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I MichiganStatc ‘—
Benzylation of Pare.Cresol
Thesis
Submitted to the Faculty of
Michigan State College in partial ful-
fillment of the requirements fit the
degree or Master of Science.
37 ‘7
Wilfred C. LBWIB
1929
Acknowledgment
To Dr. R. C. Huston, the author
exPressee his thanks for generous aid and
kindly guidance in accomplishing thie work.
102368
Table of Contents
Historical-
Early work with Aromatic compounde,...........
Use of Aluminum Chloride as a catalyst,.......
(Work of Huston and others)
Benzylation of cresols, o.....................
The prOblGM, eeeeeeeeeeeeeoeeeeeebeeeeeeeeeeee
Experimental - Part I
Condensation by the Claieen.method,...........
Preparation of 2-benzyl 4-methyl phenol,...
Preparation of 2-benzyl 4-methyl phenyl
benzoate,...............................
Preparation of 2-benzyl 4-methyl 6-brom
phenol, ...............................¢
Preparation of 2-6 dibenzyl 4-methyl phenol
Preparation of 2-6 dibenzyl 4-methyl phenyl
benzoate) Ooeeeeeeeeeeeeeeeeeeeeeeeeeeee
Part II
Condensation by the Huston Method
Y181d’, eeeeeeeeeeeoeeeeeeeeeooeeeeeeeeeeeee
Summary, eooooeeeeeeeeeeeeeeeeeoeeeeeeeeeeio
Page
10
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13
14
15
16
21
22
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1.
Part I
Condensation may be defined as, ”A reaction
between two or more molecules of the same or different
substances with or without the elimination of water or
some other inorganic compound". In this work our chief
interest lies in those types of condensations in which
water or a halogen acid are eliminated under the influence
of a catalyst that may also act as a dehydrating agent.
Reaction between Aliphatic or Aromatic alcohols or haliies
and benzene or its derivatives are promoted by a catalyst
of this type. Some of'them.that have been used are: Zn,
ZnCla,,MgClg, SnCl., P205, P015, HCl, I and A101..
A search of the literature discloses many instances
of the use of'Aromatic Alcohols or Halides and benzene or
its derivatives in condensation reactions, and as such, have
a most direct bearing on this problem, a few will be g1! en.
Historical
In 1872 Paterno (Gazz. chim. ital. 2, 20)
prepared benzyl phenol from.benzyl alcohol and phenol,
using zinc as the catalyst.
O. Fischer (Ann. 206, 113-1880) condensed
benzyl alcohol with dimethyl aniline using ZnClg. Lieb-
mann (Ber. 14, 1842) in 1881 prepared benzyl phenol from
benzyl alcohol and phenol using the same catalyst. In
1881 Merz and Wirth (Ber. 14, 187) prepared diphenyl
other from phenol by the use of ZhClg.
Meyer and wurster (Ber. o, 963) in 1873 used
a mixture of 3330. and 01130003 in preparing diphenyl
methane from benzyl alcohol and benzene. Paterno and
Fileti (Gazz. chim. ital. 5, 381) in 1875 used the suns
catalytic mixture in preparing benzyl phenol from benzyl
alcohol and phenol.
Hemiliam.(Ber. 18, 2360) in 1888 used P305 to
form.diphenyl p. xylyl methane from benzhydrol and p.
xylene. Bistryzcki (Ber. 37, 679) in 1904 used SnCl. in
condensing benzhydrol with toluene to florm.diphenyl p.
tolyl methane.
Hahn (J. Am. Chem. Soc. 43, 175) in 1921 «Ju-
densed 4-methyl benzophenone chloride with phenol with
the aid of'P01so
The use of A101. as'a catalyst began with the
work of Friedel and Crafts (Comp. Bend. 84, 1392) in 1878.
They condensed amyl alcohol with various hydrocarbons to
form emyl hydrocarbons. Their work was solely with aliphatic
5.
compounds and they stated that A101. would not bring
about condensation with Aromatic compounds. Hewever,
subsequent work has disproved this. Merz and Weith
(Ber. 14, 187 - 1881) treated phenol with A101. and
obtained diphenyl ether.
Gustavson (Ber. 15,157 and Bull, Chem. 42,
525 - 1880 and 1884) develOped the theory that the A101.
formed an addition product in the reaction, which prod-
uct subsequently broke down and regenerated the AlCla.
This theory was confirmed by Schliechen and by Buttgenbach
(J. Prokt. Chem. 105, 355 - 1925). '
That the A101. may also act as a dehydrant is
shown by Jaubert (Compt. rend. 152, 184 - 1901) who pre-
pared aniline and p. toluidine from.hydroxy1 amine hydro-
chloride and benzene. '
In 1916 Huston and Friedeman (J. Am. Chem. Soc.
58, 2527) showed that benzyl alcohol when treated with
benzene in the presence of A101. would condense to form
diphsnyl methane as thejprinciple product. Small amounts
of ortho and para dibenzyl benzene and anthracene were
turned at the same time. Two years later they described
(J. Am. Chem. Soc. 40, 785) the condensation.of certain
secondary alcohols with benzene. Methyl phenyl carbinol,
ethyl phamyl carb incl and benzhydrol were used to prepare
diphenyl ethane, diphenyl prOpane and triphenyl methane,
A101. being the catalyst. It was found that the yiehdwas
greatest where the alcohol was entirely aromatic. The
4.
presence of the alkyl group had a retarding effect upon
the reaction but ethyl decreased the yield more than.methyl.
In 1920 Huston (Science 52, 206-7) condensed
benzyl alcohol and phenol using A101. at comparatively
low temperatures, forming p. benzyl phenol. Aniscl and
phonetol with benzyl alcohol gave better yiehis of the
respective ethers. Again in 1924 (J. Am. Chem. Soc. 46,
2775) Huston has shown that temperature has a marked
effect on the yield of p. benzyl phenol. Also that in-
creasing the amount of A101. above one half mol. did not
increase the yield.
Huston and Sager (J. Am. Chem. Soc. 48, 1955-
1926) found that the normal aliphatic alcohols up to anyl
would not condense with benzene in the presence of A101.,
but that allyl alcohol gave a small yield of allyl benzene.
0f the aromatic alcohols, only those in which the hydroxyl
is attached to a carbon atom.adjacent to the ring, will
condense with benzene. The hypothesis was advanced that
tnsaturation increased the activity of the alcoholic hydnaxyl.
In 1926 Huston and Bartlett condensed phenyl
butyl carbinol with phenol using A101. and obtained p. hydroxy
l, 1 diphenyl pentane. Huston and Strickler in 1927 prepared
p. hydroxy l, l diphenyl butane from pr0pyl phenyl carbinol
and phenol by the same method.
Huston, Lewis and Grotemut (J. Am. Chem. Soc. 49,
1565) in 1927 condensed methylphenyl carbinol, ethyl phenyl
carbinol and benzhydrol with phenol, using AlCl., u: farm.
5.
p. hydroxy 1, 1 diphenyl ethane, p. hydroxy l, l diphenyl
prepane and p. hydroxy triphenyl methane respectively.
Additional evidence was obtained showing that the alkyl
group of the carbinol had a retarding effect on the react-
ion, ethyl having the greater effect, but benzhydroxy1,which is
purely aromatic, gave the largest yield. The tendency of
the phenolic hydrcxyl to direct the entering group to the para
position was noted. Additional evidence of the effect of
unsaturation of carbon adjacent to the alcoholic hydroxyl
upon its activity was obtained.
6.
Benzylation of Cresols
When introducing benzyl radicals into the cresol
nucleus, a number of possibilities exist. The groups already
substituted in the ring will have a directing influence upon
groups which are subsequently introduced.. According t)
Holleman (Chem. Rev. 1, 202‘ - 1924) the groups which direct to
the para and ortho positions are OH; NH., I, Br, C1, CH.,
arranged in the diminishing order of their activity. The
hydroxyl group of a cresol, then, will have the greater
influence over entering groups and the methyl group practically
none. In the case of ortho cresol, one position, - ortho
to the hydroxyl and the para position,are Open. Hence two
mono benzylated o. creSOls and one dibenzylated o. cresol
are theoretically possible.
6 Huston and Swartout in 1927 carried out the benzylat—
ion of c. crescl by the use of A101. on o. cresol and benzyl
alcohol and obtained mostly 2-methy1, 4-benzyl phenol and a
small amount of 2-methy1, 6-benzyl phenol. About ninetem
percent of theoretical of 2-methyl, 4-6 dibenzyl phenol was
obtained. In order to distinguish between the two isomeric
mono-benzyl derivatives, the investigatdrshenzyla ted o.
cresol by the method of Claisen.
In this process (Ann. 442, 210-1925) the phenol
dissolved in toluene is treated with an equivahit of sodium
which forms the sodium salt of the Phenol. This when treated
with benzyl chloride first forms an addition. compound attach-
ing at the double bond adjacent to the O-Na, the halogen going
to the carbon.atom.holding the O-Na and the benzyl radical
.r.
7.
to the adjacent carbon. This compound then splits off the
sodium.halide and forming a double bond between carbon and
oxygen. Rearrangement then occurs in which the hydrogen on
the carbon atom holding the benzyl group shifts to hydroxyl
position and the double bond is reestablished between carbon
atoms. It is evident that by this means only ortln substitut-
ion products can be formed.
This ring substitution is not what one would ex-
pect, but rather the formation of an Ether. It is found that
when a dissociating medium such as alcohol is used in which
to dissolve the reactants, the Ether is the principle product.
But when a non dissociating medium.such as toluene is used,
"ring alkylation" or anamolous metal substitutionfi,/fi%§%£g,
formation of the ortho substitution product.
Claisen and Tietze (Ber. 588, 275-81, 1925) have
shown that when alkali phenolates in non dissociating media
are treated with unsaturated alkyl halides only ortho alkyl
phenols are Obtained instead of phenol ethers. And also that
the alkyl is attached to the nucleus by the same carbon atom
as it is in Ethers.
Shorigin (Ber. 588, 2028-56; 1925) states that
benzyl ethers such as PhCHgOR under the influence of sodium,
rearrange to form carb inols - PhCH(0H)R, where R is para
tolyl, cyclohexyl and benzyl. But ortho cresyl benzyl ether
gave a Phenol in which the benzyl radieal was substituted in
the side chain. Phenyl and ethyl ethers of ortho cresal are
stable towards sodium,and when heated give the Phenol and
Alcohol as decomposition products. This shows that the
8.
benzyl group must be present to permit of rearranganent.
Claisen and Tietze (Ann. 449, 81; 1926) treated
2-4 dimethyl phenol with allyl bromide in the presence of
K200. and obtained the allyl ether which when heated gave
almost quantitatively the 2-4 dimethyl 6-a11y1 phenol.
In 1928 Huston and Honk benzylated meta crescl
using A101. as the catalyst. In this Phenol both orth)
positions are open as well as the para. Hence the possib-
ilities for substitution are greater. They secured 5-
methyl, 4-benzyl phenol; 5-methyl 4-6 dibenzyl phenol and
5-methyl 6-benzyl phenol. The compounds were identified by
combustion analysis, and by the preparation and analysis of
branine derivativds and benzoyl esters.
They also benzylated meta crescl by the Claie en
method and 5-methyl 6-benzyl phenol,agreeing in propertl as
with that prepared by the A101. method, was obtained. Also
5-methyl 4-6 dibenzyl phenol which was identical wi th ttat
prepared by the A101. method. And in addition, a 2-6 di-
benzyl 5-methy1 phenol, which was not obtained by the A101.
condensation, as well as 2-benzyl 5-methy1 phenol.
9.
Benzylation of Para Cresol
This reaction employing A101. as the catalyst
was first carried out by Huston in 1920. The work was
repeated in 1925 by the author. After the publication of
the work of Claisen in 1925, it was deemed necessary
to check the products obtained by the two methods to see
if they were the same. Part of the problem also is t:
prepare bromine and benzoyl derivatives of the condensat-
ion products and determine their properties. Ala: to .
discover the best prOportions of reactants to secure
maximum yields by the A101. method.
Since in para crescl only the ortho positions
to the hydroxyl are Open, the Huston method and the Claism
should both give a mono and a di-benzylated product.
10.
Experimental - Part I
Condensation of p. crescl with benzyl
chloride. Claisen's method.
54 g. crescl (1/2 mol)
11.5 s sodium (1/2 mol)
64 " benzyl chloride (1/2 mol)
125 " toluene
The finely chipped sodium was suspended in the
toluene and the p. crescl added forming the white solid
salt of the crescl. The flask was heated on an oil bath
for half an hour and cooled. Upon adding the benzyl
chloride much heat was liberated. The mixture was allcw ed
to stand over night and then heated on the oil bath for
five hours at 150 - 160°. After cooling the produst was
washed twice with water to remove the sodium chloride,
separated from the water and the red liquid heated on
the oil bath to remove the toluene. The residue was
dismlved in 250 cc. of Claisen's methyl alcoholic potadi
solution (Ann. 442, 224) and extracted with 200 cc. pet-
roleum ether in 50 cc. portions to remove the small amount
of benzyl crescl ether, the potassium salt of the benzylated
p. crescl not being soluble. This potassium salt was acid-
ified with H01 to liberate the benzylated p. crawl and
washed with water to remove the K01. From this mixture tln
desired product was extracted with 150 cc. of sulfuric ether
in three portions. After removing the other on the stem
bath the residue was fractionally distilled.
ll.
1,. —— CHsCeHB
11:10OONa + 2010H203Hs——->H3000-11
and
H30 0O-CH2CsHs + NaCl
1st fractionation. (5 mm)
up to 140 8.7 s
The temperature rose rapidly to 170°
170 - 180 (mostly 170-175) 51.4 g
180 - 255 (mostly 225-250) 11.8 g
2nd fractionation (6 mm)
Up to 140 8.0 g
140 - 162 (mostly 160-161) 48.0 g
162 - 24c (mostly 210-220)_ 15.5 g
The second fraction crystallized immedh tely i
when seeded with a crystal of 2-benzy1 4-methyl phenol which
had been prepared by another method.
A second coniensaticn using the same quantities
of'materials gave:
gave:
12.
2nd fractionation (5 m)
up to 140 o g.
140 - 165 (mostly 160-162) 30.0 g.
165 - 240 (mostly 200-220) 2.6 g.
A third condensation using the same quantities
2nd fractionation (5 mm)
Up to 140 3.0 g.
140 - 160 42.0 8.
1‘0 " 280 10.0 80
The three middle fractions were combined and
purified by recrystallization from petroleum ether in th
ice box. The crystals were tramparent prisms and melt ed
at 35 - 56°.
Combustion analysis of 2-benzyl 4-methy1 phmol.
(By Huston) .1508 g. substance gave .0980 g. H20 am
.4695 g. 00.. Calculated for Cl‘Hl‘O; 0 .. 84.8%, H . 7.12%
Found 0 - 64.954, H - 7.274
18.
Preparation of the Benzoyl Ester
21 g. of the 2-benzyl 4-methyl phenol
6.97 g. KOH
14.82 " benzoyl chloride
The phenol was dissolved in the potassium
hydroxide in about 20 cc. water and the benzoyl chloriie
added. After shaking together for an hour a white oily
liquid was formed which did not crystallize. This was
“cl-with ether and drhd over calcium chloride. After
distilling off the ether the residue on fractionating at
5 mm. practically all came over at 205-206. After stand-
ing at room temperature for about five months, it cry-
stallized. It was purified by recrystallization from
alcohol forming large transparent plates. Melting point
was 42-42.5.
' 0
1'
HsC/\ O - K + CsHsCOCl—>HscOO'C'CQHs 4 4
HSCCHS' CHBCBHB
Combustion analysis of the 2-benzyl 4-methyl phenyl
benzoate -
1.008 g. gave .5056 g. 00. and .0541 3. H20
Calculated for C2IH18°2 : 0 . 85.4%, H a 6.0%
Found 0 - 85.55%, H .. 6.05%
14.
Preparation of the mono brom derivative:
15 g. 2-benzyl, 4-methyl phenol
12 g. bromine
50 cc . chloroform
The Phenol was dissolved in the chloroform
and the bromine added slowly. A rap id evolution of hydrogen
bromide and much heat was observed. The chloroform was
allowed to evaporate at room temperature and the residue
was fractionally distilled at 10 mm. After two fractionat-
ions a portion boiling at 177-178 was obtained which cry-
stallized after standing more than two months. When cry-
stallized from about 85% alcohol the crystals were a white
(4’
silky felt. The melting point was 43-45°. ’
‘Br
H300 0 - H + Bra—$330< >0 - H + HBr
CH203H5 w,Cflgc3H5
Analysis of 2-benzyl, 4-methyl, 6-brom phenol.
The Parr bomb was used. .1 g. substance gave
.028771 3. Br. Calculated for 014111303r : Br - 28.84%.
Found Br - 28.7'Il%.
In the formation of the 2-benzy1, 4-methyl, 6-
brom phmol, the location of the bromine was assumed t) be
ortho to the hydroxyl. In order to obtain additional
evidence, 6-bran para cresol was prepared by treating p.
cresol in chloroform with the calculated amount of bromine
to produce the mono brom derivative. The temperature was
15.
kept below 10°.
This was condensed with benzyl chloride accord-
ing to the Ulaisen method as outlined in the first part
of this discussion of the experimentalpart. Using half
molar quantities in two condensations rather poor yields
were obtained of fractions which boiled at 177-1780 (10
mm) and which crystallized immediately when seeded with
a crystal of B-benzyl, 4-methyl, 6-brom.phenol which was
prepared by brominating the 2-benzyl, 4-methyl phenol.
Upon purifying by recrystallization from.alcohol the melt-
ing point was 43-450.
1‘
H.011 + Brg———+Hs $03 + am
___4/
H20OHS
Ha<‘j >ON8 + Cefiscflch——)Hs OH + No.0].
1'1‘
Preparation of 2-6 dibenzyl, 4-methyl phenol.
In all the preceding condensations a small fract-
ion of'high boiling range was obtained. To secure a sufficient
amount for investigation, three more condensations using half
molar quantities were made. From.the 170-250o fractions
(6-10 mm) there was obtained 15 g. of liquid that boiled
at 256-238° (8 mm). This agrees with the boiling point at
2-6 dibenzyl, 4-msthyl phenol which was prepared by another
method.
16.
/‘.\ 320e38
Ha Bib-Na + 203H50H201—4Hs€\ H + 2Na01
CflecsHS
Combustion analysis of 2-6 dibenzyl, 4-methyl
phenol:
.1752 g. sample gave .5555 g. 002, and .1068 g.
820. Calculated for 0218200; 0 - 87.45%, H n 6.99%
Found c a 87.41%, H - 6.65%
Preparation of the benzoyl ester of 2-6 dibenzyl,
4-methyl phenol. (By Huston).
It was anticipated that it would be difficult to
form the ester because of steric hindrance of the tw: benzyl
group ortho to the hydroxyl. A sample of 2-6 di benzyl, 4-
methyl phenol was treated with strong potassimn hydroxide
solution. It did not dissolve, but solidified. Wren treat-
ed with the calculated amount of benzoyl chloride heat was
liberated and an oily liquid formed. After extracting with
ether, drying and distilling a viscous yellowish red liquid was
obtained. It did not solidify.
CH2CeHs
CHaCsHs
.0a. 0K + 0.350001% -0 - cm. + KCl
CHgCaHG
CHaCeHS
.
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g.
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uc
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r\. .
17.
Combustion analysis of the benzoyl ester of 2-6
dibenzyl, 4—methyl phenol. (Lewis).
.250 g. substance gave .72 g. 009 and .1542 g. H20.
Calculated for C H 03; G . 85.67%, H - 6.168%28 24
Found » C I 85.55%, HI- 6.43%
Experimental - Part II
Condensation of p. cresol with benzyl alcohol.
Huston's method.
108 g. p. cresol ( 1 mol )
54 g. benzyl alcohol ( 1/2 mol )
55 g. alundnum.chloride ( 1]! mol )
75 g. petroleum.ether
The p. cresol and benzyl alcohol were dis solved
18.
in the petroleum.ether and stirred mechanically while adding
the aluminum. chloride in small portions during the course
of one hour. The temperature was kept below 25°. Hydrogen
chloride gas was evolved most freely after about two thirds
of the aluminum.chloride had been added. Stirring was cone
tinned for another hour and the reaction product allowed
to stand over night. The dark red viscous liquid was de-
composed with ice and hydrochloric acid yielding a white
oily liquid which was extracted with sulfuric ether. After
recovering the ether the residue was fractionated.
Preliminary fractionation
Up to 225° without vacuum. 68.0 g.
140 - 190° (10 mm) 45.5 g.
190 - 250° n - 14.0 g.
Residue 9.5 g.
,-
6-
Second fractionation
19.
Up to 140° (10 mm) 02.0 g.
The temperamure rose rapidly to l67o
167 - 190 (10 mm) 55.0 g.
190 "' 250 n w 15.0 go
Residue 5.0 g.
Third fractionation
Up to 100 (7 - 8 mm) 61.5 g.
165 - 185 " 54.0 8.
185 - 250 ' 85.5 8.
Residue none
The 165-1850 fraction crystallized immediately
when seeded with a crystal of 2-benzyl, 4-methyl phenol,
which had been prepared by Claisen's method, and placed
in the ice box.
With the intention of finding the-best proportions
of reagents to use to obtain.maximum.yield, a second condem-
sation.was made using the ingredients in the ratio of 5 mole
of the Phenol to one mol of the Alcohol.
aluminum chloride was not changed.
162 g. p. cresol
55 3. aluminum chloride
54 g. benzyl alcohol
75 g. petroleum.ether
The anount of
20.
Fourth fractionation
Up to 100 105.5 8.
150 - 190 65.5 g.
190 - 250 21.5 So
Residue .5 6.
The 150-190 fraction was again distilled. (10
min)
Up to 150 9.0 g.
150 - 180 502x30
180 - 250 .5 6.
Residue .5 3.
The 150 - 1800 fraction crystallized when seeded
and placed in the cold.
A third condensation using the same quantities
as in the first was made.
Third fractionation (8 mm)
Up to 140 57.5 g.
150 - 190 54.5 g.
190 " 250 19.5 8.
The 150 - 190 fraction crystallized when seeded
and placed in the cold.
21.
Yields
The theoretical yield from half a mol of
benzyl alcohol is 99 g. of the mono derivative or 72 g.
of the di derivative.
A101. "
HsC-O-H + oicH.c.H.————. 3.0
First Condensation
54 - 55% of the mono derivative
35 - 56% n " di *
Second Condensation
52 - 55% of the.mono derivative
29 - 50% ” " d1 '
Third Condensation
54 - 55% of the mono derivative
27 f 28% " " d1 "
CH2C3HS
and 330‘; >O-H + HCl
CH2C6H5
22.
Summary
Para cresol was benzylated by the methods
of Huston and Claisen. The products Obtained by both
methods were shown to be the same. A bromine derivat-
ive of themono benzylated para cresol was prepared and
identified, as well as the benzoyl ester. The benzoyl
ester ef’di benzylated para cresol was prepared and
identified. It was found that using the Phenol and
Alcohol in the molecular ratio of three to one increased
the yield.
”1.59..
.115.» 9 '49
Who.
I: 13";
T547 L677 . 102368
Lewis
