An efficient synthesis of 2,3,5-trimethylbenzoquinone by metal-free oxidation of 1,2,4-trimethylbenzene

Article abstract of DOI:10.1177/1747519819877304

The oxidation of 1,2,4-trimethylbenzene with phthaloyl peroxide has been investigated under solvent-free and optimized conditions. 2,3,5-Trimethylbenzoquinone was obtained with great purity in 92% yield at 95% conversion of 1,2,4-trimethylbenzene at 120°C for 2.5 h under solvent-free conditions. The important factors such as the efficiency of the different cyclic acid anhydrides or carboxylic acid peroxides, the concentration of phthalic anhydride and 30% H₂O₂, the reaction time, the effect of solvent system, and the reaction temperature have been studied. An important advantage of this oxidizing system, aside from the organic solvent-free conditions, is that it is non-toxic, eco-friendly, and inexpensive. In addition, this methodology will be of great use in the preparation of commercially valuable benzoquinones from the corresponding aromatic compounds.

Full text of DOI:10.1177/1747519819877304

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research-arti
7cle2019 7304CHL0010.1177/1747519819877304Journal of Chemical ResearchYerramreddy et al.
Research Paper
Journal of Chemical Research
–4
1
An efficient synthesis of
,3,5-trimethylbenzoquinone by metal-free
oxidation of 1,2,4-trimethylbenzene
© The Author(s) 2019
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Thirupathi Reddy Yerramreddy , Egan Pelton, Karl A Dawson
and Alexandros Yiannikouris
Abstract
The oxidation of 1,2,4-trimethylbenzene with phthaloyl peroxide has been investigated under solvent-free and
optimized conditions. 2,3,5-Trimethylbenzoquinone was obtained with great purity in 92% yield at 95% conversion of
1,2,4-trimethylbenzene at 120°C for 2.5 h under solvent-free conditions. The important factors such as the efficiency
of the different cyclic acid anhydrides or carboxylic acid peroxides, the concentration of phthalic anhydride and 30%
H O , the reaction time, the effect of solvent system, and the reaction temperature have been studied. An important
2
2
advantage of this oxidizing system, aside from the organic solvent-free conditions, is that it is non-toxic, eco-friendly, and
inexpensive. In addition, this methodology will be of great use in the preparation of commercially valuable benzoquinones
from the corresponding aromatic compounds.
Keywords
1
,2,4-trimethylbenzene, 2,3,5-trimthylbenzoquinone, metal-free oxidation, phthaloyl peroxide
Date received: 4 April 2019; accepted: 29 August 2019
most of the reported methods have not been advantageous
from a commercial and large-scale production viewpoint
because they require commercially non-available or expen-
sive starting materials and reagents and need large quantities
of organic solvents, multi-step synthesis in harsh reaction
Introduction
The oxidation of aromatic C–H bonds and the synthesis of
benzoquinones from aromatic compounds is a central facet of
the chemical and pharmaceutical industry. The natural
products with benzoquinone moiety exhibit an attractive
pharmacological profile as antitumor, antimicrobial, and car-
diovascular activities. In addition, synthetic benzoquinones
are important building blocks in the preparation of pharma-
ceutical ingredients. 2,3,5-Trimethylbenzoquinone (TMBQ)
1–4
13
conditions, or use toxic metal catalysts. Considering these
facts, there is still a need to develop a commercially viable,
5–7
8
Synthetic Chemistry Laboratory, Alltech Center for Animal
is a commercially valuable compound, and it can be reduced Nutrigenomics & Applied Animal Nutrition, Nicholasville, KY, USA
to 2,3,5-trimethylhydroquinone (TMHQ), which is known to
be an important starting material for the synthesis of vitamin-
E. In the literature, various processes for preparing TMBQ by
Corresponding author:
Thirupathi Reddy Yerramreddy, Synthetic Chemistry Laboratory,
Alltech Center for Animal Nutrigenomics & Applied Animal Nutrition,
the oxidation of 2,3,5-trimethylphenol (TMP) or 1,2,4-tri-
3
031 Catnip Hill Road, Nicholasville, KY 40356, USA.
9–16
methylbenzene (TMB) have been reported.
However, Email: tyerramreddy@alltech.com

2
Journal of Chemical Research 00(0)
Table 1. Oxidation of TMB to TMBQ using different cyclic
a
anhydride/carboxylic acid peroxides.
Peroxide
Conversion
mol %)b
Yield
(mol %)
c
(
9
7
5
8
92
69
Scheme 1. Oxidation of 1,2,4-trimethylbenzene to
2
,3,5-trimethylbenzoquinone using phthaloyl peroxide.
non-infringing, and scalable synthetic methodology for the
preparation of TMBQ.
17
18
Yuan et al. and Dragan et al. described a metal-free oxi-
dation of aromatic hydrocarbons to corresponding phenols
using phthaloyl and malonoyl peroxides, respectively.
However, a method for the preparation of TMBQ by straight
oxidation of TMB using phthaloyl or malonoyl peroxide has
yet to be reported. These observations prompted us to develop
a simple, efficient, and commercially viable synthetic method
for the preparation of TMBQ from a readily available starting
material, that is, TMB using phthaloyl peroxide in a solvent
or under solvent-free conditions (Scheme 1).
8
4
4
2
2
5
78
39
41
TMB: 1,2,4-trimethylbenzene;TMBQ: 2,3,5-trimethylbenzoquinone.
a
Reaction conditions: 1 mmol ofTMB, 3 mmol of cyclic acid anhydride or
carboxylic acid, 8 mmol of 30% H O , 120°C, solvent free, 2.5 h.
Results and discussion
2
2
b
Conversion ofTMB toTMBQ.
We initially examined the efficiency of different cyclic acid
anhydride or carboxylic acid peroxides for the oxidation of
TMB to TMBQ under solvent-free conditions at 120°C or
c
Isolated yield of theTMBQ.
reflux temperature for 2.5 h. Phthaloyl peroxide (generated temperature caused a decrease in the selectivity of TMBQ
in situ by the reaction of 30% H O on phthalic anhydride) because it was further oxidized to form some unknown
2
2
was found to be the most effective oxidizing agent for the side products. These results indicated that the reaction
oxidation of TMB in TMBQ among all the carboxylic acid temperature is a key factor in the oxidation of TMB to
and cyclic anhydride peroxides evaluated (Table 1).
We then examined the effect of various concentrations
TMBQ (Table 3).
We also investigated the influence of the reaction time
of phthaloyl peroxide on the oxidation of TMB into TMBQ on the oxidation of TMB to TMBQ with phthaloyl perox-
using different molar concentration ratios between phthalic ide. The rate of conversion of TMB to TMBQ reached a
acid, 30% H O , and TMB. Optimization of the reaction maximum (95%) at 2.5 h time point. A further increase of
2
2
conditions led us to determine that the use of 3-mol equiva- the reaction time induced a slight decrease of the TMBQ
lent of phthalic anhydride and 8-mol equivalent of 30% content because of over oxidation by excess H O , produc-
2
2
H O against 1-mol equivalent of TMB under solvent-free ing other unknown by-products. Therefore, we suggest that
2
2
conditions at 120°C for 2.5 h gave the highest yield of 2.5 h is the optimal reaction time at 120°C for an oxidation
TMBQ produced (Table 2).
reaction of TMB into TMBQ. These results indicated that
The dependence of oxidation efficiency of phthaloyl the reaction time played a key role in the oxidation of TMB
peroxide on TMB production at various temperatures into TMBQ (Table 4).
(
60°C–140°C) was investigated. The conversion of TMB
Finally, we examined the effect of various solvents on
to TMBQ increased with the raise in reaction temperature the oxidation of TMB into TMBQ using phthaloyl peroxide
when the optimized reaction conditions were kept (10 volumes of solvent by weight of TMB). The conversion
unchanged. The rate of TMB-to-TMBQ conversion lev- of TMB to TMBQ was found to increase under a solvent-
eled off at 120°C, and the formation of TMBQ was optimal free reaction under the previously optimized reaction con-
at the same temperature. A further increase in the reaction ditions (Table 5).

Yerramreddy et al.
3
Table 2. Effect of amount of phthalic anhydride and 30% H O2
on oxidation of TMB to TMBQ.
Table 4. Effect of reaction time on oxidation of TMB to
TMBQ using phthaloyl peroxide.
2
a
Molar ratio
Conversion Yield
Reaction time (h)
1
Conversion (mol %)b
Yield (mol %)c
a
(mol %)b
(mol %)
TMB Phthalic anhydride 30% H O
65
76
88
95
90
86
63
72
83
92
87
82
2
2
1
2
2
3
3
.5
.0
.5
.0
.5
1
1
1
1
1
1
1
1
1
.0
.0
.0
.0
.0
.0
.0
.0
.0
2.0
3.0
4.0
2.0
3.0
4.0
2.0
3.0
4.0
6.0
6.0
6.0
8.0
8.0
62
74
75
85
95
92
76
90
88
58
70
72
81
92
90
72
87
86
8.0
TMB: 1,2,4-trimethylbenzene;TMBQ: 2,3,5-trimethylbenzoquinone.
a
10.0
10.0
10.0
Reaction conditions: 1 mmol ofTMB, 3 mmol of phthalic anhydride, 8
mmol of 30% H O , solvent free.
2
2
b
Conversion ofTMB toTMBQ.
Isolated yield ofTMBQ.
c
TMB: 1,2,4-trimethylbenzene;TMBQ: 2,3,5-trimethylbenzoquinone.
a
Conversion ofTMB toTMBQ.
Isolated yield ofTMBQ.
b
great use in the preparation of commercially valuable benzo-
quinones from the corresponding aromatic compounds.
Table 3. Effect of reaction temperature on oxidation of TMB
a
to TMBQ using phthaloyl peroxide.
Experimental
All starting materials, reagents, and solvents are commer-
cially available and were used without further purification.
Melting points were determined with an X-4 apparatus and
are uncorrected. The nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker (NY, USA) Ascend 600
spectrometer using tetramethylsilane (TMS) as an internal
standard. The reactions were monitored by thin-layer chro-
matography (TLC; HG/T2354-92, GF254), and compounds
were visualized on TLC with ultraviolet (UV) light. The
purity of products was determined by high-performance
liquid chromatography (HPLC) using a Shimadzu (Tokyo,
Japan) LC-20A series instrument.
Temperature
°C)
Conversion
(mol %)
Yield (mol %)c
b
(
6
8
1
1
1
0
0
00
20
40
8
35
78
95
87
–
28
74
92
83
Method-1: typical procedure for the
oxidation ofTMB toTMBQ using phthaloyl
peroxide under solvent-free conditions
TMB: 1,2,4-trimethylbenzene;TMBQ: 2,3,5-trimethylbenzoquinone.
Reaction conditions: 1 mmol ofTMB, 3 mmol of phthalic anhydride, 8
a
mmol of 30% H O , solvent free, 2.5 h.
2
2
b
Conversion ofTMB toTMBQ.
Isolated yield ofTMBQ.
To a heterogeneous mixture of phthalic anhydride (44.43
g, 0.3 mol) and 30% H O aqueous solution (90.69 g; 0.8
c
2
2
mol; caution: heat the contents slowly, as reaction is exo-
In summary, phthaloyl peroxide, which was generated in thermic and peroxides are explosive in nature) heated at
situ by the oxidation of phthalic anhydride with aqueous 120°C, TMB (12.02 g; 0.1 mol) was added using a drop-
hydrogen peroxide (30% H O ), was found to be highly effi- ping funnel for 15–20 min. The reaction mixture was
2
2
cient for the selective oxidation of TMB to TMBQ, which stirred for 2.5 h at 118°C–120°C and then was cooled to
was best achieved using a reaction time of 2.5 h, carried out room temperature. Ethylacetate (125 mL) was added,
at 120°C, in a solvent-free environment and with a molar stirred for 15 min at room temperature, and then removed
ratio of 1:3:8 of TMB, phthalic anhydride, 30% H O , the solids by filtration, washed the solids with ethylace-
2
2
respectively. An important advantage of this oxidizing sys- tate (2 × 50 mL). Diluted the combined filtrate with H O
2
tem, aside from the organic solvent-free conditions, is the (50 mL). The two phases were separated, and the aqueous
non-toxic, eco-friendly, and inexpensive nature of such layer was extracted with ethylacetate (50 mL). The com-
chemical reaction. In addition, this methodology could be of bined organic layers were washed with water (100 mL)

4
Journal of Chemical Research 00(0)
Table 5. Effect of solvent on oxidation of TMB to TMBQ using phthaloyl peroxide.a
Solvent
Temperature (°C)
Conversion (mol %)b
Yield (mol %)c
n-Hexane
n-Heptane
No solvent
Ethylacetate
Water
Reflux
Reflux
120
Reflux
Reflux
68
76
95
88
85
66
72
92
85
81
TMB: 1,2,4-trimethylbenzene;TMBQ: 2,3,5-trimethylbenzoquinone.
a
Reaction conditions: 1 mmol ofTMB, 3 mmol of phthalic anhydride, 8 mmol of 30% H O , 1.2 mL of solvent or solvent free, 2.5 h.
Conversion ofTMB toTMBQ.
Isolated yield ofTMBQ.
2
2
b
c
and brine (50 mL), dried on anhydrous Na SO , and con- Declaration of conflicting interests
2
4
centrated to dryness under vacuum. The residue was puri-
fied by flash chromatography with a mixture of hexane
and ethylacetate (95:5 v/v) to give the title compound as
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
1
an orange-colored solid (13.81 g), yield: 92%. H NMR
Funding
(
300 MHz, CDCl ) δ 6.54 (s, 1H), 2.12 − 1.92 (m, 9H).
3
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
11
m.p. 29°C; literature reference m.p. 31°C–32°C.
ORCID iD
Method-2: typical procedure for the
oxidation ofTMB toTMBQ using phthaloyl
peroxide in a solvent
Thirupathi Reddy Yerramreddy https://orcid.org/0000-0002-8822-3422
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