmental drawbacks’
because the two processes require the rather environ-
mentally unfriendly solvents hexamethylphosphoramide
1,3-C6H4(NO2)2 (5%)
tert-BuOH, tert-BuOK
O2, 80 oC, 5h
Yield = 78%
Selectivity = 100%
OCH3
OCH3
OCH3
OCH3
Scheme 3.
Table 1. Oxidation of acetophenone by means of 1,3-dinitrobenzene catalysed aerobic oxidation process
c
Reaction conditionsa
Responsesb
Yield
Base/(mmol)
T (°C)
Ph(NO3)2
Conv.
Selec.
1
2
3
t-BuOK/4.8
t-BuOK/4.8
t-BuOK/4.8
t-BuOK/8.0
NaOH/15.0
t-BuOK/7.2
t-BuOK/7.2
KOH/4.8
20
50
80
90
80
80
80
80
80
0.12
0.12
0.12
0.12
0.12
–
0.12
0.12
–
67.0
74.6
72.9
75.8
–
91.7
13.3
73.8
52.4
39.9
53.5
61.2
75.2
–
58.2
ꢀ8
12.1
22.5
59.6
71.5
84.0
98.9
–
63.6
60.0
16.4
43.4
4
5c
6
7d
8
9e
NaOH/38.5
a Procedure: acetophenone (0.288 g, 2.4 mmol) was dissolved in tert-BuOH (12 mL) followed by adding t-BuOK and 1,3-dinitrobenzene (0.12
mmol) with oxygen bubbling through the reaction mixture. The reaction mixture was heated with stirring for a period of 5 h.
b Isolated product corrected for impurities using GC analyses.
c NaOH was added as a 30% (7.5 M) aqueous solution.
d Experiment performed without bubbling oxygen but under a nitrogen atmosphere. The isolated product was impure.
e Procedure: acetophenone (18.8 mmol) was dissolved in tert-BuOH (95 mL) and NaOH added as base. The reaction was conducted by using a
mechanical stirrer to improve mixing.

H.-R. Bjørs6ik et al. / Tetrahedron Letters 43 (2002) 4985–4987
4987
R1=R2=H
O
CH3
1,3-C6H4(NO2)2 (5%)
tert-BuOH, NaOH
TBAB (10%)
O
OH
The set-up of the new oxidation method makes it cheap
and environmentally friendly as well as very suitable for
large scale use.
Yield = 78.5%
Selectivity = 100%
O2, 80 oC, 5h
R2
R2
R1=R2=OCH3
R1
R1
Further studies are underway in order to improve the
method as well as to explore the potential of the
procedure as an oxidation method for other substrates.
Yield = 41.1%
R1=R2=OCH3 or H
Selectivity = 74.3%
Scheme 4.
Acknowledgements
Some experiments which were carried out using KOH
and NaOH as base (entries c8 and c9 of Table 1)
showed, however, disappointing results. We thought
that this was due to solubility problems. Experiments
conducted with a phase transfer catalyst (PTC) present,
tetrabutylammonium bromide (TBAB), reveal our
assumption to be correct. Scheme 4 shows results from
an experiment when sodium hydroxide was used as
base in the presence of TBAB (10%) as PTC. Other
conditions were as described above. An excellent yield
(78.5%) and selectivity (ꢀ100%) were achieved for the
oxidation of acetophenone under these conditions.
When acetoveratrone was submitted to the oxidative
conditions using NaOH as base and TBAB as PTC, a
somewhat lower yield and selectivity were obtained, but
will, in future studies, be a subject for optimisation.
Financial support for this project from the Research
Council of Norway is gratefully acknowledged. Raquel
Rodr´ıguez Gonza´lez, and Jose´ Angel Vedia Merinero
acknowledge grants from the Erasmus program.
References
1. Bjørsvik, H.-R.; Minisci, F. Org. Proc. Res. Dev. 1999, 3,
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H.; Sakaguchi, J. EP Patent 0 306 827, 1989; Chem. Abstr.
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In summary, the oxidation method presented here
requires basic conditions and molecular oxygen at a
moderate temperature in order to operate.
5. Bjørsvik, H.-R.; Norman, K. Org. Proc. Res. Dev. 1999, 3,
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The oxidation process proceeds by a composite mecha-
nism constituting by two independent reaction paths.
One of the paths is catalytic in 1,3-dinitrobenzene and
the other one is a base-catalysed aerobic oxidation
process.
7. Miller, W.; Rohde, A. Ber. 1892, 25, 2095.
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