Efficient synthesis of 2,5-di-t-butyl-4-fluorophenol

Article abstract of DOI:10.1016/S0022-1139(99)00217-1

When 4-fluorophenol was refluxed with excess of t-butyl chloride in the presence of various catalysts, e.g. Envirocat EPZG, EPZ10, EPIC, sulfated zirconia, natural kaolinitic clay, zirconium nitrate, zinc chloride and bismuth nitrate, the product obtained was 2,5,di-t-butyl 4-fluorophenol in excellent yield.

Full text of DOI:10.1016/S0022-1139(99)00217-1

Journal of Fluorine Chemistry 101 (2000) 81±83
Ef®cient synthesis of 2,5-di-t-butyl-4-¯uorophenol$
B.P. Bandgar*, S.P. Kasture, Chaya Dudhmal
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded-431 606, Maharashtra, India
Received 24 May 1999; accepted 12 August 1999
Abstract
When 4-¯uorophenol was re¯uxed with excess of t-butyl chloride in the presence of various catalysts, e.g. Envirocat EPZG, EPZ10,
EPIC, sulfated zirconia, natural kaolinitic clay, zirconium nitrate, zinc chloride and bismuth nitrate, the product obtained was 2,5,di-t-butyl
4-¯uorophenol in excellent yield. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: 4-Fluorophenol; Envirocats; Natural clay; Sulfated zirconia; 2,5-di-t-butyl-4-¯urophenol
1. Introduction
2,5-di-t-butyl-4-¯uorophenol in excellent yield (Table 1,
entries 1±5) compared with reported results [3]. Use of
Lewis acid catalysts like zirconium nitrate, bismuth nitrate
and anhydrous zinc chloride also gave 2,5-di-t-butyl-
4-¯uorophenol in excellent yield (entries 6±8). No mono-
t-butylated compound was observed. 2-6-Di-t-butyl-4-
chlorophenol (IV), 2,6 di-t-butyl-4-bromophenol (VI) and
2,6-di-t-butyl-4-iodophenol (VIII) were formed when
4-chlorophenol (III), 4-bromophenol (V) and 4-iodophenol
(VII) were t-butylated [12]. The steric hindrance of bulky
4-chloro, 4-bromo and 4-iodo substituents did not allow
substitution in the 5-position.
Synthesis of 2,5- and 2,6-di-t-butylated phenols is of great
importance because of their usefulness as an antioxidants
[1]. Generally t-butylation of phenols has been carried out
using either Lewis acid [1] or Bronsted acid catalyst [2].
Recently synthesis of 2, 5-di-t-butyl-4-¯uorophenol has
been reported in very poor yield (10.2%) using 4-¯uoro-
phenol and t-BuCl in the presence of AlCl3 as a catalyst [1].
The synthesis of 2,6-di-t-butyl-4-¯uorophenol using expen-
sive xenon di¯uoride is also described in the literature [3].
We now report a high yielding synthesis of 2,5-di-t-butyl-4-
¯uorophenol using some novel environmentally friendly
catalysts.
2. Results and discussion
When 4-¯uorophenol was re¯uxed with excess of t-butyl
chloride in the presence of heterogenous catalysts like
Envirocat EPZG, EPZ10, EPIC [4±7] and sulfated zirconia
[8,9] and
natural kaolinitic clay [10,11], the product formed was only
$This paper is dedicated to Dr. J.M. Waghmare, Vice-Chancellor,
Swami Ramanand Teerth Marathwada University, on the occasion of
his 65th birthday.
*Corresponding author. Fax: ‡91-2462-26119.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 1 7 - 1

82
B.P. Bandgar et al. / Journal of Fluorine Chemistry 101 (2000) 81±83
Table 1
Synthesis of 2,6- and 2,5-di-t-butyl-4-substituted phenols
Entry
Phenol
Catalyst
Product
Reaction time (min)
Yield (%)
1
I
EPZG
EPZ10
II
10
10
10
95
94
98
85
85
85
90
77
72
70
64
67
60
65
63
71
2
I
II
3
I
EPIC
II
4
I
Sulphated zirconia
Natural clay
Zirconium nitrate
Zinc chloride
Bismuth nitrate
Natural clay
EPZ10
II
180
5
I
II
10
240
10
10
10
10
10
10
10
10
20
10
6
I
II
7
I
II
8
I
II
IV
9
III
III
V
V
VII
VII
IX
IX
10
11
12
13
14
15
16
IV
Natural clay
EPZ10
VI
VI
VIII
Natural clay
EPZ10
VIII
Natural clay
EPZ10
X ‡ XI (3:2)
X ‡ XI (3:2)
The reaction of 4-methoxyphenol (IX) with t-butyl chlor-
ide gave both the 2-6-di-t-butyl-4-methoxyphenol (X) and
2,5-di-t-butyl-4-methoxyphenol (XI) [3]. Although the
methoxy group is not as strong a donor as the hydroxy
group, the in¯uence of the t-butyl in 2-t-butyl-4-methox-
yphenol, the reaction intermediate, is suf®cient to direct the
second t-butyl to the 5-position.
drous ZnCl2 were of analytical grade. 4-Fluorophenol, 4-
chlorophenol, 4-bromophenol, 4-iodophenol and 4-methox-
yphenol were purchased from Lancaster Chemicals, Eng-
land.
3.1. Preparation of 2,5-di-t-butyl-4-fluorophenol
The ¯uorine 2p orbital of 4-¯uorophenol can overlap with
the aromatic carbon better than the 3p orbital of chlorine in
4-chlorophenol, 4p orbital of bromine in 4-bromophenol or
5p orbital of iodine in 4-iodophenol. Therefore, ¯uorine is a
more activating group than chlorine, bromine and iodine
[13,14]. But the more electron withdrawing inductive effect
of ¯uorine makes it a less activating group than hydrogen
[13,14]. The orientation of the alkyl group in 4-¯uorophenol
is due to ¯uorine groups whereas the orientation of alkyl
group in 4-chlorophenol, 4-bromophenol and 4-iodophenol
is due to phenolic-OH groups. The alkylation of 4-¯uor-
ophenol gives exclusively 2,5-dialkylated product because
of the small size of ¯uorine, the ꢀ-donor effect of ¯uorine
and intermediate, 2-t-butyl directing effect.
A mixture of 4-¯uorophenol (5 mmol), t-butyl chloride
(10 ml) and catalyst (100 mg) was re¯uxed for speci®ed
time (table) and the reaction was monitored by TLC. After
completion of the reaction, the catalyst was ®ltered off and
washed with diethyl ether (3 Â 10 ml). The solvent was
removed under vacuum and the crude product obtained was
puri®ed by column chromatography (petroleum
ether:ethylacetate ˆ 9:1 as an eluent). Physical constant,
1
IR, H NMR and 13C NMR values of the product II match
with the reported data [3].
Acknowledgements
We thank Dr. Lalithambika, RRL, Trivandrum, Contract
Chemicals, England and MEL Chemicals, England for the
generous gifts of natural kaolinitic clay, Envircats (EPZG,
EPZ10, EPIC) and sulfated zirconia, respectively.
3. Experimental details
1H NMR spectra were obtained from a 90 MHz Varian
FT-NMR instrument whereas IR spectra were recorded on a
Bomem MB 104 FT-IR spectrometer. Envirocat EPZG,
EPZ10, EPIC and sulfated zirconia were procured from
Contract Chemicals, England and MEL Chemicals, Eng-
land, respectively. Natural kaolinitic clay was obtained from
the Padappakara mine of Quilon District, Kerala, India and
was puri®ed and supplied by Dr. Lalithambika, RRL, Tri-
vandrum. EPZG, EPZ10, EPIC, sulfated zirconia and nat-
ural kaolinitic clay were used as supplied without activation/
calcination. Zirconium nitrate, bismuth nitrate and anhy-
References
[1] S.T. Purrington, G.M. Green, J. Fluorine Chem. 76 (1996) 201.
[2] C.D. Cook, R.G. Inskeep, A.S. Rosenberg, E.C. Curtis Jr., J. Am.
Chem. Soc. 77 (1955) 1672.
[3] I. Takemoto, K. Yamasaki, Biosci. Biotech. Biochem. 58 (1994) 594.
[4] B.P. Bandgar, M.B. Zirange, P.P. Wadgaonkar, Synlett. (1996) 149.
[5] B.P. Bandgar, N.B. Gaikwad, Monatsh Chem. 129 (1998) 719.
[6] A.S. Gajare, M.S. Shingare, B.P. Bandgar, J. Chem. Res. (S) (1998)
452.

B.P. Bandgar et al. / Journal of Fluorine Chemistry 101 (2000) 81±83
83
[7] B.P. Bandgar, P.P. Wadgaonkar, Synth. Commun. 27 (1997) 2069.
[11] B.P. Bandgar, V.S. Sadavarte, Synth. Commun. 29 (1999) 3409.
[12] H. Hart, F.A. Cassio Jr., J. Am. Chem. Soc. 73 (1951) 3179.
[8] B.P. Bandgar, S.P. Kasture, Monatsh Chem. 127 (1996) 1305.
[9] A. Sarkar, O.S. Yemul, B.P. Bandgar, N.B. Gaikwad, P.P.
Wadgaonkar, Org. Prep. Proc. Int. 28 (1996) 613.
[13] R.G. Coombes, D.H.G. Crout, J.G. Hoggett, R.B. Moodie, K.
Schofield, J. Chem. Soc. B (1970) 347.
[10] D. Ponde, H.B. Borate, A. Sudalai, T. Ravindranthan, V.H.
Deshpande, Tetrahedron Lett. 37 (1996) 4605.
[14] N.C. Deno, R. Stein, J. Am. Chem. Soc. 78 (1956) 578.