sum: ammo DERIVATIVES or
OBTHO AND PARA BENZYLPHENOLS

THESIS FOR THE DEGREE OF M, S.
' Arthur House Neelcy .
‘ 1933 ‘ ‘

 

 

 

SOME BROKE) DERIVAT IVES

Of

ORTHO AND PARA BENZYLPIENOIS

some memo nmwflms 0F 0mm

LED PARA BMZYLPEEHOIS

By

Arthur Home Halo:

The-is

Submitted to the faculty of Inchigan
Stat. College of Agriculture and Ap-
plied Science as partial fulfillment
oftherequiremzrtstcrthadegroaot
meter of 861m.

m 19 35

AGIIO'LEDGIEI?

The writer viehee to express his eincere
appreciatim to m. n. C. Huston for the
counsel and assistance given him in the

completion or this work.

331.655

GOI!EI!3

Historical Data.

Definit ion of whim

Minute]. Date.

I
II

III

Preliminary Work.

Preparation of W S'bromodiml-
We

Roofefstrmmeefzmmsibrom-
uphenylmthm.

Preparation of 4 hydra]: S'bromodiphenyl-
”We

Proof of Stream. of 4 ham-m S'brmno-
uphemlnethm.

Saleem-y
Scheme of Wt ion

10
11

17

26

HISTORICAL DATA.

Historical Data

Bomlphenol was first synthesised by E. Paterno (Gaza. chin. ital...
2, 1-6; 1872) by gently heating a mixture of bensylchloride and phenol in
the presence or sine dust. Silky white needles (m.p. 84°C.) were isolated
which were soluble in ethylether, alcohol. benzene or chloroform. The: were
also soluble in alkaline solutions but reprecipitated upon acidification.
When the substance was treated with nitric acid, substitution products were
formed. With sulphuric acid. it produced a sulphonic acid, the barium salt
of which was soluble in water. It was also found that when bensylated sni-
sole was treated with mermaid acid and boiled for eight hours at 170° the
above mentioned bennyphenol and metlvliodide were obtained.

we you-s later further derivatives or benzyphenol were prepued by
Peterno and Jileti. (Gaze. chin. ital” 3, 121, 251; 1874). These were
bensyphenol acetate, prepared from acetylchloride in the cold; bensylphenyl-
bmoate. from bensoylchloride; and e. "dibromo" derivative which was later
qmstioned by some investigators. (Zincloe and Walter. Ann" 354, 367; 1904)
The bemlphenylbemzoate crystallized from alcohol in glistening needles which
melted at 86°C.

In 1875, Paterno and Fileti (Gaza. chm. mm. 5. 381) published an
article in which they described the condensation of phenol and bensylalcohol.
using a mixture of acetic and sulphuric acids as a dehydrating agent. A was
of crystal was obtained which proved to be bensylated phenol and a fluorescent
oil which appeared to be an isomeric bensylphenol.

Perkin and Hodgkinson (J. chem. soc.. 1880, 724; 1880) obtained a fluore-
scent liquid 03.1). 310-5200) by heating a mixture of pherwlacetate and bensyl-

chloride. By analysis it was shown to have the formula 02532403. This was
readily saponified with alcoholic K03 yielding an oil which rose to the surface.

This oil, upon mrther purification, gave crystals (mp. 39°) which analysis

showed to have the formula 01011100. Upon acidification and purification of the

.2- . .
mining almine solution acrystalline compound was obtained (mp. 80-31%
which had the female 0158120. This ounpound was thougput to be the smite one
that was prepared by Patel-no using bensylchloride and phenol with zinc dust,
the difference in melting point being due to impurities.

(Using molten M12 as d dehydrating agent. Liebmenn (Bern is. 152; 1882)
(Bun. 14. 13¢; 1881) succeeded in condensing phenol and bensylalcohol. They
obtained a crystalline product which melted at 3490.

In 1882, Bonnie (J. chem. Soc.. 55, 220) was able to show that the com-
pound melting at 84° was the parabensylphsnol and the oil obtained by Patel-no
and Fileti was the orthobensylphenol.

Bakunin (Gaza. chin. ital" 33, 495; 1903) prepared bensyl derivatives
of alpha and beta napthol using sinc as a catalyst.

J. V._Brlmn Born 43, 1350; 1910) prepared bensylmethylether, bullyi-
ethylether, owlylethylether and benzylallylether by boiling the correspond- .
ing aromatic bromine derivatives (as bensylbromide) with the respective alco-
hols in the presence of sulphuric acid.

Johnson and Hedges (J. Am. Chem. 300.. 35, 1014; 1913) prepared substitu-
ted phenols and others by reducing mined lostones containing hydroxyl or other
radicals in the benzene nucleons, by means of sins amalgam and hydrochloric
acid. A great many alkyl derivatives were obtained, among which are methylether
of 4 ethylmeml by reduction of p-acetylanisole , ethylhydroquinone by reduction
of ettwlquinone and etmdresorcinol by reduction of acetylresorcinol.

In an article published in 1904, Zinche and Walter (Ann.. 334, 867-385)
describe their work on bromine substitution in phenols. Using the same method
as B. Paternc had used, they condensed bensylchloride and phenol, obtaining a
product of silly white needles which melted at 84°C. When this compound was
heated by the gradual addition of the calculated amount of bromine in the cold
in chloroform. two products were obtained; one formed colorless needles and

melted at 44", while the other consisted of rhombic crystals union melted at 57°.

-3-
{he toner crystals were mist-able and changed readily into the letter at room
tenperstnre. They attributed the following formula to this empound:

“ C?
c-

As was noted above, this compound did not compare in properties with the di-
brono compound obtained by Paternal.

By agitating the parabensylphenol with a calculated excess of bromine,
Zincke end Welter were else able to prepare s tribrono derivative. It wee s
solid crystalline substance which formed needles melting at 88°C. It was
assigned the following towels:

' R Br
80;; Q.”

In 1876, the condensation of my]. alcohol and various hydrocarbons wee
sccomplished by Priedel and Crafts by means or snimirons slunimn chloride
(amt. rend., 84, 1392). They worm only with aliphatic compomds end were
of the opinion that aromatic substances would not condense by this means. They

explained the reaction according to the following mechanism.

c1
(1) 06353 + A1613 ——_., Hcl + A1101
‘0635

(2) 05115111153 + an E) A1013 + 3-0535

' Gnstuson (Born 15, 157; 1880) and Bnttgenhsoh (J. Pub. Chem. 150.
355; 1923) supported the view of the fomtion of en insteble aluminum-organic
compound es en intermediate product which subsequently brooks down, regenerat-
ing the .11313.

<The preparation.of anslins and p—toluidine'by'Jeubert (Conpt. rend., 152,
8413 1901) from the action of Karim-EC]. with the hydrocarbon in the presence

of £1013, indicates a dehydration reaction.

.1...
me addition product or e-chloronhenol and aluminum chloride was iso-
lated by Perried' (count. read... 122. 195; 1896). It was a whitecryetelline
powder, eelting at 207410° end was given the formula, agentocmclm.
it so. memorm andbensyl alcoholwes carriedout bymton
and Friedman (J. Am. M. 500., 38, 2527; 1916) by the use of A1013 as a

catalyst. They obtained diphewlnethane. some Hensylbensene and anthraeene
as hybprednets. In this reaction the 11:31; appeared to act as a dehydrating
sgut. When the reaction was curled out at a low temperature and a large or-
osss arm-um. tmmldoruwmssshighsndmyisld
of enthracene wee meh lower.

later in 1913, the sale investigetas published an ascent of the culin-
estion of beam with mioue umndnry alcohols (J. Am. Chem. Soc.. so. 7883
1’18). rheyrsud that the reactionpreoeeded methlyandwith good yield in
the ease of diphewloarbinol while in the cases at ethylphsnylcerbinel and
uttwlphenyloarbinol the yields were less, the retarding effect of the cum
group being greater then that e: the new am.

the sechsnise for the reaction was gin as follows:

- H H I
Cans-3503 ‘9' 06"! H M 06H5-g-6685 + H20

5

Bbeingaphenyl,“ ornethylmo

Huston (ed... as. 206; less) oudensod bensyl alcohol and punol in the
presence of A1513 end obtained p-bensylpimol. Later he studied the action of
phone]. with owl alcohol. Whylsthsr. phenylethylether and bowl--
ehloride. (J. M. Chen. Secs. 46, 2775; 1924). With busy]. alcohol he obtained
a sex yield of p-bensylphenol; with phenylmthylether a 45% yield of p-bensyl-
phenylnethylether and a 67% yield. of p—bensylphenylethylether was obtemd. The
results , together with the fact that a 36% yield of p—bensylphenol was obtained
with Mulchhride. bars the possibility that the busy]. alcohol is first eon-

werted into bensylchloride.

-5...

In 1925. 1.. claim (a. blew. Chem, 36, 478) publiehed an accent
“the “ablatimefphe-le. Befound thatihenthe sodillder-
ivative Of MiGMOlI .e heated. with an aim halide in a .m-
dieeeeiating“ .dim such as toluene, carbon alkylaticn took place mainly
iethe peeitienesthotothehydrewlmp. whena'diuociating“ eediu
euchasnthflaleeholerethnaieeholeaemdthealmuienteekplace
eetheeugea, toreingthe Wheethu.

The reactin- as represented by claieen are as £0110!”

Ofla‘ ocaza
th
(1) [::] + acnzcl ("9 yl ale; [:\] + Na01.
//

 

 

ONE. - __
(toluene) \-OCH R . .
(2) r] 4' 3011201 ——[: <__/ 2 A
\ _T
Gaga
H
Gaza ,9 caza
...._..__., t
\

benched-etude metieueaebaeedbyclaieen onmdlaeis theory
(J. pr., 57. ass; 46,189) for the reaction bet-eon silver cyanide and
eethyl iodide:

,c—Ag + 01131 --9 Gigs —--) lion 1- Ag!
3
'mree possibilities fer thie reaction are sit. by I. m Amara.
Wagoner and Behr (Chan. amtr. 1, 2347; 1925)
(a) The initial tuition of addition products eith subsequent emitting.
(1:) he initial («satin of mi oxygen derivativee with subsequnt
W into the o-derivative.

(c)3eyeratieneteeta1aeeetauichelidefemingtreeeno1mheto

radicals m with the sligt reactivity of the aliql gross. partial or
.mp1». roan-wt at th. soul to tote radical, and finally union a:
tin radio-1s. me first hypothesis. temlated by 01.1... is the one
that is eeet generally accepted.

Olaisea listed the factors ditch effect the reaction as tellers;

l. Ehe Underwood: Theocndensationei‘cemplexphsnolssas
ou-ried out with greater difficulty the: the sore simple once.

I. The kind of radical attached to halogen; unsaturated, saturated.
aliphatic or aromatic. It sae fond that saturated aim halides promoted
the formation of e-derivat ives, while maturated alkyl halides promised
the formation of o-derisat ins.

s. m mm of halos-s.

a.'l'he kinder-eta inthe-etalphenolate.

a. file temperature.

e. no reactial nadir.

The W at Mlbemylether to give beneylated phenol has
been studied by J. You Alpha (Ree. tree. chin" Vol. i6. 7993 19:1).
wmmm eas mm with also chloride to 160' as one a... yield-
ing a hydron'diphenyl'tham (mp. 84') and a dyestutf.

Closely related to the investigation to be outline in this thesis is
the sort done in this laboratory by D'Arcy (water's Thesis. 1m) and
rayereeather (Eater's i'heeie, 1981).

D'Arcy carried out the condensation of Hronbensylohloride and
"I byboththeilcls Isthodandthe claim-ethod. Bythe form
sethod he mepared and identified a hydra: a'broucdiphenylnethane and by
the latter 2 hadron a'broeodiphewllethsne. He failed to isolate any
2 hydrosy a'bronodiphmllethene is. the products of the 11015 condensation.
He also found, as had Wield (master's Thesis. 1929), that broninatioa
took place only in the unoccupied ertho and para positions of the phenolic ring.

.7...

Fayomather prepared and identified “hydroxy z'bromodiphemrlmthane
and z hydrouy z'bronodiphenylncthane by the A1013 md Olaisen methods
respectively. He was able to isolate 2 hydroxy 2'bromodipherulnethane
from the A1013 condensation products and also found that bromination
took place only in the unoccupied ortho and para positions of the phenolic

ring.

MBWAL DATA

the Problem Defined

z hydroay svbrmaiphmlmthae and

a hydreny S'bronodiphexwmthsm are

to be prepared by the Claim and

A1015 methods respectively. The
structures are to be determined by

the comparison of physical constants

of products obtained by the diroct
bromination of these cosmounds with

2 hydra: 3.5.5'tribromcdiphenylmethsm

and 4 hydrozy 5,5,3'tribromodiphcnylmethane.

- -10-
Experimental Data

1 - Preliminary Work.

I-brcnotolnene was prepared according to the method described m
pages 106 and 128. veins 1. of Organic anthems - Gilmau. I-brono-
bensyl chloride was prepared by a modification of the method of Jacobs
and Heidelberger (J. Biol. Chan” 20, 659; 1915) as follows; A weighed
amount of l-bronotoluene was placed in a round bottomed three neck flask.
fitted with a reflux condenser and a tube for the introduction of chlorine.
After having been washed in concentrated sulphuric acid. chlorine was
passed slowly throng: the tube mid allowed to bubble through the liquid.

i neall piece of phosphorous pentochloride was added as a catalyst. the
flask was '01le at intervals to determine the weight of chlorine added
and to insure under-chlorination. than about 75% of the theoretical

amount of chlorine had reacted. the contents of the flask were subJeoted

to fractional distillation. rho unchlorinated e-branotoluene was recovered
in the fraction caning ever frele vo-n‘c/ls a.e.. wail. the I-bromobensyl
chloride was found to distill at lls-lzs°c/ls saw. me intermediate fraction
which contained a nixture of the chlorinated and unchlorinatod product was
returned to the flask with fresh n-bromotoluono for further chlorination.
fires hundred c.c. of s-brcluotolmne was found to be a convenient quantity
for chlorination in a 600 c.c. flask.

The 2-6 dibromophonol was wowed by the following method. adopted
truthenothodofml‘auahandx. Entani (0. Anal, 2256) forthepre-
paration of 8-6 dichloronhenols 1.3 noise of phenol was treated with 220
gram of concentrated sulphuric acid in a 3 neck three liter flask equipped
with a unchanical stirrer and drOpping tunnel for addition of bromine. Il'he
mixture was heated m- three hours. with stirring to insure complete sulphur-
ation and ends album with 503% sodim hydroxide. 500 c.c. of water was

-11.. _,

added to the resulting crystalline mess and the mixture cooled. A
calculated munt of bromine was then added throw}; the funnel with stir-
ring. A light yellow mass was obtained which we divided into ten portions
each of Ihlch ms subjected to steam distillation to remove the tribrom-
phenol. After it had stopped coming over. 500 c.c. of concentrated sulphuric
acid no added and the steam distillation continued. During the last stem
distillation the flask no heated to ZOO-210°C in an oil bath. in oily sub-
stance with a strong odor of 502 case over first, followed by the crystals
of 2—6 dibromophenol.

II - Preparation of 2 hydroxy S'bromodiphenylnothene by the Claisen con-

demotion:
on _______82‘
H (An) Br (1‘. 1 '
‘+ 01332 ° “9" ,+ Nac1

One-half nol of freshly chipped sodium was suspended in 200—250 c.c.
of toluene in a three neck one liter round bottomed flask, equipmd with a
reflux condenser and on efficient mercury sealed stirrer. The contents of
the flask nae heated until the toluene reached its boiling point at which
time the melted sodium rose to the swim. or the liquid, and stirred
vigorously until all the sodium res finely divided. During the first con-
densation the suspension was allowed to cool before the addition or one-
half reel of phenol in small quantities, but the reaction between the sodiun
and phenol one often retarded so that in later condensations it see found
desirable to very cautiously add the phenol dissolved in chloroform to the

hot suspension in mall quantities, making sure that no open flames were

-12..
present in.the vicinity of the apparatus. A.vigorous reaction occurred
between.the sodium.and phenol 1n.the hot solution.with en.sctive evolup
tion.of hydrogen Which resulted in.the formation of s white mass of sodium
phonolste. After the addition of the entire quantity of phenol the reaction
mixture was heated with stirring, on.an.oil.bath at 100°C for several hours
to insure complete reaction and dlowed to cool. One-half no]. or m—‘nromo-
bonzyl chloride was slowly and cautiously added through the reflux condenser
to the cool mixture and the contents of the flask were slowly heated on the
oil beth.until a temperature or 150-155°c was reached. The heating was cone
tinned at this temperature with stirring over a period of six to eight hours.

After cooling the mixture no seabed twice with water to m the
real and distilled under atmospheric pressure to 126°C to razors water and
toluene. The resulting oil was treated with 300 0.0. or Cloison's reagent
(350 grams of m dissolved in 400 c.c. or water and mode up to one liter
with methyl alcohol) to form the potassium salt or the phenol derivative
which is insoluble in petroleum ether. 'r'he mixture was then extracted with
three separate 100 c.c. portions of petrolem other to remove my 3 brom-
benzylphenyl other formed. 200 guns of ice were added to the residue which
was neutralized with concentrated.hydrochloric acid. After cooling the
phenol derivative was removed.by'extrsction‘with three 100 c.c. portions of
diothylethor.

the diethylether and water were removed.by'distilling the mixture to
125°C at atmospheric pressure and the resulting mixture subjected to distil-
lation invacuo to purify-the phenol derivative.

The some procedure was followed.for the potroleum.ethe” 'iorects. The
distillations were carried out under a pressure of 3 m.m., the product showing

no signs of decomposition.

-. p13.-_.. .__ ._

at”

Four condensations were made according to the above procedure which

resulted in the formation or very small yields (about 4%) of 2 hydroxy

S'hromodiphenylmthane. The results are as follows;
First Condensation:

Ethyl ether extract.

13 grams phenol
7 grams 2 hydroxy S'bromodiphenylmethane
15 game tar

Petroleum ether extract
15 grams m-bromobenzyl. chloride
12 grams 5 bromobensylphemrlether

1‘30 tar

Second Condensation;

Ethyl ether extract

10 arms phenol
5 grams 2 hydroxy S'bromodiphenylmethane
7 grams tar

Petrolem ether extract
30 grams m—brmobmzyl chloride
14 .5 grams 3 brombmylphenylether

Vgrems tar

Third Condenset ion:

Ethyl ether extract

8 grams phenol
7.3 grams 2 hydroxy S'bromodip‘nemimetlwe
2 grams tar

below 70°o/s mm.
150-180°c/s mm.

above 180°c/3 nan.

95-105°c/e m.
14o-150°c/5 mm.

below 7000/3 mm.
zoo-180°c/o mm.
above 180°G/3 oom-

95-105°c/3 mm.
loo-150°c/s nan.
above 180°0/3 ads.

below 70°0/3 ml.
150—18000/3 3.1.

above 180°C/3 nan.

-14...

Petroleum ether extract

27.5 grass m—bromobensyl chloride 95-10506/3 lads.
15.2 grams 3 bromohenzylpherylether 140-15000/3 In...
10 grams tar above 180°C]: m.

Fourth Condensation:
Ethyl ether extract
5 grams phenol m below 170°C/3 M.
5 grams 2 lumber: 3'bromodiphenylmethane ISO-180°C/5 M.
2 grams tar above 180°c/3 mm.

Petroleum ether extract

18 grams n—bromo‘oensyl chloride 95-105°C/3 Ian.
20 grams 3 brombmsylphonylether 140-150°G/3 mm.
10 game tar above 180°0/3 Ion-

The four 150-43000 fractions of 2 hydrm S'bromodiphenylmthme were
combined and re-distilled twice at 3 man. presets-e and during the second
distillation came over quite constantly at a temperatm'e oi’ luv-169°C. A
total yield of 23 grams of the purified product was obtained for the four
runs making a 5.73.! average based on the phenol used. It remained a liquid
at room temperature.

Upon re-dist illation the 3 bromobenzylphemrlether cane over at a
constant temperature of 145°C at 3 mm. pressure, the average yield being
11.95 based on the phenol. It crystallized upon standing and was found to
have a constant melt for; point of tic-67°C after several rte-crystallisation.
It formed flakcy white leaflets in alcohol. In order to determine daether
or not any equilibrium exists in the formation of the 2 hydroq S'bromo-
diplzemrhmtizane and the 3 bromobenzylphcnylcthcr, four runs were made in
the mariner described above with the exception that in three cases, 5 brom-

benzylphenylether was added to the reaction mixture. The results obtained

are as follows;

-15..
Fifth Condensation - (15 greens 3 hromobenzylphewletl-xer cabled)
Ethyl ether extract
5.5 grams phenol below 70°C/5 mm.
16 grams 2 hydroxy S'bro;nodiplxona'm'thrme 150-18000/5 mm.
Petr-clam ether extract

20 grams m-bromobemyl chloride 95.1os°o/3 mm.
11 1- 15 grams 3 bromobenzylphenylether 140-150°c/ 3 none

Sixth Condensation -- (15 grams 3 brombenzylphenylether added)

Ethyl ether extract

4 grams phenol below 70°C/3 non.

15 grams 2 hydroxw S'bromodiphenylme’chane 150-1800c/3 nan.
Petroleum ether extract

25 grams m—bromobenwl chloride 95-105°C/5 n...

16 + 15 grm 5 hr cmobmylphenyleflwr 140-150°c/3 nan.

Seventh Condensation - (25 me 3 brombenzy’iphenylether added)
run ether extract
4. grams phenol below 70°C/5 mm.
12 grams 2 hydroxy S'bromodiphenylmethane loo-180°C/3 mm.
Petrolem ether extract
25 grams n-bromobenayl chloride 95-105°c/5 u.
25 4- 5 grams 5 brombenzylphenylether 140-150°o/3 nan.

Eighth Condensation - (KO 3 bromobenzylphenylether added)
Ethyl ether extract
5 grams phenol below 70°0/5 Ian.
8 grams 2 may S'bromodiphenylmethane 150-180°C/3 mm.
Petroleum ether extract
50 grams m—bromobenzyl chloride 05-10500/3 1.3.

15 grams 5 brombemymnemriether 14o-150°o/3 nan.

A

-"u- .. A -

‘

It will be noted that in the first two runs (5th and .6th conden-
sations) the addition of 15 grams of 3 bmmbenzylphem'lether resulted
in the formation of approximtely three times greater yield of 2 hydroxy
S’bromdiphenylmefixsne than the average for the first four condensations
shore no 5 bromobenzylphenylether was added.

In the 7th condensation. 25 grams of S bromobmsylphenylether was
added and contrary to expectations only 11 grams of 2 hydroiy 5'bromo-
diphenylnethane we obtained although this yield was considerably greater
than those obtained in the first four condensations and the 8th condensa-
tion more none of the ether was added.

It is appm-ent from the above data that the addition of 3 bromobenzyl-
phenyi ether to the reaction mixture substantially increased the amount of
2 hadron S'bromodiphenylmethane formed. These facts seem to indicate that
there is some sort of an equilibrium established between the substituted
phenol and the corresponding other formed as a result of the reaction.

A condensation of phenol and 5 branobensyl chloride see run in methyl
alcohol as an additional means of checking on the ether formed in the
previous condensations shieh sore carried out in toluene, one-eighth ml
quantities being used. A calculated mount of freshly chipped sodium was
carefully added in small anomts to 200 c.c. of methyl alcohol in the same
apparatus used for the Claisen condensations described above. To this the
phenol was added, relieved by a careful addition of the m—bromobensyl
chloride. The mixture was heated for eight hours to a temperature of 100-
110°C. is no carbon-aliqlated compound was formed in a dissociating medium
such as methyl alcohol it ms unnecessary to treat with Claisen's alcoholic
potash. The mixture us heated on a steam bath to evaporate the alcohol,
treated vith water to dissolve the Heel formed and extracted with three
50 c.c. portions or ethylether. After evaporation or the other the result-

ing oil was subjected to distillation. 18 game (55.0%) of 3 bromobensyl-

“‘ ‘ ' " ” ' was obtained in the fraction coming carer at 140-150" (2/: mm-

After several re-crystallizations it melted at a constant temperature

of 36-57% as had that obtained in the toluene condensations.

III - Proof of Structm'e of 2 hgr‘rczq S'bronmliphong‘l;:ethanc.

As a mans of proving: the structure of 2 referee-J S'bromodiphenyl-
methane, another Claisen condensation of 5 'bromobenzyl chloride and
2,4 dibronophenol was carried out in the some manner as outlined for the
first four condensations described above. The reaction was considered

to place as follows:

on
3’9 + 6163208:- —-——-. 36063343 and B OHCszr
Q.
One-fourth mol quantities were used and the following yield was obtained;
9th Condensation:
Ethyl ether extract
15.5 grade 2.4 dibromOphenel loo-105°c/3 man.
12 grams 2 hydrm 5,5,5'tribromodiphenylswthane 195—20500/5 3.3.
7.33. grams tar above zos°c/s m.m.
Petroleum ether extract
20 grams m-bromobenzyl chloride 95-105°c/s sum.
10 grams 3 bromobmyl, 2,4 dibromoPhenylether 130-200°o/s man.

8 grams tar above 200°C/5 nan.

me 2 hydron 3,5,3'tribromodipheny1methane imediately crystallised
and after several are-crystallisation from petroleum ether was obtained
as fine 'hite needles which melted at a constant temperature of 76-77%.
The 3 bromobenszrl 2,4 dimephemrlether isolated from this condensation
was re-cryetallised several times from alcohol, forming fine white needles

which melted at 49-50%.

~18-

L condensation in methyl alcohol siniliar to the one described above
for 3 bra-obennylphemylether was nude using 1/20 11:01 quantities of 2,4
dibronophenol and benzyl chloride.

A yield of 12.5 grams of 8 bromobensyl 2,4 dibromophenvlether was
obtained which also melted at 49-50% when re-crystallised from alcohol.
None of the corresponding 2 hydroxy 3,5,8'tribromodiphenylmethsne was
isolated.

As the next stop in the identification of the 2 hydroxy S'bromo-
diphenylnethene, five grams of the product was dissolved in 20 c.c. of
chloroform, contained in an erlemeyer flask and placed in an ice salt
water bath. A ten per cent excess of the calculated mount of bromine
was dissolved in chloroform which was allowed to drop slowly into the
solution of the phenol derivative from a funnel. no contents of the
ahmyer flask was subjected to continual agitation during the bromin-
ation uhile the flask Ins kept partially submerged in the ice salt water
bath. After all the bromine had been added. the flask was allowed to re-
main in the bath for one hour or we to insure complete reaction. A
rigorous evolution of hydroch acid took place througlout the ant ire
bromination. The reaction mixture was then poured into a beaker and the
chloroform evaporated off on a steam bath. The resulting oil imediately
crystallised upon cooling.

Since Eaxfield, D'Arcy, and Fayerveather had been unable to introduce
bromine into adv position other than tlm unoccupied ortho and para positions

I of the phenolic ring the reaction see considered to take place as rollers:

H “—8)- 08 5!"
CH < \ Br/ “‘\ CH

The crystals thus secured were pressed between filter papers to
We impmities and rec-crystallised from petroleum ether. Difficulty
m mentored in the purification of the compound. After repeated re-
crystallization a melting point. 4 degrees lower than that found for
a hydroxy 3,5,5'tribromodiphcnylmethane Ias procured. Accordingly, 10
grams of the product were brominated and after fifteen subsequent re-
crystallizations from petroleum ether fine white needles similiar to
those prepared in the Claisen condensation were obtained mich melted at
73—75°C. This difference in melting point one explained by assassins the
presence of a srnall quantity of 4 hydroxy S'bromodiphenylmethane in the
2 ludron S'bromodiphenylmemane which could not be renoved by fractional
distillation as the two mounds have practically the same boiling point.
To hn'ther wove the 2 hydroxy 5,5,3'tribromodiphenylmethane obtained
in the Claisen condensation of 2,4 dibromophenol and n—bronobensyl chloride .
to the some compound as the moduct isolated from the direct bromimtion of
2 hydroxy S'bromodiphenylmethane, the bensoyl derivative of each compound
was prepared by the method of Einhorn and Holland (in 501. 95; 1896)
(Method of Organic Chad Porter, Stevart. an]. Branch; 9% 181-182) as
follows: 2 grams of the substance was dissolved in 5 grams of dry pyridine
and a 10% excess of the calculated amount of bensoyl chloride added. After
standing over night an equal volume of water no sloely added and the mix--
hire shaken until no odor of benaoyl chloride could be detected. The mix--
ture was poured into cold dilute sulphuric acid and extracted with ether.
After being washed with cold dilute sodium carbonate the other was distilled
off. In both cases white needle like crystals were obtained. The bensoyl
derivative of the 2 hydroxy 3,5,3'tribronodiphenylmethane, obtained by the
Olaisen condensation of 2,4 dibromophenol and n—bromobenzyl chloride, melted
at 90-91% while those obtained from the product isolated from the direct

bromination of 2 hydroq S'bromodiphenylmethane melted at es.5-91°c. In

-20-
each case the compounds were re-cryatallized from petroleum other.

By the same method. the benzoyl ester of 2 hydrozy S'bromodiphenyl-
methane was prepared. It gave white plate 11k: crystal- when recrystal-
nsea from pen-clam other which had a constant melting pom: of 69-70%.

Further verification of the identity of 2 hydroxy S'bromodiphenyl-
asthma and. its derivatives was accomplished. by means of the Parr Bomb
amlyais for bromine content described by J. Lamp and H. Broderson
(J. Am. Chem. 806., $9, 2069; 1917). Following is a. tabulation of the
analysis of the various coznpmmsla together with their prOposed structural

formulae and. pigs 10a]. cons taunts:

1. 2 hydrom S'bromodiimenylmetim
OH 3
Structm-al formula: r
/ ca
| Z\_.__
Crystalline form; Liquid at room temperature
Boiling point: 167-169°c/3 um.
Analysis:
Sample Vat. of Sample ccéoifigms % Bromine found 9!, Br. Calcd.
1 .2507 9.00 31.21 30.39

2 .2305 8.90 * 30.91

 

Ave. 31006

2 . 5 bromobemzylphenylether
Structural formula
/ Br
\ >OCHZ< >
Crystalline form: Leaflets frm alcohol
Boiling Point . 145°c/3 nan.

Melting point: 36-37%

.21..

Analysis:
Sample 1%. of Sample cc. {'03. A3305 % Bromine Found. % Bromine 081ml.
1. .257? 9.90 30.73 50.39
2 .2"34 10.6 51.01

 

Ave . 50 . 8'7

5. 2 maroon: 5 , 5 . 3 ' tr 1‘0 ronodiphenylxnethane .

. Structural formula From Claisen condensation of
0!! Br 2,4 dibromoyghenol and m—bromo.

3:0 (:34 > benzylehloride.
:-

Crystalline form: Fine white needles from petroleum ether.
butting point: 70-77%
Analysis:

Sample Wt. of Sample cc. .333. A650 % Bromine Fomd % Bromine Calcd.

3

 

1 .1510 11.50 57.14 57.01
2 .1395 13 .45 55 .78
A79 56 o 96

4. 2 hydron 3,5,3'tribromodiphemlmethme.

Structwrral formula OR From direct bromination of

Br
BQCHZ/ > 2 hydroxy S'hromodiphenyln
metaane.
r

Crystalline form: Fine mite needles from petroleum ether.

Melting point: 70-75%
Analysis:
Samlo Wt. of sample 00. £3. Agfios $5 Bromine Found. % Bromine Calod.
1 .1807 13.00 57.55 57.01
2 .2112 15.00 66.82

 

Ave. 67018

-22-
5. 3 bensyl 2,4 dibromolnhenylether.

Structural formula;

Br Br
BrO 003C)
Crystalline form: Needles tron alcohol
Melting point: 49-6000
Analysis: . .
Sample wt. 01’ Sample co. %5L A3303 % Bromine Found 1 Bromine Galcd.
l .2450 17.46 56.92 57.01
2 .5413 34.45 57.19

 

Ave. 57006

6. Benzoyl ester of 2 hydrou- S'bromodiphenylmethano.
Structural formula: 0=g-< >

"" I'
O— CH-
\~.,.___

Crystalline form; Small white leaflets from petrolem ether.

waiting point: 69-70%

Analysis:
Staple Wt. of Sample ca. {’61. Agar): 1 Bromine Found % Branine Calcd.
l .1964 5.40 21.99 31.77

7. Benzoyl ester of 2 hadron 5.5,3'tribromdiphenylmethane.
stxuctural formula: o=q-< > From 3 minus 01’ two samples
r

B 6 described above.
r -
2

Crystalline farm: Whit; needles from petroleum ether.
Belting point: 90-91%
Analysis:
Sample Wt. of Sample 00. iii-H. W05 % Bromine Pomd % Bromine ealcd.
l .1373 7.95 1046.52 45.85

~25-
IF - Preparation of 4 hydroxy S’bromodiphenylmethane by the A1013 method.

A. Preprxat ion;

Br
/ CH /‘ >0H
/0H (Na) Br Q 2
( nor)

Br

One and one-luxli‘ tools of phenol were suspended in 400 cc. of petroleum
ethm- in a condensation jar partially submerged in a water bath and fitted
with an efficient meclmnical stirrer. To this suspension one-half 301 of
Hrmobenzyl chloride was added followed by one-fourth nol of anhydrous
1101,, added in anal]. portions at regular intervals over a period of from
one and one-half to two hours time. Vigorous stirring took place hiring
the addition of the dlCl3 and was continued for two hours after the last

portion of £101 had been added. Elle reaction mix-two was allowed to stand

3
over night to complete the reaction. During the addition of 1.1013 and for

a time afterwards. large volume of Br were evolved.

The complex mixture use then poured with constant stirring into a
mixture of 500 arms 01' ice and 500 cc. of concentrated hydrochloric acid
to accomplish decomposition after which it was extracted three times with

o
100 cc. portions of ethylether. 'l‘he extraction solution was heated to 125 G .

to drive off the ether and water and the residue was treated with Claisen‘s
reagent and extracted three tines with 100 cc. portions of patrolman to re-
move mrgen-alkylet ed products.

The alkaline mixture was neutralized with concentrated H31 (in the race
mar given for the Claisen. condensation) and. extracted three times with
100 cc. portions of ethylether. Both extractions were distilled under reduced

pressure after removal of the extraction solvents by evaporation.

~216-

rm educations sore carried out at various turpentine: to

mmmsctormtupmsnthsyieldofthephamlderi-

votive end 3 hmbmwlnhmlether.
m results on u follows;
First condensation: meta-s. 2.506
mm ether extract
96 grams phenol.
7 grus 4| hydra: S'hrawdiphenflntmne
1: am he
Petr-elem ether «tree»
68 pans W chloride
8 WW
resides

10m
em

mwm mm,w°a
Mathew
100m phenol
atm- lWSWWflm
10m residue
Petroleumm

55 am three-ohm man-ids
3'! gram 8 WW
3 arm residm

mm condensation mm. helos 15%

m other extract

’5 on- phone)
d hydra: SWWW
residm

agrees
16m

bolas 70%]: n...
zoo-Wok n...
above iso‘c/o m.

95.30“” “s
W]: n...
above 160°C]! In.

belas vo°cla a...
loo-180°C a...
above MEI! I...

90406.0]! I...
150-160.”! In.
sbovs 150%]: mu.

below 70°C]: 1.3.
loo-180° 0/: “0
above 180°C” m.

~25-
Petroleun ether extract
25 grams Hmbml moride

8 grams 3 brombensylphenylether
10 grams residue

ram-tn condensation Temperature, below 12%

Ethyl ether extract
93 grams phenol
24 grams 4. hydra: S'bronodiphenylnethane
13 grams tar residue

Petrolem ether extract
27 gram I-bronobensyl chloride
15 gm 3 brmbmaylphmlether
I you residue

so-los°c/s nun.
uo-ioo°o/: m...
above 160°G/3 m.

below 70°0/3 mm.
Loo-130°c/s mm.
above 180°c/3 3.3.

90-10500/3 Mole
140-ch 3.1:.

above 160°c/s u.

the tour ice-180% fractions containing the 4. moron S'brmodipherwl-
methane were Mined and re—distilled several times under a reduced measure

or 5 sun. A constant boiling point or lee-171°C m obtained for the product

which ruined a liquid.

me fractions containing the 5 bronobenzylphenylether which came over at

140-150°c/5 n... solidified and gave a constant melting point of 86-37% when

crystallised several times ent at alcohol. This compound was identical in

crystalline ten. boiling point and melting point with the 3 bromobsnaylphenyl-

ether isolated from the Olaisen condensation end was. therefore. essmed to be

them comm.

Observation or he above data will show that the taupereture at union the

various 11013 condensation- were run had a very great effect on the yield of

4 hydroxy S'brouodiphenylnsthme and 5 brembensylphem'lether.

.25.

In the first two runs et which the tamed—stare m inept at 25% the
yield a: 4 m S'bromodiphem'lnethene was low, being 1 grams (Ii-4%)
end 53; are” (2.7%) respectively mile a. yield of 3 bromobeneylphenylethed-
wee eeeured being 10 gram (7%) and 21 gram (21%) respectively; In the
thirdnndrom-thm-nm the “Increments inept intnnneinibornoodot
We the yield of 4| hydreq S'bremdiphmlmthase m granny int-eased.
being a grm (17%) end 34 arm (18%). the everege yield of 5 bronohmyl-
Nazarene (3.8%) mum {11.3%} weeleuerthnntheewerege
yielde of the on product in the first two condensation. It meet-e thet
e. low temperature (”below 12°C) revere the predation or d hydren 3W
“WM and that e higher temperature (near 25°C) retards its pro-
caution, increasing the yield of the corresponding other.

Y - Proof of structure of ‘ hydron S'hromodiphenylmethane.

rho mthod adopted for the poor of etructnre of this phenol derivative
wee einilu to that employed for the «mound prod'uced in the Cleieen con-
deneetion. in 1101, condensation using it m1 of 3,5 dibrouophenoi, 1/8 noi
beam chloridemdl/lsnolotenhydrmnclgwcemintheeanemmer
es the previous 1101, condemetione, me temereture being inept near 15%.
n1. following yields were obtained:

Fifth condusction Mature. 15°C
Ethyl other extrm

so green 2.5 dibranophenol m—m‘c/s mm.
in arm 4 hydra: 5,5.5’tribrmdiphenylmethme zoo-219°d/s Ian.
:6 arm ted- reaidue chore 210°c/s nan.

Petrolem ether extract

He product isolated.

-27- _ ‘

The fraction coming over it zoo—210°”: nan. imadieteiy crystal-
lised and m esemd to be 4 hadron 3,5,3'tribroundiphenylnethene.

It formed white needle like crystals in petroleum ether. After several
re-orystellisatione it was found to have e melting point of zoo-107%.
Home of the corresponding other as isolated in this condensation.

deeming that upon direct broninntion of d hydroxy S'brontodiphem'l-
methane bromine would titer the two uncoupled ortho positions of the
phenolic ring, e direct bruinotion see carried out in the cold in chloro-
form in the seine way es described in the previous section. It was expected
that e hydroq 3.5,5'tribranodiphexwlnethene, the some compound that was
isolnted in the A1013 condensation of 2,6 dibromophenel and n-bromobemyl
chloride, would be produced. me product imdiateiy crystallised upon
"emotion of the chloroform md was re-orystallised 1: Mar of times
from petroleum ether. ‘Lgein o great deal of difficulty was experienced in
purifying the oWthei-‘the fourth re-crystallizntion the product gave
e melting point of loo-105%. Sin additional re-cryntnnizetionn wed-o made.
we being exercised to select the nest perfectly formed crystals for each
subsequent re-crystallinetion. A content melting point of ice-107% m
finnlly attained. The ’comound had the sum crystalline form and melting
point so the 4 hydroxy 5,5,5'tribromdiphem1methene prepared in the 11013
condensation aid was essamed to be the some substance.

As Feyerecather (Renter's Ehesis. $3.0" 1932) mdpmfield (meted-Is
Thesis. 1.8.0., 1930) led been able to isolate e mll amount of the ortho
mahotitnted phenol from the pore substituted compound in his 1101: condensation,
the difficulty encountered in the purification of the 4 mud-cry 3,5,3'tribrono-

diphenyhnethane was attributed to the presence of e will amount of the ortho

~28-
substituted—phenol in the 4 hydroxy SVbrMiphenylmethane used for
brouimtion. n19 muses of the boiling point of the two cmnpounds
node their separation by fractional distillation imossible.

As e further check on the identity of the 4 hydroxy S'bromodiphenyl-
methane end its phenolic derivatives the benroyl esters of these compounds
were prepared md enelyced. 'the method used were the some es those en-
ployed for the compounds prepared by the Claisen reaction. 1.0. the method
of (Einhorn and Holland, 1.. 501, 95; 1898) methods of (Org. Chem; Porter,
Stewart and Branch; page 181-182) end the Parr Badb analysis (J. Am. Chem.
800.; 39, .2069; 1917). he tabulated results are as follow:

1. 4 hydrm S'brmnodipheiwlmethnne.
Structure]. fer-mule:

B
{Decca

Crystelline form Liquid
Boiling point: lee-ivi'c/s u.

Analysis:
sample Wt. or sample as. :0 . m3 1 Bromine Found 1 Bromine calod.
1 .2824 110.95 31.02 30.39
2 .2629 10.13 M

A79. 30.90
2. 4 hydrouy 3.5,5'tribromdiphew'lnethane.
Structural formula: Br Br
/ >cu2 Q03
:-

Crystalline fed-m White needles from petroleum ether.
neit ing point: loo-107%

~29-
Analysis:
Sample wt. of Sample on. 3.1. Amos % Bromine Found % Bromine Caled.
10

 

1 .2902 20.35 57.47 57 .01
2 .2419 17.42 57.55
‘79. 57 .56

5. Benzoyl ester of 4 hydroxy 5'bromodiphemylmethane.

BO'CHgOO-g-Q

Crystalline torn: line ehite needlee from petroleum other

structural formula»:

Helting point: 97-98%
Annlyeie:
m1. wt. .2 mp1. co. €51. meg. % Bromine Found 1 Bromine Calcd.
1 .1680 4.63 22.04 21.77

4. Beneoyl ester of 4 ludrozy 3,5,3'tribrmodiphemlnethene.
Structural formula:

Crystalline form: Elongated leaflets from petroleum ether.
lelting point: lens-152.5%

Analysing
Sample wt. of Sample 00. {.01. M03 % Bromine Pound % Bromine Called.

1 .2095 12.29 45.93 45.85
2 .1914 11.19 46 .68

Ave. “.85

~30-

TI-Smry

1.

i.

5.

2 hydroxy S'bronodiphenylmthm end 4 hydroq s'bromo-
diphmylmcthene and derivatives have been prepared and

identified.

Bromine was found to enter only the unoccupied ortho and
para. positions of the phenolic ring of 2 tum-m 3'hromo-

diphenylmethane and 4 may S'bromophony theme.

Evidence of ortho substitution in the alumina: chloride
condensation of 5 bromobsnsyl chloride and phenol was

noted but the compound was not isolated.

Equilibriun was {mm to aist batman the 2 hydrory
S'bromodiphenylmethene and the s brombensylphenylether

during their fornntion in the claieen reaction.

Temperetwes beloe 12°C were found to fever the formtion

of the phenol derivative by the elusimm chloride method.

§CH[M[ 0F comm/177m Qg —: ,,

6'
(,V/

.A b- I [1r Br C”
+ CA ”6—4 4/67 ©-C/4’-©0// (.er (067$ . 1.

Br
0.

MP /06-/07°

 

f

MP /3/5 -- A52“?

5,;

 

X l 5’0
5f 5”
' I —_...A/C/‘ CH COC/
l + 6/01 O CH _ 0H 6 5 ¢
K/ ‘0 H O 04

5/" /9//"/°
JMM

 

O CMCOC/ *OCH‘Qr

5F /67- my"
JMV MP 69-/()°

l
i

6:2"

' ' I 5"
5/, a, ’ 0H v m 5,

l ' + H0 33... H <3 _,r__.~_5 WC
\/ b -

H ”P M . (He-<3

MP 90 9/0

 

 

5/ 5r
, r— CHJ 0H J, _ 00/—
+ t/ ",(/‘/2 / r- z

5/ MP 49- 50°

 

 

. We ile- ulllll..ul7ll.ll.l ..q JEIIII .I .- I .I....I at- . A. .-.I.: d...

fl I 'll . Ill-i IIIIelfl.ll el .l . I I II I

 

 

 

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