An improved preparation of 2,6-di-(t-butyl)-4-methylphenol

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An Improved Preparation of 2,6-di-(t-
Butyl)-4-methylphenol
a
a
a
b
a
a
J. Y. Xie , J. Q. Liu , Y. H. Zhang , J. J. Li , Z. C. Li & W. C. Huang
a
School of Chemical Engineering, Sichuan University, Chengdu,
6
10065, P. R. China
b
Sichuan Polymer Science and Technology Co., Ltd., Deyang, P. R.
China
Published online: 13 May 2015.
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To cite this article: J. Y. Xie, J. Q. Liu, Y. H. Zhang, J. J. Li, Z. C. Li & W. C. Huang (2015)
An Improved Preparation of 2,6-di-(t-Butyl)-4-methylphenol, Organic Preparations and
Procedures International: The New Journal for Organic Synthesis, 47:3, 236-241, DOI:
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Organic Preparations and Procedures International, 47:236–241, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1025632
OPPI BRIEF
An Improved Preparation of
,6-di-(t-Butyl)-4-methylphenol
2
1
J. Y. Xie, J. Q. Liu, Y. H. Zhang, J. J. Li, Z. C. Li,
and W. C. Huang
1
1
2
1
1
1
School of Chemical Engineering, Sichuan University, Chengdu 610065, P. R.
China
2
Sichuan Polymer Science and Technology Co., Ltd., Deyang, P. R. China
As a typical sterically hindered phenolic anti-oxidant, 2,6-di-(t-butyl)-4-methylphenol,
also known as butylated hydroxytoluene (or BHT), is widely used in rubber, plastic, paint,
jet fuels, petroleum products, bio-diesel, cosmetics, food and pharmaceuticals due to its
1
–3
strong anti-oxidant power, low volatility and sturdiness. In addition, BHT has become
important for the preparation of other compounds such as 3,5-di-(t-butyl)-4-hydroxyben-
4
zaldehyde, 3,5-di-(t-butyl)-4-hydroxybenzyl bromide and 2,6-di-(t-butyl)-1,4-benzo-
5
6
quinone. Recently, BHT has been shown to display anti-tumor and anti-oxidant
7
8
9
activities and to be effective in protecting against hepato-toxicity. Thus BHT has also
become a lead compound for the development of various drugs and an intermediate for
the synthesis of other drugs or drug candidates. With its ever-increasing utility in the food
and pharmaceutical industries, it is imperative to understand the nature and toxicity of
impurities that might be produced during its manufacture in order to increase the purity
of the BHT produced. Herein, we report a study on the reaction of p-cresol with isobutyl-
ene to prepare BHT.
Over the past few decades, a considerable amount of work has been devoted to the
1
use of novel acid catalysts such as ion exchange resins, phosphorus tungsten heteropoly
0
1
1
12
13
acid, ionic liquids and AlCl supported on Montmorillonite to perform the Friedel-
3
Crafts alkylation of p-cresol with isobutylene. Although many of these catalysts do
exhibit desirable features such as minimal corrosion of the equipment, high selectivity,
and recyclability, their high cost, variable catalytic activity, and long production cycle
1
4,15
have limited their utilization on a large scale. In comparison, conc. sulfuric acid,
has
the advantages of high catalytic activity, low cost, and ready availability. Thus, it has
been utilized widely in the production of BHT in spite of the fact that it can result in cor-
rosion of the equipment and formation of impurities.
Submitted by October 29, 2014.
Address correspondence to W.C. Huang, School of Chemical Engineering, Sichuan University,
Chengdu 610065, P. R. China. E-mail hwc@scu.edu.cn or wencai_h@sina.com
236

Preparation of 2,6-di-(t-Butyl)-4-methylphenol
237
Table.
Preparation of BHT
a)
c)
Ratio (%)
b)
Entry Yield (%) Thiourea(g) Reaction mixture Crude BHT Purified BHT
d)
1
2
3
4
72.3
78.8
81.1
80.9
0.0
0.0
92.94 / 0.54
96.38 / 0.19
95.17 / 0.15
96.44 / 0.12
93.51 / 0.59 97.23 / 0.45
98.09 / 0.47 99.51 / 0.28
99.10 / 0.28 99.75 / 0.16
98.79 / 0.16 99.85 / 0.11
e)
e)
e)
0.8
12.0
a)Using 80.0 g of p-cresol except for Entry 4 when 1.2 kg was used.
b)Yield of pure BHT.
c)Ratio of BHT to 2,6-di-(t-butyl)-4-(hydroxymethyl)phenol.
2 4
d)Using 3% by weight of H SO as catalyst.
e)Using 6% by weight of anhydrous TsOH as catalyst.
Initially, when 3% of conc. sulfuric acid (by weight) was used as the catalyst, the reaction
was complete within 7 h. However, GC monitoring showed that the conversion to BHT
was less than 95%, even after neutralization, filtration, washing, and recrystallization, the
purity of the purified BHT was less than 98% (Entry 1, Table). One of the major impuri-
ties (more than 0.4%) generated during the reaction was a species with the retention time
of 5.4 min and the percentage of this compound increased significantly during the work-
up and subsequent recrystallization could not decrease it to any extent. On the other hand,
0
0
the contents of other impurities identified as 2-(t-butyl)-4-methylphenol and 3,3 ,5,5 -
tetra(t-butyl)silbene-4,4-quinone decreased dramatically upon work-up and recrystalliza-
tion. Therefore, it was determined that the compound with a retention time of 5.4 min
was the major impurity of the manufacturing process and that the key to improving the
purity of BHT was to efficiently control and/or eliminate the formation of this compound
especially during the work-up.
In order to devise effective means to control the generation of the major impurity, it
was necessary to elucidate its structure. Because its concentration in both the reaction
mixture and the crude product was less than 1%, it was very difficult to isolate from the
crude BHT or even from the mother liquor. It was supposed that the major impurity might
be an oxidation product of BHT based on the observation that its quantity increased dur-
ing the work-up. Treatment of BHT with various oxidizing agents indeed increased the
amount of the impurity and when BHT was treated with potassium permanganate in etha-
nol the amount of the impurity increased to about 20% by GC. However, we still were
unable to isolate it from the mixture because the similar polarity of the components made
chromatographic separation difficult. On the other hand, possible oxidation products of
BHT such as 3,5-di-(t-butyl)-4-hydroxybenzaldehyde, 3,5-di-(t-butyl)-4-hydroxybenzoic
Scheme 1

2
38
Huang et al.
Scheme 2
1
6,17
acid, 2,6-di-(t-butyl)-benzo-quinone and 3,3’,5,5’-tetra-(t-butyl)stilbene-4,4-quinone
were synthesized and isolated but their gas chromatographic retention times were differ-
ent from the 5.4 minute of the impurity. When BHT was oxidized to 3,5-di-(t-butyl)-4-
hydroxybenzaldehyde using bromine in t-butanol, the amount of the major impurity in
the filtrate after the oxidation product had been collected, was about 30%. Extraction of
the filtrate and chromatography on silica gel with dichloromethane as the eluent gave the
pure product as a pale yellow solid established to be 2,6-di-(t-butyl)-4-(hydroxymethyl)
1
15
phenol by H NMR, MS, and direct comparison with an authentic sample. To the best
of our knowledge, this is the first time that the structure of this impurity in the production
of BHT has been elucidated.
BHT can be oxidized to various products under different conditions, but the conver-
sion of BHT to 2,6-di-(t-butyl)-4-(hydroxymethyl)phenol during its manufacturing pro-
1
cess has not been studied. The process may be viewed to proceed as shown in Scheme 2.
Disproportionaton of the phenoxy radical generated from BHT would lead to BHT and
the quinone methide, which would react very rapidly with water to afford 2,6-di-(t-
butyl)-4-(hydroxymethyl)phenol, the major impurity of BHT. Scheme 2 suggests that in
order to minimize the generation of the major impurity, BHT should be prevented from
dissociating and water should be avoided during the reaction and the work-up.
Because there is about 2% of water in the conc. sulfuric acid, it was inevitable that
the water would react with the quinone methide and that the strong acidity and oxidizing
property of the acid would promote the generation of phenoxy radical. Thus these consid-
erations suggest that conc. sulfuric acid might not be an ideal catalyst for the synthesis of
BHT of high purity. The use of anhydrous p-toluenesulfonic acid (TsOH), was then inves-
tigated as catalyst. Because it does not have the two drawbacks of conc. sulfuric acid
mentioned above, the experimental results were better. As illustrated in the Table (Entry
2
), when 6% weight of the TsOH was used, the contents of the impurity in the reactant, in
the crude BHT, and in the purified BHT were lower than that when conc. sulfuric acid
was used. The purity of the purified BHT was also about 2% higher. However, the per-
centage of the impurity increased substantially from 0.2% to 0.5% after work-up. This
may have been due to the exposure of the hot mixture to air before it was cooled and neu-
tralized and this exposure accelerated the disproportionation of BHT to the phenoxy

Preparation of 2,6-di-(t-Butyl)-4-methylphenol
239
radical. Therefore in order to prevent this occurrence, 1% (by weight) of thiourea was
added as an anti-oxidant immediately after completion of the reaction and prior to work-
up. The mixture was then cooled with stirring and neutralized, the product was collected,
washed and recrystallized. As illustrated in the Table (Entry 3), when TsOH and thiourea
were applied, the content of the major impurity in the crude and purified BHT were lower
than that of Entries 1 and 2. Adoption of these measures led to BHT with a purity above
9
9.7% in an 81.1% overall yield, in particular, the content of major impurity was
decreased to 0.16% and the total amount of all the other impurities was less than 0.1%,
this will be of great importance when BHT is used in food and pharmaceutical industries.
To evaluate the possibility of the improved process to be scaled up, 1.2 kg of p-cresol
was fed in a 5L glass jacketed autoclave, the other operations being the same except that
ꢀ
ꢀ
the temperature at which isobutylene was introduced was lowered from 62 C to 56 C and
the reaction time was extended to 9 h. The purity of final product was a little higher and
the content of the major impurity was a little lower than that in Entry 3 of Table.
In conclusion, an improved preparation of BHT which minimizes the formation of
2
,6-di-(t-butyl)-4-(hydroxymethyl)phenol, the major impurity and increases the purity of
BHT has been designed. Our calculations – based on the manufacture of one ton of BHT
indicates that the higher yield of purer BHT obtained using p-toluenesufonic acid
–
requires a lesser amount of p-cresol thus compensating for the higher cost of the catalyst.
Thus our procedure may constitute a valuable alternative in the preparation of pure BHT
for the food and pharmaceutical industries. Moreover, when the improved process was
scaled up to 1.2 kg in a 5L glass jacketed autoclave, the results were as good as those per-
formed on a laboratory scale.
Experimental Section
Reagents and solvents were purchased from commercial suppliers and used without fur-
ther purification. Mps were measured in open capillaries and are uncorrected. The purity
1
of product was determined using a Tianmei GC7900 GC chromatograph. H NMR spec-
tra were recorded in CDCl on a Bruker Avance (Varian Unity Inova) 400 MHz spec-
3
trometer with TMS as the internal standard. MS spectra were performed on a Waters
Quattro Premier XE triple quadrupole mass spectrometer. Because the butylation of p-
cresol with isobutylene is a typical liquid-gas reaction process, a custom-made glass reac-
tor with a flat bottom, a cylindrical body, and three necks to accommodate a condenser, a
gas inlet tube, and a thermometer respectively, was utilized in the laboratory-scale experi-
ments. The isobutylene was bubbled through a sintered glass plate just above the bottom
thus resulting in a good dispersion of isobutylene and a comparatively long contact time
for the isobutylene and p-cresol. The gas chromatographic conditions utilized to monitor
and analyze the reaction were as follows: GC column: TM-1701 capillary column, the
ꢀ
ꢀ
inlet temperature: 280 C, the column temperature: 200 C, FID detector temperature:
ꢀ
2
80 C, nitrogen flow rate: 45mL/min, hydrogen flow rate: 30mL/min, and injection vol-
ume: 1mL. The concentration of sample was about 30mg/mL with dichloromethane as
the solvent. The retention time of BHT in the gas chromatogram was about 5.7 min and
that of the major impurity was about 5.4 min.
Preparation of BHT using conc. Sulfuric Acid as the Catalyst
The three-necked glass reactor fitted with a condenser, a gas inlet tube, and a thermometer
was immersed in a water-bath and melted p-cresol (80.0g, 0.74 mol) was added followed

2
40
Huang et al.
by 98% sulfuric acid (2.4g) with magnetic stirring and heating. The reactor was then
ꢀ
purged with nitrogen for about 20 min. When the temperature rose to 62 C, isobutylene
was bubbled through the mixture via a sintered glass plate. The temperature was main-
ꢀ
tained at 64–66 C by regulating the flow of isobutylene and the temperature of the water-
bath throughout the reaction. TLC on silica plates with ethyl acetate/cyclohexane (1/3 by
volume) as the developing solvent and GC were used to monitor the reaction. About 7 h
later, the flow of isobutylene was stopped and the reactant was cooled down to room tem-
ꢀ
perature. Water (25 mL) was added to the reactant and the mixture was stirred at 80 C,
then, 5% sodium carbonate solution was added until the pH reached 7.5. The solid precip-
itated upon cooling to room temperature was filtrated, washed with water and dried to
afford crude BHT. The purified BHT was obtained after two recrystallizations of the
crude BHT from 90% ethanol.
Preparation and Isolation of 2,6-di-(t-Butyl)-4-(hydroxymethyl)phenol
ꢀ
BHT (10.0g, 45.4mmol) was dissolved in t-butanol (50mL) at 40 C. Bromine (5.0mL,
97.6mmol) was added dropwise over 1h. After the addition, the mixture was stirred for
ꢀ
additional 0.5 h at 40 C. The precipitate was collected and dried to give 3,5-di-(t-butyl)-
4
-hydroxy-benzaldehyde (4.6g, 43.2%). Water (30mL) was added to the filtrate and the
mixture was extracted with dichloromethane (20mL£2), then the combined organic
phases were evaporated under vacuum to give a pale yellow oil which was subjected to
flash column chromatography with dichloromethane as the eluent to give a pale yellow
ꢀ
16
ꢀ
solid, mp. 136–137 C (lit. 135–136 C) whose retention time was 5.4 min in the gas
1
chromatogram. H NMR (400MHz, CDCl ): d7.19(s, 2H), d5.23(s, 1H), d4.59(s, 2H),
3
C
d1.40(s, 18H), MS (ESI): 235(M-1) .
Improved Preparation of BHT using p-Toluenesulfonic Acid as Catalyst
The three-necked glass reactor fitted with a condenser, a gas inlet tube, and a thermometer
was immersed in a water-bath and melted p-cresol (80.0g, 0.74 mol) was added followed
by p-toluenesulfonic acid (4.8g) with magnetic stirring and heating. The reactor was then
ꢀ
purged with nitrogen for about 20 min. When the temperature rose to 62 C, isobutylene
was bubbled through the reactant via a sintered glass plate. The temperature was main-
ꢀ
tained at 64–66 C by regulating the flow of isobutylene and the temperature of the water-
bath throughout the reaction. TLC (silica gel 1:3 ethyl acetate-cyclohexane) and GC were
used to monitor the reaction. About 7h later, the flow of isobutylene was stopped and thio-
urea (0.8g) was added immediately to the hot mixture which was then cooled while stir-
ꢀ
ring. Water (25mL) was added to the reactant and the mixture was stirred at 80 C. 5%
solution of sodium hydroxide was added dropwise to adjust the pH of the solution to
about 7.5. After cooling to room temperature, the white solid precipitated was collected,
washed with water, and dried to give the crude BHT. The crude BHT was recrystallized
ꢀ
from 90% ethanol twice to give the purified BHT, mp 69.9–70.6 C (heavy metals content
<
0.001%).
Scale-up Preparation of BHT in a Jacketed Autoclave
The improved procedure for the preparation of BHT was scaled up in a 5L jacketed glass
autoclave and 1.2 kg of p–cresol was fed for each batch, the operations were the same as
above except that the temperature at which isobutylene was introduced was lowered from

Preparation of 2,6-di-(t-Butyl)-4-methylphenol
241
ꢀ
ꢀ
6
2 C to 56 C and the reaction time was extended to 9h. The yield and purity of BHT
Table, Entry 4) were very close to those of the experiment performed in the three-necked
(
glass reactor.
Acknowledgement
We thank the Analytical and Testing Center of Sichuan University for NMR, MS and
metal content measurements.
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