New selective oxidation reactions by nitroarenes in basic medium involving electron-transfer processes

Article abstract of DOI:10.1021/op000095p

A new synthetic process for oxidation of methyl ketones into their corresponding carboxylic acids using a modified alkaline nitrobenzene method is described. By introduction of a more powerful oxidant, such as 1,3-dinitrobenzene, the oxidation reaction proceeds smoothly in aqueous alkaline solution at 100 °C. The procedure can also be used for oxidation of benzaldehydes and benzyl alcohols into carboxylic acids and to oxidise mandelic acid into its α-keto form, whereas prolonged reaction time results in decarboxylation and gives thus also in this case benzoic acid.

Full text of DOI:10.1021/op000095p

Organic Process Research & Development 2001, 5, 136−140
New Selective Oxidation Reactions by Nitroarenes in Basic Medium Involving
Electron-Transfer Processes
,
†
‡
‡
Hans-Ren e´ Bjørsvik,* Lucia Liguori, and Francesco Minisci
Department of Chemistry, UniVersity of Bergen, All e´ gaten 41, N-5007 Bergen, Norway, and Dipartimento di Chimica del
Politecnico di Milano, Via Mancinelli 7, I-20131 Milano, Italy
Abstract:
Scheme 1
A new synthetic process for oxidation of methyl ketones into
their corresponding carboxylic acids using a modified alkaline
nitrobenzene method is described. By introduction of a more
powerful oxidant, such as 1,3-dinitrobenzene, the oxidation
reaction proceeds smoothly in aqueous alkaline solution at 100
°
C. The procedure can also be used for oxidation of benzalde-
hydes and benzyl alcohols into carboxylic acids and to oxidise
mandelic acid into its r-keto form, whereas prolonged reaction
time results in decarboxylation and gives thus also in this case
benzoic acid.
dehydrogenation of the dihydroquinoline intermediate to
quinoline.
Introduction
1
In 1940 Freudenberg et al. discovered a method for
oxidative degradation of spruce lignin 1 that gave vanillin
, acetovanillon 3, vanillic acid 4, and several other low-
Methods and Results
Recently, in our laboratories we have studied and opti-
mised different hydrolysis-oxidation processes for synthesis
of vanillin from lignosulfonates, also including the alkaline
nitrobenzene method. Our studies revealed that this last
method was more selective than any of the other methods
we tried as well as other methods reported in the past for
the synthesis of vanillin, even if we developed the less
selective oxidation by oxygen for industrial application
2
molecular weight phenolic compounds as oxidation products.
This method is currently known as the alkaline nitrobenzene
oxidation method. In subsequent years the method was
4
2
further investigated and developed by Lautsch et al. and
4
3
Leopold, and has since then been extensively applied within
the area of wood chemistry regarding the oxidative degrada-
4
tion process and for elucidation of structural elements of
4
suggested by economical reasons. During the oxidation
the lignin biopolymer.
process using the alkaline nitrobenzene oxidation method,
the lignin biopolymer is degraded into low molecular weight
phenolic compounds that also contain carbonylic groups:
ketones, aldehydes, and carboxylic acids are formed (Scheme
Despite these former results, few synthetic applications
have been reported for the oxidation by nitrobenzene 5 or
3
nitroarenes in general. Leopold has reported that guaiacol
derivatives were oxidised to give high yields of vanillin under
the rather drastic conditions of the alkaline nitrobenzene
oxidation. The method requires a reaction temperature of
1
)
In this process, nitrobenzene 5, used as oxidant, is
stepwise reduced to aniline 8, following the reaction path
nitrobenzene 5 f nitrosobenzene 6 f phenylhydroxylamine
7 f aniline 8, Scheme 2. Thus, the intermediates 6 and 7
also function as oxidants as well as nitrobenzene itself.
Besides the reaction products 6, 7, and 8, azoxybenzene 9,
azobenzene 10, and hydroxyazobenzene 11 have also been
determined in the reaction mixtures after such oxidation
experiments. This shows that the oxidation is a rather
complex process and it proceeds by several steps since
compounds 9-11 are condensation products of nitrosoben-
zene and hydroxylamine derivatives.
As mentioned above, the alkaline nitrobenzene oxidation
process requires rather drastic conditions, which obviously
are very unfavourable for synthetic applications. However,
the reactions that take place under this oxidation process
could be in principle a valuable tool for the synthetic organic
170-190 °C, a pressure of 10-12 atm, and a pH of 13-14.
Furthermore, nitrosobenzene 6, the first stable reduction
product of the nitro group (5), is reported5,6 to be a very
specific oxidant, giving aldehydes from benzyl halides and
tosylates, and R-dicarbonyl compounds from R-halo ketones.
In the Skraup synthesis7 nitrobenzene 5 is used for
,8
*
Corresponding author. E-mail: Hans.Bjorsvik@kj.uib.no.
University of Bergen.
Politecnico di Milano.
†
‡
(
(
(
(
(
(
(
(
1) Freudenberg, K.; Lautsch, W.; Engler, K. Ber. 1940, 73, 167.
2) Lautsch., W.; Plankenhorn, E.; Klink, F. Angew. Chem. 1942, 53, 108.
3) Leopold, B. Acta Chem. Scand. 1950, 4, 1523.
4) Bjørsvik, H.-R.; Minisci, F. Org. Process Res. DeV. 1999, 3, 330.
5) Kr o¨ hnke, F. Angew. Chem., Int. Ed. Engl. 1963, 2, 380.
6) Kr o¨ hnke, F.; B o¨ rner, E. Chem. Ber. 1963, 69, 2006.
7) Skraup, Z. H. Ber. 1880, 13, 2086.
8) Manske, K. Org. React. 1953, 7, 59.
1
36
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development
10.1021/op000095p CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 01/12/2001

Scheme 2
Table 1. Results from Oxidation of Acetophenones with the
Modified Alkaline Nitrobenzene Method
R
1
R
2
3
conv.
yield of acid
1
2
3
4
5
6
7
8
9
1
1
1
1
1
H
H
H
CH
H
H
H
H
CH3O
H
H
H
100
>97
>96
>95
>98
100
∼97
>99
>98
100
>93
100
100
100
62.1
24.2
59.2
66.2
63.8
72.7
60.0
56.2
57.9
-
Ph
CH
H
Br
Cl
a
3
F
CH
CH
HO
3
O
O
3
0
1
2
3
4
b
H N
2
H
25.4
58.7
-
process chemist, as the reaction involves C-C bond fissions
NO
H
H
2
and ether bond cleavages. Thus, on the basis of our gained
NO
CN
2
4
knowledge and experiences from lignin oxidation studies,
-
we tried to further develop the alkaline nitrobenzene oxida-
tion into a more applicable method for synthetic purposes
and also to investigate the mechanistic aspects of the
oxidation process.
i
Reaction conditions: The ketone (2.4 mmol) and the oxidant 1,3-dinitroben-
zene (1.8 mmol) are added to an aqueous solution (12 mL) of NaOH (30%) and
a
heated at T ) 100 °C for t ) 2.5 h. A minor quantity (13.7%) of terephthalic
b
acid was also formed during the oxidation reaction. A trace (∼1%) of benzoic
acid was also formed during the oxidation reaction.
Our primary interests and goal in this context were to
develop a new halogen-free oxidation process, a substitute
for the haloform reaction that we earlier have developed
9
Table 2. Results from Oxidation of Benzylic Alcohols with
the Modified Alkaline Nitrobenzene Method
for application for oxidation of acetoveratron into veratric
1
0
acid.
Our synthetic experimental results using the alkaline
nitrobenzene method for oxidation of simple low-molecular
weight organic compounds revealed that an elevated tem-
perature was necessary to carry out the oxidation. However,
by introduction of the more powerful oxidant, 1,3-dinitroben-
zene, the oxidation reaction proceeded smoothly at atmo-
spheric pressure and much lower reaction temperature (100
yield
R
1
R
2
R
3
conv.
aldehyde
acid
°
C). The oxidation reactions were performed in strong
1a
2
3
4
5
H
NO
H
H
100
82.2
84.2
100
100
67.6
-
44.0
63.4
42.7
22.5
17.0
65.8
2
alkaline water solution: upon heating a few minutes, the
reaction mixture becomes dark red, which during the course
of the reaction changed to black.
H
H
H
NO
H
Cl
CH
CH
H
7.4
38.3
53.0
-
CH
H
3
O
O
3
O
O
3
A variety of methyl aryl ketones (Table 1) have all been
oxidised into their corresponding benzoic acids using the new
method. Moreover, the method was also tried with some
benzyl alcohols (Table 2) and benzaldehydes (Table 3); both
functionalities also gave the corresponding benzoic acid in
high yields. Esters have also been determined as reaction
products, although in small quantities and only when benzylic
alcohols are oxidised with a low sodium hydroxide concen-
tration. The reaction products from dinitrobenzene (m-
nitroaniline, 1,3-phenyldiamine, azoxy-nitrobenzene resulting
from condensation of nitrosobenzene and hydroxylamine
derivatives) were characterised only qualitatively, because
tars are often formed due to further oxidation of the amino
derivatives. However, in one experiment (entry 1 of Table
2
H
6
CH
3
H
1.6
i
Reaction conditions: The alcohol (2.4 mmol) and the oxidant 1,3-
dinitrobenzene (1.8 mmol) are added to an aqueous solution (12 mL) of NaOH
a
(
30%) and heated at T ) 100 °C for t ) 2.5 h. In this experiment, a reduction
product from the oxidant 1,3-dinitrobenzene was isolated as pale yellow crystals
of azoxynitrobenzene in a yield of 96% (248 mg).
2
) the azoxyderivative was isolated as pale yellow crystals
in high yield (96%). The dinitrobenzene radical anion is the
origin for the dark red colour that initially is observed in
the oxidation reaction, as it is well documented in literature.11
The colouring of the reaction mixture is observed when
alcohols, aldehydes, or acetophenones are oxidised.
We have also used the modified alkaline nitrobenzene
oxidation method to oxidise hydroxy-phenyl-acetic acid 12
(
9) See, for example: Sykes, P. A Guidebook to Mechanism in Organic
Chemistry, 6th ed.; Longman Scientific & Technical: Harlow, 1986; pp
2
96-297.
(10) Bjørsvik, H.-R.; Norman, K. Org. Process Res. DeV. 1999, 3, 341.
(11) Russel, G. A.; Janzen, E. G. J. Am. Chem. Soc. 1962, 84, 4153.
Vol. 5, No. 2, 2001 / Organic Process Research & Development
•
137

Table 3. Results from Oxidation of Benzaldehydes with the
Scheme 4
Modified Alkaline Nitrobenzene Method
R
1
3
R
2
conv.
yield of acid
1
2
3
4
5
H
H
CH
H
H
Cl
CH
CH
CH
100
100
100
>50
70.3
96.0
89.1
59.5
47.6
41.3
O
3
3
3
O
O
H
i
Reaction conditions: The aldehyde (2.4 mmol) and the oxidant 1,3-
dinitrobenzene (1.8 mmol) are added to an aqueous solution (12 mL) of NaOH
30%) and heated at T ) 100 °C for t ) 2.5 h.
(
Scheme 3
(mandelic acid) in an attempt to obtain oxo-phenyl-acetic
acid 13, Scheme 3.
After a short reaction time of 0.5 h, 20% of hydroxy-
phenyl-acetic acid 12 is converted into oxo-phenyl-acetic acid
13. Prolonging of the reaction time (2.5 h.), leads to
quantitative conversion affording 80% of the oxo-phenyl-
acetic acid 13 and 20% of benzoic acid, by further oxidising.
Also, in the present experiment oxidising the hydroxy-
phenyl-acetic acid 12, the dark red colour of the dinitroben-
zene radical anion is observed in the beginning of the
reaction.
the oxygen involvement. G. Russell and co-workers11,12 have
reported many years ago conclusive evidence for the
electron-transfer reduction of nitroarenes in basic media and
above all for the formation of carbon-centred radicals and
nitroarene radical anions by reactions of carbanions with
nitroarenes. It is, therefore, highly reasonable that in the
strongly basic medium the carbanion in equilibrium with the
ketone in Scheme 4 is oxidised by an electron-transfer
process with the formation of an R-ketoalkyl radical and
dinitrobenzene radical anion. Russell’s results were further
Conclusions
We have developed a simple and versatile method for
oxidation of acetophenones into their corresponding benzoic
acids. Moreover, the method is also suitable for oxidation
of benzaldehydes and benzylic alcohols to the corresponding
carboxylic acids and the oxidation of hydroxy-phenyl acetic
acid 12 into oxo-phenyl-acetic acid 13 as well as oxidative
decarboxylation, only by prolonging the reaction time.
The reaction mechanism of the oxidation is clearly
complex. Some general mechanistic aspects, however, can
be emphasised: electron-transfer processes are involved
according to our interpretation. For example we suggest
Scheme 4 for the first steps of the ketone oxidation.
The reactions were carried out in a sealed tube in air or
nitrogen atmosphere as well as in an “open beaker”, all
affording similar results. In any case, however, the amount
of air is too small so that molecular oxygen could signifi-
cantly contribute to the reaction mechanism, even if the
1
3-15
supported by other authors.
The oxidation of aromatic alcohols and aldehydes to
carboxylic acids can be related to the initial oxidation of the
alcohol to the aldehyde by an electron-transfer process and
in some degree (∼12%) competitive Canizzaro dispropor-
tionation of the aldehyde to the carboxylic acid and benzylic
alcohol, which is further oxidised, and direct oxidation of
the aldehyde. Of particular interest appears to be the
(12) Russel, G. A.; Janzen, E. G.; Becker H.-D.; Smentowsky F. J. Am. Chem.
Soc. 1962, 84, 2652.
(13) Ayscough, P. B.; Sargent, F. P.; Wilson, R. J. Chem. Soc. 1963, 5418.
(14) Ayscough, P. B.; Sargent, F. P. Proc. Chem. Soc. 1963, 94.
(15) O’Connor, C. J.; McLennan, D. J.; Sutton, B. M.; Denny, W. A.; Wilson,
W. R. J. Chem. Soc., Perkin Trans. 2 1991, 951.
“cage” coupling of Scheme 4 may successfully compete with
138
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development

Scheme 5
Starting materials and reagents were purchased com-
mercially and used without further purification. All of the
reaction products were known and were analysed by GC and
1
GC-MS, H NMR, and by comparison with authentic
samples.
General Procedure. To a solution of NaOH (12 mL of
3
0% solution) was added the substrate (methyl ketones,
benzylic alcohols, benzaldehyde, or mandelic acid) (4.3
mmol), 1,3-dinitrobenzene (0.606 g, 3.6 mmol). The reaction
mixture was stirred (magnetic stirrer bar) and heated to a
temperature of 100 °C at atmospheric pressure or slightly
elevated pressure by means of a closed reaction tube for 2 h
3
0 min. After a few minutes reaction time, the reaction
mixture became dark red, which during the course of the
reaction changed to black. The basic water phase was diluted
with water (150 mL) and extracted with CH Cl (200 mL).
2 2
This organic phase contained the unreacted substrate, the
unconsumed oxidant 1,3-dinitrobenzene, and the reaction
product from the oxidant m-nitroaniline, 1,3-phenylenedi-
amine, and azoxynitrobenzene. In one experiment (entry 1
of Table 2) the azoxynitrobenzene was isolated as pale yellow
crystals in high yield (96%). In some cases, the separation
of the organic and water phases was difficult due to the
presence of tars that probably were formed from the
polymerisation of aniline compounds (reaction products of
the oxidant). The basic water phase is acidified using
oxidation of mandelic acid, which initially leads to the R-keto
acid 13 which is further oxidised to benzoic acid (Scheme
concentrated HCl until pH 1-2 and extracted with CH
200 mL). This organic phase contains almost only the pure
benzoic acid derivative.
2 2
Cl
3). We suggest for this oxidative decarboxylation the two
(
electron-transfer steps shown by Scheme 5.
The R-keto acid 13 is deprotonated in the strong alkaline
solution giving the anion form 22. The first electron-transfer
step proceeds under formation of the oxygen-centred radical
An experiment under the same conditions with benzal-
dehyde in the absence of dinitrobenzene revealed that only
1
2% of the aldehyde undergoes the Cannizzaro dispropor-
2
23, which easily decarboxylates under formation of CO , and
tionation in benzoic acid and benzyl alcohol.
the acyl radical 24, which has a marked nucleophilic
Spectroscopic Data. p-Phenylbenzoic acid: C13
H
10
O
2
character, and their easy electron-transfer oxidations to acyl
1
[
198.21]. H NMR (400 MHz, CD
3
OD, ppm) δ 8.10 (d, 2H,
1
6-20
cations 25 is well-documented.
The acyl cations 25
+
•
J ) 8.18 Hz), 7.74-7.38 (m, 7H). MS (m/e) 198 (M ), 181
obviously react fast with hydroxyl ions of the very strong
basic water solution, giving benzoic acid.
+
•
(
M
- OH), 152, 126, 115, 102, 75.
p-Methylbenzoic acid: C [136.14]. H NMR (400
MHz, CD OD, ppm) δ 7.90 (d, 2H, J ) 8.18 Hz), 7.16 (d,
2H, J ) 8.18 Hz), 2.40 (s, 3H, CH
1
8 8 2
H O
3
+
•
Experimental Section
3
). MS (m/e) 136 (M ),
+
•
General Methods. GLC analyses were performed on a
capillary gas chromatograph (HP 5890) equipped with a
fused silica column (L 25 m, 0.20 mm i.d., 0.33 µm film
thickness) from Hewlett-Packard at a helium pressure of 200
kPa, splitless/split injector and flame ionisation detector.
Mass spectra were performed on a GC-MS VG 7070 E
instrument, using a HP 5890 series II gas chromatograph
equipped with a fused silica column (L 30 m, 0.25 mm i.d.,
119 (M - OH), 107, 91, 77, 65.
m-Methylbenzoic acid C
MHz, CD
1H), 7.13-7.09 (d, 2H, J ) 6.29 Hz), 2.40 (s, 3H, CH
1
H
8 8
O
2
[136.14]. H NMR (400
3
OD, ppm) δ 7.85-7.75 (m, 1H), 7.50-7.30 (m,
).
MS (m/e) 136 (M ), 119 (M - OH), 91, 65.
3
+
•
+•
1
p-Bromobenzoic acid: C H BrO [201.01]. H NMR (400
7
5
2
MHz, CD OD, ppm) δ 7.91 (d, 1H, J ) 8.18 Hz), 7.63 (d,
3
+
•
1H, J ) 8.18 Hz). MS (m/e) 202 (M ), 183, 157, 104, 75,
0.25 µm film thickness) from Chrompack, CP-Sil 8 CB low
65.
1
bleed/MS and He as carrier gas.
p-Chlorobenzoic acid: C H ClO [156.56]. H NMR
7
5
2
1H NMR spectra were recorded on a NMR spectrometer
operating at 400 MHz. Chemical shifts were referenced to
internal TMS.
(400 MHz, CD OD, ppm) δ 7.995 (d, 1H, J ) 8.83 Hz),
3
+
•
+•
7.48 (d, 1H, J ) 8.83 Hz). MS (m/e) 156 (M ), 139 (M
- OH), 128, 111, 85, 75, 65.
1
p-Fluorobenzoic acid: C
7
H
5
FO
2
[140.11]. H NMR (400
(
(
(
16) Minisci, F. Acc. Chem. Res. 1975, 8, 165.
17) Minisci, F. Top. Curr. Chem. 1976, 62, 1
18) Minisci, F. Substituent Effects in Free-radical Chemistry; Reidel: Dordrecht,
MHz, CD
3
OD, ppm) δ 8.20-7.80 (m, 2 H), 7.21-6.98 (m,
2 H). H NMR (400 MHz, CD OD, ppm) δ (-105.9)-
-106.2) (m), (-113.9)-(-114.1) (m). MS (m/e) 140 (M ),
1
9
3
1
986
+•
(
(19) Minisci, F.; Fontana, F.; Vismara, E. Heterocycles 1989, 28, 489.
+
•
(20) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem. 1990, 27, 79.
123 (M - OH), 95, 75, 69, 63, 57.
Vol. 5, No. 2, 2001 / Organic Process Research & Development
•
139

1
3
,4-Dimethoxybenzoic acid: C
400 MHz, CD OD, ppm) δ 7.67 (d, 1H, J
1.89 Hz), 7.555 (d, 1H, J ) 1.89 Hz), 7.15 (d, 1H, J
.81 Hz), 3.90 (s, 3H, CH ), 3.84 (s, 3H, CH
), 139, 121, 111, 107, 95, 79,
9
H
10
O
4
[182.17]. H NMR
Lucia Ligouri). Research Council of Norway, Politecnico di
Milano, and University of Bergen are all acknowledged for
economical support to the project. We thank Mr. Walter
Panzeri (CNR, Milano) and Mrs. Ann Margot Whyatt
(
)
8
1
6
3
o
) 8.81 Hz, J
m
m
o
)
3
3
). MS (m/e)
+
•
+•
82 (M ), 167 (M - CH
8, 63, 55.
3
(University of Bergen) for excellent technical support for
the recording and processing of the NMR spectra and for
the GC-MS data, respectively.
1
4-Methoxybenzoic acid C
8 8 3
H O [152.14]. H NMR (400
MHz, CD OD, ppm) δ 7.96 (d, 1H, J ) 8.81 Hz), 6.97 (d,
3
+
•
1
1
H, J ) 8.81 Hz), 3.85 (s, 3H, CH
35 (M - CH
3
). MS (m/e) 152 (M ),
+
•
3
), 109, 92, 81, 77, 74, 63.
Received for review September 6, 2000.
OP000095P
Acknowledgment
This work was supported by Research Council of Norway
with a visiting research grant to one of the authors (Dr.
140
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development