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BROMINATION 0F P-XYLENOL SULFONIC ACID

IN NITRO BENZENE

A Thesis

Submitted to the Faculty of the
Michigan State College
in partial fulfillment of the requirements for
the Degree of

Master of Science

by

Francis Aloysius Hughes
1937

é f/éz' H

ACKNOWLEDGMENT

The author wishes to express his
sincere appreciation to Dr. R. C. Huston
for his guidance and advice in the attainment

of this problem,

CONTENTS

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Historical-see.-o.oeeooooeooooooooooeeeeeoo

Experimental-e.eeeeoeeoeeoooeeeeooeoooeoooe
3-brom-P-xylenol.” oeoeoeeeeeeeeeoeee

P-xylen01-4’Su1f0nic 301d 0 o e o e e e e e o e o

sumry...0.0000000000000.QOOOOOOOO0.00...

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13

I N T R 0 D U C T I O N

This problemtwas undertaken with the view of
preparing halogenated xylenols in which the halogen occurs
adjacent to the hydroxyl group. The method used was first
introduced by Huston and Keeley in 1935.

H I S T 0 R I C A L

A review of the literature concerning the bromination
of 1.4-dhmethyl-2-hydroxy benzene (P-Xylenol) reveals the
following compounds together with their mode or modes of
preparation:
5-brompl.4-dimethyl-2-hydroxy-benzene.

1. Direct bromination of P-Xylenol in acetic acid
using an equivalent mole quantity of each. Recrystalize
from dilute acetic acid. Needles, H.P. 87°°

Jacobean, Ber.,;l, 27 (1878).
Auwers, Ericklentz, Ann. ggg, 115 (1898).
5.5-dibrompl.4-dimethyl-Z-hydroxy-benzene.

1. Direct bromination of P-Xylenol in acetic acid

using two moles bromine and one mole P-Xylenol

or their equivalents. Recrystalize from dilute

acetic acid. Needles, H. P. 790.

Auwers, Ericklentz, Ann., Q91, 220;§Q§, 114 (1898).

2. Treatment of 4.4'-dioxy-2.5.285'~tetramethyl-

diphenylmethane in boiling acetic acid with

bromine. Needles, M. P. 79-800.

Auwers, Rietz, Ann.,356, 169 (1907).

3.6-dibrompl.4-dimethyl-Z-hydroxy-benzene.
l. Diazotising a solution of 3.6-dibrom-2-amino-
1.4-dimethyl-benzene in absolute alcohol using
amyl nitrate and decomposing the compound
formed with hot dilute sulfuric acid. Recrystalize
from ligroin. Needles, M. P. 90-910.

Auwers, Baum, 331.022, 2344 (1896).

3.5.6-tribrompl.4-dimethyl-benzene.
1. Action of bromine on pseundocumenol along
with other products. Recrystalize from dilute
acetic acid. Needles, It P. 178-1790.
Auwers, Anselmino, Ber., pg, 3592 (1899).
Auwers, Ann.,§§§, 134 (1907).

2. Action of bromine on.P-Xylenol in the presence
of iron using carbon tetrachloride as the solvent.
Yield 75-80%.
Zincke, Breitwieser, Ber.,gg,179 (1911).
3. Action of excess bromine on cooled P-Xylenol.
Recrystalize from alcohol. Needles HtP.l75°.
Jacobean, Ber.,ll,27 (1878).
4. Action of bromine on 3.6-dibrom~5-oxy-1.2.4-
trimethyl-benzol.
Auwers, Ber.,fig, 3592 (1899).

-3-

5. Action of bromine on 3.6.3!6'-tetrabrom-
4.4'-dioxy-2.5.215ttetramethyl-dipheylmethane.
Auwers, Ann.,§§§,134 (1907).
Auers, Hof,Ber.,§g, 1117 (1896).

Auers, Ercklentz, Ann., 302, 114 (1898).

5. Action of excess bromine on dry P-Xylenol.
Auwers, Ercklentz, Ann.,v§9g, 114 (1898).

It is noted that in brominating P-Xylenol
directly the entering bromine first takes the
position para to the hydroxyl group and then when this
is complete the vacant ortho position to the hydroxyl
is attacked. If the para position can be blocked by
some method the entering bromine should then go to
the next active position or adjacent to the hydroxyl.
In considering a method for the efficient blocking of
the active para position an element or group must be
chosen so that when the bromination is complete the
element or group may be readily remeved without
destroying the compound formed. In the past the
sulfonic group has met with more or less success in
this respect.

In aqueous acid solution the sulfonic group is
generally replaced by halogen during halogemation.

l. Chlorination of an aqueous solution of

cymene—sulfonic acid produced tetrachlor-cymene.

Bromination of trichlor-cymene sulfonic acid

produced trichlor-menobrompcymene.

Kelbe, Ber.,lg, 617 (1883).

- 4 -

2. Addition of bromine to O-xylene-sulfonic
acid in aqueous solution using hydrochloric
acid as a catalyst resulted in the formation
of brompO-xylene (1.2.4.), dibrom-O-xylene
(1.2.4.) and brompO-xylene-sulfonic acid.
H-xylene-sulfonic acid (1.3.4) formed monobrom-
xylene (1.3.4).

Kelbe, Stein, Ber., 13, 2137 (1886).
3. Sulfonation, followed by bromination of
P-toluidine in aqueous acid solution gave rise
to HebromPP-toluidine as well as 0-brompP-
toluidine.

Hefner, Ber., gg, 2902 (1889).
4. Sudborough and Lakumalani stated that a
sulfonic group para to the amino group easily is
displaced by halogen. They used P-sulfanilic
acid to form symmetrical tribrom-aniline and
symmetrical trichlor-aniline employing bromine
and.chlorine as agents respectfully. Chlorination
of 2.6-dibrompP-sulfanilic acid produced 2.6-dibrom-
4-ohlor-aniline.

Sudboroughm.Lakumalani, J.chem.Soc.,lll,4l(1913).
5. 2.6-MCresol-disulfonic.acid was converted to
2.6-dichlor-H-cresol by means of chlorine in
aqueous acid solution.

Datta, Hitter, J.Am.Chem.Soo.,gl, 2033 (1919).

6. Datta stated that in removing the sulfonic group

by an entering halogen the reaction can not be easily
controlled. Hot only the mono substitution takes place
but substitution continues to the di and tri substituted
compound. One or more hydroxyl groups attached to

the nucleus accelerates the replacement of the sulfonic
acid group by bromine. Upon brominating the sulfonic
acids of the following compounds the tribrom

substituted compound was formed:

Phenol ---- 2.4.6-tribrmm-phenol
Hporesol ---- 2.4.6-tribroméH-cresol
P-cresol ---- 2.4.6-P4resol

1.2.4-xylenol ---- 3.6-dibrompl.2.4-xylenol
Datta, Bhoumik, JeMeCheme 8000, Q, 303 (1921).

7. Sodium.chlorate was used to remove the
sulfonic group in nitro-sulfonic-napthalenes.
Chlorine was substituted in its place.
Priedlander, Schenk, Ber., 25, 45 (1922).
In some cases the sodium salt of the sulfonic acid
group has.served as an efficient blocking agent for the

preparation of halogenated compounds.

1. The sodium.sa1t of P-phenol-sulfonic acid was
chlorinated in alkali solution giving rise to
2-chlor-phenol and it was also brominated in alkali

solution forming 2-brompphenol.

Takagi, Kutani, J.Pharm.Soc. Japan, 517,260 (1925).
(c. 1.,gg, 2669)

2. From the sodium salt of P-phenol-sulfonic acid
2.6-dichlor-phenol was formed by employing chlorine
in alkali solution.
Tanaki, Kutani, J.Pharm.Soc. Japan, gg;, 196 (1927).
(C.A. 21, 225)

3. Bromination of the sodium salt of P-phenol-
disulfonic acid (1.2.4) gives rise to 2-brom-phenol.
Ballard, Huston, Organic Synthesis,Vol.lg,p.l4 (1934).

The sulfonic group has also been used in acid
solution to an extent in blocking positions.

1. Blocking of the 4 and 6 positions during

nitration of resorcinol.

Kauffmann, dePay, Ber.,gl, 725 (1904).

2. The 4 and 6 positions of M-cresol was blocked
using fuming sulfronic acid during nitration.
Gibson, J.Chem. Soc.,l§§, 1269 (1923).
Hodgson, Beard, J.Chem.Soc., 121, 498 (1925).

3. IH-oresol formed 2-chlor-mpcresol and 2-brom-
Hporesol when it was chlorinated or brominated
in fuming sulfuric acid.

Huston, Peterson, J.Am.Chem.Soc., 55, 3880 (1933).

- 7 -

when the sulfonic acid group has served its purpose
in relation to blocking it is readily removed by hydrolysis
using superheated steam. In the case of the alkali

solution it is made acid before hydrolysis.

In 1935 Huston and Neeley (JtAm. Chem. Soc., Q1,
2176) tried to prepare 2-brompphenol and 2.6-dibrom-
phenol by brominating phenol using fuming sulfuric acid
as a blocking agent. They found that if too:luch sulfuric
acid was.used, sulfonation would occur to a large extent
and thus greatly diminish the yield of product. Enough
sulfuric acid for sulfonation of the phenol produced a
solid when a small quantity of bromine was added; Upon
addition of more bromine symmetrical tribrom-phenol was
produced. To overcome the obstacles of small yields and
solidification an inert anhydrous solvent was employed.
Freshly distilled nitrobenzene was found to be well adapted
to the procedure. Fuming sulfuric acid was used as the
dehydrating agent. Both phenol and cresol were subjected
to sulfonation and then chlorinated or brominated in the
inert anhydrous medium followed by hydrolysis using
superheated steam. The resulting compounds and their

yields were:

2-brom-phenol - ------ 10%
2.6-dibrompphenol ----- --72%
2-chlor-phenol - ------ 70%

2.6-dichlor-phenol -------72%

6-brompO-cresol -------- 60%
6-chlor-O-cresol - ------- 30%
2-bromAM-cresol -------- wt
.4-bromAl-cresol - ------- 8%

2.6-dibromAH-cresol -------23%
2-chlorélecresol. ------- 14%
4-chlordl-eresol ~------ 5%
2.4-dichlor-lhcresol-------25%
2.6-dichlor-H-cresol- ------ &%

In connection with the bromination of phenols
by this method it was believed that xylenols should also

fall into the category.

E X P E R I HIE N T A L

In studying the possible bromination compounds of
l.4-dibrom-Z-hydroxy-benzene it is noted that the 3 and
6 monobrom and the 5.6-dibrom ring substituted compound
are unaccounted for. The 3-brompl.4-dimethyl-z-hydroxy-
benzene should be formed by using Huston.and Neeley's

method.and runs were made to prove this.

A mixture of 13.5 grams (1/9 mole) of 1.4-dimethyl-
2-hydroxy-benzene and 33 grams (1/3 mole ) of concentrated
sulfuric acid (d.l.84) were heated with stirring at
100-1100 for two hours and an oil bath. The mixture was
allowed to cool and 66.6 grams (1/2 mole) of nitrobenzene

was added. After the addition the mixture was cooled in

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ice and 5 grams of fuming sulfuric acid (60%) was added
at such a rate that the temperature did not rise above
10°. Then 18 grams (l/9:mole) of bromine dissolved in
17 grams of nitrobenzene was added dropwise. Stirring
and ice cooling were continued for an hour after the
addition to complete bromination. The reaction was then
allowed to come to room temperature and 300 cm. of water
containing 3 grams of dissolved sodium.bisulfite was
added. The mixture was thoroughly stirred for fifteen
minutes to complete extract the brominated phenol
sulfonic acid. The water layer was separated from the
nitrobenzene by means of a separatory funnel. The
solution of the sulfonic acid was placed in a 500cm.
flask suitable for steam distillation. The water and
dissolved.nitrobenzene was evaporated off using an oil
bath at 200° . When the temperature of the sulfonic acid
solution reached 115°, superheated steam, superheated by
means of a copper coil, was passed through it. The oil
bath was kept at 200° during. the entire hydrolysis. The
hydrolysis was complete when the flask was dry and only
charred material remained. The brominated phenol was
extracted from the distillate with ether. The ether was
removed by evaporation using the steam bath. The
remaining phenol was subjected to distillation under
reducer pressure using a modified Claisen flask having a

20mm. column. The compound came over between 102-1040

- 10 -
(llmm.). Analysis and properties of this compound
indentified it as 3-brom-l.4-dimethyl-z-hydroxy-benzene.
Yield - 22% (5 grams).

After combination of two runs of the above procedure
the compound was solidified and allowed to liquify
slowly. ‘When it became slushy it was filtered by
suction until all was considered liquified ( 1 hour ).
A white solid remained on the filter paper. Its weight
was .30 grams. It had a melting point of 55-5a°. The
substance was believed to be a mixture of P-xylenol and
its mono and di—brom.substitution products.

Repeating this procedure failed to give any more of
the substance.

Analysis. Br, 6.34

3-bromp1.4-dimethyl-Zhydroxy-benzene._
Prepared by sulfonation and subsequent bromination

of P-xylenol in anhydrous nitrobenzene. A yellow liquid.
Analysis. Calc. for CBHQO Bra Br,39.76. Found:Br,39.44

Melting point (capillary)--------16.5-l7.5°.

Boiling point --------77-81° --- 0.5 mm.
102-104°--- 11.0 mm.
225.5-226°-737.0 mm.

Density ------1.4082 at 20°

Index of refraction (sunlight)--l.5630 at 20°

Molecular refraction Calc. for casgo Br: 44.83.Found,44.76

- 11 -

Derivatives:
Aryloxy acetic acid according to the procedure
of Koelsch, (J.AneChem.Soc., £3,304 (1931) ).

white needles ----- --------------M.P. 139.50

Analy31aocalc. for 0103110331.. Br,30086e Found: Br9300800

3.5-dinitro-benzoyl ester according to the
procedure of Brown, (Kreme-rs, J.Am.Phar.Assn.,1_l_,607 (1922) ).

Yellow solid -------;-----------n.1>.169.5°
Analysis. Calc. for 015H1106N23rt Br,20.22.Found:Br,20.18

PROOF OF THE STRUCTURE OF 3-BROH-l.4-DIMETHYL-
2-HYDROX!€BENZENE. (2.4 grams of the compound formed from
the proceeding bromination was dissolved in 100 cm. of
ch10roform.and cooled by means of an ice bath. While being
stirred 3.2 grams of bromine dissolved in 20 cm.of
chloroform was added slowly. After addition of the
bromine the solution.was stirred four hours. The
chloroform was evaporated off and the white solid
remaining was recrystalized from.alcohol. HtP. 78.5-790.

Analysis. Calc. for CBHBBr20: Br, 57.10. Found, Br.56.99.

6.1 grams of 1.4-dimethyl 1-2 hydroxy-benzene
was dissolved in:200 cm. chloroform. While stirring it
was cooled in an ice salt mixture of 8 grams of bromine

dissolved in 100 cm. of chloroform was added dropwise

-12-

over a period of four hours. After the addition the
mixture was stirred for ten hours. Upon evaporating
off the chloroform a white solid remained which was
recrystalized from.a1cohol. M.P. 84-850.

Analysis. Calc for C8H§OBrt Br, 39.76. FoundtBr,39.95.

This compound was a 5dbrom-P-xylenol.
5 grams of 5-brompP-xylenol was dissolved in

100 cm. of ch10roform.and cooled with ice. 4 grams of
bromine dissolved in 50 one of chloroform were added
dropwise while the solution was being stirred. Stirring
was continued for two hours after the addition of the
bromine. The chloroform was- removed by evaporation and
the compound recrystalised from alcohol. 1H.P. 78.5 - 79.50.

‘ Analysis.Ca1c. for CBHBOBrZ: Br,57.lO.Found:Br,57.12.

The 3.5-dibrom-2-hydroxy-1.4-dimethy1-benzene
thus formed is identical with the compound resulting
from the bromination of the bromine compound formed in the
procedure; therefore the former compound must be 3-brompP-
xylenol and upon bromination the active para position takes

up the entering bromine forming the 3.5-dibrom compound.

SULFONATION OF 1.4-DIMITHYL-2-HYDROXY-BENZENE
is not well described in the literature (Jacobsen,Ber,
ll, 27 (1878) ). During the-process of a run sulfonation

is supposed to take place. A run was stopped just before

r 13 -

the addition of nitrobenzene to see how far sulfonation
took place. The process was a heating of a mixture of
13.5 grams of P-xylenol and 33 grams of concentrated
sulfuric acid (d. 1.84) while stirring at loo-110° for
2 hours using an oil bath and then allowing the mixture
to cool. 200 cm. of water was added and the mixture
was stirred until all was in solution. Barium
carbonate was added until no further precipitation took
place. Carbon dioxide was then bubbled in until the
solution was saturated. The solution.was heated for
ten minutes, cooled and filtered. The water was
evaporated off and a white solid remained. The 1.4-
dimethyl-2-hydroxy-4-sulfonic acid was recrystallized from
water. Yield 80%. M.P. 156-161o (decomposes).

Analysis. Calo.for 08H1004S: S, 15.85: Found: S,15.84.

S U If] A 3'!

l. 3-brom-l.4-dimethy1e2-hydroxy-benzene was made and
its structure proven.

2. Bromination of 1.4-dimethyl-2-hydroxy-4-benzene
sulfonic acid in anhydrous nitrobenzene gave rise to
3-bromel.4-dimethyl-2-hydroxy-benzene.

3. ‘ l.4-dblathyl-2-hydroxy-4-benzene sulfonic acid was

prepared in a good yield.