k b preparation im

of nm am io jm para

mmm momwrnjiTE^ memo and paba chesols

i$sr

m m BELMDT CTQgfir

A THESIS
Submitted to the School of Graduate Studios of Michigan
State College of Agriculture end Applied Science
in partial fulfillment of the
for the degree of
DOCTOR OF H&LGS0FHT

Department of Chemistry
1950

ProQuest Number: 10008324

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field made this work

331632

INTRODUCTION

B e n z y la tio n b y •th e F r ie d e l^ C r a fts
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p-Oresol and p-Bromobenzyl Chloride. ............ .*6G

-S^brosJQbansyX ether*•............. .67
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2~J^roxy~5-m©thyl~S f-bix)rso<lIpIienylmethQiie.••**••*74
4 -MetiiylphQByl-2 -broinobe^yl ether.*** •••• •*****. .75
5-Hydrozy^S-iaethyl-S'-brosodlphenylr^thaiie**.**.. *76

78
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iw rn o m o rx m

^hen it vmm shown that a group of diphonyiEiethanea
prepared in thin laboratory under the direction of Dr* R.C.
Huston (l) showed promising specific bactericidal activity (2)
a program wan begun to expand the series*
She compounds tested to date consist mainly of the
chloro- and broaoderivatIves of o~ and p~benzylated phenols*
This work is to extend the series to include the oand p-iaonobromob©nsylated o~ and p-cresole, as well as the evaluation of activity of the phenyl benzyl ethers produced as
biproducis*
The in vitro and in vivo bacteriological investiga­
tions were carried eat by the 1X1 Lilly Research Laboratories,
Project M e r 275.

X*
h is t o r ic a l

The preparation of diphenylmethanes has been as*
by a variety of means* Of those the oldest is
that of Xexsa (3) * who obtained diphenyXmethsne by heating
acid in the presence of sodium carbonate*
A mere c o m m method is that of zinck© (4) * who
jeasyl chloride and benzene with a large amount of
sine duet* This reaction was utilized successfully with a
large master of benzene hoaologs {5j* It has also been
to the benzyXation of toluene to yield the 4- ate

In addition, the reaction has been found useful
in the preparation of the phenolic derivatives of the dt-*
l^ienylmethane series (7)« In this method one mole of the
benzyl chloride and two moles of the phenol ere combined,
using mossy sine m catalyst to achieve e less violent reac­
tion then la obtained with the zinc dust used previously*
However, in this reaction the reducing action of the zinc on
the benzyl chloride caused low yields» ate severely limited
Its application*
To overcome this, Meister {8} , In a method sugges­
ted by

V*

Baeysr (9), used a sulfurie-aeet1c acid mixture as

a condensing agent for benzyl alcohol ate benzene (10)*
This reaction m s also used to condense benzylsloohol ate phenol (11)*

2.

Later liebm&im (12) condensed benzyl alcohol with
phenol In the presence of zinc chloride, ate reported only

that zinc chloride, not zinc,
i« This thesis m e supported by the fact
that the vm of the chloride rather than the metal resulted In
a better yield of dlphenylmethsne from benzene ate benzyl chlo­
ride (15}*
Zlno chloidd© m e also used by Ronnie (14) to pre­
pare bonzylphesols* Ha had stated that AlGlg. ate BaGlg exerted
aa the Ztelg* From the products of the zinc
tea mm also able to obtain a s m U amount of the ©-isomer by precipitating the p-benzylphenol as
the barium salt, ate recovering the o-bonsylphenol in the aqueous

pentoxide to condense both
ate benzyl ethyl ether with benzene*
The best-known ate one of th© most useful methods of
In 1877 by Fried©! ate Crafts (I?)*
It Is discussed in a separate section.
known method, also using an acidic typo
v* Baeyor (IS). This reaction con­
cerns the condensation of two modes of benzono* or one of its
bomologs, with mthylal, in the presence 0 f concentrated
sulfuric fited* It has been need to obtain a nmber of sys>*

m e tr ic a l, p h e n o lic
o f

well m a considerable

th e

amber of

The reaction has

addition to the list of acidie
fluoride* Oaloott,
o-cresol with dlbensyl
in the

fluoride to obtain 3S4

resulted in a 33 percent yield of
v+ 15 percent of the dibenzylated
product, and 54

fc

method using sulfonic aeld esters
vms reported by FoeMi |M}« By refluxing benzene sulfonic
at high temperatures ho
products, but only in
f s i r y ie ld .
FegteS o

for fourteen days to obtain, upon saponiflcation, the same

phenol reported by Fatemo (25) • This
by Henaie (14) as the p-benzylphenol.

A u w ers

developed a method for the preparation of dl-

pyridine ate subsequent treatment of the Intermediate with
sodium eaasbosate and ao&ium hydroxide, lie reported the
p ro d u c ts a s 5 ,5 ,3 * ,5 * —te tr a b r o ia o - d ,^ f - d i5 ^ r o x y d ip h e r iy !- -

methane (2?) and formaldehyde (the latter was not isolated),
rather than the stilbene derivatives obtained when potassium
hydroxide was used instead of pyridine

{2 8 }*

Auwers and Bletz {£9} ate ^obn ate Jawetz (30) have

,

n@

q u a n titie s o f 3*1

to 100-150° until the evolution of hydrogen bromide
This reaction yielded ©~ and p^&erivatives in th© case of pi
no! ate o-oresol, m well as the dihensylated products of
ate p-xylenol*
Eohn ate Xawetz (30) used equimolar quantities of
»,5-dibromobenzylbrotede ate potassium hydroxide
with an mums of dihy&rie phenol in the presence of water*
Harden ate Brewer (31) used this aqueous alkali
method in the condensation of
teds with a series of substituted phenoXa*
this method gave higher yields than those using either
toluene ate zinc, or boiling toluene ate anhydrous sodium

A method frequently utilized in the preparation of

diteenylmethanes is the production of the benzoplienone deriva­
tive

HB& subs©quant reduction to the desired product*

K&llavits ate Hers (32) obtained benzophenon© by
©©adensiag benzole acid with benzene, using an excess of
phosphorous psntoxid© at elevated temperature*
A more common method for tbs preparation of the ke­
tones introduces the acyl group into the phenolic nucleus by
condensing tbs proper fatty acid with phenol in the presence of
zinc chloride, sometimes using glacial acetic acid m a solvent*
This Is known as the Mmncki Reaction {33} and was used by John­
son ate Late {34} ate by Doime. Oox ate Siller (35) to prepare a
series of acyl derivatives of reaorcinol which were reduced by
method (36) to the alkyl derivatives. Kcmiarcrasky
by
sol# add with resorcinol, using the above method*
This reaction is little used with monohydric

Another method for obtaining the ketone is the Haesch
» It has- been used extensively by H m m

ate

©©workers In the preparation of diphenytosthte® derivative*
By condensing p-chlorobertzonlfcrlle with resorcinol in ether un­
der a current of hydrogen chloride and in the presence of sin©
chloride , ha obtained a 65 percent yield of 4*-chl<>ro-2,4-difeydroxybensopheiione Iraida* This gave the ketone when boiled
with water; ate reduction of this by ClQsmensen,s method gave
© 33 percent yield of the 4f-chloro-£,4,-dihydroxydlphenyl-

6*

&m& authors applied this method to a number of
similar condensations (42)*
13a®

preparation of ketones from acyl halides

«ad aromatic compounds in ifc® presence of aluminum chloride has
been used extensively (43)« A 98 percent yield of benaophenori®
m a obtained by reacting equimolar quantities of benzoyl chloride
and aluminum chloride ^Ith benzene in carbon disulfide (44)»
MLuene and benzoyl chloride yield phenyl p-tolyl ketone in
yields up to 9®
Bailer (46) obtained an 83 percent yield of d-methyl3-^chlorobenzophenone from «>*efcXorote&uene and benzoyl Chloride*
With o^brosotoluenet however, he obtained only 3~hydroxy»4*isethyXbensophsnono, the bromine atom having been replaced during
h y d r o ly s is *

Who reaction of o-bromobensoyl chloride and flM&t~
^lor^banEeai® with aluminum ^hXcayii® gave a 43 percent yield of
SMsromo-Sf4 *-dichlorobonsophonon© (47)*
STiedol* Crafts and e o m a m * also developed a method
for the preparation of symmetrical bonsophenones using benzene*
or benzene heffoologs and phosgene in the presence of aluminum
ehloiide (48) *
la the case of unsubstituted alkyl ether® of phenols*
the reaction with acid chlorides usually gives p-aeyl substitu­
tion.
Although early reports stated that aluminum chloride

(49) Bebn (SO) obtained thymyl methyl ketone by the reaction of
thymol with acetyl chloride to the presence of aluminum chloride.
Bltrobenzene a s used as a solvent, fhto reaction* which gives
good yields i t the position p* to the phenolic hydroxyl group to
open* was later improved by RosenEmM and Schulz (31}#

shown to be sattofeetery* ©sod yields are obtained only if the
reaction to carried m& to ^.trohenzcne, or if %h& hydroxyl

% and m t* *
*

uA^«vK*eja* -**&«££ swyuaiwu***™ ims4&RZisa&^. t o

th e

a- or p~hydroxyketone* Tblm to known as the MLei
was able to rearrange resorcinol monoaeyl eaters to 80
chloride instead of the aluminum
-* .»u»jgi t&ss?wuKfd gate only poor yields with
ester® of phenol* m-cresol or guaiaeoX.
Cox (35) rearranged the benzoyl esters of <*► and
p^creaoX to give over 90 percent yields of the ketones, fhs
rearrangement of the beasayl aster of m-eresol gave 32 percent
p-benzoyl-m*-<3r©sol and 30 percent of o-henzoyl-m-eresol»
Hhto work was repeated by Hoaenmund and Schnurr (56)*
l&ese workers also prepared o-(2-hromobenzoyl) p-eresol and
o- (d-brombbenzoyl) p-*er©seX from the corresponding esters to
practically quantitative yield*

Xl#rmxm

mmmtte&m (57) used this method to pre-

m & u s e fu l m e th o d f a r e ith e r

m

p ~ b e n s y la tia n t d e p e n d in g *

<m m ® s m m m m

in the
re v ie w h e re seam s un**
w i l l b e lim ite d

n e c e s s a ry *
b o to e

o f th e

in the bennyXqtiGn of aromatic

first described in 1877 (SO}* It then made
thesis of a large smtoer of
toe reaction of benzyl chloride with
as the ssajor product Mphenylmethan© (02) * with anthracene a bi­
in small yield (63}* This reaction* which can take
at high t^^eratnrv® without catalyst* em be carried out
of eetaof aluMnum chloride (65)*
A father blproduct is the result of the self-condensa­
tion of benzyl chloride catalysed by aluminum chloride to

a

resinous* polymeric product (86)* tois lad Boeaeken (87) to the
conclusion that benzyl chloride would be unsuitable for the
SriodadL-Crafts synthesis* This condensation of benzyl chloride
may also only involve two molecules* as shown by Wbrtyporoch
and Bamik (68}* T^bcn carried oat in nitrobenzene solution* to

can be minimised by running the

* after the desired aiphenylmethane derivaobtained* further biproduets may be produced
W

aluminum chloride on the product* toe treat*

th e a f fe c t

m eat o f

with 66 percent of aXun&mim chloride

fit# TWGm

la the formation of benzene and

anthracene (69)
f a r th e

the reaction, of two moles of benzene
VdLth OHS o f

a s to e

Be obtained
W ith 4

u s in g to e

f ir s t

by

an excess of
and aluminum
equivalent of
m m able to

a 30

benzene,
Wn#m a n

used it mm-

the yield of

and that of

reduced*

effect of aluminum chloride on

was first

IX ,

to® benzylatiGn of phenols has been studied extensive­
ly by Hasten end ©©workers (75}* toe beet yields of condensation
products were obtained toen one mol© of toe bexsyl chloride m s
condenaed with 3 moles of toe phenol in toe presence of § mole of
aluxnimBa chloride at SD-35°# using petroleum ether as solvent*

In the ©as© of halogen substituted reactants beszylatlon usually
took place p~ to toe phenolic hydroxyl group to give toe 4-

the 2-ehXor©-,, or B-bromobensyl chlorides with phenol equal
quantities of toe o- and p-benzylate& phenols were obtained#
Vfooa toe nucleus of toe benzyl chloride contained bromine, ap­
preciable yields of toe helogen&ted phenyl benzyl ether were
isolated, in addition to toe diphenylmstjaane derivatives.
toe benzylaticm of phenol by means of benzyl
and aluminum chloride w « first reported by Huston (76), By
treating 1 mole of benzyl alcohol and .1*1 sssle of toe
with 0*5 ml* of stasizmm chloride at 20-30°, a 45
of p-benzylphenol was obtained* Slightly higher yields of to©
p—banzyXaiod product war© repeated toon anisoX© or plienetol©
were substituted for phenol* Petroleum. ether or carbon disulfide

Similar treatment of o-cresol yielded sot only
2-methyl-4 -bensylphenol# but also small quantities of toe

and toe dibcszylated
(7 ? )*

12*
Condensation of tors© moles o f p-cresol with one
mole of benzyl alcohol In petroleum ether solution gave a &
percent yield of S-bemyl-d-metoyl^oncft# and SO percent of
2#6-dIb®nzyl-4^0thylpbenol (70) * These proportions of the
reactants m m found to- give tbs highest yield of monebenzylated pxo&uat (ft)*
toe same' reaction with m^erosol gave two xaonobensytote d p rc & u c tm

3 - ia e ti^ - 4 - b a n s y lj^ e n o l a n t 3 ^ s e tb y l-6 - b © n z y l-

pkenel to approximately equal quantities, as well as toe dibonsytoted 3**methyX~4#S-dlbemylphenol (S0}#
W m benzyl alcohol msm used to benzylate 2*6-dIoblorophenol* 3^diobtoro-4-Iyd3xw£ydl^b33^l33Betbane was obtained, with
2,6-dichlorK3pb®nylbenzyl ether m Mproduet*
toe eondengation of alcohols stosr than benzyl alcohol
gave similar results* MetliylphesyX ©afbtool

a 35 percent

yield of p-hydrQoywl,l-dIpheiyletIian©, ©thylphonyl c^ifbinol a 30
percent yield of p-liydroxy—l,.i-di|tie2[ylpropa^; and benzhydrol
to carton disulfide gave « 40- percent yield of p-hy%oxyiriptonylrasthan©* Ho o- substitution produets ware isolated £81}*
Phenylpropyl oarbinol gave a 20 percent yield of
4~( «x phenylbutyl} phenol and 8 percent of 2~{ <* ptonylbutyl)
phenol (82)*
Btootl^lphenyl oarbinol m s condensed with phenol, ufjjTtg ai.ntnimm chloride at 100° to obtain a 72 percent yield of p(

* <h -dtoethylbeszyl} phenol (85). t o m mathyldipheiyl carbi­

ne! m

used, the yield of p-alkytoted product increased to 80

vlto trlphenylcarblncsi, to 90
supply additional evidence o f the
uamsturation of the carbon adjacent to
group os. the reactivity ©f this hydraryl
toward the catalytic affect of aXmnimua chloride (34)*
hem beau made of too
obtained Wing cither toe benzyl chlorides or benzyl

out under Identical

as the work of

it appears that toe yields ere

(87) and

Indicate that In to©:

w ith pheaod
g o p * t o to e p h e n o lic

It should be noted, however, that in toe acylation of
relative yields of ©~ and p-derivatlves can to controlled

the
the

choice of solvent. Thus toe mild reaction conditions usin^
nitrobenzene result mainly in toe forraaticm of p-derivatlv*
toll© carbon disulfide is conducive to the formation of o-

of the Jriodel-Crafts
been toe concern of a large number of workers* It was orlgi—
by M e d a l and Crafts (90) that the reaction

14,
A tham toich bm undergone many variations and has
h e w applied widely is that of the Intermediate carbonium loo.
tola oaiioneid theory, first suggested by Walker (91) and wm*
l&etely reviewed by Price (92) # proceeds as shorn below:
1*

BCX-H

S.

A K a i_+ a +-+ 03H6 ^ = i E Q gH g-t-H C l + A lC Ig

If, as shown* the dlsjaaeeiaant 8. occurs in one step* the resosane© energy of the aromatic substance used not be overcome*
In the preseme of such ©leetrophllie agents m alu­
minum chloride, boron fluoride,' and others, this mechanism is
net only applicable to the reaction of alkyl halides, hut can
also be used in the ease of alcohols, ethers, esters, or olefins,
which can all be converted to toe necessary earbonlum ion*
The presence of toe carbonlum Ion has also been used
widely to es^lain toe rearranged products obtained from alkyl
halide and aliphatic alcohol condensations ( 9 3 ) .
This mechanism is further supported by toe fact that
aluminum chloride reacts with ethyl chloride to give conducting
solutions* Transference expertesnts show tout toe aluminum is
contained la toe anion (94),
The eleetrophilic character of toe substituent group
la this synthesis Is shown also by the fact that the reaction
usually takes place at the points of high electron density that is, o~ or p~ to o~, p-orie&blsg groups present In toe
aromatic nucleus* In the case of nitrobenzene the deactivation
of toe melons is sufficient to prevent the reaction*

15*

The activation of the aromatic nucleus by aluminum
chloride is a debatable subject* Prins (95) assumed that the
Catalyst polarizes or Ionizes benzene to give a negative phenyl
i®w

Price and Ciskomki (96), and many others, belles that

the carbanium ion is able to react with an aromatic nucleus
without activation* This may be expected, due to the basic
properties exhibited by aromatic nuclei la several reactions (97).
However, this basic character m y also cause the formation of ac­
tive complexes with the acidic catalysts* This type of activation
of the ring m y explain the mechanism of to© Scholl reaction, in
which ring closure in polynucloar ketones is accomplished by the
elimination of hydrogen In the presence of aluminum chloride.
Actual attempts to isolate these complexes have consernad a mstoer of workers* Gustawcm has observed the formtion of Algols, 6Gs%and Algols,

by allowing benzene or

toluene to react with almalimm chloride and hydrogen chloride (98)«
Iberis and eewosker® {99} claimed that no Isolatable
ooiGplax could b© obtained unless a third component, a hydrous ha­
lide or alkyl halide, were added to the hydrocarbon-aluialJium ha­
lide mixture*
These data were used by Schaarscluoidt (100) as an expla­
nation of to® activation of aromatic rings; but there is m yet no
evidence that these complexes play a part in the actual reaction*

to the Presence of
J& u & toum C h lo rid e ?

Tfcs problem of the

nuclear halogens to

to® presence of alumtom

concerned a number of

of halogen to the

condensation will occur
Xsbila to
As too reactivity of too

to

th a n t o bO B zene,

to the former* f!
with themselves m

to toe- reaction of 9

to hessene at

1mm (Ml)*
(102) noted m similar condensation of bromoout st 70-00°, which gave a S0
This reaction may
to the

of halogens, under the influence of
* to compounds containing ether, carbonyl,
and carboxyl groups, has been investigated by Henitsescu and
coworkers (103).
The first evidence of migration of nuclear halogens
mm

found

to

toe methylation of o-dlcfclorobensaeaa with aluminum

to ora jaolar rstio of brojaobenzene to aluminum chloride, and

Iodine, some benzene, unchanged io&obemeae, and a little di~
lodobenzene, most of whldh sif too p-dl-iodobensene.

Seas© by-

Ohlorobenzen© a t unaffected under similar condi­
tions, even after being heated several days*
In to© ease oat ©felarotoluene appreciable rearrangeim n t

is noted when It is treated with aluminum chloride tod

hydrogen chloride* This rearrangement is asefibed to to© shift
of tbs methyl radical* and not to© chlorine atom (108)* It was

13*
found, to

limited number of compounds studied, that the

©•* tod p-orionfcing groups C2%, <M and G1 produce in a methyl
radical sufficient reactivity to pemlt a change of position
of the latter in too molecule*
u n d e rg o e s a r a p id re a rra n g e m e n t

t o m treated with a 1
to 1 molar ratio of aluminum chloride in the presence of hydro-

authors
p e rc e n t tm c h a n g e d }* m -

group is q :

*-*■

with a
of aluminum
to form, toe

q u a n titie s *

of

for eight hours there
to re ©

•*

of la
less than 5

in a reaction using four parts ’
broiaohensens to one part alusiyield i# increased to 20 percent, leaving 40

19,
percent

the unchanged bramGbQuzane. Mien nitrogen Is passed

tta»a#t the reaction, the yield of benzene is Increased to 42
percent; with hydrogen chloride, to 78 percent benzene; and
with hydrogen, to 83 percent benzene (and 10*5
brcmobensans)* In the presence of phenol 55
isolated, very little dlbroaobonaes©t and ecsna
CM.orobenzei3S ia« not affected tom treated as above*
The p-dibromobenzsne yielded benzene; bromobenzene; a
mixture of dlbromobenzenes%1,5,5 and 1,2,4
as- well as broad derivatives of
At a lower temperature of reaction, with a
proportion of aluminum chloride, or in the presence of a vola­
tile solvent such m carbon disulfide,, the mobility of the

or ebloronapbtkalena to toe beta isomer’vms noted by
.L10). tlaing alpha lodonaphthaXene he obtained free lo&ine
tod no rearrangement product.
In the ease of dibrcsaonaphthalenes, heating with
aluminum chloride resulted in the production of snail amounts of
Isomeric

chloride are very similar to those of the above

Tw the presence of a volatile solvent no haloipn si*
graftat was noted by Bwgpisr (HE) toon he heated o- and ptolorophenols with aluminum chloride in dry carbon disulfide.

Be obtained crystalline compounds to which, he gave the formula:

These gave the original chlorophenols on hy-

^sst<m ant Sufcer (IIS) produced p^jytesay&lpheByl in
2S percent yield by the reaction of one Esole p-fluorophonol
with two moles of aluminum chloride refluxed %& an excess of
bonzene fear 2*5 hoars#
to Gxtonslro series of papers on the nobility of
halogens in phenols was published by I&bn and coworkers.

Mien trihconopbenol in benzene was treated with aXxm & ~
mm chloride* a good yield o f bromobenzene was obtained# as well
to a small -atmunfe of phenol* Thader similar conditions trichlorophenol isa® not effected (114) •
The treatioeisfc of p-bromophenol with aluminum chloride
in benzene (80°) ga*e little bromobanzene; the replacement of
the benzene with toluene at 100° Increased the rat© of reaction
to gdire la-bromotoluene and phenol.
Tribromophenol when treated m abow g aw the same

the extent of
shows that the bromine

to tetra~ and
o -* a n d p * t o

the hydroxyl group are raoorod to give
bromophenal*
If both chlorine and bromine atoms are
fereniial debromimtl<m takes place (116)#

a n d sx~

21*
tm- their
m m & »

of the broi$x> derivatives of
to that of the phenols m m

(1317)* behavior

ob-

v&eu refluxed in benzene with aluml.

s s m chloride

& b & bromoben**

treated with an equal weight of
chloride and rofluxed in benzene gives
heating removes even the
to the
m-aresol shea

group to give
to react as above

SS*

noted by similar treatment (220)

benzene* but yields

The reaction of 5,S~&ibrorao-*4*
with benzene and aluminum chloride
derivative* vfoieh on further

splits and loses the halo**

that In the above
Kehn et al usually used three moles of aluminum chloride to one

m is of the halogenatad phenol, and a temperature of about 80°.
The usual procedure of carrying out the Friedel~
Oxafta oondawwtlon In this laboratory employs petroloma ethar
M a aaltoat, i* test balsa 30°, and tasas In moat instances only

22.
of aluminum

toy be

.

that the bromine

this reason it
used w i n be lees

liable to
* w i n be stable*
eat £fArey (IBS)
,»5t4*in 29 percent yield.

Mo defcalogona-

tlon products were

In yields of 15

migration of asm

in 48

or

yield by condensing p-x

With

in the presence of

chloride
chloride,

to

of the

in

of

in this, or in

yield) tod 4 ~hydroxy~ 3 ,5 ,J

Easton and

reacted 2f€^diehloroph©nol

as
4-*hydroxy-*3^S-dii^orodipheiiylsietMne and the

* to give
ether,

In this, and in further work, no migration of the halo**
gem is expected nor was found, duo to the evident stability of
chlorine under these conditions*

23.
S a d ® and Beadlay (225) prepared 4-*ehloro^r-hyarenq^i-

(24 percent yield} and
aetotoe (52 percent yield} without

in the weak of Huston tod
Gben (126) t toe reacted
give a ©sail yield of
to the

On

a pa?©**

by toe

in the

of o~©hloro~

(#3$;
noted In toe

of toe bromine derivatives shown below, Huston mi

of J mole of aluminum chloride to give a 17 percent yield of

eafbiml tod 2,6-dibroBophenol to

Bhaton end
butyl tod tertiary emyl alcohols with oaletaft chloride* 5&ey did obtain to©

to condense tertiary
using

24#
* but could not condense too alcohols witothe p**
that this ©hlortaae Is not
Xm m m m t toe mtomtm instances was any evidence of

migration or removal reported*

However, toon too work

(151} it was found that by using a 0*6 molar quantity
Of

&lori&©f in a one mole reaction* at about 30°, it
to obtain W percent yield© of p^tertiaryalfcyl
hut in the case of to© coMensation of teav
, a 53 percent

of p-teriiary
alto**1

Wrmt, toe shew© data it m j he concluded that bromine
is. most easily removed, or replaced by a catloneid agent, when
©■*•or p** to m strong o,p-»director* This is not the ease if
chlorine derivatives are used with aluminum chloride. In the
utilization of brcmwbemylchloridQS is this problem it may be
assumed tost if toe temperature is kept low, toe reaction run
is © volatile solvent, tod toe aluminum chloride mad in only
catalytic amounts* this type of migration or replacement* al~
to<yi^i it may occur, d l l be at a tottwn»
The problem of nuclear halogen migration does not oc­
cur in toe Clalsen method of O-alkylation of phenes#

25,
m m m m s m: the, auasim method *
M the WzteM%«®!c&£t8 tem tism yieMs
the isolation ©f pur© o**«ubflrtito.to&
of toe p# position, or the

ramson toe method of Claisea, ©Xthsugk restricted to- active
r* has tosn fount useful*

too sodium phenoxide with m active halide of. too
m inert solvent auto os toluene* The

aliyl oar

no definite eosaiaples of p*
(In too alkylation of sodium
and Ktoll {WBf
of too p-alkylated product* This

a 74

error* Qlalscn (135) mentions
in to© ease of too sodium salt
of sntkrmnol*}
in basic medium hod boon »©**
in too

of resoreinoX and

nol, ©t
to react in the tautomeric

f&wi%

* As toe *»»*«!> ^K/laisen Reaction* has toon applied to toe acetoacetic ester condensation, ketone-ester condensation to form
1*5 diketo330» end such aldol reactions as too condensations
of ethyl acetate with bexisaldehy&G to fossa ethyl eixmamate*
It is toou&fet desirable m t to give s v other reactions this
same name, although this reaction is already designated to
the literatus© as such*

26*
g&m both 0- ©mK O^al&ylatioiu ©laisea, in a footnote

(13 5 )

M #*m that thB react!©a of a 3 W bromide, calcium carbonate
and phenol in acetone, yield© not only th© sllyl other but al~
M m little ally! phenol, is the conditions used caused no
Tmsasmagement of the other,. O-^alkylation must have taken j&aee*
Bot is the reaction of th© alkali mite of phenol (136) and <*
«®d @ saphthol (137) with benzyl chloride, in alcohol, the e®~
peoted phenyl benzyl ethers sbi® obtained,
la %mo ms&me® and Bushier {138) found that by aXXo®?~
ing sodium phsnolaie to react with benzyl chloride (using no
sclvent} a M percent yield of benzyl phenol m e obtained* Use
•addition of copper increased thin to 95- percent* f s use of
toluene gave only 13 percent of the benzyl phenol; but vfeem the
raaeties mm mamled out in water only th© ether, and no benzyl
phenol, m © obtained* The authors did not folly identify the
products sad did not pursue the reaction further.
I N M

and Both (139) attempted to increase the

mount of 0-*aXkylati©zi noted in th© preparation of phenyl ally!
ether* Th& &■© of potassium or sodium phemlst©* rather than
the ©aleium carbonate, in alcohol or acetone solution caused no
iij^r©7©®enfc in th© yield of th© G-alkylated preset. But when
© wmaa^dissociatingw Bedim such ©a benzene or toluene vms mod,
th© amount of C~aXkylati©n increased from 1 to 3 percent to 60-70
tfcSseeafe* the formation of the allyl ether aemfeastn® accordingly.
Tito jnotofit sngefi * e identifies , o—allylphonoX slit « *u««n
T,««Mrit o f a,o-4 lBllyliitasiBel

m fetseodsefc (1.4 0 ) •

27,
0a more easgplet©
ils© found to occur

(133) this o-alkylsbenzyl halides, l-bromo-3, and ©ixmaigyX hr*>-

mid©, Busch (MI) confia^d

work and also showed

that while benzyl ehloride and
Ussoeiatiiig*

& in a ”nc8>»*
a little O-al^ylation,

th© more reactive

m trace of

Schorigin (142) and H*0* Sssarfcout (143) used th@
reaction to prepare S-^othyl-S-benayl phenol from sodium o**
eresolste end benzyl .chloride in toluene in 31
La (144) obtained
while Xlotik (143)
lata obtained

®

mixture of

in 49
awKrew**
of the two possible

to form o-hylroxyfcriphe3^X~
methane from sodium phenolate, but obtained mainly CWalkylation*
M h© used an ©excess of phenol (147) f,which is a ^dissociating
solvent”, this is to be expected; and when th® work was repeated
by Busch and Knoll. (130) without excess phenol, the o-^lkylsted
derivative a s formed, with only a 0.5 persist yield of th©
other* Haser alkylated th© silver salt of hydrosynaphtha^uinom ty a 1*0 addition of reactive alkyl halides (148)* fhis
reaction resembles th© C-alhylatlon of th© non-tauiomerle phe­
nols above in that only very reactive alkyl halides give C-alkylaSSohx- asd as reported by OXaieen, cimaiayl and benzyl halides give

o f tli© Chalky1 derivative than does the allyl

OAo

0

OR

0

OH
R

has also boon used in the
i&s produced by the roacsalt of 2-mothyl~
m a solvent (149).
in this laboratory
hem utilised the
to obtain purs

to a great ©xtont
(ISO)* In no case

mechanism has yet been
for C&al3en*a mthod o f
i into account the

motors tthiiah influence tbs

29%
reaction:
1# TJtm typo of
Z+ Tha type of alkyl

i*.E or Ag}*
§* lbs
6% Hie medium in lahich the reaction is carriad oat*

mlxturo*
of the phono! to

ms

the reaction* lbs alkyl halide
of the

tore not been
and are of mash

tbs affect of the

In x&iieh tbs reaction is carried out,

addition of the
to the

courses by isblcb tbs

shift of the ether*
&« The reaction of the metal

1 halogen to form the

the twm enol and alkyl

$* A X~8
tbs alkylated aromatic nucleus*

30,
m © first hypothesis la not correct, as the phenyl
other mill not rearrange under the conditions of the
work of Schorlgin indicates that in tbe presence
of sodium, and under extreme conditions, mxm rearrangement oc­
curs, but not to yield the 0-b©nsylate&
a rearrangement should occur it may he

«

If snob

that sos® p-

found.)
t* suggested by the work of Wia
the removal of the metallic ion to leav
activated in the ©* position by a proton shift*

CNa

OH

m i s does not explain the fact that there is no palhylation, and that the difference in reactivity of the alkyl
halides causes either predominantly 0- or C-alkylatlon. This
mechanism, should show the highest O-alkylation for the most re­
active alkyl halides (154) , which is not the case*
3br this reason Clalsem (133) and other workers (155)
favored the addition-hypothesis which was developed by Michael
to explain the formation of methyl isocyanide from silver cya­
nide and methyl iodide (155) * Using this mechanism the reaction
would proceed as shown:

ON*

©*« production of tlae Q-alkyloted

in a "nonthe presence

fl medium may
of phono! produced in the reaction:

-b^SkOX*
As this

solvent it will

of 0-alkyl derivatives from sodium

the formation
active alkyl

3Si
as&ECALs
Aluainm a.Chloride Aa&ydrous Sublimed*
Gteiioral Chem* B* & A*
B«K. 32
OliXoride B*£* 293
Benzoyl Peroxide E*E* 713
47 and Dow (B

b *&*

m

’
Dibroisi&e SEP (Pam)}
Seienti;CX{5 Go.
3*5 Binitrobemoyl CSalorid® 3J£* 2634
m a&l AXooiiol 93

Solvents

:* PX135
Methanol CP 1* & A. A-4X8
Parafonaal&ehyde 3«£* 421

{Dried over Pg%5

Petroleum Hther (Benzine) CP Baker
Pyridine SJE« P2X4

(BistiXlod from BaO)

Haney Catalyst Passder Ho* 23G2GB
Sodium Peroxide CP Ba&er
Sulfuryl Chloride E*K* P322
p-Toluene Sulfonic Acid E*E* 984
SaXfonyl Chloride B*K* 383

m-Tcluidine

P8G2

p-KLui&ln© E*K» 254
Zinc Chloride, General Chemical, Lot 0*262

Tm «os*aen methods are available for the preparation
of m*hrcciotolttene* *&m first* a San&aeyer reaction replacing
the amino group of m*boluldln© with bromine by the us© of a

of the method than la found in

Tm moles {214 g*} of p-toluidlne wore dissolved in
800 ml# of glacial acetic add in a three liter, three red:
flash# fhis mm refluxed fee two hours, then cooled. Hhile it
M s being stirred a slight excess of bromine (320 g#* 102 ml#*
2.03 moles) was added; then the stirring was continued for one**
half hour with the. temperature being kept at 50*55°. 'The reac*
d m mixture was poured into 10 liters of cold water in a hat*
tery ja r to which had hem added 25 g« of sodium bisulfite*
«jha product was filtered off, washed with water and dried in
the Bueehner funnel to about 500 g. It was thou returned to
g liter flaak aad refluxed with 500 ml* of 95 percent ethyl

35*
To this 5D0 elU of eoneentrated
alssly, end reflux continued* After three hours the mlxm m

pms>& Into a beaher acd the liyaTochloride filtered off*

wmi washed with chilled alcohol* The
suspended in 800 ml* of water in a two liter
of 140 g* sodtusa hydroxide ia ?00 sol* of water

was isolated w d added to a cold mixture of ©DO ml* of 93 percent
ethanol and 500 ml* concentrated sulfuric acid in a five liter,
three neck flask equipped with a stirrer* I M s was cooled to 10°|
and a solution ©f 8*05 moles (148 g.) of sodium nitrite in 280’sal*
of water was added* The reaction was stirred for twenty minutes*
After the stirrer mm removed a long bulb reflux condenser a s put
In its place and 35 g* of copper bronz© mm added slowly*

{Se­

duced copper powder may also he used, but 30 g« to 80 g* arc ne­
cessary*} The flask was kept free so that it could be moved easi­
ly* It was then heated on the steambath to accelerate- the reac­
tion* When the evolution of gases became too vigorous the reac­
tion mm cooled immediately in an leebath* Uien the reduction had
subsided, it was heated on the sieambath. for ten minutes while helag observe continually in case further coolie was necessary*
Ihen the color of the solution had changed from a redbrown to a yellow, two liters of water were added,, and the pro­
duct m s steam distilled* The resulting oil m s washed
with 200

portions of 10 percent sodium hydroxide, ones

56*
mSM. mtar* twice with ISO adu portions of concentrated sulfurlo acid* and finally with 100 ml* of a 5 parent sodium
solution* This sulfuric acid caused considerable

37.
TBS PHEPAHATXOJJ OS' BHOMDBSfCTL CHLQHIH83
tee major problem in tee production of tec necessary ben­
zyl chlorides i« the prevention of over—chlorination, mainly in 0 a
sldeehain, but also in the nucleus*
t o method yielding pure p-bromobenzyl chloride is the
ehlorometeylation (ISO) of hromobenzene* Begrettably, the presence
of a halogen on the ring makes this reaction difficult and decrea­
ses tee yields (Ml)*
In this eblonomateylation method a crude oil, formed by
the reaction of fbrmalin a M hydrogen chloride in m tower at 600
and in the presence of zinc chloride monohy&mte, Is treated with
bro^iohenzene to give a 46 percent yield of p-bromobenasyl chloride,
4#4v-Dibromodiphenylia3than© (&«?* 64°) mm also isolated* A fur­
ther disadvantage of this method is that it is limited to the pcompound.
The replacement of tee hydroxyl groups in tee three isomeric broraobenzyl alcohols yields tee terse benzyl chlorides la m
pure state. p-Bromob©nzyl alcohol yields 91 percent of tee p-bromobensyl chloride teen refluxed with concentrated hydrochloric
acid (8 5 ) * The o- and m-bromobenzyl alcohols can be expected to
react similarly* Although the method will result in a pure pro­
duct, it Is severely limited by tee difficulty of tee preparation
of tee alcohols.
Dippy and Williams (168) hrominated benzyl chloride in
the presence of a trace of Iodine* They obtained a SO percent
yialA of p-bxoraobaozyl ohlorido (M.P. 30°). Howerer, ths purity

38.
of this product is hl^&y debatable,
Another method for promoting sideehain Chlorination
tee reaction in tee vapor phase at 200-600° {163},
most eosaaonly used Is tee direst chlorination
of tee brrootoluenes using a ooteimMon of ll^it (below 8808 £ in
wavelength) end thermal activation {67}*
This photoeMorinaiioa involves the
chlorine by light into- free chlorine atoms,
reaction chains by substitution at tee
bond* In tee- ease of tee toluenes on appreciable amount of
chlorination will occur in tee absence of light (164),
Jacoba and Eeidelborger (is5) passed the theoretical a-

(166} used 8*1 mole phosphorous pentachlorlde to
six moles- of o-ohlorotoXuens end chlorinated tee sideehain in tee
xO
has been used In this laboratory
{128* 129} for tee

of halogenated benzyl chlorides* To
mm continued until 75 per-

found that in the si&achaln
ehlorlnation of
chloride as a

, tee use of phosphorous pentamm not to be recommended. as it Increased

tee yield of
A source of
auXfuryl chloride

chlorine, other than tee gas, is
(168) allowed toluene and sulfuryl

39.

at IX,^ to

benzyl chloride and chloro-

teaed the same reaction at 130° to obtain
mm

of benzyl chloride*
cmtU bode

led to the

banzai chloride and benae-

uaeof

of m :

1& the
of stemxe

a rapid and

the dark, whereas the light promoted reaction with

■$m typified by tea

pemds m the

to form free

of the

This slow
by removal of u
0
it

from the sulfuryl
O
ii
# 5 + "~g

+

+

ca*4- 5gi-*a*4»•+■ a M x u - ^ m + -aeycBt

40*
This ©hlorixiBtion t» loss successful in the neighbor­
hood o f groups or atoms showing strong electron repulsion

(-

%m

effects)* teas tee lu&rodnetiaa of a second halogen into

and a third halogen cannot be added* A bromine substituent is

reaction is inhibited by smXX quantities of Sulfur, iodine or
oxygen* The inhibiting effect of oxygen is overcome by the vi­
gorous evolution of' gases*
tele reaction was used for tee preparation of-tee ©~*
m* and i^hrembenzyl chloride*

M l reactions,

the purification of tea fi-

nal products, must be
te lar^e port on tea efficiency of
tee reflux condenser* %

m given off in an

Ice-salt bath and

liquids to tee r@ae~

tiom, ©

can be obtained*
to be no violent that it
feely. Ibr a one stole

a 2 liter

a reflux condenser were
reaction mixture through tbs

redox condenser.
to be redistilled, as tea crude pro*
duets contained
tloa. In tee ease of tbs
bad te be

poisoned tbs free radical reacchloride this redistlllation
use* A on© foot yeask©
mm* fraction token for tee

and sulfuryl chloride ware mixed
tee exact amount of

peroxide addod.

censes an

reaction.) The reaction was heated

cautiously to 93-97°* At

As point a vigorous evolution of

gas took place, and rapid
When tee reaction bad

(Excess peroxide

of tee mixture was necessary.
, heat was reapplied and reflux
no longer given off* At this

tee reaction was eca?q?l©t© and the mixture was

42,

fractionated.
total tim ter tea reaction was 20 to 30 minutes,

1 mole eulfuryl chloride 135 g*
0*5 g*

Initiation Chloridea*

B»X*

ortlio
o

msta

mm melted to facilitate
Tb© reaction

vary vigorous, and rapid

The excess p-bromotolusne mm removed at ?0~75°/lB tm»
93 percent of one mole used) \ the major portion of tee p-bromobenzyl chloride distilled over at II5-X20°/18 im. It mm neces­
sary to heat tee sideam, as tee product crystallized very easily*
Beerystsllisatlon mm accomplished from 95 percent
ethanol, giving fine, whit© needles in an average yield of 78
percent (based on tee pure crystalline product} * Xt melted in
tee range of 40-42°* literature values vary from 38-39° (ITS) f
40® (153). 41® (174). to 90® (IBS).

vious resetions. However, in m m cases tee reaction had to be

tee excess m-bromotolueiia ms removed by distillation
st 81-84°/l2 urn*, the m-bromobenzyl chloride at 118-121&/2M sea*,
through a 6 inch SVmske column. A smell fraction mm obtained

44*
t u 1;be

intaxmedlafcii range, boiling aafe&y at

m u

$bi* «ae not identified*
average $£®M ©f m?$mmQb8B5s&l .©fcXoride mm
$&*S percent* It® boiling point ©greed witb that given by .
Olivier (HO0/!® jam*} {X7S}* Bcflsover* tb© m^bromol^Bzyl
e&XarM© did not solidify* and thm did not give tb© rselting
polat ©f

cited In tbe above reference*
A m &H €assE»mt of higb boiling material «a* Isda**

M l ©ad crystallised from aleoboX to give Tsfoit© flafcsw m l tin g at 30*®°'* tbls m

not farther identified*

& all the above reactions a m&$£ wmrnA of rod
frames nas noted m tbo cc^eriser* fbis «&» especially 1mm
in tfee case of p-*brossotoXnose*least so In tbs ease of m^bfoiaotoluene* It «mmo* possible tbat this is MadLae resaoved
daring tb® jps&etien*
It sbouM also be pointed ont tbat in tbs case of
m^broiaotolxjene a smcb more violent reaction nas obtained s&sn
tbo snlfuryl eblori&e « a not predistilled*
Ibr tbes© reaeons It
tbis reaction farther*

m & m

advisable to investigat©

IB&a- aljsoaaol % n m m % w m e m l ?

eia

$h& ts€t3* p m p o s M n ^

r©n«z©d p-bayojsot^nsjrl

bensyl liall&e*

1gr
£&tSmem

by^tpoly-

and Somegr {1 7 6 }

la isater tmlsil no fnsrtliar lachry-

the addition of the formaldehyde without easeesaiv© repolymarizatioiu The method of Siegler (180) as modified by
c&lmaa and Ostlin (101} proved fairly successful*
In this procedure parufor?saldehyd© i& d©poly­
merised at about 300° and driven into the react!cm by a
stream of nitrogen* It m s found that by using trioxana
(

ot

heating the inlet tub© m f&r- as

Boa? a three mole run a t & m liter* three neck flaaic
mm used; it wee fitted with reflux condenser* droppiBg funnel
and stirrer*
Eeaetantet
0 naalag magnesium 70 g*
3 melee p-dibro^benaene 708 g*
2800 ml* ether ( M « d m m soditsa}
7 moles fermXdehy&e (irdoxaae) 070 g*
•The trlexana

mem

dried over phosphorous penloaci&s

fee? two days*
Slfty ml* of the solution of dibroinobenzene solution
in ether mm mm. into the reaction flsak* and the reaction
started by the addition of a small amount of ethyl bromide.
The remainder of Mi© halide solution was added as rapidly as
the reflux rate would permit (3*5 tee*} without cooling* The
mixture mm left overnight, then filtered under a stream of
nitrogen* So unraactod mgueeim m a found.
The dropping funnel was then replaced with a 12 xm.
inlet tube for formaldehyde addition* In a 500 ml* flask at**
taehed to the inlet tube the trioxans m s heated In order to
depolymerize it* and the formaldehyde was driven into the re­
action flash by a stream of dry nitrogen.

(Oare must be taken

to keep the inlet tube above the reaction mixture.) After 6
to 7 hours the reaction was found to be completed* as shown
by a negative mcfcler*© ketone tost. The reaction nix-

hydrolysed in

saing im and 03 percent

l* It mm

with ether and dried over
the ether wee reaaeved by
Benste eolunm. The

from Hgrc&a gave large, flat Mate

mm obtained la the one

A yield ® t only

seltisg point witlx the
of

ceasEmsmosr w s m t t m * ws&mzmmta,

m m

c s m e d out

a mm
m / m - 24/40}

a»l and reflux eondenser. Stirring m e accomplished by means
of a Harshberg stirrer (182) of niebrome wire*
To assure adequate mixing it m s found necessary to
use two glass—rod rings with attached wire stirrers#. The
stirrer m s placed in the flask through a glycerine seal*

of the glass joints with silicone stopcock grease was found to
be essential to
Is not to be

The use of rubber
L* due to the corrosive action of the ro­

actants.
Distillations were carried out in a 250 mi* and a
50 ml* distillation flask with straight* heated columns*

Bea­

ting of the flasks m s accomplished by mans of Glaseo mantles f
ears being taken not to heat the product m e n it m e not under
vacuum*

In order to be able to collect three fractions without

breaking the vacuum am inclined rotating receiver w

used (183) *

the fractions being collected in 50 ml* Brlonmoyer flasks *
Other apparatus* similar to the usual distillation
beads* m e not found to be suitable* due to the high viscosity of
the products.

The use of rotating reoeivors utilising an Krlen-

m&ex flask with

receivers* sach as the modified
&so found to be unsuitable* as

action m s carried out at r am
m s not found to be necessary* The stirring m s continued
for the times Shorn under the specific reactions*
At the inclusion of the reaction the red* oily
aluminum chloride addition product settled out of the mixture*
This m s hydrolysed by being poured* with continuous stirring;*,
into a mixture of SDO g* of ice and 300 mi* of concentrated
hydrochloric acid* The reaction products ware then extracted
with fear W O ml* portions of ethyl ether*
After removal of the solvent the remaining oil was
treated with ZWO ml* of Claisen solution (See Claisen Method,
Experimental*)

extracted with four 100 ml* parties®® of

petroleum ether to remove any 0-beBzylatad products*

52*
The alkaline# aqueous fraction m s then ael&lfled, in 300 g* o f crushed lee* with 6 IF hy&mchXGric acid*
This solution m s extracted with four 100 si.* portions of
ethyl ether to rasters the phenolic products#
The others used to extract both the 0- and tbs
O-ulkyXated fractions were m m m ed m

be aide- to

Mis steambath* Xa no

It and
Mis extras*

tioa of the acidified

hut it mm% b©

I that the

of the

la open to

* duo to the

which these

\well m to the

Inaccuracy of

(Coming Class 6950)

Correct

con-

The fractions containing the desired
at least once* Mien
from hexane* This advent caused leas loss of product* due
to solubility la the cold solvent* than did petroleum ether*
which* however* way also be used* S&eae crystallisations
wore

until Mbs products reached a constant s&Xting

point* The crystals were then redistilled, using a MCXeod
gangs to determine the pressure* The products were crystalUsed feom Immm and their molting points determined by the
caplllary-tub© method {IBS}*

53*

condensed, using the general
in the preceding section* The reactions
mam m m

«&>

for periods of 60 to 78 tauae*
of the aiaisen solution with petroleum

by the acidification

After TmmmX of- the excess and unreaetsd o-cresol
g*l by distillation under & cli^itly reduced
reaction

f*7 g*
"/8 am*

18*4 g*
24*9 g*
11 #*4
16*8 g*:
7*0 g*
21*7 g*

M l fraction® boiling from I70-1S6°/^
This eojapound crystallised w ry easily,

it necessary

to heat the sldearm with a Mcrobumer

the distilla-

tioa* The solid obtained was

from hexane until

the long* Milts fluffy needles had

a constant

54*
petal#. ^easldars'ble heating was necessary to dissolve
Mils compound in hexane* Ptem the filtrate of the cryataMixatioa there was Isolated 32 g. of an unidentified
Ml*

This- probMily contains some impure product} but it

©ould not be serrated to the pure state#
The average yield of pare product of four o f
the reaction# mm 21 percent (S7*0 g»)«. Om reaction# car­
ried out under a stream of nitrogen, mm mm at 23° and
gave a ytaldef only 10*1 percent ( M g*i*

Mter removal of 102 g. of the unused o-cresol
at 8S-90°A& seu the product was distilled*

55*

X0«X g*
80*8 g*
263 ■&#

8«5 g*
8*5 g*

A H fractions boiling
twice and the high and low
tion discarded* The

of each fraefractions were then

crystallised with difficulty at 0-10°. Ae the crystals
contained a considerable amount of edit they were dried
m clay plates* The white,, crystalline product was them
and again dried on clay plates until the
had reached a constant melting point., this
cation procedure decreased the- yield of pure product to 5*4
percent {7*5 g.)# The combined filtrates, on evaporation
of the solvent, yielded 25.3 g* of an unidentified oil* The
product, isfeioh raus obtained In the for® of short, white
fluffy needles* ® 9 found to have the foMowlng
constants:

ealed

28*83

found

28.85, 29*07 percent

need to absorb the oily impurity
product were extracted with ethyl
ether* The M X

by distillation and
tm n hexane* It yielded «aXy
at 40-41°*

These reactants nmm used in three
The two
30 hours.

m

et xs-xg®*

a jsueh aroHfr yield of the desired product*
red-colored reaction mixture was hydroas: described In the
The treatment with Glaisen solution and
a trace of an oil* the quantity v s insufficient
for
was purified m shown belows

57—?

91*5 g#
10*0 g*

S5-140°/2 xM*

5*7 g»

X40-28O°/2 mau

4*0 g#

180~X90°/2 mm*

44#7 ■g#

190-200°/2 mm*

35*1 S*

300-205°/2 mm*

9*1 S*

57.
5*1 g*
sift-aas^/g bnw

9.3 g.

Tar
of 92 g*

f,duo to the eea© with which It
fro® hexane four
A total of 42*g g*, of par® product, and 22*5 g* of
isolated. The average yield for
* was 39*4- p&&~

in the .form of fine, matted white

SSSW

Br calcd

S0.B3

Br found

2830* S9.X4

The on© reaction run at X0«*X5° yielded only X0.5
{143 g*} of the same product.
oMBSSQk AM>
In order to compare both the products and the
yields of the a h M m chloride catalysed condensetIon of
o-eresol with p-breBXJObenayl chloride end with p-hromoheaxyl
alcohol, both condensations were run. The results, using
n—bromobenzyl ^diXorXd©, ere given in the preceding section*
The condensation using p-biemobenayl alcohol was carried otrt

58*

alcohol {62*4 g*)
*37 mole o-arasol (40*0 g*)
*25 mole aluminum chloride (53*4 g.)
200 ml* petroleum ether
The o-cresol was dissolved In 200 n&* petroleum ethers
and the p-bromohenzyl alcohol, which proved to he only
sli^rfcly soluble In the solvent, was added as a solid*
With vigorous stirring the aluminum chloride u s added
mmt a 1*5 hour period v&th the reaction at 21-27°.
After 15 hours the reaction mixture was
in Ice and concentrated hydrochloric acid* The
extracted from the hydrolysis mixture with four 255 ml* por­
tions of ethyl ether* This m s dried over anhydrous potas­
sium carbonate* After removal of the solvent the resultant
oil was purified, as in M l previous cases*

Distillation?
62-70°/3 mm*

12.0 g*
4*9 g*
7*8 B*
1)3#$ g#
28.6 g*
5*8 g*
21*8 g*

The fractions boiling from 165-215°mm* were redistilled*

59#
crystallization from
needles melting at

gave fine, matted
A mixed melting point
s, which had
p-bromobensyl chloride

by the

of this
was 26 percent (24 g*) 9 which is slightly less
the condensation of o-croeol and p-bromo-

msb

m

In this reaction an excess of o-eresol (
with one-half mole of benzyl

in 200 ML# of
of
was carried out as in
Ho

mm found*

60-9QP/3 a *

-160°/3 m »

The three fractions boiling from 150—195° wots ro&istilled

61#
2*6 g*
Ter'

7*7 g*

The fraction boiling from 165~X70®/2 a®* was crystallized
from hexane to give 6#1 g* of product melting at 80-61°*
A Mbced malting point with a sample of S-hydroxy-S-methyl4*-brtmiodIphenylinetha!5©, prepared by the Claisen method
I7S-173°/0 m»«#

61.6-62*2°) showed only & small

The fraction isolated at
9*4 g* of white needles after crystallization from hexane*
These crystals malted at 75*5-79*0°* Further crystalliza­
tion did not shorten the range of this melting point* Both
the benzoate (M.P. 42*0-43*5°) and the p-tolueus sulfonate
(M.P. 48*0-51*0°} of this compound were prepared* These do
not agree with the melting points of the corresponding deriva­
tives of 2-liydroxy-5-methyl-4*-bro&odiphenylmethana (63.5-64*0°
and 59*5-71*0° respectively) • 2te further attest mm made to
identify this product*

This product, extracted from the basis GXaisen
ether, was distilled as shown:

71 -100°/2

iam*

3*2 g*
1*0 g*
21.7 g*
13*1 g*

68.

63*

0*5 j&alB sodium (IX.5 g*}
0.5 mole crosol {54*7 g*)
0*5 mol© brc^benayl chlertde (103 g.)
300 ml* toluene {dry}
Mm sodium, freshly out into smll cubes,
in the an© liter flask with 100 ml* of toluene* Xt
;* fm 1*5 hours until
It had t a @ t m O X flnid

At thi# time
100 ml* of toluene, mm

of the eroaoX,
and with

the host- f n m 1&e
flask; hut- for this reason it must bo- run carefully for ap­
proximately 1*5 hours*

{It has recently been pointed out

{187} that for the syntheses of sodium
hydride is laore oonvonisntly handled than

which m s refluxed Bor «
to insure
L, viscous
the brcaaobenzyl chloride .

of fro® one to two hours
of the reaction* To this
was added one-half sole of
in 100 ml* ©f toluene,
during this addition, which re—

Lhsmrnt&r or a saturated solu* Phenolic bum
glyeerol*
(let the undissolved brotlon of bromine In
use.)
(186)
In no ease use orga*
mine settle out
nic solvents.

64.
reaction was stirred and reflexed at 105-110°
for the times shown under the specific reactions* A deeply
colored reaction mixture resulted* It was acidified with
& If hydrochloric acid In ice to remove the sodium chloride
formed* This acidic extraction was found preferable to the
usual water extraction, as the latter dissolved some of the
sodium salts#
The toluene was separated and the aqueous layer
further extracted with two 100 ml* portions of toluene*
The toluene was then distilled off at atmospheric pressure,
the last traces being removed by distillation under a slight
vacuum to Insure complete separation id the next step*
The residual liquid was cooled and treated with
250 Ml* of Clsisen*s solution* (188) and the insoluble
oxygen-henzylaied product extracted from the potassium
phenolatos with four 100 ml. portions of petroleum ether*
(Btbyl ether cannot be used, due to the solubility of the
methanol!© solution of the phenolates in It,} The presence
of toluene in the reaction mixture causes the formation of
an emulsion in this separation.

* 350 g* Km in 250 g* BgO, diluted to one liter with me­
thanol. Concentrated aqueous (50 percent) KQH cannot "toe
used, as the potassium salts are Insoluble in It* There­
fore they form either tm oily layer between the petroleum
ether a™* the K00t or partially dissolve in the ether.

65.

The Claisen solutlon was then acidified in 500 g,
Ctf crushed Ice with 6 H hydrochloric acid, The Ice servos
to dilute the methanol concentration* me well as to cod
the reaction. It was than extracted with four WO ml, por­
tions of ethyl ether, Tbs ethyl other was removed on the
staambath; then the residual oil was fractionally distilled.
The results off these dietIllations are given belosr; but it
3R*st be noted that the accuracy off Mi© temperatures and
is open to question* due to the ease with
L*late superha&is* and the possible inaccuracy
off the finger isanomater used., Correct, values are given with
the auEsmrized physical constants off these compounds. Tim

crystallised ffrcsa hexane. The

at least

reerystalXiaed until they reached a con~

line

were then redistilled using a

stout

After crystalllzs—

Hclood gauge to
tloa from hexane
In those runs In

added to the reaction

ether f®m&& in
mixture# Mils

took place

the sodium creaolate

had been, formed* and before the

©expounds extracted from the
purified in the earn fashion as was the
U However* 95 percent ethanol, ru~

they than hexane, was used an crystallization solvent
for these ethers*
<M m S 0 ! AHD o-BHGL^mraX CHLOHim:
These reactants ware combined using the general
procedure described above* Beaetion times off 16 to 19
hems warn used in the five reactions run#
The 3-hydroxy-3-m0tl2yl~g-bromodip]:iei»ylriethanQ
was separated from Mi© S-^aetliylphesyl-S-broirobenzyl other
W extraction with Claisen solution, The two products
war© then purified by distillation and crystallisation*

W*
60-170°/2 HH*
®3S*

13* 4 S*
0,6
3*5 g*
27*7 g*

mm*
Tar

2*9 g«
5*4 g»
ssa* fraction was redistilled twice

above*. Short,
were Isolated in an average yield (3

whits

Br
Br found

29*13, 28*85 percent

67,
18 grSBBB o f Mb©
war© added to the reaction

h, yields off 4*4

(4*7 g*} a M 8*2 percent

-) off 2-hydro3Qr-3-s©thyl-

9*6 g*
5*2' g*

r*S g.

10*5 g*

crystallised from 90

ethanol vs

in an

flat wfeit#

off 18

t9 ^*)

46*6-47,
Br ealed

28.8S

Bff found

28.93, 28*90

Twelve grass off an unidentified oil were
ffsom the filtrate off this crystallization* This may eontain Impure product, but further purification was
la the reactions In which this ether m s added Mi the
reaction mixture the yield off the 2-2^tlylphei2yl-B-t>ro32K>benzyl
ether, after subtracting tbs added amount, m s decreased to an

average yield off 31 percent; (1§ g*) in the

reactions*

o-CSESOX j\BB i&-8IJ0M8OT$m,
cff SS to 85 hours were used in
the four

were eonmixture
to a

color which on cooling became a deep

then violet.
.and other
and

1*0 g*
0*5 g»
0*8 g*
9*4 g*
3*0 g*
0*0 g*
Tar
r?0-190°/2 asa.
d fro® hexane to
.* The two

4*0 g*
m m redistilled and crystal—
an average yield off 8 percent
which were run for S5 hours,

Br oalod

m<M percent

Br found

28.53, 28*86

12*9 g*
' 8*9 g*
1*1 &*
12*# g*

four

in an

of 21
run 86

yield
had been

» la the m m of
msage ytoM.off 18

m

for 85

of this

obtained*

1*5950
4
Br ealod
Br found

29*11,

Ooolittg this liquid la a dry ioe-acoton© bath r©*the formatIon of a glass-like solid

fQi
CEI&MlSSs
using the
w&m tasea In the

quantities as
allowed to reset

tor from four to

honra* Of the lire reactions,

two were wqa in the

of an added quantity of the

tn all the reactions these

tte so&tai ere»©~

Oil addition of the p^tqramQbenzyl
a bright orange edtn
tion which
and removal of the toluene
of Ida g* of the crude pro*

10*0 g#
0*S g*
30*0 g*

#b g*
fhe

2m* e e redistilled

this distillation the si&escm had to he
%due to the esse with which this compound
# After three erystallizations from hexane the
isolated in the for® of long* flat white noodles

Br ealed

38.85 percent

Br found

38.89, 38,91

fchai this crystallization caused a 3d percent
tmm the redistilled product to the final, pure
11m
Ihs two reactions In which the
m s added to the reaction mixture, as la­
under the general procedure, shotted a marked increase
in yield, In the reaction in which IS g* of this other m e
added the- final yield of the C-bromobeazylstad product was
increased from the 8,7 percent to 83,8 percent (31.6 g.) j
the quantity of the 2-E©ihyXphenyl~4~
ether added to SS g. increased the yield to only
17 percent {33,6 g*)* H d s offset has teen noted

hy Quil©

1»
iso-mP/t

170-X85°/2

7,7 g.
33.1 g.
1.6 g.

72*
X8O—X70®/2 m

f m H e i iei redistilled twice <***d cry—

froa& 95 percent ethanol to give long, flat white
needles in an average yield of IS percent {31*9 g*)* In

other had been added to the reaction Btxtur© the yield of
saas increased to 22 percent {50*0 g.) after subthe quantity added from the amount obtained*

Br found

28*53, 88.62
used to determine the accuracy of a
{iSt>* A

of 271.1 s s found in the one determination
rssn

277*21*
Am n

m um am

In this reaction one-half mole of the sodium
naa prepared as before* lo this was added one5 g.) of benzyl chloride over a on© hour period*

m s reflu&ed for 6 hours*
$h© extraction and purification of the product
serried out as in the previous oases*

Instillations

ssa*
6Q-X20o/S « u

ISQ-UEP/S

140-16ff»/2
163-8IS°/2
219-E40®/2

® * twwstloa boiling at 140-163®/® mm. aas waistmed t*tee,
fisA then tnw crystallized from hwoane three tisseo to gSto
Mne, asfctaft i&tte needles.
B.P.

14&-VS$»/g mt,

S,f,

30.2-30.6°

BSf ©Sind

Non©

Br found 2ta©
"Bias© data agroe wiili tM-ae gfcson % Sahorlgtn (142) and %

Huston, a^rtout ami lar&vjall (77)*
m m u, ebiee

mu
tapt,
usa*
ess*

lTO~240°/2 an.

fbe fiaetlona boiling from llfl-l?0°/2 art. wwre redistilled
four tlsma to give a clear, light stwor colored liquid.
Ba>»

318-124°/S an.

*s^

1.5750

B*»

1.0665

Br ealod Hons
Br found Homo

mtm: crystallised from

un­

til tfc©
of the tta&© j reactions which M l been n m* *161
24 and 29
«&££& Bad
(11.8 g.),
Bad tlia

ias 20 percent (37*2 g.5* One reaction,
n m 18 hours, gave a yield of only 8.5 pareoat
B j© product consisted of short, white needles and
constants?

b*p.

m *

Br calod

28*83 pemsal '

Br found

28*79, 29*02 percent

tbs boiling point of this expound m determined by the
careful distillation of

pur© product is found to b©

considerably lower than the toxaperatures given in the dis­
tillation of the crude mixture* USd.8 superheating m s
consistently found in all four of the reactions run*

mm
Distillations
83-100% TO*

.3*0 g*

100-180^/4 TO*

17*1. g*

180-190^ TO*

7*3 g*

190-220^/4 TO*

2*0 g*

22Q~25Q°/4 TO*

5*4 g.
3*0 g*

the fractions boiling from I50-190°/4 to* were redistilled*
The distillate m s crystallised, with difficulty* from 93
percent ©thanol (at 0-10°) • The product m m filtered and
dried in a vacuum deasinator at 10°*

ether, in the

form of a flocculent, powdery mass* m m obtained in an
average yield of 14 percent (19*3 g«) •

ethanol without difficulty to give flat wiait© needles
bromine content of this
£&& found t o '

* Uhia value ©or-

to the bromiis©

for tho 2-bromo-

other of

mossM*
were run using these
Ibr both a ruction time of M hours mm used*
TSie

purification of the 0- and <!r-hroiaohenaycrude) m s carried out as in all

77*
TO* T O redistilled
teles* Some difficulty in distillation was aT OT O r o l
to the tendency of the product to solidify in th© sidearm* fhe resultant crystalline compound was rocryetalliaod
t&m hmmm to give vary short* white fluffy needles in an
average yield of 16 percent (2 2 g*}*

Br found

s*

of 31 g* of crude
ether from the Clatsea
solution treated reaction Msture*

8*3 g*

SO

g*
7*4 g#
11*0 g*
7*0 g*

^1*4 ■g* ■
fhr

H * 0 g#

ffee fractions boiling from 160—203°/3 t o * were redistilled*
Boring fr»*V distillation it was necessary to heat the sldeayPiwith a ssierotmmer to prevent crystallization of the

78*
ttampouad* Bis crystalline product was recrystalXlsed
twieo. twm 98 percent ethanol to give short, fist white
needles la 10,6 percent (15 g,) yield,
137-l&l0/8 t o *

-Hr
Br found

29,13* 28,87

p -o^oi m z

mmmmi

Bos to the relatively excellent yield of this
reaction only two such condensations were necessary, One
of thaw© wro run without the addition of the d-rothylphenj
4-hroinohenzyl ether; in the other this ether was added to
the reaction mixture.

65—85 /3 mm.

"9*3■g*

83~X7S?/3 TO,

33,3 g*

175-190°/3 TO,

13*4 g«

X9O~22G0/3 TO,

30*9 g*

gB0-S4O°/3 TO,

2,2 g*

240-250°/3 t o *

7,1 g*

^Ear

3*8 g*

The fractions boiling from

TO, and 240-250O/S To ,

remained red oils; while all the other fractions boiling
fro® 85-340°/3 t o , crystallized very easily, making it ne­
cessary to boat the ai&esm during the distillation* Bias©

were redistilled twice and were then crystiaXliaod f r o

* fluffy white needles were

in 41,9

«& g*} yi@M* Mum 14 g* of
ether were added to the

reaction ir&acfcure* this yield of 2^ydroxy-.5-methyl-4»m m decreased slightly to 39,7 pej»

61 .6 -6 S.20

Br ealed

28,83 percent

Br found

28,76* 38*82

10*5 g*

1*8 g*
7*3 g.
The
very

boiling from X45-X$5°/4 &s* crystallized
it necessary to hast the distillation
with a microbumor to prevent cryin the sidearm*

compound ms- crystallized

ethanol, It showed remarkably low solubility
in this solvent, even When heated*
loth reactions, the mss with, and the one without*

€0*
athor* It

obtained in

ot abort + ttm , Hat white needles,
B.P.

X61-165?/2 as.

H.P,

10i.5-102.0°

Br calcd

38*83 percent

Br found

28 *79 * 38*68 percent

An In. the same

using o~cresoI# one-half

of sodium o-eresolate and one-half mole (64 g.) of
chloride m m

to react In toluene for a

o f six hours.
The extraction

of the product®

carried out as in the

<fhe fractions boiling from 135-210°/3 mm* were redistilled
twice* and the low and high boiling fractions discarded*
*ph<5> intermediate frsctions obtained ware crystallised from
hexane until a constant melting point was achieved* Timm
eryst&lXi&ations had to be carried out at about I0°* She

81*
.

product was isolated in tha tom. of fins, white* fluffy
noodles.
B,P.

144-147^/3 jam*

* J f*

36*2-36*8^

Be calcd

Hone

Br found

Horn

Urns data agree with those given by Huston and Lewis (78).
*-aeim£mBHL bslctl snsit
Bistillation;
40-125°/3 iam*

2*7 g.

135-L50°/3 » .

6.5 g*

i50-X9#/5 turn.

3*6 g.

The fraction boiling from XB5-150°/3 m * webs redistilled
once and then crystallised twice from 95 percent ethanol
to give 3*5 g* of thin, white plates* The amount isolated
was Insufficient to determine the boiling point accurately,
M.P*

40*^41*#

Hr calcd

Bon©

Br found

Hon©

This melting point agrees with that given by Staa&el (190) w
and by Boston a M Leeds (78) •

82.
wmmm of y m m m > mmtcjuu cm zzxim
to the liable ©a the following page are given the

constants of the compounds prepaired, »»«&
which Tsejpe isolated*
to# yisMs are based oat the quantity of pure pro­
duct obtained. As a considerable aismmt of the desired pro­
duct in lost during purification, the yields reported are
l<m&T than those actually given by the reaction.
The boiling point# given vmm obtained by the dis­
tillation of the pur© product under reduced pressure* fMs
pressure mas assured usiiig a tilting type Hctood gauge
'• iiu*
to© products of these distillations wore cxystalsithsr hexane (for phenolic compounds), or from
93

ethanol (for the ethers), and dried at soem temperaci^ystals obtained mr© used to detomiln© to© melting
given an the table, by the capillary-tube zsethsd (185).
point's or© imeorrec-

ted*

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85.
PROOF OF

A inusbar of methods ax1
© available illicit xssy be used
to promt that structures of the confounds obtained,
16 determine the structures of

o* and p-benay-

prepared by Boston et al* {191} * each of the
chlorides was condensed with 2,4-dibramopbanol by
the CXaisen method, and with 2feHaiba?oBiopheiioX by tfcs Frie&elGrafts method* fhe condensation products wore proved to be
identical with those obtained by the broiainatian of the eondenH
sation products of phenol and the hxomh&msyX efclorides,
A number of degradattve methods are available* Gzl«
aatiou to the bemopheaenes can be accomplished by chromic acid
or alJsalin© potassium pertmsnganate (192 )* TO
rdroxyl group its methyl ether must -be
to the oxidation* Although th© msthyiene group Is
Much store liable to oxidation than is the Methyl group, the
latter way be oxidized to give rise to a earboxylie add W produet*
If the benzophenones can be prepared from the &Iphenylmethaaes they can be aplit 'by treatment with sodium aside
in

benzene under

£ ~ 0 ■«*S*
II
0

r e f lu x a s show n b y

Haller*

-h s - c »
I
Olfc
-f RfH 4- £*- c - m
I
0£h

(2 0 9 )

87,
T&e problem of the separation of the four products would bo

to alternate method of splitting of the beasojifeenones entails the preparation of their oxMes.

This m y

prove to he difficult, especially in eases where o-posltione
on both rings ere occupied*
If these oximes can he prepared, their syzz and
anti forms m y he separated partially by fractional crystallX*
station from a glacial acetic s o M * mte y mixture (193)*

These

benzophenones can than he rearranged to the
m a m of the Beckmann rearrangement, These can he
using concentrated hydrochloric acid at ISO® (194) to gits
In spite of the original geparatioi
of the isomers, the purification of these products would be

Because the above methods introduce difficulties
in separation, a need for fairly large quantities of
er the necessity for the syntheses of other compounds
methods were found to he preferable*
These consisted of the dohalogenation of the bromobensylaied cresols to the known benzylsted compounds} and in
the ease of o-ereaol, the rearrangement of the ©them formed
as by-products In the GXaisen C-bossylatlon, to the parahrosa©**
benaylated products identical to those obtained by the FTiedelCraffcs method*

n»
CO*
MAmmmsme of i m

mmxL

A s Claisen BearrangaMenfc of ally! ethers of enols
end phenols (103) requires the following group of atoms In
order to tom the rearrangement take place$
^-0-C-G~C=C~
•

i

i

i i

As the ’benzyl ethers contain the requisite group
of atom, numerous attempts have men. made to rearrange these,
mtag conditions similar to those used for the allyl
ethers did m m affect rearrangement (196),
Gombexg and Buohler (358) believed that they were
with a rearrangement In the reaction of
to give bsjszylphenol# However, as
shown by Clalees {197}, this reaction Is net his to a re­
arrangement of the ether* A s phenyl benzyl ether, when
oouM not be rearranged by the ©oMItions used by
and Buchlsr#

phenyl ether; but as he worked in the presence of concentrated
hydrochloric aeid, it is probable that the reaction took pimm
by flitting to give the benzyl chloride which subsequently
reacted to give the benzylphenol.
t.99) prepared a small quantity of 4-»
by heating the benzyl phenyl ether with
■yrt«« chloride* Short (3QG) treats the other with anhydrous
Sis® chloride at 160°* or at 100® when a stream of hydrogen
through* Be obtained phenol, some o-

found this reaction to be intexraolecular with
as 2,4-dIbenzylphenol vms
all conditions tried, ami as in the presence
mors than half tbs benzyl groups became attached
to the aaisole nucleus.
(202) found that heating phenyl benzyl
others to

&t& sodium fear 88 hours usually resulted in

a

to a carMnol. A w , 22 g. of
1*5 g* of toluene, 3 g« phony]

mol, and 5*7 g*

* A i a did not hold true to r om

did succeed in re-*
ethers in small yield, without the
presence of
for

hours under reflux
contained a 10

5 to give a
yield of

, and

was found, to be mush more rapid and
idsan some a i m or copper mam added to the ether*
Bowever, even then the reaction temperature mm% be kept at
2 SCP# q<s at a lower temperature no rearrangement takes place*

Sefluxing the phenyl benzyl ether with a pi^ee of zinc to r 18
gave © yield of 27 percent of a mixture of o~ and p~

©ml a 20 isiaaii yield of o—# p-dibaasyXiiMiol;
o f phenyl benzyl ether proceeded
without zlae, that of o< natj&thyl benzyl ether west
rapidly. The possibility of halogen impurities la the o©&*

benzyl ether

as w e n as sow 8,
et si* (f?)*
group shifts
to the position p~ to the
of the

other the

la the
does net take

©r

of the Sther using Z & m and Boat*

and five grams of zinc, were heated to

for 23 hours,

reaction mixture was then treated with Claisen solution and

with ©thyX ether. After removal of the
by distlXiatiGn to

0 gaswm of. a yellow, viscous liquid boiling at ISSklTS^/

su
XI* Rcarrangeiiamt of tee Xttor using

B d and teat.

A t o method as teteteped by Aort and Stewart (201)
petstte the reaction to be earselsd out at a loser temperature
than the 250° used before*

Therefore leas deeoKgpoaitim w edd

be expected*
Fifty grama of the S-^thyl|di«^lbre^beiizyl ether
were eoisMne& with 3*0 grams of ate chloride ant heated to
ICO*5. At this temperature anhydrous hydrogen chloric Crus,
throng ooncentrated sulfuric acid) m m “bubbled through the

molten mixture* The reaction vessel m m shaken occasionally.
It m m found that two hours m m sufficient time in which to
complete the reaction.

Tim hot mixture m e then poured into 20G in!, of
water, and the product m m extracted from the acid solution
with ethyl alter*
Alter removal of the solvent , treatment with Clai~
sen solution showed no t m m of the original oxygon alkylated
eompomda.
A © phenolic fraction, recovered from the acidi­
fied Glaisen solution, m m fractionally distilled. In each
case a low boiling fraction (B*P* 50~65°/3 mm,, 185-189°/
70S ass.) was Isolated* Ala m e stem to be o-cresol (B*P*
191°/760 m*l W preparing its aryloxyaeetlc a dd derivative
(204), M.F, !52-X53°* A mixed melting point with the same
derivative prepared from a sample of o-af^d (M.F.
dojwad no depression*

A e higher boiling p-bronotenzylated o~cresols
ware distilled ©t least twice, than crystallized from hexane
until a constant melting point m s reached* These cojnapounds
m m thee redistilled and recrystallised. The physical con­
stants are given on the text page,
X» each case oils which probably consist of the

93.

CH.

BH

Cte

BR__

H0 <
O

f

-

)

0

'

"

-

c

B.P. 173-176°/2 xanu
H.P. 55.4-65.8°

B.P. 136-X40°/S mm.
M.P. 46.6-47.2°

CH 3

CHa

br

Br

OCH
o

B.P. 157—162°/3 nm,

■

“

O

e H *

B.P. 172-175°/3
M.P. 46.4-46.8°

M.P* liquid

B.P. X52-X55°/2 m .
H.P* 70.8-71.2°

|.P. 1 ^ 5 ° / |

o

94*
I& &Xk eases the
arrattgamBnt of the

mm, obtained

obtained by the reayl ethers * Tfcleh

by-products of the Claiseti method eo&as the products o f
points of

1to 2*riedel-Gra:£ts

end the BeiedeX-Crafts condense-

t%m

no
*&$ mde to rearrange the

ethers of

95.
M

- A1 ALLOY A3© ACglSOOS A2XAH

so develops by Bapa and eosorkers (205),
i to be

to this problem*

the

not attack the phenolic hydros group.

procedure ten
no*

m

to 96P » $ s r

She reduction, uhll*

of the phenolic compound
sodium hydroxide end heagrams of Bsney^s Hi « AX alloy

to the eolation* in

The

all portions, and

for an additional hour.

hot and the filtrate
of benzene, care being taken
not to let the
cooled and then acidified to oongo
solution into concentrated by-

by

of

b y

*)

After

purified by distillation

other

so b -*

creas in all

Ho yields are given in these inactions, as smll a—
mounts of compound tuere used, and as each reaction i»» carried
out only ones. However, it may bo stated that the yields isere

9ft.
excellent in all eases*
The physical constants of the three
■0—

In the literature ares
(i).
ISO-

# O V s u @-s s j

o

constants agree with those of the thro©
reduction
shosn e& the

of the .sine

97.

CHS OH

CH. OH

Bromine Position
g»

3*

4*

B.P. 137—X60°/ 162-167°/ 163-164°/
2

sm *

2 m »

B.P. 148-153°/2 am.

3 e e l*

H.P. 30.2-50.6°
M.P. 41.4—
42.0°

4G.3—
49.4°

50*6—
51.0°

CH»

CHs
OH

Bisoiiano Position
2*

(IX)
4t*

3*

B*P. 158-161°/ 174-176°/ 172*175°/
2
2 ram*
2 hie*

B.P* 144-147°/3 im*
M.P* 36•2*36*8°

H.P. 47*5*
48.1°

58.899#2°

61*662.2°

Bromine Position
3*
3.P. 173-176°/
2 mm.*
M.P* 65*4—
65*8°

(III)

3*

4*

173-175°/ 185-185°/
3 mm.

46*446*8°

2

B.P. 155-158°/3 rmt

mm.

75*4—
76.0°

M.P* 49 *6—50*2°

t& order further t© prove the structures of tbs
reduction products (X* XX« XXX) tbs three bensylated eresols ^lere prepared by tbs benaylation of tbs e- a M p~
sxesols* as described previously* Mixed ssslting points
using these products a M those obtained by the reduction

$9 « solution of 3 ml. a t pyridine and 1 si* of
beaascyl chloride (la a ten inch test tube) was added X
S®0®. ^ b&e

This mixture* protested by a drying

tube, m e Heated la the steamhath for ono-half hour* it
m e then poured Into 10 ml* of water, Tbs benseate nas
extracted with ethyl other* This ether solution m e washed
■with dilute sulfuric acid* 10 percent sodium carbonate solu«
tion and miar.

The ether was evaporated off and replaced

by 9$ percent ethyl alcohol. The white crystals obtained
from the ethyl alcohol on cooling ware filtered off and
dried at room

TO 2 grams of phenol in 5 ml* of
added B grama of p-toiuene sulfonyl chloride. The solution
mm heated in the ste&rabath for one-half hour. The purifi­
cation of the p~boluene sulfonate mm accomplished m in the
case of the bansoate*

fbr the preparation of these derivatives the pro­
cedure of Eoelaeh as given in Shriner and Fuson (206) m e used#

These were prepared by the acme pyridine method used
in the preparation of the benaoatea* However* this preparation*
and the subsequent crystallisation, of this derivative proved to

be so difficult that only a few were attempted*
Th© 3 *5-dirdtrohenzoat© of E-hydrtHsy-S-methyl-d*Inromodipi^nyliaetliaiio (M.P* X57-1580} was found to contain
15*96 percent Br (Caled 16*96 permit Br) * This was the
only 3#5-dinitrobe&zoat© which could he prepared from the
three P-bromohenzylated o- and p-oreaola* ds ©an be seen
from the bromine determiiiation, this compound is Impure*
&

farmer attempts were mad® to prepare thee© derivatives*

The henaoates for the nine o- and
benzylated ©~ and
wore
ly for only seven of the compounds* In the case of 4~
and S-hy&noxy-Stlieso derivative were IsolaMteioh could mtt b© crystallized*
Mm attej^t to

mphtlylurethanes

of these ism
The

and the bromine eon-

of the derivative© prspared Is given la the table on the
by the
eapillary—tub© method, the bromine content was determined ly

ioi.
HE
«

M

1
1
1
V

$
5 £
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ft
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If t S
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to

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IS

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■&

m mmmm, iwm m
tto Bsnay

method of Papa and co*
r* the m o m familiar

pertKsid© fusion method was used (207)*
approximately 10 grains of
sodium peroxide* 1 to 1*S grains of potassium nitrate and 0*40
to 0#4B grams of earn sugar was placed in a Parr tomb. TU
this wars

0*20 to 0*00 grams of the sample to be ana**
were mixea thoroughly.
Use bomb wm placed in a shield, and tto ebax^e
over a Bunsen flams*

eceomplleh this* beating

mm necessary far up to throe minutes*
The melt w s cautiously washed into 200 ml* of hot
water in a 400 ml* beaher and digested for tern minutes*
An excess of 0*1 H silver nitrate m e added to the
solution, and the precipitate m o coagulated by boiling for
15 minutes*
39» solution % 6 thou acidified with concentrated
nitric add*

To reduce any silver bromate formed in the re­

action, hydrazine sulfate mm added to the tot acidified soIuh
tion mill no evidence of nitrogen evolution was noted*
*&m excess silver nitrate present was determined by
the Yolhard method (208) using standard ammonium thiocyanate
(approximately 0*1 Bj and f©rric-ar®K>nium sulfate solution as
indicator (5 ml*/200 ml* solution). The addition of 3 ml. of
nltrobejpasene to the solution before titration removed the

IDS*

order to determine the

effective-

coefficients of tbs

of these compounds in
or
mad© it

to get an accurate
to

of the alcohol solution on the addition of the
very inconsistent*
in tit© order of from ten to

were inaccurate because of
a eolation, s M the contribti^

effect of the

That the

of
©f in©

by the
concentration of alcohol
m

.

phenol has a

* <jba author 1* iMsbtod to Dr. W.L. ifelimarm and Mr, B.P.
Homan for those determinations.

yield from the em&m to ito final pure product* tor this
reason statements based ©a the quantitative relationships of
the yields of the reaction produets mmt to made with asm

10&.
to practically ail cases, war© highest !&»» p~br©n©b©nzyl
chloride mm used to to© condensations* and lowest to to©
case ©f m^bwmobmmvX chloride* to© mm exception to this
wa® toad to th© two condensations of p-hromobonsyl chloride
m& sodium o^eresolate* which were isolated to yields of
only 8*7 and 8*8 percent* it to interesting to m to that to
the sideehato ehlortnation of the three- brcaaotolnenes (tietog
sultoryl toXarid®, and catalyzed by benzoyl pereocid*) the
yield of jnbrsmbenzyl chloride to the highest, and that of
m^brtmohemyl chloride the lowest* of the toy©®* The initia­
tion temperature necessary for this chlorination m s lowest
to the case of p-hreraotolucne, highest for jiwbroznotalueac*
It has t om stated that to’the Jnedel-Orafts
bonayXation of phenol the presence of bromine to the nucleus
of benzyl chloride favors toe formation of toe phenyl t o e *
benzyl ©ttor (191). This has not t o m found to to true to
m y extent to the brcmtonzylation of o-cresol, to which only
e m U amounts of oxygen alkylated fractions ©me Isolated.
Tim cjaantities of these products were insufficient tor puri­
fication m 3 identification* Bowever, to toe m m of p-ercsel* where toe position pare to to® phenolic hydroxyl is
blocked, the aluminum chloride catalyzed condensation with
p-bromohensyl chloride gave m average yield of 24 percent of
tfc# d-i^bylphenyl-d^hromohenzyl ether and only 4*S percent
©f the 2—hydrc^xy—5-i®cthyl—4f—broi?x)dip1ieByliaethane•
The fact that to® addition of the oxygen hensytoted

207*
product to toe

in to© Claieen sslhod beazy—
of G-benzylfited product has b o m
* These wea&sm

•of 3~chloro*t or 5-bromo~
of a large
ofm

to increase too

and

of

of ©~ and p-cresoi to©
addition of

out in too

toXoride* •In toe m m of the

atom- to- to©
of 2—hydroxy—
from -8*7 percent to 22*8 ■
of £&'$* of too other Ineiroaasd toe
yield of too yea# product tc
toon 14 g» of too
W it h

to o -O ta u m

ohloridot too yioM of
to© little affected (41*9
addition of too other, 39*7 permit wito
14 g. of turn other added) *

In the

®»& Q-bromobeiEsyX
©f IS g* of
in toe yi«

of

from the 13

without the
of 01 g*

tosuffiei®a& to

of toetoto, ft. to

cause an

©f too
to® throe p f s p of

and ortho

*

3 % or 4*
to thair

p* 97}
of

contain the theoretical

in removal of this bromine oil tiro®
as to

constants obtained agree with
to to®

[Bm p. 96)*

to further pr<>of of structure the o-> m~, and
others of o-eresol, which mrs obtained a® hi-

XD9W

product® to too eon&eneations of

broKBObenzyl chlorides sad

sodium o-ereeoXate* war© rearranged to give the para broso-

ben&ylated o-erasola which war®

to be identical to those

obtained by the ihrIe&el~Czufbs

(Bern P* S3).

the chlorination of p-brojaotoluene* one reaction m s run to cosalcohol and o-croaol in the presence of alomtorn
was fbund to bo identical to that isolated from the re-

was made to Isolate or purify
k

7jtU*rf»*4w A jS

ftt

boiled at

obtained from the filtrates of some of
hexane war© Itoewiee not
All the
to toe m i MlXy % Go*

# a total of IS* were
Laboratories for tasting.

1X0*

were prepared by toe &&*»*
dteX—Grafts synthesis:
4-hydroacy-l

The

-broiaodipliQnylEKJtlian®

were prepared by the CXsi-

of O-alkylation of

fh© structures of the G-toMnohensylated cresols
were proven by reductive dehalogenation of the eorrespon-

$t*e o*-* an,
mm

f in the

the para

ethers of o~ereaol
of 3n0Ig and HCl, to gire
identical to those ob-

tained bjr the

role of the addition of the
ethers to the
further

> obtain the phenol coefficients of
mot successfulr due to their lo®r solubility*

hare been tested hr the H I Ml*
& $©» Beeeareh laboratories for -specific bactericidal aeti-

118,
HE3EBEMCE3
1*

S#G« Huston and a *L* Honk, J, Am, Chem. Soe., 54, 1S06 (1932);
H*C. ffijston, A. Beeley, B.L. Fayerweather, E A S*Aroy, F.H.
Hatfield, M.K. Ballard and W.C. Lewie, J. Am. Cham. Soc., 55,
2146 (1933) ;
a.0. Huaton, R.L. (Julie, P.S. dan, 17.U. Headley, S.W. Barron,
L.S. Banr and B.O. Hate, 1, Aa. Chon. See*, 55, 4639 (1933)*

8.

K.Q* fanes, Personal Cosmunioation.

3*

A. fans, Ann.. 183. 84 (1870).

4.

A . Ztaeke, Ann*, 139. 374 (1871) j Bar., 6, 137 (1873).

5.

Th. Zinoke, Ann., 161. 93 (1872); Bar*, S, 799 (1872)} Bar.,
9, 1761 (1876)|
~
J.T. -aalker. Bar., 5, 686 (1872);
8, Hazzara, Jb., 402 (1878)j
®. Weber, Jb., 402 (1872) ,

6.

Pleeeuda and Th. Zinoke, Ber., £, 906 (1873);
P. SeaCf, Ann., 23S. 329 (1886).

7.

H. Sohlff, Bar., S, 288 (1872); Bar., 5, 43S (1872);
S. Patamo, Gaza. ehlm. ltal., J, 2 (1372); Getz. ohim.
ital., 3, 121 (1873);
E. Patomo and S. Mazzara, Sees. chia. ltal., J3» 303 (1878);
Ber.. 11. 2030 (1878);
S. Bazzara, Gazz. ehla. ltal., 11. 347 (1881);

Th. Zinoke, Ann., 334. 367 (1904);
IS. Bakunin, Oazz. ehtm. ital. 53, 434 (1904).
8.

0. Melster, Bar., 6, 963 (1873);
7, Heyer and C. Burster, Ber., 6_, 964 (1873).

9.

A. v. Boeyer, Bar., 3, 28 (1872); Ber., 5, 280 (1872); Ber.,
3, 1094 (1878).

10. A. ▼. Baeyer, Ber., 39. 3018 (1902).

1X3*
SX» Mm B » t a m and Tiletl, Gaaz. ehim. ital., 3, S82 (1875).
IS*

A. Uefcaano, Be*.* JA, 184S(18815; Be*., 1§* 152(1888).

13.

C. Ketedal and. 7«M. Crafts, Ana. ehim. at pliys.(8).
449 (1SBA).

14.

JUH. Bennie* 7. Cham. Soe.. 41. 280 (1888).

15.

SiHt Hannio, 7* Chain. Soc.,

IS.

7*0. Kef* Am.* 898. 854 (1892).

1.

40S (1886).

17* C. m e d a l and 7.B. drafts, Compt. rend.. 84. 1451 (1877).
18. A*, 7. Baoyer, Ber., £* 963 (1873).
19. H. Caro, Bar., jgg* 947 (1B92); Be*., Jj®, 255 (1893)f
8. Ifaehlatt aad P. Sam, Ber., 27, 2896 (1894)$
1. Eahl. Bm.* 31, 144 (1898)»
20* 7.B, Kiedarl, 7. rriedorl, 3. Shapiro and M.E. HeCrsal, 7.
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31.

W.3* Caloott, U
H 4 » r and 7. Salnmeyer, 7. Am. Chem.
3oe», J&, m o Usao}*

22*

J.F. M e i a t and F.T* Soaaa, J* Asa*Clxsm* See*, 59. 470
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23.

3. FoeXdi, Bear.. 61. 1609 (1928).

24* W.H. Ferlcin and W.R* Bo&gkinson, X. Chem. Soc*, 724 (188G).
25. S. Fatf0i?BO* Bar* , 5. 268 (1873) * Boy.* 6 . 1201 {1873}.
26.

K* Anrnx*! Beg*.,,
34. 4286 (1901).

27* Km Mlw0T0p Bey.* 36* 1878 (1903) 5 Ber*, 37, 1470 (1904).
28. &* Atiwys* Bey*. 28* 2899 (1895) 5 Bey*. 28* 2908 (1895).
29* Km Atmers and IS* Hteta, Ber., 38* 3302 (1905) *
30. Mm Kcfim and M*
45, 251, (1924) *

Monatsh, » 44* 198 (1923) | Monatsh*,

31. W.C. Harden and J«H« Brewer, 3V Ais* Cheia* Soc*» 59* 2379

114,
32*
446
33* M* V*
M. T*
M*. V*
at, 906
34.

a»d 7* Mufe^ Ber*,
Ber** JL, 538 (1873)*

447 (1872) | Ber*, 6*

and Schmidt, J. prakt. Chem., 25. 346 (1881);
and Sieber, j, prakt.Chem*, jgl, 147 (1881)$
# 7* pmkt* Chem., 25, 273 (1382)$ SSonatsh.,
and 2P*W# Lane, 7# Am. Chem* Soc., 43. 348 (1921)

35* A.B.X*
36.

B A Cocc and &« Hiller, J. Am* Chem. Soc., 48.
* Ber., 46, 1837 (1913).

37*

and at* v. EostaneekX, Ber*, 27, 1997 (1894)#

38*

and G*H. Palmer,!* Am. Chem* Soc*, 7, 275 (1885)

39.

.Kaiser, X. prakt. Chem., 43, 86 (1891)$
*

40*
41.
62*

X* ir*

1, X. Am.- Ohem. Soc*, i
511. 605

X* Am* Chem. See** 48. 791
SOC*, 48* 2358 (1926)4

$ X* Am. Chem*

, X* Am* Chem*. Soc*, 48j 803 (1926) *
43. 0# Priedel

X.E* -Crafts, Cosrpt. rend., 84, 1458 (1877)#

44# X*F*>ltoria, 1. Thomas and B A Brow, Ber*, 43, 2940 (1910).
43* P, Bearcat, Ball, coo# ehim., (3), 15, 945 (1896)*
46* G* Bailer, Ber*, 46, 1497 (1913)*
47* X. Heiaeahclmer, R. Hanasen and A* WRoehtercwita, X* prskt,
Chem*, 119. 318 (1928)*
48* 0* priedel, X.M. Crafts and SU Ador, Compt. rend., 85, 673
(1877)*
49* 0* Priedel and X*H. Crafts, Cosapt. rend*, 04. 14^5 (1877).
50* E* Behh, Qersan P** 95,901 (1897) $ Chem. Centr. 1098* X,
1223*

.

115

Roaenmsmd a M K* Schula, Areh. Fhsrm&z. Ber. dent* Ges«|
MS* 308 (1987)| CSiom. Oentr* I9g7, X, 3184.

m * . E. 2*l©s and a. Mnk, Ber*, 41, 4876 {1908}f
K* Ifete* and W. Pfaffendorf, Bar.* 43t 814 (1910).
S8i H* Mam®, "Organic Reactions ,* VOX. I, John S&Xey and Sons,
tmmw ^BW M t f H.T*, 1948, pp. 348ff.
34* Pope,
gt£* B.H* 0OSE, J« &3SL+ wtistiaf uwu* | t»a.
86# E.W* Bosennamd and W* Sehnarr, Ann., 460. 86 (1988).
i,-^,A* Stto3®or aid L.W.
•*

J. Am. Chont* 800 *,

£>«W* Sates, 7,A. Shtesnor and P*H. dose Jr., Tt

to. Chest. So©., M , 4687 {1933},
88* C»S«. Coulthard. J. Marshall and P.L* Pyman, J,
880 C193©}#

»w»,

§9, E.O. ©alXesffiiy, Chem. &nr*# jg* 2&7 (1935} $

0.0* Price, Qua, Be*.,

37' {1941}j

0, Kr&anzXein, "Aluminium ChXorXd In dor
t, "tohyirous iUnminm Chloride in Organic Chemi­
stry,* A.0.S. Monograph. 87. Boinhold Publishing Corp., mm
M k » E E * l«l|
P.E.
<8*0 *,
7^5—SOS*

W

Pxooesses in Organic Syntheses,* 3rd
Book Co., Inc., Jte? Toik, H.T*, 1947, pp.

AS* 'Crafts, Ball., so©* ehim.. 87. 48 (1877) f
60, 0*
,,j&#
84. MSI
{1877}; As
tot. ©him* at phys.,(6) 1,
Compfc, read.,
M M (18771s
478 (1884)| ton. ©him* at pfeys*, (6} J|t 460
&U

W.H. Pes&Xn and W.B* Hod^dLnaon, J. Chem. Soc., 37, 786 (1880);
P. Scuff, ton., ^Q* 288 (1883) 1
E. Louise, Ann. ©him. e* physu, (6), 174 (1885) s

2X6*
B* Oeigy and W* Keenly, Ber*, 18, 2402 (1885);
H* Gaaalrer, Ber*, jgj* 3021 (1892); Ber*, 25, 3025 {1892} 5
3T* 3 t o a % Ber*, Jg* 1?09 (183$);
H* Moses,

g$» 3627 (19001*

OB* O^Srle^l and Jf*M* Crafts, Aaaa, ehim. ©t phys., (6), 1,
83, X* Limitnc and i* Lombard, Boll* see, chlm*f (4), £, 539 (1930),
84, C*B* Henitzeecu, B.A* Xaaeesou end C*H. Xanescu, Amu* 491,
210 C x m li
85, J, Boesekan, lee, tm*tr. ehim., 24, 8 (1905),
86, 0* Frie&el and X*H* Crafts, Boll, see# ehim., (2), 43, 53
(2885) ;
G,

Ber*» 27, 3235 {1894}*

67* X* Boeseken, lee, trar* ehim* , 23, 98 (1904) ,
60,

and j* Ihrnik, Asm,*- 491, 265 {1931},

69. 0. .aedmimRumHltl* Ber*, j£7, 3235 {1M 4}|
H. 8eh02X# C* Seer and E* ISeisanan, Ber., 55* 330 (1922).
70, CmFried©! and X*H* Crafts* Bull* see* ehim,, 41. 325 (1884}.
71* X.E. MT, Amu, 398, 254 (189B).
72* H.C, Huston and ?«&« Frie&emam, 1* Am* Chem. 3oe., 58. 2527
73* 7. Merz end W* ifeitfc, Ber., 14, 189 (1881).
74*

B.C. Hoston* 1. Abu Chem. See, # 46, 2775

(1924)*

75*

E*C« Ihaston, A* Heeler* B«L» Fayerwesther, H#H. D^Arcy, F*H*
Maxfield, m*M* Ballard and W.C. Latsis* 1. Asa* Chem. Boo*, 55.
2146 (X»)|
R.C. Huston, R.L. Guile, P*3* Chen, W.N* Headley, G.W. £&rren, L.S. Baur and B.O* Mate, X* Am. Chem. 3oc*, 55, 4639
(1933)*

76.

Ii*C. Huston, Science, 52, 80S {1920};
JUG. Huston, J* Am. Cham. Soc., 46, 2775

(1924)*

** rawwm, H*A* Sseprtosfc aad 0*E* S&r&well. f * Jtou Cfcem*
S©e»* M , 4 m (3M0h
B*0* m&tom am W*C* Xewia* J* ito* Cfcem* 3oe.# S5* 2379 (1931)*

79* fr*E* MaacfieM* lfoafcer*s Thalia, Miehtgaa State college, 1929*
ao*

susd A«Lt

1• Am*

So0» , 34* 1506 (1^2)*

ai* B*C* Eoaio&p W*C* Lewis anti W*H* Grotemut, 3T* Am* Chem, Soe.,
,*a&4 E*W* ^feyio3clert J. Am* Qfetm* Soc* , M , 4317

N?

i, 1* Am* Cham, Soc*, 60,

am

T*B* i*rl©toaa3m, 1* Am* Chem* 8o*«v 3 8 . 2537

$ 3* Mm Cham. Soc* , 40, 785
i* *« **
and 0*0*

,23k*
X* 4m* Cheia. Soc*, Jg* 3955 (1928);
,* J* Am* Ghm. See*, jgS, 2432 (1954)*

l#

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»**.ehigan State College, 1949*

B.H* Baraale* J* Chem* So©*, 41, 37
m<

1.
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, »* wwmmzmv and H* i^aiseh, Bar** 32* 1129 {1889};
| Bey* jBS* 1203 (1S9Q)*

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90* 0.

and

»# 4m* ehim* Qt phys., (5) M * 433

91* J*W* Walker, 1* Chem* So#*, 84* 1082 (1904)*
0*0, Price, Chem. Ber*., 29* -44 {1941}.
93* 7«C* Whitmore, J, Am* Chem. Soc#, 54* 3274 (1932);
£•&« Otdle, PhD thesis, Michigan State College, 1939;

C*»* Benitseaea aofi J. Oereat, Ber,, 7pB« 1SS3 {1937).

124 ,

E.c. Hasten
sasao {i m } .

E*P* Bldridge, 2*. Am* Obem* Soc*, jig,

Igg, w.JT* Headley, Bachelor*© Thesis, Michigan State Coll©ge, 1928*
128* P.S* Chon, Ifoster*© Thesis, Michigan State College, 1930,

P* 3 c&0 rigl&, Bar* * ft* 2502 (1926) #

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3201 (1926)*
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Suggestions for further Investigation
A . CLAISEN METHOD
1.

Carry out identical Claisen method C-alkylations of
phenols in benzene, toluene, p-xylene, hexamethylbenzene, naphthalene, and anthracene to determine possible
increase in yield by increase in temperature of reaction,

2.

Does the Claisen method give ANT alkylation para to the
phenolic hydroxy group?

3.

Further investigation of the effect of adding the cor­
responding ethers to the Claisen reaction mixtures. Miy
does the ether of o-bromobenzyl chloride and o-cresol
decrease the yield of C-benzylated product?

4.

Can the o-alkylated product be prepared by the reaction
of o-chloromercuriphenol and benzyl chloride? If so, in
better yield than by Claisen Method?

5.

Use Ag salts of phenol in the Claisen method alkylation
and compare yields to runs using Na salts.

B. FKEEDEL-CRAFTS CONDENSATION
6.

Can the Friedel-Crafts method yield be bettered by using
ZnCl2 - HC1 rearrangement of the phenyl benzyl ether ra­
ther than the direct AlCl^ alkylation? This may avoid
the by-products caused by the action of the catalyst of
benzyl chloride.

7.

Purification of phenolic fractions into o- and p-alkylated fractions may better be accomplished by Ba salts.
The o-alkylated are water soluble, the p-alkylated in­
soluble, in water. This may not always work, but may be
an improvement on the separation by distillation.

8.

What is the red gas given off when the sulfuryl chlorideperoxide catalyzed chlorination is used with bromotoluenes? (Bromine?) Hhat are the low B.p. by-products?
Is Br removed or is it replaced by Cl?

9.

Brominate the nine diphenylmethanes prepared (in the phe­
nolic ring) and retest their pharmacological activity.

East Lansing, Michigan

Hans H. G-yorgy
12 January 1950