125
785
THS

 

THE REACTION OF ETHYI. GRIGNARD
REAGENT WITH HALOEENZOIC ACIDS.

Thesis for the Degree of M. S.
MICHIGAN STATE COLLEGE
Edward Simon
I95I

 

q..‘_

 

 

”W‘gd" .

 

 

 

 

 

 

THE REACTION OF ETHYL GRIGWARD REAGENT WITH HALO-BENZOIC ACIDS

by

333329 SIEUN

A THESIS
Submitted to the Graduate School of Michigan
State College of Agriculture and Applied
Science in partial fulfilment of the
requirements for the degree of

Masrzn OF SCIENCE

Department of Chemistry

1951

ACKN 0.3L ED GED!

The writer wishes to exyress his appreciation to
Dr. R. L. Guile and Dr. R. C. Huston whose guidance and

helpful counsel have made this work possible.

0167"" i P’
‘Vw‘.

' I”: .
an.) L)

Pr .r-n

I rr ‘HQ
\‘1‘ 19:)..‘U

Page
THE REACTIOH CF ETHYL GRI‘NARD REAGENT WITH HALO-1:32:28 ACIDS

l
2
9
Experimental - - - - - - - - - - - - - - - - - - - ll
- - - - - - - - - 54
I 44
45

Introduction - -

Historical - - - - - - — - - - - - - - - - - - - -

Theoretical - -

Discussion of Results - - - - -

Bibliography-~-----------------

INTRODUCTION

Although the Grignard reaction is as old as the century.
very.few attempts have been made to investigate the reactions
of acids with the Grignard reagent. The reasons are understand-
able: there is very little use for the tertiary alcohols that
result. and the reactions of esters and ketones are more
economical of the reagent. For these very reasons. the
reactions of the Grignard reagent with esters and ketone have
been thoroughly investigated ~- and many controversies have
raged over the preposed mechanisms of their reactions.

This paper is written with an eye to filling the gaps
in the knowledge or the Grignard reactions and -- within the
limits of the title. to finding the most favorable conditions
for the reaction of the Grignard reagent with aromatic acids --
as has previously been done in this laboratory with some or the
aliphatic acids (44).

{‘0

HIST CRY

In the past fifty years since Grignard (33) showed that
alkyl magnesium halides reacted with carbon dioxide to yield.
upon kwdrolysis. alhyl carboxylic acids, there have been some
sporadic attempts to investigate the reaction or organic acids
with organo-metallic halides. In.l9C4. Grignard (38) reacted
the RCOOEgX complex formed.from addition of carbon.dioxide to
allLyl magnesium halide to produce tertiary alcohols. he postu-
lated a mechanism which involves the formation of a hetone inter-
mediate to account for the products thus formed (see THLOEY).
In.this wise, he made 2-methylofi-ethyl-5-heptanol by reacting
180ml magnesium bromide with carbon dioxide and further
reacting the addition.complex formed with two moles of ethyl
magnesium bromide. A generalized formulation of the reaction:

algx + COQ———-—-9RCOOL'{:X

 

qt
' a
noocrgx + a nus-3x _, “5:0 a; a - g..- ou + sawmx.

Also in 1904, Grignard (:54) produced diethyl phenvl
carbinol by reacting phenyl magnesium bromide with carbon dioxide
and the ensuing complex with ethyl magnesium bromide. He also
obtained a small amount of the misaturate of the alcohol
(l-methyl-l-phem'l 2-methyl-ethylene). Bhen he reacted the
magnesium bromide, instead of the expected diethyl-benzyl

carbinol. a great deal of gas (ethane) was evolved and the

products were mostly toluene and dibenzyl. Only a minute
amount of the expected alcohol was isolated. Grignard postuo
lated that the methylenic group ~- the only difference between
the benzoic and phenylacetic acids. contained hydrogen atoms‘
active enough to reduce the Grignard comolex to the gas and
thus form the complex 05H5~CH(EgBr)-CCOHgBr.

In 1904 and 1905 Zelinsky (86) and Reuben (39) produced
secondary alcohols by reacting alkyl magnesium compounds with
formic acid. Grignard (54) also tried this reaction and
postulated that the complex produced when two moles of the
magnesium compound had reacted was of the structure:

OMgI
HCOCH 4 2 R'lfggI — A, R' - C': - H + R'H.
MEI
In 1906 Bayer and Conyany (Bl). through the efforts of

 

Simonis and Arand. patented a process.for making tertiary
alcohols from benzoic acid and sodium benzoate by reaction
with the Grignard reagent. They reported producing diethyl-
phenyl carbinol.

In 1909. Eimonis and Arand (68) reviewed the reactions
of the Grignard reagent with organic acids. They objected to
Grignard's hypothesis of the RC(OfigX)BR' complex intermediate
claiming that, if it does exist. a hetone should be realized
through the hydrolysis of the comglex after addition of the

first two moles of the Grignard Reagent:

 

0113)! Ion
mach. + 1190 ——~» a—c\—n' mung» 11.9.3! 4- ago.
one): on o

and an aldehyde when fox-mic acid was used:

 

Dial 021
I Z Rearr.
3-0-11 4- H O ——-———)R- 41 f 4: 3.6.1] + 320
\ 2 \ I
Oflgx 0H 0

They found no ketone upon hydrolycing their reaction at that
stage.

5511301118 and Arand went on to investigate the products
of the reaction'of dicarboyxlic acids with the Grignard
reagent feeling that only those acids as a class hadn't
been investigated. One mole of phthalic acid was reacted
with 8 moles of ethyl Grignard to yield 3% dicthyl phthelido
and 20% prepicphenone-o-carboyxlic acid:

0
”/x coon “/\ con \ <1!
+ ‘9 ' k /_:-‘=.
236

The products produced were the same as those obtained when
Bauer (7) had phthalic anhydrido react with ethyl magnesium
bromide. When 4. 5-dibronophthalic acid was reacted with

8 moles of ethyl Grighard reagent. the products were
3.3-diethyl-5,Godibromophthalide and 4.5-d1bromo—2-
prepiOphenone-lacarboxylic acid:

B 0011 0;: Ii Br \xfi‘:
+-8 02 H 5"*Br«———9 4
Br ~coox ”wcu c1 B 6/
9 ‘3 \121‘15

can?)

In 1925, P. M. Porter (76) investigated the reaction of
'yfiketo acids with the Grignard reagent to see if the product
was the same as that produced when the usual esters were used.
i.e.. the )fialkyl substituted lactone as obtained by Grignard
and Moissans (35). When.levulinic acid was reacted with methyl
magnesium iodide 55.1% iso-caproiclactone was produced. The
yield reported by Grignard was 35%. The general reaction:

at

. f
R-giCHZCHZCOOH + 2 R'MgX-————€> R-C-CHZCHZj 3 O
O

Ivanov (49) extended the original carbonation reaction
of Grignard by reacting three moles of normal butyl.magneaium
bromide with one mole of carbon dioxide and obtaining 5-butyl-

5-nonanol. His formulation:
n-Bu
/

 

vs. 2 11-8111; 3131’ ,
n-Buhgor-+ COBr——~q7n-BuCOOH5X r+ ‘ N-Bu-C-OH.
anu

In 1932, Ivanov working vith Nicoloff (50) utilized
the active methylenic group of phenylacetic acid to form the

reactive complex C6H5CH(NgX)COONa:

1-03H7Mg31 4 CGHS-CHZCOONa ——->c6H5-CH -Coor-ra +— i-C

 

3H7H,
and reacted the complex with saturated aldehgdes to obtani
657’; yields of d—phenyl-g-lactic acids:
, OH
C6H5CH-COOITa fl RCRO a R-cH-cH-cooa.
TLEX C6H5
In the sane year, with Pihova and Christova, Ivanov (51)

reacted o-chlorophenyl-CH(MgX)-COOHgCl with saturated ketones

to ootain(chhlorophenyl-CB-lactic acids:

1ng C 1
i" CHZCHQVHS / -— __CH-C 001:
\ H COOTTgC 1 C/ h L
n = o HO-o -CHOCHZCI~'3 .
+' \\ “
\/ 1 Gaga-120113 cagczrgca
heptanone

8-prop ~2-(o-chlcro-
phenyl -3-hydroxy-
hexanoic acid

In 1933, Ivanov worxed with Pchenichni (52) to investiga

(4.

e

163:

the possibilities of 1,4 addition to o(- Q-unsatur‘ated ac

COOH
U ("HI-CIT CQOEJ + i_C LT I'm-(‘1 C02 C PT _."T{ CTI_(TILI
ii vi. li2 k, l 3.i7..€3v -————-’ 6 -5 2/: ii a; 1.
COOH

-pheny1cthylene malonic
acid.

lCOOH
033CHBCH303-COCH.4-1—Csfl7figCl-——> CHSCHBCK=CH~E§

_ COOH
5-methyl-2-carbogyl-crotonic acid.

which indicates that only the usual l.2-addition.takes place.
However. when 5~butenyl carboxylic acid was reacted with

phenyl magnesium'bromide and the complex treated with carbon

dioxide. the product was 3-phenyl~2(otobutenyl)-3~hydroxy-5-

octeno-l-oic acid:

CHSCHBCH30H-CI ~c - . COOH.
635

In 1954 Ivanov and Spassov (47) while investigating the
evolution of prepane when adding esters to various Grignard
reagents. investigated the evolution of ethane when bensoic
acid was added to ethyl magnesium bromide. They found that
only the calculated amount (one mole) of ethane was evolved
due to the active hydrogen of the carboxylic group.

In 1946. Huston and Bailey (44) investigated the reactions
of some of the aliphatic acids with various Grignard reagents
and investihated the conditions for the best yields. They
found that addition of the acid to an excess of Grignard
reagent and stirring the reaction mixture two hours in refluxing
ethyl ether gave the largest yields of the tertiary alcohols

(average 65%). The reaction also produced an average of.lQ%

ketone. For example, when 0.5 moles of butyric acid were added
to 1.75 moles of ethyl magnesium halide, prepyl dietivl carbinol
was obtained in 64.6% yield and ethyl prepyl ketone in 10% yield.

THEORI'K‘ IC AL

The reaction of organic acids with the Grignard reagent

is usually written:
3

n'cooa + s inegic———---> an 4— mt - on.
A

This formulation explains very little of the reaction
and.gives no indication of the by-products obtained.

Huston and Bailey (44).follow the lead of Grignard
(38, 34) and Ivanov (49) who suggest the mechanism for the
reacti n of the Grignerd addition product fermed when carbon
dioxide is bubbled into a solution and then further reacted
with another mole of Grignard reagent to.form a tertiary
alcohol:

nngx .4 002 -—————> 33002.ng (s4).

Huston.and Bailey suggest that. since the first step
of the reaction of the acid with the reagent is undoubtedly:
I. RCOOH.4— R'ng —————-’RCOOMgX. +— R'H,
that the same mechanism holds for the remaining reactions:
In the second step. a second molecule of the reagent
adds across the carbonyl group:
oagx
II. RCOOth —F' R‘EgX ————Av R-éih' .

(33‘ng

10

However. this addition product now contains two electro~
negative grozps in the form of the ~(OM23X). on the same carbon
ate . The complex is highly unstable Lufifiu-flia is split off

leaving a ketone.

OMgX
111- R- R' -—+— R-C-I’i' +— max-0-3m
Ohgx‘ ' g
The ketone continues the reaction with a third mole of

the Grignard reagent and a tertiary alcohol is formed:

a: n!
' non '
Iv. a-f-n' +-R'1'~J:;;T: ——~> s-clz-n' >— a-c-on +1.:g,(on )x.
' I
O 01ng R'

 

. ROCEDURE

. ctr-AT on 0 THE. gunman mast-7g:

 

The reagent was prepared by the method recommended by
Gilman (28). Using 165 g. of ethyl bromide (1.50) and 56.4
of magnesium turnings (1.50) in 6 molecular equivalents of
dry ethyl ether. The ethyl bromide was redistilled technical
grade and the magnesium had been obtained especially prepared
for the Grignard reaction. The ethyl ether was dried as
recommended by Fieser and Fieser (22) over sodium wire. The
magnesium was weighed and transferred to a 5~necked.flask
equipped with a glass hirschberg stirrer. condenser with a
calcium chloride drying tube and a 500 ml. drapping funnel.
The magnesium was covered with 200 ml. of dry ether and the
stirrer started. The ethyl bromide was weighed and transferred
with 100 ml. of dry ethyl ether to the dropping funnel. a
drying tube being placed over the mouth of the funnel. The
time of addition was limited only by the rate of the reaction ~-
averaging two hours for addition and the whole stirred a half

hour following the addition.

 

The reagent formed was analyzed as recon-mended by Gilman
(29,50) using water to hydrolyze an aliquot and an excess of

standard sulfuric acid was added. heated to 75-80o and then back

titrating with standard sodium.hydroxide to a phenolphthalein
end point while hot. In all cases, the analysis showed

approximately 95% ethyl magnesium.bromide (88).

 

All the acids were recrystallized.from petroleum ether.
They were added to the Grignard reagent over a one hour period.
The reaction was vigorous and immediate but care was required
due to the rapid evolution of the gas (ethane) formed. After
addition of the acid the reaction was stirred three hours.

When attempting to force the reaction benzene was added (500 ml.)
after addition of the acid and the solution distilled until
boiling at 76° C. The reaction mixture was hen refluxed at

75° c. for two hours with stirrix'xg.

Where possible. the acids were added in ether solution.
Benzoic. orthochloro-benzoic. orthocholoro-benzoic. metachloro-
benzoic. metabromo-benzoic and orthoiodo-benzoic acids were
all added in this wise. The metaiodo~benzoic. parahalo-benzoics,
and all the nitro benzoic acids, due to their insolubility in
ether and benzene, were added to the drOpping funnel dry and
covered with 400 cc. of dry ether. They were then washed into
the reaction flask at aerate commensurate with the vigor of
their react10n. In some cases it was necessary to use a copper
wire inserted in a glass rod. to prevent clogging. Addition
was complete in all cases. After the first hour of stirring,

a white solid was seen to come out of solution.

13

 

Three.forms of hydrolysis were employed inuthe initial
phases when eiperinenting mith.benzoic acid. The detrimental
effects of strong acid to the anticipated tertiary alcohols
(43). (i.e.. the tendency of tertiary alcohols to chlorinate
or dehydrate in acid solution) suggested that the saturated
ammonium chloride method was best (23). But subsequent treat-
ment with acid of the solid formed after ammonium chloride
hydrolysis. showed that as much as act of the product was,
absorbed and unremoved through three washings with ether.
Hydrolysis with ice water (43) was discontinued due to the long
filtration process and the loss of product through absorption.
It was finally determined to use the ice and acid method of
Fieser and Fieser (23). Thus, 300 ml. of 10% sulfuric acid was
poured over 150 g. of ice in the drOpping funnel and.added to
the stirred reaction in an ice bath over a one hour period.
Stirring was continued one hour after addition at which time
a two-layer system was clearly defined and unreacted particles

of acid could be observed.

 

The hydrolyzate was filtered.free of unreacted acid. it
any, and placed in a.2 liter separatory funnel and.extracted
three times with 150 ml. portions of ether. The ether layer
was then washed with water, twice with 5% sodium carbonate
solution to remove any acid in the other layer, and finalhy

water; then dried over anhydrous sodium carbonate.

14

The ether was distilled off and the residue placed in
a.distilling pot and fractionated over a two-and oneuhalf foot
glass helix ~ packed column under'vacuum using a nitrogen
atmOSphere. The alcohol would come over without traces of
dehydration.

Unfortunately, all the alcohol fractions contained
minute traces of ketone and unsaturates as determined by use
of 2,4-dinitrOphonyl-hydrazine (41) and bromine in.chloroform.
Yields were based upon these slightly inpure.fractions.

The pure alcohols were obtained only upon redistilling
the alcohol fractions three times under the same conditions.
Once distilled, the alcohols had no tendency to dehydrate under
vacuum so long as no air was present. Thus all fractions were

redistilled using a pine splinter to prevent bumping.

“77" "’?"'r‘[?'?(‘ 'C‘ 2"” F?“ 1.7 731‘.
DL¥¢L‘I. Jt‘ act-.1 Cg T11; I‘QQUCALOi. I

 

Tertiary alcohols dehydrate when treated with phenyl-
isocyanate and chlorinate when treated directly with acid
chlorides. The py'idine Variation of the method of Cchotten
and Baumann was found to give low yields of the solid paranitro
benzoates: ;.

One milliliter of the alcohol was placed in 5 ml. of dry
pyridine (prepared by redistillation from barium oxide and
collected over potassium hydroxide sticks). One gram of

panitrobonzoyl chloride was added. The mixture was refluXed

15

in a 50 ml. flask for one hour and paired hot over 15 g. of
ice. The solid was then filtered and allowed to stand over
night in a large excess of 5% sodium carbonate. The oil was
then extracted with ether and washed w th water.<iilute

361. water again and then dried over sodium carbonate. The
ether was then evaporated off and a thick oil obtained. The
oil was taken into solution in alcohol and water added dropwise
Just to the cloud point. he paranitro benzoate crystallized
out upon cooling and standing and was readily recrystallized

from alcohol.

16

“ ““75““. fi'“"
.i N no

(“..n?"""T"“"‘T(‘ rad-1 any?“ ,.7 in'fifgf‘q- l" .
Id! ‘-Ju‘ L ' ' '- " _ .

L-4L“-"-n_ Jug 'v‘o ‘AI ‘mulva¢b¢d'hr‘.

       

Although the phenyl diethyl certinol had been prepared
previously (40. 34, 81). no solid derivative is reported. The

other tertiary alcohols appear nowhere in the literature.

SYNTHLE E OF DIETMYL PIZEYL CAiEIEQL}

1). Fy reacting one mole 80.1 g. of diethyl ketone with
one mole of yhenyl magnesium bromide, 25.0 g. of e clear color-
less oil was obtained which contained no trace of a carbonyl
group and reacted positively with the Lucas reagent. eith pere-
nitrobenzoyl chloride it formed a solid ester h.P. 80° C.

Mixed E.P. 80° C. Refractive index. n£g°= 1.5145. B.?. 759/5nm.

2). Using the recent method of Swain and Boyles (84)
to insure large yields of tertiary alcohols, 63.6 g. (0.40;) of
Eromine were added slowly and with continuous stirring to 9.1 g.
of magnesium (0.40i) in 100 ml. of dry ethyl ether and stirred
until the bromine color had disappeared. Then 20 g. (0.15%)
of progiophenone were added over a period of one hour with
stirrieg. .SE of ethyl magnesium bromide in 100 ml. of ether
were added slowly to the mixture and stirred one half hour
thereafter. The reaction mixture was hydrolyzed ty adding it
to 500 cc. of 13% sodium csrhonzte at ‘30 C- A Yield or 10'5 5°
(70% yield) of phenyl dietheyl carbinol was obtained. Refractive

0
index nag 3 1.5142. Perenito benzoate E.P. 80° C.

l7

1‘ !.ff"‘"1“(\"r"' Cw fi"-7,-T:".,'\Y'r‘\ Hunt-try 'xT"'fl!"f'f p-vfin'rnn'r .
h -L' “ll~~ *Lr '-‘s. ‘ ‘ILI ‘.;‘.. AK v‘w..\" ; in. 0‘ “-1 L‘ *p. n-AI'L-’ V‘“|‘- J Ai‘JLI .

One mole of diethyl ketone was added to 1.3 mole of
parabromo-phenyl magnesium bromide and 40 g. of a heavy color-'
less oil obtained. B.P. 1109/2 mm. P-nitrobenzoate h.P. 142° C.

Obviously the procedure used in the above two cases was
limited by the availtbility of the correctly substituted
halogen aromatics. Since the method of Swain and Boyles worked
so well with prepiOphenone, and most of the intermediate ketones
were known, the product from the addition of ethyl Grignard to
the correctly substituted prepiOphenones could be considered a
valid proof of structure coupled with the melting points of the

derivatives and the results of dehnlogenation.

A’-;-'\ fir).’.P~-\fiTv—fv «1,7.

" infiyr-‘w? -".‘(~ I. f' r-.g-‘ :‘3 . ~§ " (‘9'? txu‘ .. .v V‘ m - .a‘ 27‘ . ‘
- - I- t ‘ .9 - a'
I" .1.-. w". LLwA ..L'.JIH..~¢UH...

-

.‘ ‘,.I .-- ‘ : . ‘ x I- ,‘..- D ;| . 'l‘
L"A--- u.‘_.;$ ‘L’ ...L I» A. ..,‘. ‘Jaa-..'\/IL~’ u-an da-ct- L'
A

.0

 

The pera~chloro- and parabromo-propiophenone were
readily synthesized using the Friedel Crafts reaction of Collet
( 2. 13). One mole of the halobenzene and one mole of probionyl
chloride (made using phosyhorus trichloride and prouionic acid
on the water bath) (1, 48) in an excess of carbon disulfide
were stirred while one mole of anhydrous aluminum chloride
was added over a 2 hour period. The whole was then refluxed
6 hours on the steam bath. then poured over one kilo of ice.
The 082 layer was removed and washed with 10: sodium hydroxide
solution. dried and evaporated. The hare-halo probiophenonea

crystallized out very nicely with cooling and were recrystallized

18

7!

from alcohol. Para-chloro-prOpiOphenonc n.P. 35-60 0., Oxime
s.r. 63° c. (10). P-bromo-prOpiOphenone r.p. 44° c. Acetoxime
u.P. 90-10 (10). The reSPective yields were BC e and 93.

The above ketones were reacted with magnesium bromide
and ethyl magnesium bromide in the manner of Swain and Loylea
(84) as oreviously descr had. The alcohols yroduced: P-chloro
yhenyl diethyl carbinol B.P. 129-309/1 mm. P-bPOmOthRYl
diethyl carbinol s.9. 1149/2 mm.

2'!!! lf'\H‘.’('~ {‘11 q! f ‘* f“m '9.
iii J.

? If Q, "I‘ i)?! 1"", IL-‘I. "Ih‘ [‘4‘
ALE-J‘s.— Ul +1; -' LL; {3. 1111140 LU‘ .

‘5‘}; Li A5\AIJ.—|¢U.

IS:

The preparation of the ortho and meta halo-prepioghenone
was undert aka n following the method of Elsen, Gibson et al (19)
as modified by Keneford and Simpson (54).

.rOJippfl’HOHt was pre spared using the method of Lhiiner
and Turner (80) as modified by Baddeley and Kenner (E) by
reacting Ext: of pr01Wion l chloride (195.0 g.) and 154 g. (F U)
of benzene with 5-2.5 ii of anhydrous alumimun chloride in an
excess of carbon disulfide. However, uy: n workirg u and
distilling, only SOS yield was obtained (reported 8J.~f) (5)
and this appeared in ure. The distillatiOn residue was totally
polymerized. Redistillation only lost more proeioyhenone and
another run was necessary. And this run too yielded iMyure
prepiOphenonc. The grogioghenone was used in that impure

condition (traces of u1£ atuiati n).

19

One hundred grams of p:0pio;henone ($.753) in 33 5. of
glacial acetic acid were added to 43C ml. of fuming nitric acid
(density 1.5) at minus 100 over a two hour oeriod. Only m-nitro
prOpiophenone (7di) could be isolated upon pouring upon ice,
filtering and making the filtrate basic and extracting with
ether. This reaction was attempted three times and only m-nitro
propiophenone could be isolated since the redistilletion.of the
proyioyhenone still yielded a product impure enough to break
the delicate temperature balance required for tne ortho nitration.
The m-nitro prOpiOphenone was recnystellized from alcohol, M.P.
102° C. and reduced in SnSlg and concentrated H31 (6). The
reaction wee.mede basic and extracted with ether. The toiling
point of the m-amino prOpiophenone was 1459/10 mm. M.P. 42° C.
from alcohol. Senicexbaeone E.F. 196° C. dec. The yiel' upon
reduction was 9&2.

Three Sendmeyer reactions were run to get the three
orthohalo-pPOpiOphenones. Since the methods used are the
same as those used with the ortho-amiuo prepiophenoae. they

will be given now:

3)," T 2“,. _ I ”7‘7.” “Y Qt! ‘51 1.531 1! 2‘1 3}); KENT "a“; ' " "-21 w. I- ,
4 iiui :.n;t;..LUn 1‘ lu"...;..‘~..'u.u ; . .u. 4.4.1. .i.-...'». - u 4;. o

 

Using the modified cozzditions of Leo; "1rd eat: Loyd (64 ),
50 g. (0.20m) of m-amino prOpiophenone were dissolved in 80 g.

of HBr(38%) and 100 cc. of water. 20 g. of KeROa'in 350 cc.

{‘3
0

water were added at 0° C. L Solutioa of cuprous bromide
(made by treating 54 g. of CuL04 in 60 cc. of water and 53 g.
TBr witn 50 g. Nafiflfig and 20 g. Nedfi) was added and stirred
one half hour. The whole was then warmed on the steam bath
for four hours and then.eteem distilled and the oil collected
was extracted with ether. The ethereal layer was treated
with.dilute team. then.dilute dCl. water and the n d: ied end
distilled. The yield wee 31.0 g. of mofiromo propiophenone:
5.2:. 155°C/i4 mm. Recwetallized from 11- :roin in? . 41-2° c.

H o
Semi-carbeZOAe d.P. 180 dec.

““91" -~. m'r -\ , \:~ 3.: \-: r'sr-.n 11...». x..- r. ,-.-.1 - ~-
. . 1 (J5. . r {7 v - .,...t- :1
I" 3 A A-‘U. “Ll-LU a.a.....w.¢il itt: 3...:

.t‘a‘ 5.....‘... .. 1...

 

Thirty grams (0.23L) of m-amiHOprooiOphenone were
dissolve' in 30 cc. of concent'eted ddl and 60 cc. of water.
The amino was diazot ized us in; inLQfa aqueous H="qa,et 5° C.

The slush was added to a solution of cuproue chloride in 60 cc.
of HCl and 52 cc. of water. After one hour at room temperature
the mixture was keot at 50-630 for 30 minutes. The ketoue

wee collected from ether and "stilled at 1?W19/lxo". and

crystallized u:on cool: 1;: 3&.P. 48-90 C.

5.
:-

.-—3
v. "

’EPJ ”.5 «'7': T7177 27-1930 P112'T‘I-‘Il‘rfifTTIi“373 (69):

 

Thirty two grams (0.22A) of m-emino propiophenone were
placed in 110 g. concentrated H31 and 103 cc. of water and

cooled to 5° C. in on ice bath with sti ring. Sixteen grams

21

of Nehoa (0.25%) in 80 cc. 01 ice we ter were added from a
separatory funnel with the stem below the surface end the
whole stirred 10 minutes.

no aqueous solution of RI (36.3 g. (O.LL1) in 103 ml.
of water) was added directly to the diuzo-comgound and the
reaction allowed to stand overnight. The flask was then heated
on a steam bath until the frothing stoPged. A heavy organic
layer settled out. The aqueous layer was decenteu and the
residue msde alkaline with Neon pellets. It was then extracted
with 150 cc. of ether and dried. A heavy oil (cr‘de wt 43 g.)
was obtained upon distilling off the ether. It ra used to
crystallize from alcohol, alcohol and we ter, yetr oleun other.
or upon freezing and recourse was made to vacuum distillation.
At 160° C. decomposition began and continued even when the
heat source was removed until a tempereture of 218° C. was
reached. The not conteined or‘y chercoe

A second attempt to make the m-iodopropiophenone in the
Same manner failed even though much more care was taken to
sash all truce 01‘ base iron the et211 lever and nitrog en

passed during distillation.

‘3’ r. ‘04.? .oszllo” “.1.

h? "' ‘ n m: n ~'\<r“':-\r: r‘.’
tibial ‘3lkz‘gfilw0‘ 0114-54.: I. “sir-4.0 51‘ iii“ ui;-.a.-LJ U12; {LAM-xi.” 3

 

Tertiary alcohols were prepared from the two sveiletlo
m-halo~pr0p10phenones using the netnods of Swain end Lcyles

(Op. cit.). The alcohols formed: m-ChlorOphenyl diethyl

r,‘ f.
1.1“

culbinol and m-Lromophenyl di- eti1Jl carbinol boiled at 125° C./14 mm.

and llé—léoo “ ./14 mm. respectively emu yielded tr 1e p-nitro

, 1,. . _. ., ‘P r " 1':- 0 _. . ~ 9 1
Leuaoutee 1..1-’.'5 535 (n and IQ'T o

n‘nvm'vv-r‘mw-r A \ +n -.:-n r. 'wu- ‘1'»... "-4- V-
- 1 . w . . - . . 0
1 o? 0111o-n'

k- .Av;.. .._---- a ...1.¢"~-J ‘ .'. -c‘ .11. Li- Ia'v,.-A.~.

Crtho-amino propioyheuone was mudeec001d1n5 to the
method of Claessen and hadaell (ll) as modL ied by flowers
and Buesberg (4).

Crtho-nitro Leuzoic acid was made in 501 yield by
el1uline permanganate 01 idation of o-nitlotoluene by the
method of Helmet and Getewood, (77).

The acid chloride was made by reaction of 800 g. of the
acid with a large excess of thionyl chloride. 2‘18 t1ionyl
chloride was distilled off was well as possible on the steam
bath. Although Antwers claims the o~nitrobenzoyl c21loi'ide
was purified by vacuIm distillation, the acid chloride tenus
to uecompose when heated unu no utte11rt was made to distill
it. The crude aciu olloride was adéed to the sodium salt of
ethyl-methylecetoacotece in ether.

Tue ethyl methyl acetoacetete was made eccordiug to
the method of Geuther '26) by uduiug l.tH of ethyl ace oecetete
'(lgb 3.) to 1.53 01 NaOLt in ex cess alcohol and than adding
1.6% (858 g.) of methyl iodide and heeting the reaction to

160-l70° C. for six hours. The Ieaction w~° then cooled and

the NaI filtered off. The etF?l methylecetoecettte distilled
over at eo-ao.5° C./14. m. The yield was 93,25.

One mole of ethyl methyl aceto acetate Wis added to one
mole of sodium ethylete in alcohol and 1.1; of ortho-nitrobenzoyl
chloride in 100 cc. of ether was slowly added to he sodium salt.
The alcohol and ether were distilled off as formed and the
reaction stirred and heated to 100° C. for 6 hours. The reaction
was then cooled and the Real filtered off. then the filtrate
was distilled. The ethyl-CX~(o~nitro tenzoyl)-c¥-methyl aceto-
ecetete came over a brilliant red at 210° C./20 mm. The yield
was 833': (12137 g. ).

The ethyl~C¥-(o-nitrobenzoyl)~CX-methylacetoecettte was
placed in 600 ml. of 1:1 sulfuric acid and refluxed for 10 hours.
The reaction was then cooled and diluted to 2 liters and then
extracted with ethyl ether. The ether layer was washed with
water. The ether was distilled off and the yellow oil distilled
at 1450/1 mm. The yield upon hydrolysis was 33; (63 g). The
solid crystallized from petroleum ether and was recrystallized,

n
l

. 85° C. dec.

J

H.P. 47°. The semicarbezone M.
The o-nitroprOpioghenone was reduced (68) by addition

in glacial acetic acid to tin and concentrated nCl and refluxing

.for 2 hours. After being made basic, steam was passed until

110 more oil was delivered. The oil was extracted in ether and

dried over potassium carbonate. The other was distilled st

;140°C./14 mm. when it SlOWlY crystallized into pale yellow crystals

:3. 45° c.

n'fivrfl'fr" p. "" 3- '~ "\ :T llfi“ (‘ "a“ P“ “‘7 r" “'y—"v w f?‘a A ‘ -.-r r wv-mr. ‘1‘ ' ,—-- ‘
- I ‘ . ' ' ' . ' r.—

. _ . I. , .- .
.... l... l.i....._:.._.‘J 14.9 0“: - .l"....,.-'.. K “k. _‘. .._'| 4‘.-. La: 0-.., “i 3,:qu . 1‘11 .._\2. .‘ ..\.v.a;..

 

TAe ortho chlorop509103hennae B.P. 659/: mm. refractive
iudex l.CElD 2,’- -di LAtlo yucnylrydllzrno H.?. 3050 C. cod the
OrtflO-LBUECQlOle“1td.18: B.P. lP7O/l4 mn.. semicerbezone
H.?. 1820 C. were made by the Condutyer 1eeo*ion pre Vlfiu"'

described in yields of 701 end 723 reSpectlvely.

‘ 'Y'Wf‘ r-“f 7‘!“ ' 7 ( ‘79: “‘4 '7??? ‘CI ‘-‘.' -~. I T. A T?" at $37 "‘ 751.7 7" (”“1 " O
Ini- '. .|--'( o #1.!) K.- .;.ot.r-.${ Lc'I5. V}! O- C-w‘k)‘: .n‘J d-'.é I) --1‘\4'11t.l4.

 

‘The synthesis was attexpted in the srre m cnner as that
for the m-iodOpPOplOthnone. Lgain, the oil decomgosed upon

attempted distillation.

(~1an ["4- .~ r‘tw Icryv \f‘ \ vr‘ -. 12“”.
W—Lil‘ahhm-i‘lkl L'Aq D- ..~..........)-.4L A‘Ja ‘AJ.

Para-amino propiophenone was made in the same manner as
the o-emino prooioghenone (4): .SE 8?4 g.) of p-nitrobenzoyl
chloride were added in dry ether to one mole of ethyl-methyl
ecetoecetete in one mole of LeC t drni heated to 100° C. for
6 hours. In attempting to distill the resulting oil. decomposi-
tion occurred at 170° C. and, upon cooling, a solid was obtained.
The solid was recrystallized from alcohol K.P. 57° C. and was
added immediately to 1:1 sulfuric acid and refluxed 12 hours.
P-nitro‘pr0p10phenone was extracted from the diluted reaction
mixture in ether. The ether was distilled off and the yellow
solid recrystallized from alcohol. 3.9. 114° C. Yield 43 g.

(total yield 25%).

r‘*-'r\

The p-nitrogrooioohenone (0.3oo, was reducei using tin
and concentrated H01 (5). The p-dmino profiiophe one was
recovered from a sodium hydroxide solution of tho hydrochloride
salt. 2.9. 140° c. Yield 32.2 g.

The attempt to make the p-iodoprooiOphenone by the Diezo
method as previously described felled again at the distillation
steo. Decouposition occurred at 170° C. and only eidrcoel
remained in the pot. A solid derivative of the oil was obtained:
9,4-dinitr0phonlhydrezone M. . 199° C. dec.

Para-iodopropiOphenone was finally made uoiug Kimura's
(58) anhydrous aluminum chloride preparation of p-iodoucetOphenone
as a guide. Che hundred and ten g'ame (0.833) of anhydrous
aluminum chloride were covered with 300 cc. of carbon dieulfide
in e three-necked flask cooled to 20° C. in a water both.

168 g. (0.83m) of iodobenzene were added to the cooled and
stirred mixture and then 76.4 g. (0.833) or propionyl chloride
were added and the whole stirred one half hour in the water bath
while stirring. The mixture was then placed on the steam both
and very slowly heated until the carbon disulride refluxed.

The reaction was allowed to continue until the evolution of H01
was hardly visitle (thirty minutes). Then the solvent was
distilled off end the oily residue was poured slowly into one
kilo of ice while stirring vigorously. The solid ftroed was

filtered off and teren up in ether. The other layer was then

tr

Washed wit h dilute K2335 end l.tcr, and then dried over iZCGJ‘
The etiler we 3 than d Mt lle:d off L.i to: so id .QC'"”toiiiZed
three times from alcohol. By the third recrystallization rll
trace of free iodine ‘Lei dice~»v.‘ed. A faintly brown plate-

like crystal resulted. m.P. 128° 0.. 4-minitroyhco"lr'oiazone

rm. 199° c. dec. The yield was to;

(iemn (NI

‘ V3Itt1‘t TYWWL 2.7.7371‘17
L'ni... T {T n 4‘3113

-.:7‘$ I. I
“’1 ij-*\:¢:ll“ —‘.r ‘J J 5- Lu.“ 3". ‘rg'l‘

 

The p-iodOphenyl diethyl cerbinol was prepared in 30%

yicli in the manner of Swain and Boyles (cit. pre.). B.P.

or;
2L].

1% 0C./4 mm., refractive index n d- 1.5785. h.?. of p-nitro

benzoate 134° C.

“7 "“" mm.“ 3"!" :m C K f3, Irr‘M1yr\v-.
I: I. {rt-J“: L 1-. .VLL'\.r\..,|" HE" lTL a} .

Since dicthylthcnyl carbinol is 3 Known compound e-Id has
teen made previously Ly on indcoendcht method which yields a
solid derivative, dehelogenution of the ring of its halo-
derivatives ought to be an acceptable proof of the structure,
if the p-nitrohenzoate has the some mixed melting point as that
of the known comgound.

Using the method of Schwenk. Papa and Ginsberg (71, 78,
75), 2 g. of eech of the alleged alcohols were placed in a
300 cc. Ehrlenmeyer flock in 20 m1. of ethanol and 4 g. of
Honey Nickel alloy added. The Shrlenmeyer was fitted to a

reflux condenser and immersed in an ice both. 150 cc. of

 

‘2‘.

.2 2.. :1 . “.3?

I».

A...
..

”gunk. m. . .1

C
l".

chilled lfifi Kesfl were added through the reflux condenser and,
when the initial reaction Med subsided, a low flame we” gleced
under the Thrlenmeyer. Ahen the reaction ceased after bePOXi-
motely 2 hours the flask was heated on the steam beta until
the solution was clear and color ess. The so ution was tnen
decanted ot and, when cool. extracted with etner. The ether
layer was washed with water and dried over Kagoc3. The ether
was then distilled off and the resulting oil was treated with
p-nitrobeuzoyl chloride and pyridine and refluxed one hon

and the ester wo‘ked up. In each case, the p-nitrobenzoate

formed had the r.?. 50° 0.. the mixed 3.?. 80° c.

, ..._.E:_£{ .235 i.§.,.fi,.3..m...<

28

mo.mm onw.o

 

 

 

 

 

 

 

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29

 

 

 

 

 

 

 

 

 

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0.69200V H .02 mqmfie

PfiYSIQéL PROPERT ES OF THE ALCOHCLS

r

Dietnz; phegz; c§£b1n911
B.P. 117° o 19 mm.

n52 1.5148
D
p-nitrobenzoate H.P. 80° C.
2" S S 3
Skuflxxx zsauuxxal
calculated 80. 44 90 82
found
- o e b no :

3.9. lag-30° o 14 mm.

poultrobenzoate M.P. 122° C.
£fl§é¥£1§fi
Carbon yxggogen ori
calculated 66. 49 7. 62 170 85
found

m-c§;or03hegy; gigtgz; ggrbinol:
B.P. 128° o 14 mm.

(5
(.2

nD 1.5308
p-nitrobenzoate M.F. 86° C.
.énélzélét
Carbon I won legggg;
calculated 66.49 7.62 17.85

found

o-g319gggneaz; gleggx; gggb1nol:
13.9. 140-1" :1 25 m.
n22 1.5298

p-nitrObenzoatc E.P. 122° C.

égglz§1§2
9211.12 n W1 o e 911122119.
Calculated 66.49 7.62 17.85
Found
-b one he ‘ 1 t1 . b :
B. P. 115.160 Q? 3 mm.
n22 1.5472
D
p-nitrobenzoate %.9. 142° C.
12311111: .
suyaua1 H "en éazmguu:
Calculated 54.11 6.80 52.86
Found
m-bromor e t: r no :

9.9. 113-14° o 14 mm.
n32 1.5470

D
p-nitrobenzoate 3.9. 137° C.
éngLZSISX
Qggbog 1’ 0 en Bag mgng
Calculated 54.11 6.20 32.86
0- on: e v d e ‘b o :

B.P. 138-4o° a 13 mm.
22

n c 5490
D 1

p-nitrobenzoate H.P. 153° C.

Aflfllzfiléfi
Qgrbog fizggggen
Calculated 64.11 6.20
Found

g-Iogoghegz; gigthy; gagbgngl:
3.9. 125° o 4 mm.

n?“ 1.6786
9 o
p-nitrobenzoate £.P. 164 C.

fl 7 vs a:

Carbon ' o’e'
Calculated 45.64 6.21

Found
m-iodqgheny; ggetgz; ngbinol:
B.P. 127° o 1 mm.

28
n 10 5812
D

 

”nitr0benzoate 172.17. 1160 C-
énglxgigz
Carbog Hzgrogen
Calculated 45.64 5.21
Found
0 o‘he ie t b no :

B.P. 118° o 2 mm.

n32 1.6760
D

p-nltrobenzoate M.F. 93° C.

A s 5:
Carbon 1* oven
Calculated 46.64 6.21

Found

1.?

32.86

£I221u1
43.64

‘ om

43.64

43.64

34

DISCUSSIOH OF RESULTS

Since benzoic acid is both inexpensive and plentiful.
it was used to determine the proper conditions under which the
other acids were to be reacted. The first reactions were with
one mole of the acid added to 5.3 moles of the Grignard reagent.
(See Table l) Cnly 29% of the tertiary alcohol was obtained in
this manner and.4.6% ketone. The'unreacted acid was recovered
and found to make up for the percentage difference. This was
the eXpected yield. However it was decided to force the re-
action by increasing its temperature to see if the yield could
be increased. The reaction was.forced and the diethyl phenyl
carbinol was obtained in 28.6% yield and the yield of ketone
rose to 8.1%. This showed little improvement in.yieids of the
desired product. Forcing the reaction in.some manner increased
the rate of the ketone.rormation step (III see THEORY) and had
no effect upon the rate of addition of the Grignard reagent to
the intermediate ketone. since the tgtg1_yield of product is
greater than that of the unforced total yield.

Since solvents sometimes affect rates of reactions. the
presence of a preponderance of benzene may account for the
altered yields -- rather than the tengwrature increase. "then
the reactions with the other acids were forced in the same

preportions. the yield of ketone was generally increased

(3-1
(3'!

(except in the cases of m—chlorobenzoic acid and m-bromobenzoic
acid which produced only traces of the ketones in both cases)
and the yields of the alcohols would remain the same or
diminish. Thus. when o-chlorobenzoic acid was reacted with
3.2 moles of ethyl Grignard 41.4% tertiary alcohol and 7.45%
ketone were obtained. fihen.the same reaction was forced. the
yield of the alcohol decreased decidedly to 29.4% and the
yield of ketone increased to 9%. than cabromobenzoic acid
reacted with 6.2 moles of Grignard reagent 54.6% tertiary
alcohol was obtained and 3.8% ketone. when forced the same
reaction yielded only 23.4% alcohol and 6.4% ketone. The
p-bromobenzoic acid reacted with 3.2 moles of Grignard reagent
produced no ketone fraction and 34.2% tertiary alcohol while
the forced reaction yielded 1% ketone and 32.6% tertiary alcohol.

Thus it appears that the unforced reaction gives better
yields of tertiary alcohols (although traces of ketone appear
in every case) than the forced reaction-~or. at any event.
less by~products are obtained.

Since relatively low yields of tertiary alcohols were
obtained as compared with ester and acid chloride and ketone
reactions with Grignerd reagents and benzoic acids were
.recovered intact after hydrolysis. it was decided that the use
of a greater excess of tho Grignard reagent might induce more

of the acid to react:

36

When benzoic acid was reacted with 4.2 moles of Grignard
reagent. 49.2% tertiany alcohol'was produced and only a trace
of the hetone. This appeared to'be a sufficient excess (44)
to permit all the Lensoic acid to react-~at least etoichio-
metrically. Thus all the acids were reacted in the ratio of
1:4 to 134.5 moles of Grignard reagent (See Table II):

Crtho-chlorobenzoic acid now gave a yield of 48.1%
tertiary alcohol reacting with 4 moles of the reagent;
m~chlorobenzoic acid yielded 66.53 alcohol with 4 moles of
reagent; p-chlorobenzoic acid reacting with 4.5 moles of ethyl
Grignard yielded 71.4fi alcohol and no isolatable ketone.

Ortho-bromobenzoic acid yielded 33.6fl alcohol and no
ketone when reacted with 4.5 moles of the Grignard reagent.
Reta-bromobenzoic acid yielded 64.0% with 4 moles of Grignard
and the p-bromobenzoic acid gave the enormous yield of 76.6%
alcohol with 4.3 moles of Grignard reagent.

The iodo-elcohols would decompose upon working up and
no true yields can be reported.for their reaction. Part of
the iodo product would distill as the dehalogenated alcohol
and part as the unsaturate and part would distill as the
iodo-alcohol, slowly decomposing upon standing.

57

 

Yrufit‘r “qr-Her!

"'3 éaouuCI-IJJ FROM .nAoTIQfi OF THE ACIDS WI ‘

(331 GM A712
In Order 9; Decreasing Yield

   
     

 

 

 

Ratio of

Roles of Gr. to Yield of

Radar M W
l. p-bromo benzoic 4.5 76.6%
2. p-chloro benzoic 4.5 71.4%
3. m—chloro benzoic 4.0 66.3%
4. mpbromo benzoic 4.0 64.0%
5. Benzoic 4.2 49.2%
6. o-chloro benzoic 4.0 48.1%
7. o-bromo bensoic 4.5 38. i

The order of reactivity of the acids is therefore:
p—bromo~, p-chloro-. m~chloro-. m-bromo-, benzoic. o~chloro-.
o-bromo-. and then presumably followed by the iodocompounds.

Thus in each of the series of halobenzoic acids, the order of
reactivity is para meta ortho in a decreasing scale with
the bromo compounds edging out the ortho compounds in reactivity.

Both the ortho-benzoic acids gave lower yields of
tertiary alcohols than benzoic acid and the met&- and para-
benzoic acids gave greater yields than the benzoic acid. This

reactivity shows some correSpondence to the order of solubilities

38

and ionization constants of the acids -- yet shows no direct
correspondence to either. According to Dippy and Watson (16)
there is a--"...connection of roughly linear'characteristics
(which) exists in a number or cases between the values of log
K for the same reaction of a series of m- or p-substituted
benzene derivatives and those of leg K for the corresponding.
benzoic acids." (16) According to Jenkins (64). this linear
relationship can be extended to the ortho compounds too.

In Table III. the ortho, nets and pars compounds are listed
with their yields and also with.the pKa's or the acids. Since
the yields can be taken as a function at the k of the reaction.
they are divided by the pKa's to see if a somewhat linear
relationship can be seen. The same is done with the negative
'log of the solubilities of the acids in water at 25° C. to

see if this is a determining.factor too:

 

 

T*LE II
1 e. 9 _ g __ e o _‘ 0!. o L. .0 Se 0” ‘
2 ' . . .
Yield of Iield/’ -Log % Yield/-

A ' SO . o S . o
m-br0mo 640 $5 3.86 170 O 2.71 230 6
ngromg 58.§g_ 2.85 :;§.5 2.05 ‘el§.2 .l___
___ $6.6 2;.4 A13.
p-chloro 71.4% 3.98 18.0 2.92 24.5
n-chloro 66.5% 5.82 17.4 2.65 85.0

ggxgogo 48-;gp

 

 

       

39

The bromo compounds could hardly be taken as a proof of
the linear relationship of pKa to reaction rate. Certainly a
sloye that shows such deviation should be considered a curve.
There is a little better correSpondence of the solubilitios
and reaction rate as seen in the last column. however. when
we look at the chloro series. we see a marked correlation of
slepe in both columns 4 and 6. Certainly this is one of the
Cases where such e relationship as Dihpy suggests will hold.
In the light of what follows. there would have been greater
correSpondence of the p-chloro comgound, if only 4.0 mole
ratios had been used instead of 4.5. And that eXplains the
lack of close correlation of the bromo compounds, which were
reacted in mole ratios of 4.5. 4.3, and 4.0 rather than all
the same. Since, there isn't a definite linear increase of
yield with excess Grignard reagent (es will be shown later).
no mathmnticsl account can be taken of these differences to
obtain the desired slepe. The writer believes that there is
a linear relationship of ‘ste to pKe in this reaction for
each series of substituted acids end else points out the
linear reletionship of the solubility with the rote of reaction.
This should not be too suryrising since ester soluLility would
certainly be effected by the degree of ionizction. This
relationship scald certainly have been more strongly established
if the nitro comyounds had reacted for. in that series, the

order of the pKa's is mete, para, ortho (68, 32, 70).

40

By a fortunate accident, it was found thet the yield
of alcohol could be increased even further by addition of a
greater excess of Grignerd reagent. nlthough the usual 1.5
moles of ethyl Grignerd reagent had been prepared. only 42.0
grams (0.25n) of o-chlorobenzoic acid was available. This
amount was added to the reagent with the exhectetIOn that no
further excess of Grignsrd reagent could affect the yields
(enolizetion (43) did not appear to increase with excess
Grignnrd reagent). then the product was worked up, it was
found that the yield of o-chloroyhenyl diethyl cerbinol hed
increased to 67.5% in this 6:1 ratio. It was decided that
the increase in yields of alcohols with increase in excess
Crignerd reagent be investigated. Using benzoic acid to

determine the best conditions:

TLELE IV

 

 

 

Ratio of Ethgx to 'Yield of- ‘lncreese/“Q
.ugengoig acid Alcohgl_ role Increment
3.2 29.0%
4.2 49.2% 20.£%
5. :3 65. or: 19. 8:2
6. o 94.. 4;: 29. 4:2:
7.0 95.0% 0.5%

 

 

L ‘2—

41

As can be seen in Table IV, the yield of alcohol
increased almost linearly from 3 moles to 6 moles. Apparently.
little or no increase occurred from 6 to 7 mole ratios.

Thus & retio of 6 moles of Grignerd reagent to each
mole of acid was now reacted with the evai able acid to see
if their yield. too. would increase under these new conditions:

The o-chlorOphenyl diethyl carbinol yield increased
from 43.1% for 4,0 moles to 67.$% with 6 moles. The yield of
p-chlorOphenyl diethyl carbinol increased from 71.4% with 4.5
moles to 93.1% with 6.0 moles of Grignerd reagent. The yield
of m-bromoghenyl diethyl carbinol increased from 64.0% for
4.0 moles to 91.0% with 6.0 moles of reagent. O-bramo benzoic
acid increased its yield to 89.3% alcohol and p-bromo benzoic
acid increased to give ~L~.O;T_ tertiary alcohol.

In this case. all the acids were reacted in equal mole
ratios and Dippy's relationship should get a.feirer test.
Unfortunately. there was no mochloro benzoic acid available
f0: this experiment. Eat its yield could be filled in since
the yields of the other two compounds are known and the pKa
of m-chlorcbenzoic acid is known. The m-chlorobenzoic acid
should yield 89.1% tertiary alcohol when reacted with 6 moles

of ethyl Grignerd.

 

 

 

 

 

Agig $439321; Me 2: ., ie I"

pnbromo 95.0% 3.95 24.0

m-bromo 91.5% 3.86 84.5

9;bromo 89.Qfi 2.85 23.2

- 23.8 averegg_
p-chloro 93.1% 3.98 23.4

m—chloro (89.1%) 3.82 (23.3)
szthrQ. 67.5% 9.90 sols;

 

23.3 average

This method of reecting the aromatic acids with 5 moles
of excess Grignard reagent in refluxing ethyl ether brings this
reaction into the realm of more successful reactions. It is
now possible to prepare tertiary alcohols of the form
Ar-C(OH)R'8 in.yields which would actually surpass those
usually obtained by using the correSponding esters or ketones
with less interfering by-products. As a laboratory tool,
this method would save the time required for esterificstion--
though admittedly. requiring the use of large excesses of
reagent. ’

The fact that twice the theoretical amounts of reagent

are required to produce near molar yields would appear to

indicate that some equilibrium step is being forced in
accordance with the Bess Action Lew. However. it is equally
possible that the excess reagent increases the rate of re-
action. making the reaction appear as one of a lesser kinetic
order than when molar quantities are used. It is suggested
that this reaction is ripe for kinetic studies and would

readily lend itself to such an investigation.

44

§UEMARZ

1. The halobenzoic acids react readily with ethyl
Grignard reagent to give tertiary alcohols and traces of
ketones.

2. The nitrobenzoic acids didn‘t react with the
ethyl Grignard.

3. The yields of tertiary alcohols can be increased
to 70-95% by addition to excess Grignard reagent.

4. The rates of reaction of the halobenzoic acids
show a linear relationship with the pKa‘a of the acids.

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Ashenasy, Luerbach, Zait. ghysik. Chem. 49 217 (1904).
.‘:.l.1‘-.-‘3er8, Ber. if; 9‘36 (19 5:3).

fiuwers, fuesberg, jer. §§_1179 (lGQO).
Eaddeley, Hemmer, J. Chem. Soc. ‘9'56 303-9.
erger, tiger, Ber. §§_lCll (1305).
Baler IL, 1331'. .221 £7.40 (1&5).
Bethmaun, Zeit. physik. Chem. §_339 (1800).
Bright, Hrircoo, J. Thys. Chem. QZLVS7-QG ( 93: .
T“'0Lln-u..n. .Lluutriun. nod-Cu :1. if}. 143%‘6 (19:4).
Clemson, Hivdhvll, liar. l; 5531 (154379 )-

holl t, Compt. rend. l§§_7l7 (1397).
001161;. CCIWtho rent}. a 1577 (15398).
Comanducci. Res cetelli, Cass. chin. ital. 36 790 (1006).
Dvrwin Lirshmaz, fisher, J.fi.C.S. 5? 53-8 (1350).
Dipgy, hatson, J. Chem. Soc. lGEC 436-40
Dippy, Lewis, Lillians, J. Chem. 502. 1337 021.
Dippy, Lewis, ‘IIilliaIm, J. Chem. C'oc. I135 sea-e.
Dorsch, hc'i.vain, J.A.C.S. §§_B;60 (1933 .

Slam, 0115-1011, Johnson, J. Chem. Soc. L333 1138-36.

fuler, Zait. physik. Chem. ?; St? (1396).

fivcns, Ecrgan, Tats.on, J. Chem. Soc. L92: 1167.

‘

'ieser, "Elyfii1Lnts in Organic Cher stry”, 2nd Ed.,

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Part II. pp. 406-12, D. C. Heath & 00.. New'York, (1941).

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Gautier, Ann. chin. phys. (4) L7 191 (l 8C9)

Giant—her. Jukrb. 91.1511; Chm-1. 353675 5:24.

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0.1131911, deck, (.113. John, Rec. trav. chin. $4212.34. (.1933).
50.211.311.111, 211x011, J....C.t . 3;}; 13739 ~32} (19134)

V. Grignurd, lxn. chin. (7) 9? (1991 .

'J. i}.i.;m.‘d, 231111.. soc. chin. (23) £3.33. '75 (l"&:-).

7. 6:1 nerd, Moissanc, Conpt. rend. 1&5 154 (1907).

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