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SOME BROMO DERWATWES
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THESE FOB TEE FEGREE OF M‘ S.

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1933

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SOME BROMO DERIVATIVES OF MoCRESOL. II.

SOME BROHO DERIVATIVES 0F H-CREBOL. II.

A Thnail
Suhmdttad to the Faculty of
MICHIGAN’BTAIE COLLEGE

In Partial Fulfillnont of tho
Roqniromento for the negro.

of
Inster of Science

Department of Chomlatry

BY

Walter John Petoraon

Juno. 1935

\

._ 5 Q ~

W

The writer wishes to IXprOBI
his sincere appreciation to
Dr. R. 0. Huston.
whose guidance and helpful suggestions
have made possible the completion of this work

331-659

C OMEHTS

A. Historical.Dnta Page
1. The bromo whoreeols . . . . - . - . 1
8. The eulphonation of m-eresol . . . 5
3. Hitro mnoresols . .. . . - . . . . 10
4. Chloro-bromo mporesols . . . - . . 14

B. Experimental Data
1. The preparation of 6 bromo n-oresol - 15
2. The preparation of 2 bromonnnoresol - 22
3. The preparation of 2.6 dibromo
mperesol . 51
4. The Bactericidal Properties of
Derivatives of mnoresol . 41

5. Swnmarya-.--.----....- 45

Hi storioal Date

THE BROMO MbCRESOLS

The investigation of the brcmc derivatives of macroscl
'3! undertaken for several reasons. An examination of the
literature revealed that. compared with the number of known
halogens»derivatives of other phenolic compounds. only a few
of the bromc mpcrescls had been prepared and conclusively
proven e

Huston and Hutchinson. therefore. in 1929 began a
series of researches in an attempt to clarify some of the
existing inconsistencies in the literature in regard to the
structure and preperties of some of the bromo-mpcresols.
they succeeded in preparing four new derivative. (Huston and
Hutchinson. J.A.C.S. 54, 1504. 1932)

It was shown that when mpcresol is treated in the sold
with one mole of bromine. two definite mono bromine macresols
are formed. namely. 4¢brcmc mpcrcscl. (mtp. 55 . 56°). and 6
bromo uporesol. a liquid boiling at 206 a 208°. The structure
of these compounds was proven by the preparation thru the
corresponding toluidine by diazctization.

It was also shown that when macresol is treated in the
cold with two moles of bromine two definite dibromo macroscls
are formed. These two isomers are 2-4 and 4-6 dibrcmo mp
crescl. Both of these are crystalline. and each have a melt-
ing point of 65°. The formula of the 4-6 dibromo mpcresol
was definitely established by the preparation thru the corre-

sponding toluidine.

The results of the researches reported in this thesis
are a continuation of the work begun by Huston and.Hutchinson
on the brcmc mpcresols. It was felt that if possible. it
'wculd be well to investigate the as yet unreported 2 bromo
and 2~6 dibrcmo mporesols. and perhaps to further verify the
work already completed on the 6 bromc compound.

Before proceeding further it might be well to review
briefly the literature on the brcmc mécrescls as it stood be-
fore the work of Huston and Hutchinson.

Neville and Winther in 1883 (Ber. 15, 2991) prepared a
upbrcmonmpcresol by the diazctization of mnbrcm01m toluidine.
They obtained a mono bromo m-crescl melting at 56 a 57°.

Claus and Hirsch (1' pr'. Chem. 2. 59. 59) prepared age-e
tribrcmo upcrescl by treating mpcrescl with bromine in chloro-
form solution. Their product melted at 84°.

Werner (Bl. Soc. Chem. 2. 46. 276) using much the same
method as described by Claus and Hirsch.obtainsd a product
melting at 81°. 82°. Werner need water as a solvent instead
of chloroform.

2-4-6 tribromc mpcresol has also been prepared by.Auwers
and Richter (Ber. 32. 3382). These workers obtained the com»
pound by the reduction of 2-4.6 tribromc 5-oxy benzyl bromide.
The reduction was accomplished with zinc and acetic acid.
Their product melted at 84°.

Gibbs and Robertson (J. Chem. Soc. 1914, 2. 1885) pre-
pared 4-6 dibrcmo cresol by the diazotization of 4-6 dibrcmo

.mntoluidine. which in turn had been prepared by the brominan
tion of acet-m-toluidine in the cold. This dibromc mpcresol
melted at 55°.

One year later Walther and Zipper published an article
(J. pr. Chem. 91. 364 - 414) in which they described the pre-
paration of 4 bromo mporesol. This compound, melting at 62°
was obtained by the addition of a calculated quantity of bro.
mine in carbon tetra-chloride solution to mooresol in the
same solvent at -5° to ~10°.

Euros and Balada (Gas. Ceskoslavenskeko Lekarnistra 6.
107 a 190. 1926) make the statement that by bromination of
mpcresol at ordinary conditions without the aid of catalysts
or solvents. gr4-6 tribromc m-crssol is formed.

Hodgscn and floors (J. Chem. Soc.. (1926). 2056 . 2040)
prepared 4 bromo m-cresol from the corresponding amino com-
pound by diazotizatient A.melting point of 38° is reported.

Darenso and Levy. (Compt. rend. 193, 292. 1931) report
e.msltina point of 63° for 4 brcmc mpcresol which they claim
to have prepared by direct bromination in glacial acetic acid
in the cold. Since this work appeared in the literature
shortly after Huston and Hutchinson had completed their work_
on the 4 bromo mnoresol it was thought wise to repeat the
work of Darren and Levy. This was done and a crystalline comp
pound prepared which melted. after repeated crystallization

at 53°. 56°. exactly the same melting point as was obtained

for 4 bromo macresol by the bromination of m-crenol in chloro-
form in the cold (by K. a II.) .

Euros (Chem. Listy. (1927) El. 221 o 227) makes the fol-
lowing rule for substitution of ha1050ns in mpcreuol. "Chloro
or brono substitution products of mpcrecol follow the same
rule as for slogan substitution in amino or hydroxy deriva-
tives of benzene. In m-cresol. halogen derivatives in the 4
and 6 positions are most likely.”

we see then. in a review of the literature that little
conclusive evidence is given as to the exact structure of the
bromc upcresols. one finds that whereas considerable work has
been done with tribromo m-creool with quite consistent results.
relatively few consistent results have been reported for the
mono and dihaIOgcn deriVatives. This can probably be explain-
ed by the peculiarity of the effect on directing preperties
when a methyl and a hydroxyl group are situated mate to each
other as in m-crescl. Both being strongly'para directing. a
mixture of 4 bromo and 6 bromo mpcresol usually results in
the case of the monobrono derivatives while a mixture of 2.4
and 4-6 occur in the preparation of the dihmlogcn derivatives.
Difficulty in the separation of these isomers has undoubtedly
been the reason for the lack and inconsistency of reeults in

”16 93.13 t e

TILE SULPHONATION OF Lia-GREECE:

Gonoidoroblo work hao boon dcno in this laboratory in
tho preparation of halogenated phonolo. Sumo difficulty has
boon onoountorod in obtaining ortho halogen substitution. In
moot caooo thio has been accomplished by protecting tho para
position or the porn and one ortho position with oulphonio
acid groupo.

Haxtiold (1930) used thin nothod for tho preparation of
2. d dibronophonol. His was an adaptation of n.nothod used
in tho propnrntion of 2, 6 dichlorOphonol (M. Tnnako and K.
Kntani. 0.A. 21. 2255). Binco tho halogenation of oulphon-
oted phonolo hao been quite thoroughly diacucood in Bollordo‘
work on “rho Preparation and.Bonzyintion of OABromcphonol"
(Ihooio 1932) tho writer will make no attempt to roviow thio
phnoo of oulphonation. oxoopt in no much no it concorno up
oroool. Quito o thorough dioouooion is also givon by Bette
ond Bhoumick (J. Amer. Chem. Soc. 43. 303. 1921).

Probably the moot outotanding work on tho oulphonation
of mnoreool in that which was accomplished by Glenn and Krauoo
in 1887 (Bar. 20. 3089). Thooo workoro otato that when one
mole of unoroocl is permitted to react with ono molo of con-
oontrated sulphuric acid for from three to four days. five.
oixtho of the croool is oulphonatod. resulting in tho 4aoul~
phonic acid. (pare to tho OH) Comploto oulphonation can aloe
be accomplished by heating two or three hours on the steam
bath.

The m-oreeol para sulphonic acid crystallizee in three

tonne depending upon the solvent used in crystallization:

1. From (111. 332304 57,13. 75 rage 16
2. From Cone. H3304 3,15 95 53120 1.72:
3. Elimination of H20 $.2.118 $320 0

Clone and.Kreuso treated this mpcreeol p-eulphonic acid
with phosphorous pentubromide in an attempt to reylaco the
sulphonio and hydroxyl groups with bromine and thou obtain
a dibromo toluene. all um tZ-zxey obtained. however. was a
mixture of dibromo and tribromo.m-creeol. out of which a
small amount of tue tribromo derivative woe isolated. melting
at 73°. 81° 0.

These workers also prepared a.wporeool dioulphonic acid
which they decided was the 4.6. This was obtained by treat-
ing one mole of mpcreeol with four to six moles of oulphurio
acid at room temperature for from four to five days or at
120° . 140° for a few hours. Claus and Krauee.meintein that
overheating may result in a change to the monoculphonic acid.

It in somewhat surprising that though.a number of workers
have reported a 2.6 dibrouo m~creeol culphouio acid, none of
then.huvc cicceeded in successfully'hydrolizing the oulphonic
group and thus obtaining the 2-6 dibromo.mpcreeol. Claus and
Bruno: (J. pr. (2) 39. 568) obtained good yieldo of the di.
bromo Mncrecol oulphunio acid by‘brominating the poticeium

salt of the peruculphonic acid in acetic acid. This compound

crystallized out of water. A melting point of 140° is report-
ed. Claus snd.Dreher also reported that bromination (1 mole)
of the disulphonio acid gives the 2. 6 dibromo wuoresol 4
sulphonie said. (J. Pr. (2) 39. 572.)

In more recent years. two English workers. namely Haworth
and Lapworth (3.0.8. 125. 1299. '24) have done a great deal to
clear up some of the questions in regard to the sulphonated
doritntives ofzmncresol. It appeared somewhat remarkable to
these workers that mncrecol should not yield a sulphonation
product corresponding with phenol o-sulphonic acid. Consequent-
ly one of their workers. h. L. Wilson. on making a preliminery
inVestigation of the question found that monoculphonation of
sporesol. either with sulphuric acid or with ohloro-sulphonic
acid. usually led to the mixture of two acids. the nature and
proportions of which.vary with the agent and the conditions
employed during the eulphonstion process; by fractional crys~
tallisation of their salts a partial separation of the two
eoids was effected. One of these acids had properties very
different from those of the true oreeolsulphonie aside and
was ultimately found to be identical with Verley's m—tolyl
hydrogen sulphate, céh4CH303053 (Bull. Soc. Chim.. 1901.

25. 45)

The View that phenyl sulphuric acids are formed during

the eulphonstion of phenols and even that they represent in.

termediete stages in the sulphonation process. was at one time

widely held. receiving its principal support in the formation
of the supposed Bunnphthylsulphuric acid during the sulphcnn-
tion of Bannphthol. (Armstrong; Ber.. 1882, 15. 202. 204.
207: Hietski. ibid. p. 305). Since the discovery that this
compound was in reality Bonaphthol l-sulphonic acid. the ides
that phenyl sulphuric acids may be formed in appreciable quan.
tities during ordinary sulphonstion of phenols. has not been
considered very seriously.

Hnworth and Lapworth endeavored to replace the sulphonic
groups by the OH, Cyano, and amino groups. but these experi.
ments were unsuccessful. in order to determine the constitu-
tion of the monoculphonic acids it was necessary to convert
them into the corresponding methyl others. stcrth and Lup-
vorth.found that when the sulphonuticn was carried out at
120° the main product one the 4usulphonic acid. but at lower
temperatures considerable quantities of the 6 sulphonic acid
could be obtained, although the total sulphonntion was re-
duced.

The disulphonic acid prepared by Hewerth and anworth
appeared to be identical with that prepared by Claus and Kruuse.
and its constitution proves to be 4.6.

These workers were not able to introduce s third sul-
phonic group by the action of three molecular proportions of

chloro-sulphuric acid; only m-cresol 4-6 disulphonio scid be-

ing isolated.

Here it might be well to mention something concerning
the relative amounts of 4 and 6 obtained when concentrated
32:304 acts on mooreeol. moresol culphonated for one hour
et 30° 4- 35°. yielded the 4 and 6 sulphonic acids in the ratio
2.? to 1. When the sulphonation was carried out at 100° the
two acids were formed in the ratio 19 to 1. At 120° after
an hour's heating the main product was the 4 sulphonio acid.
He other products than these were detected.

10

HITRO H-CRESOLS

The nitro deritativee o! mpcresol have been prepared
by a number of workers.

The prooeedure which.has been most generally used is
that reported by etaedcl and holb (Ann. 253. 210. 1390).
fiberasol was nitrated in glacial acetic acid at .150. The
resulting mixture was poured into several volumes of ice
water and the oil which separated steam distilled. The 701»
stile product. which after purification.melted at 56° was
proven to be the 6 nitro mpcreeol. Out of the reaction.nix~
ture a good.yield of 4 nitro was isolated. melting at 129°.
These workers report no 2~nitro.m-cresol.

All subsequent work on the isomeric monsonitro mnorssols
does not differ much either in regard to preparation or pro.
portion. but it was not until recent years that anything de-
finite was determined in regard to the 2 nitro deriVative.

Khotinsky and JaoopsonaJacopmann (Ber.. 42. 5097. 1909)
claimed to have prepared a crystalline methyl deriVative
melting at 88°. These authors nitrated macresol according
to Staedel's directions (Annalen 259, 210. 1881) and separ.
sted the volatile 2 and 6 nitro mncresols by distillation in
steam. According to Khotihsky and Incepson . Encepmann. the
solid which separated from the cold aqueous distillate was 6
nitro uncresol while the aqueous solution contained 2 nitro

nitro m-oresolz and the latter, obtained as an oil by ex.

ll

treating with other. and treating with.methy1 sulphate and
alkali. yielded the oryetallino derivntive melting at 98°.

Gibson (I. C. S. 25. 1269. 1933). who repented the work
of Khotinely'nnd Jaoopson~JecOpmenn. found that lithough the
yields of 4 and 6 nitro mpcroeol were satisfactory. that of
the suppooed 2 nitro m-creool was very swell. Ciboon found
that better reoulte were obtninei by a method einilar to that
used by Knuftnln and do Pay (Ber.. 37. ?23. 1934) for the con-
version or resoroinol into 3 nitro reeoroinol. X-oreeol who
firot sulphonatod. the product one nitrated. and the result.
ing nitro mpcreooleulphonio acids were Lydrolized with super-
heated steam at 163°: 170°. the yield of the yellow oil thus
obtained amounted to 891 of the theoretical and tron it Gibson
was able to prepare crystilline uoetyl. benzoyl and methyl de-
rivatives. accompanied in each ooze t: eoee oily product.

The 2 nitro macreeol crystallizes in.fine yellow needlee melt.
ing at 39°.

The methyl ether of he 2 nitro m-oreeol melted it 54°
whereas the methyl ether of the 6 melts at 63°.

Gibson. in order to determine the orientation of the
groupo in these three nitro compounle oxidized the methyl de-
rivative of each to the correspon in; nitro~methozy benzoio
acide. the propertiee which are known (Ber.. 28. 2353. 1889).

Quite recently A. Corbellini and C. flavazoni (Atti R.
Accn‘i. Linc-oi. 1951 (vi) 1:. 13:2 . 137) reported mm. a rep-

etition of the eerieo of reaction: enployod by Gibson (1. C.

12

8. 1925. 123. 1270) showed that the nitro mporeeol m.p. 41°
ie not 2 nitro but 6 nitro.

During the course of this work on the bromo mporeeole
the writer hae been able to demonstrate that Corbellini and
c. Rerezeoni were undoubtedly wrong in their conclueione in
regard to the work of Gibeon. Work by Hodgeon and Beard (J.
c. B. 127. 498. 1926) in the reduction and subsequent dia-
eetieation of 2 nitro m-ereeol also eubetantiatee the work of
Gibson. ‘

The 2 andno and 6 amino m-oreeole. in which we were para
ticularly intereeted. have received but little attention in
the literature.

Kehrmann and Stampa (Ann. 322. 18) mention the 0 amino
m-ereeol but give nothing so to preparation or melting point.

Auvere. Boreohi and Weller (Ber., 84. 1315. 1921) ob-
tained 6 amino mporeeol by reduction of the 6 nitro compound
with.etannoue chloride and hydrochloric acid. A melting point
of 157° . 1599 in reported.

The only reference to be found on the preparation of 2
amino mpereeol ie that by Hodgeon and.Beard (3. C. S. 127.
498. 1925). These workere reduced in a water solution of
eodium carbonate and sodium hydroeulphite. obtaining a com.
pound melting at 150°. From this they attempted to prepare
2 bromo mporeeol by the Sandneyer method. A very poor yield
of product. melting at 56° . 57° ie reported.

In regard to the nitro nnoreeole, it wae felt that if

the para position could be protected by'a nitro group and the

13

positions 2 and 6 filled with bromine. subsequent reduction
and renewal of the amino group through diazotisation would
result in the as yet unreported 2. 6 dibromo mpcresol.

This compound 2. 6 dibromo. 4 nitro mpcreeol has been
studied rather extensively by several workers. It was first
obtained by Claus and hirsch (3. pr. (2) 39, 61) by nitrating
2.4-6 tribromo mpcreeol with nitric acid in acetic acid solu-
tion. These workers also obtained it by bromination of 4
nitro mporesol.

Zineke also prepared this bromo nitro macresol, but the
nitration was carried out with sodium nitrate. (3. pr. (2)
61. 564). .

Raiford (Amer. Chem. Jour. 46, 426, 1911) in a study of
the chlortmidoquinones prepared 2, 6 dibromo 4 nitro mpcresol
by a method very similar to that of Zinoke. His product
melted at 134°.

Reduction of this compound with stannoue chloride and
hydrochloric acid gives a hydrochloride melting at 225? The

free base liberated by ammonium carbonate melts at 176°.

14

CHLORO . BROHO MbCREUOLS

Since such very few conclusive results are reported in
the literature in regard to either the chloro or bromo mp
creeole. we would also expect but little in regard to the
chlorobrcme.mpcresols. Such.is actually the case. They are
considered briefly here because they provide a convenient
means of proving the position of the bromine atoms in some
of the compounds to be discussed later.

Walther and Zipper (J. pr. (2) 91. 378) obtained 4 chloro.
6 bromo m-cresol by bromination of 4 chloro mpcresol in car.
ben tetrachloride. This product melted at 70° . 75.5°.

Raiford and Learell (J. A. 0. 8. 80s.. 36, 1509) were
successful in synthesizing 2. e dichloro 4 bromo macresol by
diasotization of 2 chloro, 4 bromo. 6 amino m-creeol. Needles
out of ligroin melted at 65°.

The only remaining ohlorobromo mnoresol which is re-
ported in the literature is 4 chloro 2. 6. dibromo m-cresol.
This compound, melting at 70° - 75.5° was prepared by Walther
and Zipper (J. pr. (2) 91. 378) by bromination of 4 chloro

Ibcresol in acetic acid.

EJCPER RENTAL PART

15

THE PREPARATIOH OF GoBROMO HoCRBSOL

In the preliminary work with the bromo mocresols, con-
siderable difficulty was encountered in the distillation of
the Various derivatives under ordinary atmospheric conditions.
without obtaining a great deal of decomposition. For this
reason it was decided to repeat the work of Huston and Hut-
chinson in the preparation of 6 bromo mpcresol. thus obtain»
ing enough of this compound for comparison. and determining
its boiling point at t‘ga. It was decided to use this pres-
sure throughout the whole of the work.

One mole of.m-cresol (108 grams) was brominated with
one mole of bromine (160 grams) according to the method re.
ported by Hutchinson. The brominated mpcreeol after several
distillations under 4‘gm. pressure gave the following trace
tions:

75°. 85° - . a a u - e n . 16.8 grams liquid

85°~lOO° a - - . a w a . a 44.5 grams liquid
1000.115“ - . - - - . . - . 27.3 grams liquid
115°oll7° . - - - . . - . . 65.8 grams solid

The first fraction boiling at 75 . 85° on refraction-
stion came over at 80 a 81° (4 mm.) This fraction corresponds
to that which Hutchinson reports as having a boiling point of
200 . 208° at 731 mm. of pressure. and is undoubtedly the s

bromo npcresol.

16
Analysis by the Parr bomb method gave the following

results:
Wt. of cc. .1 N Calculated Found
Sample Agnoa Br. in C7H70Br
.2226 11.85 42.73% 42.61%
.2017 10.72 42.78% 42.55%

The large fraction boiling at 115 . 117° (4mm.) gave
upon recrystallisation. a product melting at 56 . 57°. This
corresponds to Hutchinson's 4 bromo mpcreeol.

The two fractions which came over between 85° and 115°
after repeated fractionation were separated into 6 bromo and
d bromo mpcresol.

The benzoyl. benzeneeulfonyl and toluenesulfonyl esters
of the 6 brome mncresol were prepared by the method described
by Porter. Stewart and Branch (Page 181, Einhorn and Holland.
Ann.. 501, 95; 1898).

After repeated crystallizations from alcohol the melt-
ing points were determined and the compounds analyzed for
bromine. Following are the results:

Esters of 6 Drama HeCresol

M, P. fit. of cc..lfl Calculat- Found
Sample agnoa ed for Br

Bensoyl 87.5° .2065 7.12 27.49% 27.58%
Emall white needles out of alcohol

Benzene sulfonyl 92.0° .1606 4.9 24.46% 24.34%
Small white plates out of alcohol

Tolyl sulrcssl 72.s° .2009 5.9 25.45% 25.523
Pine plateolike needles out of alcohol

17

Since the proceedure for the proof of the 6 bromo de-
riVatiVe as given by Hutchinson was long and difficult, and
gave but mediocre results, it was felt that some other method
might be attempted which would. perhaps give better yields
and further substantiate his results.

For this purpose. mpcresol was nitrated in 140 gram lots.
in accordance with the method of Staedel and Kalb (Ann. Chem.
259, 210; 1890). and the isomeric nitro products that result-
ed were separated by steam.

140 grams of macresol was placed in a soliter. coneoked
balloon flask equipped with an efficient mechanical stirrer.-
To the cresol was added 140 grams of glacial acetic acid and
the mixture cooled to «8° 0. A.mixture of 400 grams of gle-
cial acetic acid and 200 grams of HH05 (Sp. Gr. 1.5) was
cooled in the ice box and then added very slowly to the orig.
inal mixture from a separatory funnel. During the operation
the temperature should not rise above 0°. after the addition
was complete. the mixture was poured over 1,000 grams of ice
and after about an hour a liter and a half of water was add.
ed. This was then allowed to stand over night. during which
time. a heavy. reddish. black 011 separated, which was partly
crystalline. The oil was separated from the aqueous portion
above it and placed into a flask prepared for steam distillao
tion. The two isomeric products could now be separated since
the para compound is not volatile under these conditions and
can be obtained in the crude form by allowing the distilla-

tion residue to cool.

18

The crtho compound in the distillate upon recrystalliza-
tion from petroleum ether. melted at 56°.

The para compound can be further purified by repeated
crystallization of its sodium salt from water. These crystals
may then be decomposed by treatment of their aqueous solution
with dilute hydrochloric acid. and the free nitrocresol sub.
sequently crystallized from hot water. from which it separ.
ates in nearly colorless needles melting at 127° . 129°.

The yield of both isomers can be considerably increased
by extracting the aqueous portion of the original mixture
with other, evaporating and again steam distilling.

Yields covering a number of nitrations were:

6 nitro -~ 38 grams.
4 nitro ... 53 grams.

For the preparation or 6 bromo.m~croeol we were naturally
especially interested in the 6 nitro product.

From the 6 nitro macresol. the 6 amino hydrochloride
was prepared by a.modifioation of a method reported by Rai-
ford.and,Leavell (J. A. C. 3. 36. 1505: 1914). also (Am, Chem.
Journal 46. 419: 1911).

Thirty grams of the nitro product was dissolved in the
smallest possible quantity of hot alcohol. (1 gram to 1 cc)
And to the hot solution-f more than the calculated amount of
stanncue chloride (114 grams) dissolved in cone. H01 (114 cc).
During this time the flask was shaken and the mixture kept

hot in order to preVent the inmedinte separation of crystalls.

19

Next one volume of cone. HCl was added and the solution set
aside to cool. Fine white crystals separated which were free
from.tin compounds. The hydrochloride melted at 212° with
considerable charring.

Attempts to change this hydrochloride to the amine were
unsuccessful. Ammonium carbonate was used for this purpose.
a compound of no definite crystalline structure which turned
red upon standing in air was repeatedly obtained. hehrmann
(Annalen 322. 19; 1902) claims to have isolated the amine by
Just such a method but reports no melting point. He does.
however. mention that in the ammoniacal filtrate a reddish
brown compound was observed which he suggests might be an
oxidation product.

Since it seemed impossible to obtain the pure amine by
this method an attempt was made to accomplish the reduction
by the use of sodium,hydrosulphite. Hodgson and Beard
(Journal of the Chemical Society 127. 498; 1925) used this
successfully in the reduction of 2 nitro macresol.

d-nitro mpereool (33 grams) was dissolVed in 400 so of
water containing 60 grams of sodium carbonate. This was treat-
ed at the boiling point with 126 grams of solid sodium hydro.
sulphite. 6 amino macresol was deposited on coiling in al:
most colourless, fine needles with a melting point of 157° a
139°. (This agrees with the m. p. reported by Auwers.
Borsohe and Weller,(B. 54 (1921) 1315).

30

For the replacement of the amino group with bromine it
was found that good yields were obtained by the use or the
hydrochloride rather than the amino. To accomplish this dine
sotizaticn a modification of the method reported for the pre-
paration of p.bromotoluene by'Bigelow (Organic Synthesis Vol.
V p. 21) was used.

A mixture of 5 grams of crystallized cupric sulfate. 2
grams of copper turnings. 13 grams of sodium.bromide. 3 grams-
of concentrated H2804 (Sp. Gr. 1.84) and 83 cc of water was
reflexsd over a flame for three to four hours until the color
became yellowish. (If the color of the solution has not been
discharged after heating for three to four hours. a few grains
of sodium.sulfite may be added to complete the reduction).

When the hydrobromio acid e cuprous bromide solution was
ready for use. the diazonium solution was prepared. A solua
tion of 10 grams of amine hydrochloride and 16 grams of con-
centrated sulfuric acid (hp. Gr. 1.84) in 80 cc of water was
cooled below 20° and diazotised with a solution of 6 grams of
sodium nitrite in 125 cc of water. This required about twenty
to thirty minutes when the temperature was maintained between
15° and 20° by means of an ice bath.

A one liter round-bottom flask containing the hydro-
bromic acid cuprous bromide solution. was arranged for steam
distillation. After the coppersnlution was gradually added
from a separatory funnel and a vigorous current of steam pals-

ed through the mixture at the same tide. This proceedure

21

required about an hour. The oil in the aqueous distillate
wee separated with other, washed, and upon evaporation of
the other and distillation 4 grams or yellow oil boiling at
81° - 82° (4mm.) was obtained. Analysis for bromine by the

Parr bomb method gore the following reoulta:

Wt. of co .1 N Calculated Found
Sample Agnoa Br. in C7H7QBr
.1950 10.41 .4278 .4270

To further prove the structure. a portion was brominnied
in chloroform solution with one.mole of bromine. Crystals
were separated from a large fraction of oil (undoubtedly 2.
6 dibromo mnereeol) which melted at 64° a 65°. The crystal-
line product was the 4. 6 dibromo product. described by'Hute
ohineon.

The 4. 6 dibromo mnoreool was proven by preparation of
its benzoyl eater. Repeated crystallization from ethyl el-
oohol gave a melting point of 84° - 85°. '

Various attempts to nitrate the 6 bromo‘mpcreaol were
unsuccessful. In each one. 2.4.6 trinitro mnoreeol (m. p.

109° a 110°) was isolated.

22

THE PREPARATION OF 2¢BWOMO HbCRESOL

Since the preparation of 6 bromo mpcresol was so easily
accomplished by working through.the corresponding amino com.
pound. it was felt that a similar method might be worked suc-
eeesfully for the preparation of 2 bromozm-cresol.

For the preparation of 2 nitro m—cresol. a method was
used which was first suggested by Gibson (I. C. S. 125. 1269;
1923) and later modified by Hodgson and Beard (1. c. s. 127.
498. 1925). .

The original method used fuming sulphuric acid which
contained 6 . 7%'803. Although reasonably good protection
in the four and six positions is accomplished with this
strength.of sulphuric acid the crude nitro product does not
crystallize readily but has to be purified by preparation of
the acetyl derivative. which is later hydrolised with also.
holic eodium.hydroxide solution. The method or Hodgson and
Beard. which obviates the troublesome process of purification
by acetylation consists in using stronger oleum (15% 803 in-
stead of 6.7%) for the initial disulphonation.

The author found that an even stronger oleum (23% 803
instead of 15%) gave improved protection. Following is the
method eventually decided upon.

To a cold solution of 108 cc of macresol in 400 cc of
fuming sulphuric acid (23% 803), a.mixture of 100 cc of rump
ing sulphuric acid and 46 cc of nitric acid (d. 1.5) was

23

gradually added. After twenty hours. the liquid was diluted
with 500 cc of water and superheated steam.passed through

the heated solution. Below about 145° a little unchanged
cresol distilled. but above this temperature up to 180° nitro-
eresol passed ever. leaving a black tar fromiwhich no crystal.
line compound could be isolated. Only the first third of the
steam distilled 2 nitro macresol ommes over as an oil (which
partly solidifies); the bulk of the distillate solidifies in;
mediately. The 2 nitro macresol can be recrystallized from
petroleum.ether in bright yellow. fernalike. rhombie groups
of needles melting at 39°.

After purification of all fractions 45 grams of 2 nitro
sporesol and 39.9 grams of oil (macresol) were gotten from
a typical nitration experiment like that Just discussed. The
m-cresol fraction boiled at 80° o 89° at 4 mm.

A.methcd adapted from.the work of Hodgson and Beard was
also used in the reduction of the 2 nitro macresol to the
corresponding amine.

Thirty-three grams (33) of 2 nitro m-cresol were dis-
solved in 400 cc of water containing 30 grams of sodium care
boasts. This mixture was then treated at the boiling point
with solid sodium hydrosulphite (126 grams). 2 amino mpcresol
was deposited. on cooling, in colorless. elongated, hexagonal
plates. mtp. 150°. yield 20 grams.

The 2 amine compound was then converted into the corre-
sponding bromo derivative by application of the method used
by Bigelow (Org. Synthesis Vol. v. p. 21) for the preparation

of pobromctoluene from the corresponding toluidene.

 

 

 

24

A.mixture of 5.6 grams of crystallised cuprio sulphate.
2 grams of copper turnings. 14 grams of sodium bromide, 3
grams of sulphuric acid and 90 cc of water was refluxed over
a flame for from three to four hours.

When the hydrobromic acid 4 cuprous bromide solution
was ready for use. a dissonium solution was prepared. {A so.
lution of 11 grams of 2 amino m-cresol and 17.6 grams of con-
centrated sulphuric acid (Sp. Gr. 1.84) in 90 cc of water was
cooled below 20° and diazotised with a solution of 0.3 grams
of sodium nitrite in 12 cc of water. .Ihis required about
twenty to thirty minutes when the temperature was maintained
between l5 and 20° by means of an ice bath.

A one liter round bottom flask containing the hydrobromic
acid . cuprous bromide solution was arranged for steam dis-
tillation. .After the ceppsr solution was heated to boiling.
the diasonium solution was gradually added.from a separatory
funnel and a vigorous current of steam passed through the re.
action mixture at the same time. This proceedure required
about one hour. The aqueous solution was then washed with
dilute sodium carbonate and water and extracted with ether._
Distillation gave a yield of 7.5 grams boiling at 83° . 84°
(4 mm.). all of which became solid.

Recrystallization from alcohol gave characteristic
large. hexagonal plates. m. p. 58.5° - 59°.

Since protection of the 4 and 6 positions was so easily
accomplished in the preparation of 2 nitro mperesol by the

use of fuming sulphuric acid. it was felt that a simular

25

proceedure might be used for the preparation of 2 bromo mp
cresol directly.

i To a cold solution of 108 grams of m-cresol in dégflcc|i
of tuning sulphuric acid (zsz’soa) 53 so or bromine were add.
ed.very slowly. After twentybfour hours, the liquid was di.
luted with 500 cc of water and superheated steam passed through
the heated solution. The bulk or the 2 bromo macresol came
over at 180° or above. It was often found necessary to allow
steam distillation to go on for as long as 2 to 5 hours at
180° in order to secure complete hydrolysis. The distillate.
which was a yellow oil. was extracted with other. and eventu-
ally distilled. using an eight inch column and vacuum of 4 mm.
Following are the fractions from 93 cc of oil (one run):

809.850....34ngrm
85° a 95° 0 o d o 29.0 Brena
95° «103° . . .. . se.e grams
103° «112° . ~ . . 4.0 grams
112° allt° . . . . 13.5 grams

The first three fractions consisted of a mixture of 2
bromo and 6 bromo mporeeol. These two isomers were separated
in the following manner:

The three fractions were refractionated a number of
times until the bulk was separated into an 80° . 85° fraction.
This fraction which had consistently refused to crystallize
or its own accord, was then seeded with a crystal of the 2

brcmo m-cresol prepared by diasotization. The fraction

crystallised immediately. After standing in the ice box
over night a fraction (representing about .n. third of the
weight) of uncrystallisable oil was decanted from the erysc
talline portion. This oil fraction. which it was decided,
must be the 6 brcmo macroscl was fractionated. using an eight
inch column and a 4 mm. vacuum. The bulk of the oil came
over at 80° 0 81°. This was proven to be the six by prepare
stion of its benzene sulfcnyl ester. which when crystallised
out of alcohol. melted at 92° e 93°.

The crystalline fraction or 2 bromo n-eresol upon re.
crystallisation from.alcohol gave a melting point of 58.50
to 59°.

The fraction.from.llz° - 1140 was analysed by the Parr
bomb method and found to be 2.6 dibromo.m-cresol. the proof
and preparation of which.will be discussed later.

A.method suggested by Ballard for the preparation of
crthc bromo phenol was also used in the preparation of 2
bromo mncresol. This method yields very good results but
the proceedure is long and.ineffioient as compared to the
sulphonation proceedure Just described.

One mole (108 grams) of mneresol and 3% moles (350
grams) of concentrated sulphuric acid in a three liter. three
necked flask were heated on a steam.bath.for three to four
hours. At the end of this time the reaction mixture was
cooled, the stirring motor attached and.the mixture made ale

kaline by adding a solution of seven moles (280 grams) of

sodium hydroxide dissolved in 700 cc of water. This was
done very slowly.

: The alkaline solution was then cooled to room tempera-
ture and brominated by adding slowly one mole (160 grams).
of bromine. stirring constantly. (During this Operation the
temperature may be permitted to rise to 40° - 50°) Stirring
was continued for about half an hour after all the bromine
had been added. (The mixture should still be alkaline}.

The reaction mixture was then transferred to a three
liter flask set for steam distillation. During this distil-
lation the reaction mixture was heated on an oil bath to
about 150°. This remOVed any tribromo.m-cresol which should
not appear as more than a trace.

When no more tribromo m-crcsol was obserde in the disc
tillate. the steam distillation was stepped and the reaction
mixture. still on the oil bath was cyaporated to a thick
pasty mass. This was allowed to cool and was then acidified
with about 800 cc of concentrated sulfuric acid. This had
to be accomplished slowly on account of the rapid evolution
of HBr.

The mixture was again steam distilled. this time from
an oil bath heated to. 200° . 210°.

When no more oil appeared in the distillate. steam dis-
tillation was stopped. The brominated.m~cresols were then
extracted with other. the ether evaporated off and the resin

due distilled under vacumm of 4 mm. The following fractions

28

were separated from a yield of 103 cc of oil:

so . 03° . . ~ . . - . - 35.7 grams solid
85 . 100° 0 . . . . - a n 21.4 grams liquid
100 0 110° 0 o d o . o - o 20.0 grams liquid
110 . 120° . . . . . - - - 43.9 grams liquid

The fraction 80 0 85° remained liquid until seeded with
a crystal of 2 bromo:m~crescl. When placed in the ice box
overnight, 13.1 grams of the 35.? gram fraction was separan
ted as an oil by simple decantation from.the crystalline poro
tion. This oil upon distillation boiled at 80 . 810 (4 mm.)
and was proven to be 6 bromo macroscl by the bensene sulfonyl
ester preparation used in the previous sulfonation.

The crystalline 2 bromo mpcresol fraction gave large,
characteristic hexagonal plates out of ethyl alcohol. melt-
ing at 58.50 9 59°. By repeated fractionation with a column
the three other fractions can be separated into 2 bromc and
2.6 dibrcmo mporesol. (b. p. 114° - 116°) the proof and pre-
paration of which will be discussed later.

Several Parr bomb analyses were run on the crystalline

2 bromozm-cresol fractions (b. 9. 83° at 4 mm.).

Wt. of cc .1 N Calculated Found
Sample A3N03 hr. in c7H703r

.2314 12.42 42.78% 42.94%
.2005 10.00 $2.731 42.02%

.1808 9.62 42.78% 42.57%

since Hodgson and Board (J. C. S. 127, 499. 1935) had
prepared 2 bromocaamethoxy toluene by diasotization of the
lethyl ether of 2 amino mooreool. it was felt that this com»
pound mush! be prepared by a simple methylation of 2 bromo
nnoreeol.

2 Drama upcreeol (10 grams) was dissolved in 15 cc of
methyl alcohol and 1.2 grams of sodium added to form the so-
dium crooolatc. When this reaction was complete the theore-
tical amount,(? grams) of methyl iodide was added. the mix.
turo refluxed for five hours and allowed to stand overnight.
The alcohol one then evaporated of! and.the reoidue washed
with water to remove the sodium iodide formed in the re-
action. The other was extracted with ethyl ether and was ob-
tained by evaporation of the solvent. Recrystallization in
ethyl alcohol gave long flat plates. melting at 39.50 . 40°.
Hodgoon and Board reported a melting point of 55.50 . 36.50
for this product.

. Analysis of the methyl ether of 2 bromo mpcreool for
bromine yielded the following:

we. of co .1 3 Calculated Found
881111310 1131103 Br. in 0311903:
.2283 11.7 41.13% 40.98% v-

A small portion or 2 bromc mporesol brominated in 001‘
eolution in the cold with one mole of bromine yielded e.
portion of nnoryetellieable all (probably 2. 6) and a crye-
telline fraction which upon purification in pctroleun.ether

save a melting point of 65°. This agrees with the melting
point for 2. 4 dibromo n-ereeol. Once purified. it crystal-
lieed very easily out of most solvents. differing from the
4. 6 dibm aerosol in that respect.

the beneeyl. benzene enlfonyl and toluene enlfonyl
esters of 2 brooms-cresol with their melting points and
analyses for bromine are reported below:

i. P. Wt. of no .18 Union. Found
Sample Agnes for Br

Beneoyl ester 09° .1836 6.33 27.49% 27.58%
Small white plates tron alcohol ' ‘ f

Benzene eulfcnyl 11° .2131 6.5 24.46% 24.39%
Small white plates from alcohol

Toluene euli’cnyl 85° .1988 5.0 23.43% 23.347;

Small needle like plates from alcohol

51

THE PREPARATION OF 2-6 DIBROMO MpCRESOL

It was felt that a convenient method for the prepara-
tion of this compound would be through 4 nitro. 2. e. di.
brcmo Increscl. by subsequent reduction and finnally replace.
ment of the amino group by hydrogen through.the diasctizetion
reaction.

For the preparation of this nitrobromo derivative a
method was first used which had been reported by Raiford (Am.
Chem. Journal. 46. 42s. 1911).

Pure tribromo macresol was the starting point in the
preparation of this compound. Thirty grams was dissolved in
300 cc glacial acetic acid. the liquid cooled to lO°and then
10% more than the calculated amount of sodium nitrite added
during half an hour. while the flask was continually shaken
and the temperature kept down to that given above. When the
nitrite had all dissolved. the dark liquid was poured with
stirring into 5 volumes of water. and the mixture set aside
for some hours to allow the precipitate to subside. At the
end of this time the yellow solid was filtered off and dried
on a clay plate. A yield of 90% was obtained. The crude
product softened at 65° and was completely melted at 113°
(when it appeared to decompose). which suggested the possible
presence of two compounds. It may be stated at once that

isomeric mcncnitrcdibrcmc macrescls. vie:

OH on

N02 BF BO 5" I 32

CH3
BF ' and N01,

were isolated from the mixture.

The best method of separating the compounds present was
found to consist in dissolving the dried crude product in
hot chlorofomr (1 gram to 1 cc) and treating the solution
with two volumes of ligrcin (so . 60'). Precipitation of
the high.melting isomer (para compound) took place at once.
After half an hour this was_filtersd off and crystallised
from.bensene. when a compound.melting at 128° with decomposi-
tion was secured. Repeated crystallization from the same
solvent gave pale yellow plates melting at 134° with decomp-
osition. The substance so obtained has the nitro group in
the para position as respects hydroxyl. and is 2. e dibronc
4 nitro mncreeol. A small yield was obtained.

When the filtrate from the chloroformpligroin mixture
specified above was allowed to evaporate. it left a yellowish
red. sticky mass which. after repeated crystallizaticns from
alcohols. gave a small yield of deep yellow needles melting
at 87°. This compound is isomeric with the nitro product
mentioned above. and has the nitro group adJacent to the hyb
droxyl.

Due to difficulties encountered in the separation of
the isomers it was decided to use some other method to obtain

the decried nitro dibromo product.

33

Para nitro macresol. (m. p. 129°) the nonvolatile pro~
duct previously mentioned in the nitration of macresol. was
the starting point for this proceedure. Fifty-eight grams
of the compound were dissolved in 450 cc of glacial acetic
acid. The mixture was cooled to about 15° . 80? and a mix-
ture of 40 cc of bromine dissolved in 200 so of glacial ace-
tic acid was slowly added. After the addition was complete.
the whole was poured with stirring into 6 volumes of water.
and.the mixture set aside for some hours to allow the precic
pitate to subside. 4At the end of this time. the yellow brown
solid was filtered off. and dried on a clay plate. The crude
product was then crystallized several thmes in ethyl alcohol.
A yield of 56.9 grams of pure product was obtained. melting
at 134°.

It was decided that this proceedure was much.more effi-
cient than the method suggested by Raiford.

The hydrochloride of 2. 6 dibromo. 4 amino mucresol was
next prepared by the following proceedure ~ Fifty grams of
the panitro compound was dissolved in 200 cc of hot alcohol.
and to this solution was added 130 grams of stannous chlor-
ide dissolved in 130 cc of concentrated hydrochloric acid.
during the addition. the flask was shaken and the mixture
kept hot in order to prevent the immediate separation of
crystals. Next one volume of concentrated hydrochloric acid
was added and the solution set aside to cool. Crystals of

the amino hydrochloride soon separated out. These were

54

filtered off and recrystallized as follows: The crude mater-
ial was dissolved in warm.water and the solution filtered
through paper. after which one volume of concentrated hydro-
chloric acid was added to the filtrate. Upon standing. eo-
lorless needles were separated. When heated above 225’ the
substance blackened but did not melt. (Raiford. Ame Chem.
Journal. 46. 426: 1911)

The free amino was easily prepared from the hydrochlor-
ide by treatment of an aqueous solution of the latter with
ammonium carbonate. The precipitated base. after being fil-
tered off. washed well with water and dried on a clay plate
melted at 175° . 176° with blackening. It is readily soluble
in alcohols. benzene. chloroform.and a solution of sodium
hydroxide. less soluble in ligroin and practically insoluble
in colorless crystals melting at 176°. (Raiford. Am. Chem.
Journal. 46. 425; 1911)

For the replacement of 3H3 with hydrogen it was found
that the diazotization could be carried out Just as efficio
ently from the hydrochloride as from the free base. The ams
monium carbonate method of releasing the free amine was
found to give very small yields. and the Operation itself was
cumbersome.

The diasotisation was carried out according to a pro-
ceedure used by Bigelow. Johnson and Sandborn (Org. Synthe-
sis. Vol. 6. 16) for the preparation of mpbromo~toluene.

To a cold mixture of 48 cc of 95% ethyl alcohol and 12
cc of sulphuric acid in one liter round bottom flask.

35

provided with an efficient mechanical etirrer. was added 20

grams of the hydrochloride of 2. 6 dibromo. 4 amino mpcreeol.
The solution was otirred.and cooled to 10° and a solution of
9 grams of 0.3.P. sodium nitrite in 16 cc of water was added
from a eeparatory funnel. During this addition. the temper.
ature of the mixture was not allowed to rise above 10°. At.
tor all the nitrite solution had been added. the mixture was
stirred twenty minutes longer to complete the diaaotization.

To the diazotized solution vac added 3 grant of capper
(reduced copper powder) which.had.been washed with ether. The
stirrer was replaced by a long efficient. reflux condenser.
.A bath of ice water was prepared for cooling the flask when
the reaction became too vigorous. The flask was warned can-
tioualy until a vigouroua evolution of gas began. It was
then lmmereed in the ice water to prevent loss through the
condenoer by too rapid eraporation of nitrogen and acetaldeo
hydo. When the reaction had moderated. the flask was again
warmed. and finally the mixture was heated for ten minutes
on a steam bath. at the and of the reaction the color chang.
ad from reddish brown to yellow.

After the addition of 120 cc of water. the mixture was
steam distilled as long as any oil came over. The crude..
hoary yellow oil was washed with water. extracted with ether.
and after the evaporation of the other was distilled at 4 mm.
The bulk of the yellow oil (8.3 grams) came over at 114°.1ic°.
This boiling point corresponds with that of the fractional

 

 

56

assumed to be 2. 6 dibromo m-cresol. obtained in the prepar-
ation of the 2 bromo m-creeol by'eulfonation.

To further prove the p eitiuns of the bromine a portion
was brominated in carbon tetrachloride solution with one.mole
of bromine. The product after repeated crystallization from
ethyl alcohol had a melting point of 81°. which corresponds
to the melting point of 2-4-6 tribrouo mpcrecol.

Analysis for the 2, 6 dibromo m-crosol by the Parr bomb

emethod gave the following renultc:

wt. of cc .1 1 Calculated Found
.2057 15. 5 50.157: 60.52%

Since. in the preparation of 2 bromo unoreeol by eul-
phonation. a portion was coneietently eeparated which gave
evidence of being 2, 6 dibromo Inoreeol. an attempt
vac made to develop a proceedure which would give a fairly
good yield.of thie product. The following method was eventu-
ally decided upon.

' One mole (108 grams) of mpcreeol and one mole (98 grame)
of concentrated sulphuric acid in a two liter three necked
flack were heated on a water bath for three hours. At the
end of thie time the reaction.mixture was cooled and made al-
kaline by adding a solution of 160 grams HaOH in 373 cc of
water. (Thie must be done very slowly). The alkaline eolup

tion vac then cooled to room.temperatnre and brominated‘by

 

 

 

37

adding slowly two moles (320 grams). of bromine. still stir-
ring constantly. (During this Operation the temperature may
rise to £09 a 50°). Stirring was continued for about half
an hour after all the bromine was added.

the reaction mixture was then transferred to a three-
liter flask set for steam distillation. During the steam dis.
tillation the reaction mixture was heated on an oil bath to
about 180“. This removed the tribromo nbcrosol which appear.
ed as only a trace.

As soon as no more tribromo upereeol appeared in the dis-
tillate. the steam distillation was stopped and the reaction
mixture. still on the oil bath was evaporated to a thick
pasty mass. This was allowed to cool and then acidified with
about 800 cc of concentrated sulphuric acid. This had to be
done slowly on account of the rapid evolution of hydrogen
bromide.

The mixture was again steam distilled. this time frml
an oil bath heated to 200° a 210°. The sulphonic acid was
hydrolysed by this proceedure and the brominated cresols dis-
tilled over as a heavy. pale yellow oil.

After the distillation was complete. the brominatcd
cresols were extracted with ethyl other. the ether eraporated
and the residue distilled under 4 mm. pressure.

Following are the fractions from 80 cc of distillate

(one run):

 

l I . I- '. V . i. V .13 y I) . ‘1. Us.) . t. 11 y | I l 11‘" . ‘0 .hi . {t‘ll A e .‘ “M! t
A -‘e'.’ el.‘ 1411. In! It. s s . Ilr 1t . .. 0' w .4 . .. t mil}. 1‘! I t. III 0V. .‘n‘II .. I O1 .A\.‘l .d .l .ta'lltltel 'IA . e
. . O 4 ‘ . ‘..“ ‘

   

T . . .
- {'59. yti. It -Wéi.
. .‘

It‘ll. Ixo.

 

 

38

100 9 110° - o c a - a o 16.3 grams

110 o 120°(moetly 114-1150) 45.8 grams

120 . 150° . - . a . . . 4.3 grams

130 O 145° 0 9 a a a a c 16.9 grams
The last portion crystallized and on purification from ethyl
alcohol was found to be tribromo~mpcresol (2. 4. 6).

Analysis of the 110 e 120° fraction which on distillac

tion with an eight inch column (4 m.) boiled at 114 . 115°
gave the following Parr bomb analysis:

Wt. of cc .1 3 Calculated Found
haMple ‘Agfloa Br. in C7haaBr2
.2145 16.07 60.15% 53.95;

A.portion or 2. e dibrono sporesol chlorinated in car.
bon tetrachloride with one mole of chlorine. gave a crystal-
line compound which. when recrystallised repeatedly from
alcohol had a melting point of 70.5°. (Walther and Zipper
J. pr (2) 91. 378).

To recheck this 4 chloro. 2. 6 dibromo mooresol. a.por-
tion of 4 chloro.mncresol (m. p. 55°) obtained from.H. Chen
of this laboratory. was brominated in carbon tetrachloride
with two moles of bromine. Identical crystals of the same
melting point were obtained.

The benzoyl. benzene-sulfonyl and toluenesulfonyl esters
of 2. 6 dibromo macresol were prepared. Following are the
melting points and results of analysis by the Parr bomb
method:

 

'T-hgvm

 

 

 

39

Esters of 2,6 dibromo mpcresol

m.p. Wt. of cc .1 H Calcul. Found
Sample Ag 303 for Br

Bensoyl 91° .2354 12.7? 43.24% 43.40%

Fine white needles from alcohol

Benzene sulfonyl 96° .1633 8.07 39.41% 39.521
Small white plates from alcohol
Toluenesulfonyl 122° .2190 10.45 38.00% 38.09%

Fine white needles from alcohol

Several attempts to nitrate the 2. 6 dibromo mporesol
yielded rather peculiar results. When four moles of nitric
acid were used in glacial acetic acid. a compound of fine
yellow crystals was separated. An analysis for bromine sug-
gested that two bromine atoms were present and one nitro

group. It melted at 78 . 78.09.

Wt. of cc .1 3 Calculated Found
Sample AgNO; Br in 07H503HBr
.2189 13.0 51.47% 50.79%

The only nitroobromo nocresol reported in literature
with this melting point is 2. 6 dinitro 4 bromo anoresol.

The writer will make no attempt to explain these peculiar
results.

Since the benzoyl. benzene sulfonyl, and toluenesulfonyl
esters of 2. 4 dibromo m-creeol and 2, 4, 6 tribromo m-cresol
had not yet been prepared. these esters were prepared by the
usual method. Following is a table of melting points and re.
sults of Parr bomb analyses:

 

 

 

Esters or 2. 4 dibromo Incresol

m.p. Wt. of cc .1 H Calcul.

Sample names for Br

Benzoyl 81° .1806 9.75 43.24%
Fine white needles from alcohol

Bensene sulfonyl 92° .2445 12.o7 39.41%
Small white plates from alcohol

Ioluenesulfonyl 89§°' .2269 10.8 38.00%
Small white plates from alcohol

Esters of 2. 4. e tribremo unoresol

n.p. Wt. of cc .1 n Calcul.
Sample . A8303 :0! Br

Bensoyl 85° .2093 13.77 53.45%
Small white needles from alcohol
Bensene sulfonyl 117° .2996 18.42 49.28%

Small white plates from alcohol
Toluene sulfonyl 115' .2225 15.4 48.09%

40

Found

43.18%

< 39.49%

38.13%

Found

53.59%

49.20%

43.17%

 

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41
THE. BACTERICIDAL PROPERTIES OF DERIVATIVES
0F li-CRESOL

In the preparation of the bromo derivatives of mncrosol.
a number of nitro. amino and sulphonic acid deriVatiwes were
also prepared. It was felt that if the phenol coefficients
were determined for each of these. some interesting conclu-
sions might be drawn as to the relationship between bacteri-
cidal properties and chemical constitution.

The method used for these determinations is known as
the P. D. A. method.

Organism - A twenty-four hours old broth culture of
Staphylococcus pyogenes aureus.

Temperature - 37°.

Proportion of culture to Disinfectant - Five-tenths cc
of the broth culture was used. added to 0 cc of the disinfec-
tant solution.

Incubation . The subcultures were incubated forty-eight
hours at 37° 0 and the results tabulated.

Determination of the coefficient . Subcultures were made
every five minutes up to and including fifteen mdnutes. To
determine the coefficient. the figure representing the degree
of the weakest strength of the disinfectant that killed in
the ten mdnutes was divided by the figure representing the
degree of dilution of the weakest strength of the phenol con-
trol that killed within the same time.

 

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Following are the results: .
Phenol
Compound Coefficient
l. 3 methyl 4 bromo phenol 9
2. 3 methyl 6 bromo phenol 6
3. 3 methyl 2 bromo phenol 5
4. 3 methyl 2 nitro phenol 4.5
5. 3 methyl 4 nitro phenol 3.0
6. 3 methyl 6 nitro phenol 4.3
7. 3 methyl 2 amino phenol 6.0
8. 3 methyl 6 amino phenol 5.3
9. 3 methyl 6 amino (hydrochloride) phenol 3.8
10. 3 methyl 4‘E3 sulphonate phenol . less than 2.0
ll. 3 methyl 4 Ha sulphonate 2. d dibrome
phenol . less than 2.0

12. 3 methyl 2-4 dibromo phenol 16.0
13. ~3 methyl 2-6 dibromo phenol 19.0
14. 3 methyl 2-4-6 tribromo phenol .23.0
15. 3 methyl 4 nitro. 2, 6 dibromo phenol 7.5
16. 3 methyl 4 amino. 2, 6 dibromo phenol 5.0
17. 3 methyl 4 amino (Hal) 2. 6 dibromo phenol 6.5
Conclusionete

l. The halogenated cresols increase in bactericidal

efficiency with the increase in number of halogen atoms
added to the ring.

42

 

#9922 '-

 

45

2. Amino. nitro. and 802033 groups added to the ring
retard vary greatly the efficiency of a brominated.m~cresol.

3. Bitro. amino. and monobromo groups substituted into
any one of the isommric 2. 4, 6 positions approximately double
the phenol coefficient of mmcresol: additional bromine sub-
stitution does not increase the phenol coefficient except
in the case of dibromo and tribromo m-cresols.

The fact that the sodium sulphonates of m-cresol and
their bromine derivatives show a phenol coefficient of less
than mOoresol itself can be explained in part to the fact
that sulphonates though quite easily prepared, crystallise
with one (1) to three (3) moles of water.

 

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44
SUMXKWY

The results of this work on the bromo macresols may be
summarised in the following way.
6 bromo:m»cresol has been prepared by the following
methods:
1. Diasotisation of 6 amino m—cresol
2. Bromination of the disulphonic acids in alkaline
solution and subsequent hydrolysis.
3. Bramination of the disulphonic acid in the
presence of fuming sulphuric acid and subsequent hydrolysis.

2 bromo.m-creeol has been prepared by the following
methods:
1. Diazotisation of 2 amino mpcresol.
2. Bromination of the disulphonic acid in alkaline
solution and subsequent hydrolysis.
3. Bromination of the disulphonic acid in the pre-
sence of fuming sulphuric acid and subsequent hydrolysis.

2, d dibromo macresol has been prepared by the following
methods:
1. Diazotisation of 2. e dibromo 4 amino n-oresol
2. Bromination of the paransulphonic acid and sub-
sequent hydrolysis.

 

 

 

 

 

 

45

The benzoyl. benzene sulfonyl and toluenesulfonyl esters
of these compound have been prepared.
The phenol coefficients of all intermediates produced

in this problem have been determined.

 

 

 

SOME BRono DERIVATIVES or m-CRESOL.II.

. NJ. Pcttrson.
so ' 0 ”o: 0
I 4*.— _m._ _ ML. "°‘ mug-2w "h ":3. “1"”
n It s cm cu;
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cm C“! a“ s C": '1
m 9 9e' Imp“. Ion ton m

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37" cu. m CH: CH: " b' n. C“:
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er nz-ue mp sn‘ sot-er m . ' m p t
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O 00" o" 0’ ‘3
Ur .0 o, g, Br Br
CH3 CH3 rm cm tn.
mp. Ill. MP 85‘ mp 659 60' m p '1!" m p R"

 

 

 

 

 

 

 

 

 

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