Studies in asymmetric synthesis

Citation preview

STUDISS m

A8YMM3TEIC 8YMTH2SI8

(A b s tra c t o f th e s is subm itted by J .A . R eid f o r degree o f Ph. D. ) It

has been shown by McKenzie and h is school th a t

when o p t i c a l l y a c tiv e

e s te rs o f a -k e to -a c id s

(R .0 0 ,0 0 2 # * )

and a O rig n a rd reag en t (R*MgX) in t e r a c t the d ia s t e r e o isom erid es [R.OR * (0M gX).C 02#*3 are produced i n unequal amounts.

The s u b s titu te d g l y c o l l ic a c id s , o b ta in e d by

h y d r o ly s is , were o p t ic a l ly p u re .

a c t iv e ,

alth o u g h not o p t ic a l l y

The analogous re a c tio n s using o p t ic a ll y a c tiv e

e s te rs o f y - , ^ - , £ - .......... k e to -a c id s had v i r t u a l l y not been s tu d ie d . I n the p re s e n t in v e s t ig a t io n the in t e r a c t io n of ( - ) -m en th yl e s te rs o f u > -a c e ty l f a t t y acid s [CH^.CO.

C02C^q H^

and phenyl magnesium brom ide has

been s tu d ie d w it h a v ie v /to o b ta in in g asymmetric sy n th e s is and to r e l a t i n g t h is to th e le n g th o f th e ch ain i n t e r ­ vening between th e carb o n yl and carbomenthoxy groups. The in v e s t ig a t io n has e n t a ile d th e p r e p a r a tio n o f th e above type o f e s te r s when n = 0 , 2 , 3 , 4 and 8 , and t h e i r tre a tm e n t w it h p h e n y l magnesium brom ide. h y d ro x y -a c id s or ( w it h n = 2 and 3) la c to n e s ,

The o b tain ed

a f t e r h y d ro ly s is of th e r e s u ltin g e s te r s , were o p t i c a l l y

a c t iv e , except i n th e case o f n = 8.

W ith n = 2 o r 3 ,

th e degree o f asymmetric s y n th e s is was dependent on r e a c tio n c o n d itio n s . The a d d itio n o f a G rig n a rd re a g e n t to a ca rb o n yl group has p r e v io u s ly been found to occur a s y m m e tric a lly o n ly when the c a rb o n y l group i s i n a m olecule c o n ta in in g a " fix e d c e n tre o f asymmetry".

I t has now been found

t h a t an asymmetric r e a c tio n occurs when an o p t i c a l l y a c tiv e o r g a n o -m e ta llic compound adds to a k e to n e .

T h is

type o f r e a c tio n has been s tu d ie d u s in g ( -) -m e n t h y l bro m o a c e ta te , acetophenone and z in c .

The

^ -h y d ro x y

o b ta in e d on h y d ro ly s is was o p t i c a l l y a c t iv e .

a c id

The e x te n t

o f the asymm etric s y n th e s is was found to be rem arkab ly c o n s ta n t, ir r e s p e c t iv e o f a wide v a r ia t io n in r e a c t io n con­ d it io n s . Th e o rie s o f asymm etric s y n th e s is a re discu ssed and a th e o ry in v o lv in g energy d iffe r e n c e s o f two t r a n s it io n s ta te s i s proposed as an e x p la n a tio n o f th e r e s u lt s o b tain e d in t h i s in v e s t ig a t io n . ^ - H y d r o x y - V - p h e n y l- n - v a le r ic a c id (n = 2) has been p rep ared and re s o lv e d .

STUDIES IN ASYMŒTRIC SYITTHSSIS

J oan A. R e id ,

B. Sc.

(London)

T h e s is s u b m itte d t o th e U n iv e r s i t y

o f Lo nd on f o r

th e D egree o f D o c to r o f P h ilo s o p h y

C h e m is try D e p a rtm e n t B e d fo rd C o lle g e f o r Women, ( U n i v e r s i t y o f L o n d o n ), London, N.W . 1 .

F e b ru a ry ,

1950.

ProQuest Number: 10097961

All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion.

uest. ProQuest 10097961 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346

CONTSms

Page AQKNOUliEDGSMSNTS

...............................................................................

vi

GENERAL NOTES..............................................................................................

v ii

I.

1

INTRODUCTION

...............................................................................

la .

D e fin itio n

IL .

T o t a l a s y m m e tric s y n th e s is

Ic . Id ,

o f as ym m e tric s y n th e s is

A s y m m e tric s y n th e s e s in v o lv in g G rig n a rd re ag en t s ... ... ... ..# ...

... ...

2

...

3

P re s e n t i n v e s t i g a t i o n ...........................................1 5

n . PREPARATION OF ( - ) -MENTHYL E S T E R S ................................... I la .

( - ) -M e n th y l p y r u v a t e

...

1? 17

IIL .

( -)-M e n t h y l la e v u la te

lie .

(-)-M e n th y l - a c e t y l - n - L u t y r a t e , [(-)-m enfchyl 4 - k e t o - p e n t a n - i- c a r L o x y la t e ] ... 18

Ild .

( - ) - M e n t l i y l ^ - ace t y l - n - v a l e r a t e [ ( - ) - menthyl 5 - k e t o - h e % a n 4 - c a r L o x y l a t e ] ........................... 2i

lie .

( - ) -M e n th y l w -a c e t y ip e l arg ona te [(-)-m e n th y l 9 - k e to -d e c a n -1 - c a r h o x y l a te j ........................... 26

Ilf.

N o te on p h y s ic a l p r o p e r t i e s o f ( - ) -m e n th y l u - a c e t y l f a t t y a c id e s t e r s i n r e l a t i o n t o s tru c tu re . . . ... ... ... ... ...

Ilg . III.

^

............................................... 1 8

( - ) -M e n th y l "brom oacetate

...

...

INTERACTION OF PHENYL MAGNESIUM BROMIDE AND ( - ) -MENTHYL Ü -ACETYL FATTY A CID ESTERS Ilia .

In t r o d u c tx o n

IIIL .

P r e p a r a t io n o f

...

... phenyl

...

...

28

...

30

...

32

...

32

magnesium Brom ide . . . 33

il

IIIc .

M ethod o f e s t im a t io n o f d ip h e n y l

Illd .

C o n d itio n s employed f o r t h e G rig n a rd r e a c t io n , and i s o l a t i o n o f th e p ro d u c ts ...

34

Ille .

O u tlin e

35

Illf.

I n t e r a c t i o n o f ( - ) - m e n t h y l p y r u v a te and p h e n y l magnesium b ro m id e

Illg .

....................

o f G r ig n a r d r e a c t io n s s tu d ie d

I n t e r a c t i o n o f ( - ) -m e n th y l l a e v u l a t e p h e n y l magnesium b ro m id e ...

... ...

37

R e a c tio n c o n d i t i o n s ... I s o l a t i o n o f y - h y d r o x y - y - p h e n y lv a le r ic a c id and i t s la c t o n e ( y - p h e n y l - y - v a l e r o 1 a ct on e ) . . . ... ... ... ... ... ( i i i ) C o n v e rs io n o f y -h ^ ^ d r o x y -^ -p h e n y lv a le r ic a c id i n t o i t s la c t o n e .................................. ( i v ) R e c o n v e rs io n o f y - p h e n y l- y - v a le r o l a c t o n e i n t o t he a c i d . . . ... ... . #. ... ( v ) R e la t io n s h ip b e tw e e n r e a c t i o n c o n d itio n s and y i e ld ... • .. ••• ». . ... ( v i ) R e la t io n s h ip b etw e en r e a c t io n c o n d it io n s and degree o f asym m etric s y n th e s is ( i . e . s p e c ific r o ta tio n o f p ro d u c t). ... ( v i i ) F u r t h e r o b s e r v a t io n s ,f r o m la r g e s c a le e x p e r im e n ts , on th e r e l a t i o n s h i p betw een r e a c t io n c o n d it io n s and r e s u lt s . . . ... ( v i i i ) O p t i c a l e x a m in a tio n o f y - h y d r o x y - y -p h e n y lv a l e r i c a c id p r e c i p i t a t e d fro m a l k a l i n e s o lu t io n • .. • .• ... ... ... ( i x ) N e u t r a l p ro d u c ts o b ta in e d . . .

Illj. Illk .

IV .

V.

36

and

(i) (ii)

Illh .

33

37 3^ 40 4-i 4-2 4-5 4-6 55 59

I n t e r a c t i o n o f ( - ) m en th yl f ^ - a c e t y l - n b u t y r a t e and p h e n y l magnesium brom ide

...

60

In te r a c tio n o f (-)-m e n th y l ^ - a c e t y l-n v a l e r a t e and p h e n y l magnesium b ro m id e

...

64-

I n t e r a c t i o n o f ( - ) -m e n th y l ^ - a c e t y l p e la r g o n a t e and p h e n y l magnesium b ro m id e

67

INTERACTION OF ACETOPHENONE, ( - ) -MENTHYL BROMOACBTATB AND Z I N C ..............................................................................

68

CORRELATION OF R E S U L T S ................................................................

77

iii

Page V I.

DISCUSSION OP CONCLUSIONS IN RELATION TO THEORIES OP ASYMMETRIC SYNTHESIS .....................

V II.

V ia .

P r e v io u s w o rk

V IU .

P re s e n t i n v e s t i g a t i o n . . .

...

...

PREPARATION AND RESOLUTION OP ( ± ) -y-HYDRCXYy-PHBNYIiV.ALSRIC ACID (3-HYDROXY-3-PHBNYLBUTAN-1 -CARBOXYL IC AC ID ).......... ...................................

92 102

i 13

V ila .

I n t r o d u c t io n

.................................................

115

V IIL .

P r e p a r a t io n ( - ) - y - h y d r o x y - y - p h e n y lv a l e r i c a c id .................................................

115

V IIc .

R e s o lu tio n - p r e l i m i n a r y e x p e rim e n ts

11 6

V lld .

C o n d itio n s f o r i s o l a t i o n o f y - h y d r o x y y - p h e n y l v a l e r i c a c id and y - p h e n y l - y v a le r o la c t o n e fro m th e "brucine s a l t of th e acxd . . . ... ... ... ...

117

R e s o lu t io n u s in g b r u c in e i n aqueous me d i um ... ... ... ... ...

11 7

V ile .

V III.

.................................................

92

EXPERIMENTAL

................................................................

1 20

V illa .

P r e p a r a t io n o f (-)-m a n th y l p y r u v a te

120

V IIL b .

P r e p a r a t io n o f ( - ) -m e n th y l l a e v u l a t e

121

V IIIc .

P r e p a r a t io n o f ( - ) -m e n th y l ^ - a c e t y l n -L u ty ra te . . . ........ ...................................

V llld . V llle . V lllf.

P r e p a r a t io n , o f ( - ) -m e n th y l O - a c e t y l n—V a l e r a te ... ... ... ... P r e p a r a t io n o f ( - ) - m e n t h y l -a c e ty lp e la r g o n a te .................................................

122

123 127

P r e p a r a t io n o f ( - ) - m e n t h y l "brom oacetate 131

iv Page V lllg .

G r ig n a r d r e a c t i o n s .............................................. (i)

(ii)

(iii)

(iv )

133

P a r t i a l a s y m m e tric s y n th e s is o f a t r o l a c t i n i c a c id .................................

134

P a r t i a l a s y m m e tric s y n th e s is o f y - h y d r o x y - y - p h e n y lv a le r ic a c id and y - p h e n y l- y - v a le r o la c t o n e ... ... P r e c i p i t a t i o n o f y - h y d r o x y - y - p h e n y lv a l e r i c a c i d , fro m an a l k a l i n e s o l u t i o n , w i t h 5 N - s u lp h u r ic a c id ...

132

136 139 140

( v ) I n t e r a c t i o n o f ( - ) -m e n th y l -a c e ty ln - v a l e r a t e and p h e n y l magnesium b ro m id e ... ... ... ... ...

145

I n t e r a c t i o n o f ( - ) -m e n th y l ^ C - a c e ty lp e la r g o n a te and p h e n y l m agnesium b r omi de ... ... ... ... ...

R e fo rm a ts k y r e a c t io n s (i) (ii)

(iii)

VIIIj.

P h e n y l magnesium brom ide s o lu t io n ( c o n t a in i n g 0 *1 2 5 g- m o l. PhIvîgBr) . . . De t e r m in a t io n o f amount o f d ip h e n y l form ed ............................................

P a r t i a l a s y m m e tric s y n th e s is o f r - p h e n y l- g - c a p r o la c t o n e ................. ..

(v i)

V lllh .

132

146

...

149

P a r t i a l a s y m m etric s y n th e s is o f p - h y d r o x y - p - p h e n y lb u t y r ic a c id

...

149

P r e p a r a t io n o f (_ ± )-P -h y d ro x y P - p h e n y lb u t y r ic a c i d ....................

...

152

P r e p a r a t io n o f 2 - h y d r o x y - 2 - i s o b u t y l 4 - m e th y l-h e x a n o ic a c id ... ...

152

(+)-y-hydroxy-y-phenylvaleric acid (i) Preparation ( 1 X) R e8 ol u t Xon

...

153

.....................

153

...

154

...

...

...

Page IX .

8UMMAEY

X.

REPSRaNCBS

.....................

................................................................ 1 58

............................................................................... 160

vi

I

e x p re s s my s in c e r e

P .P w .S ., f o r th is

h is i n t e r e s t

th a n ks to P r o fe s s o r B.jS.

and a d v ic e i n

T u rn e r,

c o n n e c tio n w it h

in v e s tig a tio n . I

am in d e b te d to M r.

P . R o b in s o n f o r p h o to g ra p h in g

th e d ia g ra m o f th e G r ig n a r d r e a c t i o n A p p a ra tu s . The w ork was c a r r i e d

out d u r in g th e te n u r e o f an

a s s is t a n t s h ip , w h ic h was made a v a i l a b l e b y t h e D e p a rtm e n t o f S c i e n t i f i c I

t o P r o fe s s o r T u r n e r

and I n d u s t r i a l R e s e a rc h .

am g r a t e f u l t o them f o r p e r m is s io n t o in c o r p o r a t e

w o rk i n s h ip I

a Ph.

D.

r e c e iv e d

T h e s is .

th is

P r i o r t o h o ld in g th e a s s i s t a n t -

a tr a in in g

C o u n c il, w h ic h I g r a t e f u l l y

g r a n t ,f r o m H e r t f o r d s h i r e C o un ty a ckn o w led g e.

vii

GBIŒRAL NOTES 1 . A n a ly s e s w ere c a r r i e d 2 . M .p . s . 3.

o u t "by D r s . W e i le r and S tr a u s s .

a re u n c o r r e c te d .

S o lu t io n s p r e p a r e d f o r p o l a r i m e t r i e u n le s s

o th e r w is e

s ta te d .

If

use w ere

e t h a n o lic

no c o n c e n t r a t io n i s

m e n tio n e d m easurem ents w ere made on t h e hcmogeneous u n d ilu t e d l i q u i d . if.

R o ta t io n s

o f s o lu t io n s w ere m easured i n

w a t e r - ja c k e te d 2

tu b e

a t 25 -0 *1

cfca. u n le s s o th e r w is e

an a l l - g l a s s

th e le n g t h b e in g

s ta te d .

5 . R o t a t io n s o f homogeneous u n d ilu te d l i q u i d s w ere m easured v /ith o u t

te m p e r a tu re

g la s s t u b e , t h e le n g t h b e in g

c o n t r o l and i n

i

an a l l -

dm.;» u n le s s o th e rw is e

s ta te d . 6 . Where r e l e v a n t

th e e r r o r s ,

o f th e r o t a t o r y p o w e r, a re

in c u r r e d d u r in g m easurem ents in d i c a t e d .

The e r r o r

in v o lv e d i n d e t e r m in a t io n o f r o t a t o r y pow er o f homo­ geneous l i q u i d s was -

0 .0 1 ^ #

I. INTRODUCTION

1

.

INTRODUCTION

l a. D e f i n i t i o n o f asym m etric s y n th e s is The id e a o f asym m etric s y n th e s is to d a y ) was f i r s t ved t h a t ,

d is c u s s e d hy F is c h e r

(a s we u n d erstan d i t (1 8 9 4 ).

H a vin g o b s e r­

d u rin g th e s y n th e s is o f m anno-heptose from

(*»-)-mannose,

o n ly one o f th e two p o s s ib le d ia s te re o is o m e r id e s

was fo rm e d , he suggested t h a t an o p t i c a l l y a c t iv e g l y c e r a l dehyde s h o u ld be form ed b y th e f i s s i o n o f a m anno-nonose, p re p a re d b y re p e a te d c y a n o h y d rin r e a c t io n s on (+)-m annose and th e subsequent p r o d u c ts .

The f i s s i o n p ro d u c ts should

c o n s is t o f th e o r i g i n a l mannose t o g e th e r w i t h th e o p t i c a l l y a c t iv e

g ly c e r a ld e h y d e .

The f i r s t

asym m etric s y n th e s is a c t u a l l y p u t to th e t e s t

o f e x p e rim e n t was a tte m p te d by F is c h e r (1 901 ) u sin g the f o llo w ­ in g s e r ie s

of r e a c t io n s

( s i m i l a r to th o s e suggested i n h is

e a r l i e r p u b lic a tio n ) * * * /0 H CEO. (CHOH)^. CHg.O.CgH^^.OHO------->CHO. (CHOH)^. CHg. 0 . CgH^. OH CN * OHO. ( CHOH) . . CHpOH ^ ^

ki +

(n o t ac co m p lis h e d ) .O H HO. CÆ , . OH ° ^ CN

(w h e re C = asym m etric carb on a to m ). M arc k w a ld ( 1 9 0 4 ) c la im e d to have accom plished the f i r s t a sym m etric s y n th e s is

a f t e r many o th e r w o rk e rs had f a i l e d .

M a rc k w a ld c a r r i e d ou t th e

d e c a r b o x y la tio n o f th e h a lf - b r u c in e

s a lt

o f m e th y le th y lm a lo n ic a c id and o b ta in e d m e t h y le t h y l-

a c e tic th e

( is o v a l e r i c )

( - ) - a n t ip o d e .

p r e c is e

a c id w h ic h c o n ta in e d a p re p o n d eran c e o f T h is le d M a rc k w a ld to fo r m u la te

d e fin itio n

th e f i r s t

o f an asym m etric s y n t h e s is , v i z . ,

t h e s i s w h ic h y i e l d s

an o p t i c a l l y

m e t r i c a l s u b s ta n c e s w i t h th e

a id

a syn­

a c t iv e p ro d u c t fro m sym­ of o p tic a lly

a c tiv e

sub­

s ta n c e s as in t e r m e d ia t e s , b u t w i t h no p ro c e s s e s o f f r a c t i o n a ­ t i o n in v o lv e d .

It

is

o b v io u s t h a t F is c h e r had t h i s

co n cep t o f w hat c o n s t it u t e d c la s s ifie d

same

an as ym m e tric s y n t h e s is , s in c e he

o n ly th e h y p o t h e t ic a l f o r m a t io n o f th e g l y c e r a l ­

dehyde as an a sym m etric s y n th e s is and d id no t in c lu d e

th e

f o r m a t io n o f th e m anno-heptose fro m ( + ) -m annose. I n th e y e a r i n w h ic h M a rc k w a ld c la im e d th e f i r s t

asym­

m e t r ic s y n t h e s is , M cK enzie (1 9 0 4 ) began an i n v e s t i g a t i o n i n t o a sym m etric s y n th e s e s u s in g o p t i c a l l y a c t iv e a c id s as s t a r t i n g m a t e r i a l s .

e s te rs

P ro d u c ts e x h i b i t i n g

of a -k e to o p t ic a l

a c t i v i t y w ere o b ta in e d b o th b y r e d u c t io n o f such e s t e r s as ( - ) -m e n th y l p y r u v a te

and subsequent h y d r o ly s is ,

G rig n a r d r e a c t i o n on s i m i l a r e s t e r s . v ie w e d more f u l l y

l a t e r i n th is

and b y t h e

T h is w o rk w i l l be r e ­

S e c t io n w i t h s p e c ia l r e f e r ­

ence t o th e p r e s e n t i n v e s t i g a t i o n . lb .

T o t a l A sym m etric S y n th e s is The ty p e o f asym m etric s y n th e s is w h ic h has b een d e s c rib e d

above i s

known as a p a r t i a l

had th o u g h t i t

asym m etric s y n t h e s is ,

p o s s ib le t h a t an o p t i c a l l y a c t iv e

v a n 't H o f f sub stan ce

m ig h t h e form ed fro m s y m m e tric a l compoimds im d e r th e e f f e c t o f an u n s y m m e tric a l p h y s ic a l f o r c e .

T h is was n o t r e a l i z e d

i n th e l a b o r a t o r y u n t i l Kuhn and c o -w o rk e rs ( 1 9 2 9 ,1 9 3 0 ) e f f e c t ­ ed a p h o to -c h e m ic a l d e c o m p o s itio n b y means o f ( + ) - and ( - ) - c i r c u l a r l y p o la r is e d

lig h t.

An a b s o lu te asy m m e tric syn­

t h e s i s was c la im e d b y K a ra g u n is and D r ik o s ( 1 9 3 3 ) , who i n ­ flu e n c e d t h e c o u rs e o f th e r e a c t i o n b e tw e e n c h lo r in e and t r i -

I

a r y l m e th y l b y c i r c u l a r l y p o la r is e d l i g h t ; a sym m etric

th e d e g re e o f

s y n th e s is was e x tr e m e ly s m a ll, as i n o t h e r

a b s o lu te as y m m e tric s y n th e s e s so f a r c la im e d . I c . A sym m etric s y n th e s e s in v o l v in g G r ig n a r d R e a g e n ts As w i l l b e d is c u s s e d l a t e r ,

th e p r im a r y i n t e r e s t i n t h i s

i n v e s t i g a t i o n was th e s tu d y o f a s y m m e tric s y n th e s e s r e s u lt in g fro m th e a d d i t i o n o f an o r g a n o - m e t a llic compound, such as a G rig n a r d r e a g e n t ,

to a c a rb o n y l g ro u p .

Thus, i t

i s nBcessaiy

t o r e v ie w a sym m etric s y n th e s e s , and r e l e v a n t r e l a t e d o b s e rv a ­ t i o n s , w h ic h have some b e a r in g on t h i s

ty p e o f r e a c t i o n .

F i r s t to be c o n s id e re d w i l l b e e x p e rim e n ts c a r r i e d o u t b y M cK enzie and c o -w o rk e rs u s in g o p t i c a l l y a c t iv e e s t e r s o f cK-keto a c id s and G rig n a r d r e a g e n ts (s e e T a b l e ) .

The

ty p e o f r e a c t i o n in v o lv e d i s

E.OO.COoI#

+

E'MgX

=»E.C(OH)E'.OOgR^

?E.C(0H)E'.COoH

(e x c e s s o f one a n tip o d e ) w here R*^ i s

an o p t i c a l l y a c t i v e a lc o h o l r a d i c a l .

I n th e e x p e rim e n ts o u t li n e d ab o v e, th e g l y c o l l i c

a c id

Interaction of a-keto esters and Grignard reagents (McKenzie et al) B â te r ( - ) -m e n th y l p y r u v a te

( - ) -m e n th y l b e n z o y lfo r m a te

( - ) -m e n th y l a -n a p h t h o y lfo rm a te ( - ) -m e n th y l ^ - a n is o y lf o r m a t e ( - ) -m e n th y l ^ - t o l u y l f o r m a t e ( - ) - b o r n y l p y r u v a te

( - ) - b o r n y l b e n z o y lfo r m a te

R (w h ere R ’MgX used) Me Bt is o b u t y l Ph a - n a p h th y l 2 -to ly l 2 -a n is y l Me Bt is o b u t y l t e r t -b u ty l p ro p y l Ph a -n a p h th y l p -to ly l Me Bt Ph Me Me Ph TT is o b u t y l Ph a - n a p h th y l £ -to ly l Me Bt i^ b u ty l a - n a p h th y l 2-to ly l

S ig n * o f p ro d u c t None + (s a lt) + (s a lt ) + + (s a lt) + 4"

None

s a lt s a lt -(s a lt None

+ ( ?) + (s a lt) +

R e fe re n c e McK. ( 1 9 0 6 ) McK. ( 1906 ) McK. and W ren ( l 9 0 6 ) McK. (1 9 0 6 ) I McK. and W ren ( l 9 0 6 ) McK. and C h r i s t i e (1 9 3 5 ) I McK. and R i t c h i e ( l 9 3 2 ) McK. 9 0 4 ) and McK. (1 9 0 6 ) McK. ,1904 McK. ,1 906 McK. 1 906 McK. ,1 906 McK. ,1904 McK. 1906, McK. and C h r i s t i e ( i 935 McK. and R i t c h i e (1 931 a McK. and R it c h ie 1931 a, McK. and R i t c h ie ,1 931 a McK. and R it c h ie A 9 3 2 ) McK. and C h r i s t i e McK. and C h r is t i e McK. and W ren I S O: McK. and W ren (1 9 0 6 McK. and W ren ( l 906 McK. and Wren ( l 906 McK. and C h r i s t i e (1 9 3 5 ) McK. (1 9 0 6 ) McK. (1 9 0 6 ) c f. te x t McK. ( l 906%,) McK. and C h r i s t i e ( l 9 3 5 ) c td .

c td . E s te r ( - ) - b o r n y l a -n a p h t h o y l fo rm a te (-)-lD o r n y l ^ - t o lu y lf o r m a t e + ) - b o r n y l b e n z o y l fo rm a te ^ - ( 3 - o c t y l p y r u v a te - ) - 6 - o c t y l b e n z o y l fo rm a te ( + ) - 3 - o c t y l b e n z o y lfo r m a te ( + ) - a m y I p y r u v a te I ( + ) - a m y l b e n z o y lfo r m a te

F o o tn o te *

( - ( s a l t ) in d ic a te s in d ic a te s ( ±

, R* . (w h e re R ’ MgX used) Me Me Ph Bt Ph Me a -n a p h th y l a -n a p h th y l Bt Ph a -n a p h th y l Me Bt a -n a p h th y l

S ig n * o f p ro d u c t

— + ( S m a ll) None None + + +

R e fe re n c e McK. McK. McK. T c f> McK. McK. McK. McK. McK. McK. McK. McK. McK. McK.

s ig n o f r o t a t i o n o f b a riu m s a l t , s ig n o f r o t a t i o n o f f r e e a c id .

/ s o l u t i o n o f a c id + ; b u t s ig n o f a o f s o l u t i o n o f K s a l t v a r i e d w i t h c o n c e n t r a t io n ,

and R i t c h i e ( l 931 a and C h r i s t i e (1 9 3 5 ! abd C h r i s t i e (1 t e x t )' and R i t c h i e 931b and R i t c h i e .1 931 b and R i t c h i e ,1 93113 and R i t c h i e ( l 9 3 l b ) and M ü lle r 1h 9 0 9 ) and M ü lle r 11 9 0 9 ) and M ü l l e r 11 9 0 9 ) and M ü lle r 11 9 0 9 ) and M ü l l e r 1 (1 9 0 9 ) and M ü lle r 1 (1 9 0 9 )

o b ta in e d d i r e c t fro m th e r e a c t io n m ix tu re was f a r fro m o p t ic ­ a l l y p u re .

I n most c a s e s ,

y ie ld e d a rac e m ic g l y c o l l i c g ly c o llic

on c r y s t a l l i s a t i o n , a c id .

t h i s p ro d u c t

H ow ever, m e t h y la n is y l-

a c i d , o b ta in e d by the a c t io n o f MeMgl on

( - ) - r a e n t h y l a n is o y l f o r mate o r o f a n is y l MgBr on ( - ) - m e n t h y l p y r u v a t e , was o b ta in e d o p t i c a l l y p u re b y subsequent re p e a te d re c ry 8 t a l l is a t i on fro m b en zen e. g ly c o llic

A ls o , m e th y l ^ - t o l y l -

a c id , p re p a re d fro m ( - ) -m e n th y l £ - t o l u y l f o r m a t e ,

was o b ta in e d i n an a lm o s t o p t i c a l l y p u re s t a t e

a fte r

re p e a te d

r e c r y s t a l l i s a t i o n fro m b e n z e n e /lig h t p e tro le u m m ix tu r e . From some o f th e s e e x p e rim e n ts th e g l y c o l , o b ta in e d b y th e

a c t io n o f excess G rig n a rd r e a g e n t, was i s o la t e d as a b y ­

p r o d u c t. R.C0.C02R'^

+

3E'MgX

^ E E 'C (O H ).C R 'R '(O H )

I n one c a s e , t r i m e t h y l a n is y l e th y le n e g ly c o l was o b ta in e d fro m ( - ) -m e n th y l a n is o y l form a te and MeMgl and was found to be laevo ro ta to ry . W ith re g a rd t o th e

in f lu e n c e

o f c o n d itio n s on th e e x te n t

o f a s ym m etric s y n th e s is M cKenzie (1 9 0 6 )

rem a rk s :

’’The mode o f fo r m a t io n o f th e G rig n a r d re a g e n t and th e c o n d it io n s under w h ic h i t s

a c t io n on th e k e to n ic e s te r i s

condu cted d o u b tle s s i n many cases in f lu e n c e

th e e x te n t to

w h ic h an as y m m e tric s y n th e s is

W h ils t the

ta k e s p la c e .

a c t i v i t y o f th e m ix tu r e o f un equ al amounts o f ( d ) - and ( l ) p h e n y lm e t h y lg ly c o llic

a c id s does not v e r y a p p r e c ia b ly v a r y

w ith v a r ia t io n re a g e n t i s

o f th e c o n d it io n s under w h ic h th e G rig n a rd

em p lo yed , th e

case i s

d i f f e r e n t when magnesium

i s o h u t y l io d id e a c ts on ( l ) - m e n t h y l h e n z o y lfo r m a te , s in c e , when th e G rig n a rd re a g e n t i s m o is ,

o f io d id e

to 1 m o l.

m e t r ic s y n th e s is is

added i n th e p r o p o r t io n o f

of e s te r,

th e

e x te n t o f th e

i s much le s s m arked th a n when th e

added i n th e p r o p o r t io n o f 1 ^ o l s .

o f io d id e

asym­

re a g e n t

to i

m ol.

of

e s te r. M cK enzie and M ü lle r ( 1 9 0 9 ) th o u g h t i t

m ig h t he p o s s ib le

t o c o r r e l a t e d e g re e o f asym m etric s y n th e s is w i t h th e m agni­ tude

o f th e

o p t ic a l r o t a t o r y pow er o f th e a lc o h o l r a d i c a l ,

h u t t h i s was no t c o n firm e d h y R i t c h i e

(1 9 3 3 a ) who commented

as f o llo w s "The e x te n t

o f any asym m etric s y n th e s is

ap p ears to depend as much upon th e

o f th is

ty p e

c o n d itio n s o b ta in in g d u rin g

th e G rig n a r d r e a c t io n as upon th e r o t a t o r y power o f the d ir e c tin g

system ;

th e a c t i v i t y

on r e p e a tin g such a s y n th e s is s e v e r a l t im e s ,

o f th e p ro d u c t has been found t o v a r y m a rk e d ly .

The case re c o rd e d above i s , is

how ever, th e

o n ly one where th e r e

th e l e a s t doubt about th e s ig n o f th e r o t a t i o n - a r a t h e r

p u z z lin g r e s u l t . "

H ere R i t c h i e was r e f e r r i n g

to th e s y n th e s is

in v o l v i n g is o b u t y l magnesium io d id e upon ( - ) - b o r n y lb e n z o y l fo rm a te when M cKenzie o b ta in e d a d e x t r o r o t a t o r y and R it c h ie

a

la e v o r o t a t o r y p r o d u c t. M cK enzie ( l 9 0 6 )

a ls o a tte m p te d a few asym m etric syntheses

Interaction of

and vC keto esters and Grignard reagents

( - ) - m e n t t iy l e a t e r o f — —

C o n c lu s io n s

j

A c e t o a c e t ic

StMpcX.

R e a c tio n w i t h e n o l fo rm o f e s t e r o n ly

E th y la c e to a c e tic

EtMgX

Some r e a c t i o n ( a p a r t fro m t h a t w i t h ; e n o l) o c c u rre d , ■ K s a l t s o l u t i o n fro m h y d r o ly s is ( a f t e r ^ re m o v a l o f m e n th o l) a lm o s t i n a c t i v e .

D ie th y la c e to a c e tic

EtMgX

K s a lt

s o lu tio n

! 1

D ie th y la c e to a c e tic

PhMgX

K s a lt

s o lu tio n " p r a c t ic a lly

I

L a e v u lic

StMgX a -n a p h th y l MgX

L a e v u lic

PhMgX

I Î 1 j

1

i

!

.................. .

'^ p r a c t i c a l l y I n a c t i v e " . in a c tiv e " .

S o lu t io n s and p r o d u c ts so c o lo u r e d as not to p e r m it o f a c c u r a te i n v e s t i g a _____ t i on. Aqueous s o l u t i o n o f Ba s a l t o f a c id fo u n d to he " d i s t i n c t l y l a e v o r o t a ; to ry " . C o lo u r o f s o l u t i o n e v id e n t ­ l y d id n o t a llo w o f q u a n t i t a t i v e in v e s tig a tio n . "The a c t i o n o f PhMgBr y ie ld e d a s l i g h t l y l a e v o r o t a t o r y p r o ­ d u c t , h u t i t s a c t i v i t y was p re s u m a b ly due to t h e f o r m a t io n o f th e asym ? m e t r ic l a c t o n e . " ( R it c h ie , 1 9 3 3 h ).

00

$

u s in g ( - ) -m e n th y l e s t e r s an alo g o u s

to th e

o f p - and y - k e t o

a c id s i n r e a c t io n s

a b o v e .( see T a b l e ) *

A s y m m e tric s y n th e s e s have a ls o b e e n o b served when an o p tic a lly

a c t iv e

a c y lc a r b in o l has b e en t r e a t e d w i t h a

G rig n a r d r e a g e n t and o x i d a t i o n o f th e o r i g i n a l asym m etric c e n tre

o f th e

r e s u l t i n g g l y c o l has b e e n e f f e c t e d .

(1 937> 1 9 3 9 ) a c c o m p lis h e d th e ( + ) - e t h y l b e n z o in ( i l l )

( +)

CHPh(OH).CO.Ph + E tM g B r I (-) PhCH(OH).COJÎt + P h M g B r II

as ym m e tric s y n th e s is o f

b o t h fro m ( + ) - b e n z o in ( I )

( - ) -p h e n y l p r o p io n y l c a r b in o l

Roger

and fro m

(II).

(+)

(+)

>CHPh(OH). C (O H )E tP h p -fo r m

(+) PhCC.CPhSt(OH) (-) (+) y* III > C H P h (O H ).C (C H )B tP h ^ a -fo rm

The above p r e p a r a t i o n o f ( + ) - b e n z o in was term ed a u n i l a t e r a l a s y m m e tric s y n th e s is b y R oger s in c e o n ly one o f th e p o s s ib le

two

fo rm s was o b t a in e d .

As w o u ld be e x p e c te d fro m t h i s

o b s e r v a t io n T if f e n e a u

and

L e v y ( 1 9 2 7 ) had o b ta in e d d i f f e r e n t p r o d u c ts b y t r e a t i n g ( - ) - b e n z o in w i t h e t h y l magnesium b ro m id e and ( - ) - p h e n y lp r o p io n y lc a r b in o l w i t h p h e n y l magnesium b ro m id e r e s p e c t i v e l y , a lth o u g h i n b o t h cases th e p r o d u c ts w ere rac e m ic compounds. O th e r o b s e r v a tio n s a n a lo g o u s to th e

above have been r e c o rd e d ,

o n ly one o f th e two p r o d u c ts t h a t c o u ld be e x p e c te d b e in g fo rm e d , a lth o u g h p r e f e r e n t i a l o x id a t io n o f th e o r i g i n a l o p t ic a lly a c tiv e

c a r b in o l group has n o t a lw a ys b e e n

10

a c c o m p lis h e d t o g iv e a new o p t i c a l l y Brokaw and Brode

(1 9 4 8 ) f a i l e d

s y n t h e s is h y t h e i n t e r a c t i o n

a c t iv e

c a r b in o l.

t o e f f e c t an a s y m m e tric

o f e i t h e r m e t h y l- or e t h y l -

a c t i v e -a m y l k e to n e w i t h e t h y l o r m e th y l magnesium b ro m id e r e s p e c tiv e ly .

N o r was an a sy m m e tric s y n th e s is e f f e c t e d b y

th e i n t e r a c t i o n o f a c t i v e -a m y l magnesium b ro m id e e t h y l k e to n e . to

T h is i s

th e o n ly r e f e r e n c e w h ic h can be fo u n d

an a tte m p te d a s y m m e tric s y n th e s is in v o lv i n g

r e a c t i o n b e tw e e n an o p t i c a l l y s y m m e tric a l k e to n e .

and m e t h y l-

an a d d i t iv e

a c t i v e G r ig n a r d r e a g e n t and a

The s e r ie s o f r e a c t io n s w as:

CH2.CH2.GH . CH2Br CH_

CH^.O%.CH. C%.GLCH2.CH2

CH^. CHg. CH. CHg.C.CH^ CH

C H yC O .C H 2 .C H 2

CH2

tH2MgB: OH

s u

CH2 .C H g.C H .C H 2 .c .C H g .C H 2 CH2

CH2

The r e a c t io n s d is c u s s e d above ( e x c lu d in g th e

la s t

e x a m p le ) have a l l in v o lv e d a d d it io n o f a G r ig n a r d re a g e n t t o a c a rb o n y l grou p i n o p t i c a l l y a c t iv e

a m o le c u le w h ic h a ls o c o n ta in s an

c e n tre .

A tte m p ts have

a ls o b ee n made to

11

e ffe c t

an a s y m m e tric s y n th e s is by t r e a t i n g

an i n a c t i v e

c a r b o n y l compound w i t h a G r ig n a r d r e a g e n t i n an o p t i c a l l y a c tiv e

s o lv e n t .

B e tti th is

and L u c c h i ( l 9 4 0 )

c la im e d t o have a c c o m p lis h e d

ty p e o f a s y m m e tric s y n th e s is b y t r e a t i n g

dehyde w i t h m e th y l magnesium io d id e a lly

a c tiv e

b e n z a l-

i n benzene and an o p t i c ­

s o lv e n t such as d i me t h y lb or n y l ami n e .

t h i s w o rk has b e e n c r i t i c i s e d

S in c e

th e n ,

a d v e r s e ly b y T a r b e l l and

P a u ls o n ( 1 9 4 2 ) , who c o n s id e r t h a t th e supposed as ym m e tric s y n th e s is was due t o

im p u r itie s .

A ls o , th e l a t t e r

a u th o rs

w e re u n s u c c e s s fu l w hen t h e y a tte m p te d a s i m i l a r ty p e

of

a s y m m e tric s y n th e s is u s in g ( + ) - m e t h y l - s - b u t y l e t h e r as s o lv e n t f o r b e n z a ld e h y d e

th e p r e p a r a t io n o f p h e n y lm e th y lc a r b in o l fro m and MeMgBr.

The e f f e c t o f an o p t i c a l l y a c t iv e

s o lv e n t

c h e m ic a l co u rse o f a r e a c t i o n i n v o l v i n g in

an o p t i c a l l y a c t i v e

B o nn er ( l 9 4 7 ) .

on th e

s te re o ­

a G rig n a r d re a g e n t

s o lv e n t was a ls o i n v e s t i g a t e d b y

No asy m m etric s y n th e s is was e f f e c t e d when

C H j.C H C l.O C g H j was t r e a t e d w i t h p h e n y l magnesium b ro m id e t o g iv e C H y (C gH g )C H . 0 C2 Hg u s in g m e th y l te tra m e t h y l - a - D g lu c o s id e , t e t r a - a c e t y l g l ^ c o s y l bromocamphor as o p t i c a l l y

a c t iv e

c h l o r i d e , b r u c in e

and a -

s o lv e n t s .

So f a r no m e n tio n has been made o f asym m etric s y n th e s e s w h ic h have b e e n e f f e c t e d b y u t i l i s i n g p e r t i e s o f some G rig n a r d r e a g e n ts .

th e

re d u c in g p r o ­

V avon, R iv ie r e

and

12

A n g e lo ( 1 9 4 6 ) and V a v o n and A n g e lo (1 9 4 ? ) have e f f e c t e d a a e r i e s o f a s y m m e tric r e d u c tio n s

o f k e to n e s ,

c o n t a in in g no

a s y m m e tric c a r t o n a to m , w i t h th e a id o f i s o t o r n y l magnesium "bromide t o g iv e th e

o p tic a lly

a c t i v e c a r h i n o ls .

In th is

case

d e g re e o f a s y m m etric s y n th e s is was dependent on th e

s t r u c t u r e o f th e k e to n e . In

c o n c lu s io n some o t h e r r e le v a n t

m e n tio n e d .

Bergmann and H a r t r o t t

p a r a tio n o f o p t ic a lly

o b s e r v a tio n s may be

(1 9 3 5 )

a tte m p te d th e p r e -

* a c t iv e CH3 . (CH 2 ) 2 *C H (C H ^ ).C ( 0 H ) (P h ) 2

fro m C H y (CH 2 ) 2 'GHGH^.C 02 B t and PbMgBr b u t o b ta in e d o n ly th e in a c tiv e

a lc o h o l.

They r e j e c t th e i d e a t h a t th e

goes é n o l i s a t i o n b e f o r e i t

e s t e r u n d e r­

r e a c t s w i t h th e G r ig n a r d re a g e n t

or t h a t th e i n t e r m e d ia t e k e to n e fo rm e d e n o lis e s b e f o r e f u r t h e r r e a c tio n ,

and s u g g e s t t h a t the

to th e f o l l o w i n g e q u i l i b r i u m H

Ph

1

I

i n th e

r a c é m is a t io n i s

due

r e a c t i o n m ix t u r e :

/ P h

Me - C - C - CH;F======^Me - C = C(;

I

I

Pr

I

Ph

Pr

H o w ever, C a m p h e ll and Kenyon r e s o lv e d h y d ra t r o p i c a lly

tre a te d

(+ )-p a r tia lly

a c id w i t h PhMgBr and o b ta in e d an o p t i c ­

a c tiv e g ly c o l. CH,

OH, OH

I

1 ^ 1

^

Ph - C - CO pH— I ^ H F u r th e r , to fin d i f

-------------- >Ph - C - C - Ph 1 1 H Ph

an e q u i lib r iu m m ix tu r e was o b t a in e d , t h e y

13

d is s o lv e d 1 :1 : 2 - t r i p h e n y lp r o p y l e n e i n P M ^r

s o l u t i o n and a f t e r

a d d in g 1 m o l.

h e a te d th e s o l u t i o n u n d e r r e f l u x . unchanged compound ( 4 . 5 g . case t h a t no e q u i l i b r i u m

4 m o l. p r o p o r t io n s o f p r o p o r t io n o f w a t e r

D e c o m p o s itio n y ie ld e d th e

fro m 5 .0 g . ) , p r o v in g i n t h i s

had b e e n e s t a b lis h e d .

V a r io u s s u g g e s tio n s h a v e b e e n advanced as to f a c t o r s c o n tr o llin g

asymneftric s y n th e s e s o f th e

a d d i t i o n o f a G r ig n a r d re a g e n t t o la tte r

and an a s y m m e tric c e n tr e

m o le c u le .

M cK enzie and h is

ty p e in v o lv in g th e

a c a rb o n y l g ro u p , when th e

a re p r e s e n t i n th e

same

c o lle a g u e s w ere i n c l i n e d to

f a v o u r an e x p la n a t io n i n v o l v i n g

" in d u c e d asym m etry" i n th e

c a rb o n y l g rou p u n d e rg o in g r e a c t i o n

( c f . R it c h ie , 1 9 4 7 ).

One

o f th e more r e c e n t d e f i n i t i o n s

o f " a s y m m e tric in d u c t io n " ,

advanced b y K o rtlim ( 1 9 3 2 ) , i s :

"The a c t io n o f a f o r c e ,

a r is in g i n

a s y m m e tric m o le c u le s , w h ic h in f lu e n c e s a d ja c e n t

s y m m e tric a l m o le c u le s i n m e tr ic " .

such a w ay t h a t th e y become asym­

He th o u g h t t h i s e f f e c t c o u ld be e x h i b i t e d b o th

i n t r a - and i n t e r - m o l e c u l a r l y .

T i f f e n e a u , L e v y and D i t z

(1 931 , 1 9 3 5 ) fa v o u r th e e x p la n a t io n t h a t one o f th e two bonds o f th e c a r b o n y l group i s an o p t i c a l l y and P a r t r i d g e

a c t iv e

a t t a c k e d s e l e c t i v e l y when t h e r e

system e ls e w h e re i n

th e m o le c u le .

(1 9 3 6 ) have s u g g e s te d t h a t " i t

is

is

Kenyon

a d iffe r e n c e

i n e n e rg y a s s o c ia t e d w i t h th e d ia s t e r e o is o m e r ic in t e r m e d ia t e p r o d u c ts w h ic h i s

r e s p o n s ib le f o r th e o n e -s id e d a d d i t i o n " .

V a r io u s w o rk e rs have s u g g e s te d t h a t th e

d eg ree o f

14

as y m m e tric s y n th e s is w i l l he c o n t r o l le d h y t h e p r o x im it y o f th e w ill

a sym m etric ta k e

c e n tr e to th e

p la c e

L e v y and D i t z ,

(c f.

c e n tr e

Brokaw and B ro d e , 1 9 4 8 , and T if f e n e a u ,

1931 , 1 9 3 5 ) .

H o w ever, t h e r e

s y s te m a tic i n v e s t i g a t i o n i n t o a s y m m e tric s y n th e s is

a t w h ic h th e r e a c t io n

has he en no

th e e f f e c t o n th e d e g re e o f

o f in t r o d u c in g a c a rh o n c h a in o f i n ­

c r e a s in g l e n g t h [ - ( G H ^ ) ^ - ] b e tw e e n th e o p t i c a l l y

a c t iv e

c e n tr e and the r e a c t i o n c e n t r e . A ls o , i t s y n th e s is

a p p eared fro m th e ahove id e a s on asym m etric

th a t, i f

such s y n th e s e s ( i n v o l v i n g

and a G r ig n a r d r e a g e n t ) w ere a r e s u l t

an a - k e t o e s t e r

o f asym m etric in d u c t io n

w h ic h p re s u m a b ly must he an e l e c t r o n i c m echanism - th e n th e i n t r o d u c t i o n o f a m e th y le n e c h a in s h o u ld d e c re a s e th e e x t e n t o f a s y m m e tric s y n t h e s is .

H o w ever, i f

w ere due t o e n e rg y d if f e r e n c e s c re a s e i n th e d e g re e p e c te d .

a t some s t a g e , no such d e­

o f asy m m e tric s y n th e s is w ou ld he e x ­

M o r e o v e r, f u r t h e r in f o r m a t io n as t o th e e x p la n a t io n

o f t h i s ty p e

o f asy m m etric s y n th e s is c o u ld he o b ta in e d h y

th e s tu d y o f th e ta in in g

as ym m e tric s yn th e s e s

i n t e r a c t i o n o f a G r ig n a r d r e a g e n t ,

con­

an asym m etric c e n t r e , w i t h a s y m m e tric a l k e to n e , w i t h

a v ie w to o b t a in in g an asy m m etric s y n t h e s is .

Thus, i t

was

d e c id e d to s tu d y th e i n t e r a c t i o n o f an o p t i c a l l y a c t iv e hromoa c e ta t e

and acetophenone i n th e p re s e n c e o f z in c , i . e .

15 Me + B r CH2 . CO2B *------ — — ^Ph - 0 - CH2 -CO 2R *

Ph. CO.Me

OZiiBr h y d r o ly s is Me

\ Ph - C - CH2 -CO 2 H ( o p t i c a l l y a c t iv e ? )

I

OH Id .

P re s e n t

In v e s tig a tio n

Th u s , th e p r e s e n t i n v e s t i g a t i o n e n t a i l e d th e f o llo w in g s te p s : ( 1 ) p r e p a r a tio n o f (-)-m e n th y l e s te r s

of

-a c e ty l f a t t y

a c id s - C H ^.C O .(C H 2)n»C 02H ; ( 2 ) i n t e r a c t i o n o f th e s e e s t e r s w i t h p h e n y l magnesium h ro fflid e , w i t h s u b seq u en t h y d r o ly s is and i n v e s t i g a t i o n o f th e r e s u ltin g

h y d r o x y -a c id f o r

o p t ic a l a c t i v i t y ;

( 3 ) e s t a b l i s h i n g w h e th e r th e t h e s i s was dependent ( 4 ) p r e p a r a t io n o f

above ty p e o f asym m etric syn­

on r e a c t io n c o n d it io n s ; ( - ) - m e n t h y l b r o m o a c e ta te , and i t s

tr e a tm e n t w i t h acetophenone i n th e p re s e n c e o f z in c , w i t h sub sequent h y d r o ly s is

o f th e p r o d u c t.

o b ta in e d w o u ld be exam in ed f o r It

w i l l b e seen fro m th e

use th e m e n th y l e s t e r .

It

The h yd ro xy a c id thu s

o p tic a l a c t i v i t y . above t h a t i t

was d e c id e d t o

had been o b served t h a t asym m etric

s y n th e s e s i n v o lv in g m e n th y l e s t e r s te n d t o be g r e a t e r th a n

16

w h en , f o r

e x a m p le , h o r n y l o r s e c o n d a ry o c t y l e s t e r s

used (M cK en zie and M ü l l e r , 1 9 0 9 ) . grou p has a r e a c t i v i t y many o f th e

are

A ls o , th e m e n th y l e s t e r

c o n s id e r a b ly lo w e r th a n t h a t o f

o t h e r e s t e r grou ps

(T r ie b s , 1 9 4 4 ).

II. PSSPARATIOH OP (-)-M B N TH Y L ESTERS

17

II. lia .

PREPARATION OP ( - ) - M B M H ïL

( - ) - M e n t h y l p y r u v a te P y r u v ic

a c id was p r e p a r e d a c c o rd in g to t h e method i n

O rg a n ic S y n th e s e s t io n

SSTBRS

of ta r ta r ic

( C o l l . V o l.

I,

p.

4 7 5 ) "by th e d r y d i s t i l l a ­

a c id w i t h p o ta s s iu m h y d ro g e n s u lp h a te .

was o b ta in e d i n 39% y i e l d , b a se d on t a r t a r i c b .p .

58°/7m m . , w h ic h i s

p u b lis h e d v a lu e s , a lth o u g h t h e r e

e .g .

in

a c id ,

It

and had

agreem ent w i t h some o f th e

5 8 ^ /7 mm.

( H e n r i and P ro m ag eo t, 1 9 2 5 ) ,

a p p e a r to be some d is c r e p a n c ie s i n th e l i t e r a ­

tu re . The ( - ) -m e n th y l e s t e r was p r e p a re d b y th e P is c h e r S p e ie r m ethod u s in g

k m o le c u la r

p r o p o r t io n s o f m e n th o l.

E xcess m e n th o l was removed b y steam d i s t i l l a t i o n , lo w y i e l d

o f m e n th y l p y r u v a te

1 2 8 -1 3 0 ^ /8 mm.) was a t t r i b u t e d

and th e

o b ta in e d (24% o f c ru d e , b . p . to th e

steam v o l a t i l i t y

of

m e n th y l p y r u v a te w h ic h was s u g g e s te d b y th e f a c t th a t^ to w ard s th e end o f th e

steam d i s t i l l a t i o n ,

an o i l w h ic h w ould n o t s o l i d i f y . o b ta in e d f o r p u re 10 mm., n^^

th e d i s t i l l a t e

The p h y s ic a l c o n s ta n ts

( - ) -m e n th y l p y r u v a te w e r e , b . p .

1 .4 5 6 5 , c y ^

- 4 6 .6 4 ^

c o n ta in e d

1 3 2 .5 -1 3 3 .5 ° /

> ^5780

5 -5 5 .7 4 ° . These v a lu e s a re com parable to th o s e r e p o r t e d 5461 b y M cK enzie (1 9 0 5 ) , b . p . 1 3 1 - 1 3 2 ^ 1 0 mm., and b y R oger and R itc h ie th e s e

( l9 3 2 ),

a u th o rs p re p a re d

- 4 6 .5 4 ^ * ^5461

" 5 5 .4 6 ® ( t = 0 . 5 d m .);

the e s t e r by th e

same m ethod.

18

Ilb ,

(~ )-M e n th y l la e v u la te ( - ) -M e n th y l l a e v u l a t e was p re p a r e d fro m l a e v u l i c

h y th e P is c h e r - S p e ie r method o f e s t é r i f i c a t i o n , m e n th o l h e in g f i n a l l y

rem oved h y d i s t i l l a t i o n

( - ) -M e n th y l l a e v u l a t e , h . p . y i e l d w i t h th e

r 125^ ^^5461

0 ,0 7 1 .5 /f ,

excess

i n v ac u o .

1 51 ^ /2 mm. was o b ta in e d i n 71%

f o l l o w in g p h y s ic a l

1 .4 5 7 3 ,

a c id

c o n s ta n ts :-

0 .9 7 6 5 ,

M cK enzie

- 61. 14° ,

0 .9 7 1 ,

( l9 0 6 ) ,w h o p r e p a r e d th e e a t e r ^

h y th e same m ethod, r e p o r t e d h . p . 1 69/ i 2 mm.; d, 0 . 9773; o - 6 0 . 6 ^ f o r t h i s compound. The s e m i-c a rh a z o n e c r y s t a llis e d

fro m a lc o h o l i n p r is m a t i c n e e d le s , m .p.

1 56-1 56 . 5 ° . lie .

( - ) -M e n th y l W - a c e t y l - n - h u t y r a t e

[ ( - ) -m e n th y l 4 - k e t o -

p e n t an-1 - c a r h o x y la t e ] In r in g

th e e a r l i e r w o rk ,

r in g f i s s i o n

of 5-

and 6 -mem hered

compounds h y o x id a t io n was o f t e n fo u n d to g iv e

a c e ty l-n -h u ty r ic

a c id

(c f.

( 1897) e ffe c te d h y d r o ly tic

B e ils te in .

III,

3 8 5 ).

V h r la n d e r

f i s s i o n o f c y c lo h e x a n -1 : 3 -d io n e

h y h o i l i n g w i t h h a riu m h y d ro x id e s o l u t io n and o b ta in e d t h i s compound; c y c lo h e x a n e -1 : 3 - d io n e was p re p a r e d hy r e d u c t io n o f r e s o r c i n o l w i t h sodium amalgam and w a t e r . o f a c e t y l s u b s t i t u t e d d ic a r h o x y li c

a c id s and d i - a c e t y l

s u b s t i t u t e d a c id s has a ls o b e e n used f o r a c e ty lh u ty r ic

a c id , e .g .

(i)

The h y d r o ly s is

h y d r o ly s is

th e p r e p a r a t io n o f o f a -a c e ty l-g lu ta r ic

19

a c id p re p a re d fro m a c e to a c e t i c (F ittig

e s te r

and W o l f f , 1 8 8 3 ; B e n tle y and P e r k in , 1 8 96 ) o r fro m

m e th y l a c r y l a t e and a c e t o a c e t ic e s t e r (ii) ly s is

and p -io d o p r o p io n a te

( A lb e r t s o n , 1 9 4 8 ) ,

h y d r o ly s is o f y y ' - d i a c e t y l h u t y r a t e , of a -c a rh e th o x y --k e to c a p ro a te

and ( i i i )

h y d ro ­

p re p a re d b y th e i n t e r ­

a c t io n o f m a lo n ic e s t e r and a M annlchbase(% N .Π2 .CH2 ^CO. (M a n n ic h and F o u rn e a u , 1 9 3 8 , H a rrad en ce

.

HCl )

and L io n s , 1 9 3 9 ) .

T h is compound has a ls o been p re p a re d th ro u g h th e i n t e r ­ a c t io n o f g l u t a r i c

a n h y d rid e and m e th y l magnesium brom ide i n

e q u im o le c u la r p r o p o r t io n s

(Komppaand Eohrmann, 1 9 3 4 ) as

w e l l as b y th e h y d r o ly s is o f 1 : 6 - d i m e t h y l - 6 - h y d r o x y p ip e r id - 2 one w h ic h i s

o b ta in e d by th e i n t e r a c t i o n o f g la t s r m e th y lim id e

and m e th y l magnesium b ro m id e (L u k e s and G o ro c h o lin s k y , 1 9 3 6 ). I n 1 942 a m ethod was p a te n te d f o r th e p r e p a r a t io n o f a c e t y l h u t y r i c a c id b y th e i n t e r a c t i o n o f k e te n e and v i n y l m e th y l k e to n e (H o p ff and Rapp, 1 9 4 2 ) . and T u te r y a n (1 9 4 6 ) p re p a re d

T a te v o s y a n , M e lik y a n

a c e t y lh u t y r ic

a c id b y th e

f o l l o w i n g s e r ie s o f r e a c t i o n s ; ^ c o p .C p H c NaCH ^ ^ C 02 .C 2 H 5

+

,cajï 9 -? ' /OOgCgHc C & - 0 =C-CH2C1 ----------------^ CHt-C^c-CHo-CH ^ KOH

p -H Ol H /COpH CH5.CO .(CH2) 3.CC^H w h e re a s M y d d le to n and B a r r e t t

d u c t o f m .p .

,

i n 50^ y i e l d ,

3 8 . 5^ i n

a c id ,

79% y i e l d .

o b ta in e d a p r o ­

The 1 -d e c e n e -i C - c a r b o -

x y lic

a c id used b y M y d d le to n and B a r r e t t was somewhat p u r e r

(m .p .

21j;, 5 ^ )

th a n t h a t used i n t h i s

1 - D e c y n e - iO - c a r b o x y lic

a c id ,

m .p .

in v e s tig a tio n

(m .p .

2 1 ^ ),

3 9 .7 -4 0 ^ » was p r e p a r e d

fro m th e dib ro m o compound b y b o i l i n g w i t h a l c o h o l i c p o ta s s iu m h y d ro x id e s o l u t i o n a c c o r d in g t o K r a f f t

( 1 8 9 6 ) , who re c o rd e d

m .p .

crude a c e t y le n ic

4 2 .7 -4 2 .9 ^ .

The h y d r a t io n o f th e

a c id was th e n a c c o m p lis h e d b y h e a t in g a s o l u t i o n i n a c id w i t h m e r c u r ic a c e t a t e . ( CH^.COgHg) c h lo r ic

. CO. ( CH2 )^ 0 0 2 Hg/ 2

a c id .

fro m t h i s

The m e rc u ry s a l t

r e a c t i o n m ix tu r e b y f i l t r a t i o n , filtr a te

s till

S h e r r ill

and S m ith , 1 9 3 7 ) .

e t h e r e a l s o l u t i o n to

d ry n e s s ,

p r o d u c t fro m l i g h t p e tr o le u m p e l a r g o n ic a c id o f m .p . p u r ific a tio n

c o u ld be rem oved but

an e t h e r e a l

c o n ta in e d some m e rc u ry s a l t s

w h ic h w ere b e s t rem oved b y p r e c i p i t a t i o n (c f.

com plex -

- was decomposed w i t h h y d ro ­

Some o f th e m e rc u ry s a l t s

e x t r a c t o f th e

a c e tic

as th e s u lp h id e

C o n c e n t r a t io n o f t h i s

and c r y s t a l l i s a t i o n (b .p .

3 7 -3 8 ° in

6 0 -8 0 ^ ),

78 % y i e l d .

o f t h i s p r o d u c t was e f f e c t e d

o f th e

gave ace t y l ­ F u rth e r

v ia i t s

b is u lp h ite

d e r i v a t i v e , w h ic h was p r e p a r e d b y s h a k in g a ben zene s o l u t i o n o f th e k e t o - a c i d w i t h a s a t u r a t e d s o l u t i o n o f sodium

28

i D is a lp h it e

(c f.

d u c t fro m t h i s l i g h t p e tr o le u m

A braham , Mowat and S m ith , 1 9 3 7 ) .

p u r i f i c a t i o n p r o c e d u r e was c r y s t a l l i s e d (h .p .

4 0 -6 0 ^ ), g iv in g

5 8 .2 -5 8 .8 ^ .

M y d d le to n and B a r r e t t

C h u it e t

( 1 9 2 6 ) m .p .

( 1 9 3 7 ) 5 8 -5 9 ^ .

The p r o ­

s m a ll n e e d le s , m .p .

(1 9 2 ? ) r e c o r d m .p .

5 9 -5 9 # 6 ^ and S h e r r i l l

The s e m ic a rh a zo n e had m .p .

M y d d le to n and B a r r e t t

fro m

5 9 .5 ^ ,

and S m ith

1 3 5 . 5-4 3 6 . 5 ° ;

(1 9 2 7 ) r e c o r d m .p . 1 3 6 . 5 ° .

( - ) - M e n t h y l ^ - a c e t y ln e l a r g o n a t e was p r e p a r e d h y th e F i s c h e r - S p e ie r m ethod i n 75% y i e l d w i t h h . p . T h is

compound had th e

2 0 9 - 2 1 0 ^ 3 m i.

f o l l o w i n g p h y s ic a l c o n s ta n ts :

1 . 2, 6 1 9 , 0 .9 3 9 , -5 5 .0 2 ° . Jj y / OU 54 6i The s e m ic a rh a z o n e m .p . 1 0 0 .5 -1 0 1 c r y s t a l l i s e d fro m aqueous n 2 0 -5 °

a lc o h o l i n r e c t a n g u l a r p l a t e s . Ilf.

N o te on p h y s i c a l p r o p e r t i e s o f ( - ) -m e n th y l f a t t y a c id e s t e r s i n r e l a t i o n t o s t r u c t u r e The p h y s ic a l p r o p e r t i e s

o f the

Ü -a c e ty l

( - ) -m e n th y l e s t e r s

O -a c e ty l f a t t y

a c id s (C H ^.C O . (C H 2 )j^ # C 0 2 (-)-m e n th y l)

t a b u l a t e d b e lo w

(s e e

n

M o l. w t.

0 1 2

2 2 6 .3 s o lid

3 4 8 1___

-

25k.k 2 6 8 .4 2 8 2 .4 3 3 8 .5

* M cK en zie

a ls o

(2 0 °)*

0 .9 7 3

0 . 965( 5) 0 . 960( 5 ) 0 .9 3 9 ( l 9 0 5 )#

a re

g r a p h ).

d25°

0 .9 8 5

of

h 250

1 .4 5 3 9

-ra ]2 5 ° - [a ]2 5 ° ' ■‘5780 5461 to .02° ± 0 . 02° —

(1 0 °)°

1 .4 5 7 3 1 .4 5 8 8 1 .4 6 0 0 1.4 61 9

e R o g er and R i t c h i e

6 3 .4 8 6 2 .0 2 5 8 .7 4 4 8 .5 9 (1 9 3 2 ).

1 1 3 .1 ® 7 1 .8 4

7 0 .1 7 6 6 .5 0 5 5 .0 2

29

,25 *

100

1.010

169

190

95

1 .0 0 0

168

189

90

0 .9 9 0

167

188

85

0 .9 8 0

166

187

80

0 .9 7 0

165

186

76

0 .9 6 0

164

105

70

0 .9 6 0

163

184

66

0 .9 4 0

162

183

60

0 .9 5 0

161

182

'

It

w i l l be seen t h a t th e 2 a te d fro m th e e x p r e s s io n ( ^ n l i n e when p l o t t e d a g a in s t n ; v a lu e

o f 4.64- f o r

is

a g reem en t w i t h th e v a lu e

in

(c f.

m o le c u la r r e f r a c t i o n s

- -1 ~ ) do l i e on a s t r a i g h t + 2 ^ th e s lo p e c o rre s p o n d s to a

th e r e f r a c t i v i t y

G la s s to n e , 1 9 4 0 ) .

(c a lc u l-

o f th e -CH 2 -

g ro u p .

T h is

( 4 . 6 2 ) p u b lis h e d b y ïï i s e n l o h r

W i t h in th e range

s t u d ie d ,

th e r e

a p p e a re d to be an in v e r s e l i n e a r r e l a t i o n s h i p b e tw e e n th e d e n s it y ana th e v a lu e

o f n.

30

The molecular rotation of (-)-menthyl pyruvate is con­ siderably larger than that of the higher homologues, which might be expected in view of the proximity of the carbonyl and carbomenthoxy groups. (-)-menthyl laevulate

The molecular refraction of

(n = 2) is minimal.

The number of

compounds examined was not sufficiently great to enable any conclusions to be drawn, as to the relationship between [m] and n over the whole series; all values for [M] might lie on a curve when plotted against n, or exaltations or depres­ sions might be observed at regular intervals such as when (n + x) is a multiple of 5 and x is a constant. U

p:.

(-)-Menthyl bromoacetate (-)-Menthyl bromoacetate has previously been prepared

b y the treatment of bromoacetyl bromide with menthol, either in chloroform solution (Cohen, 1 911 ), or with no diluent (Smiles, 1905; Christopher and Hilditch, 1912).

Smiles’

(1 9 0 5 ) attempt to prepare this ester from bromoacetic acid and menthol in the presence of sulphuric acid gave an ester of low specific rotation.

In the present investiga­

tion (-)-menthyl bromoacetate was prepared by treating bromoacetyl chloride with menthol (no diluent), and also by heating bromoacetic acid and menthol at 1 0 0 ^ in the pre­ sence of gaseous HBr.

Bromoacetyl chloride, b.p. 1 21 -1 25°,

was prepared from bromoacetic acid and thionyl chloride, in 7Q% yield; in one experiment redistillation of this

31

product gave a liquid, b.p. 1 2 5 .5 -1 2 7 °.

Published values

i n c l u d e : - 1 2 ? ° (de W ild e , 1 8 6 4 ) , 1 3 3-1 3 5 ° (M e y e r, 1 9 0 1 ) , and 1 2 7 - 1 2 7 . 5 ° (A s c h a n , 1 9 1 3 ) . C rude

( - ) -m e n th y l b ro m o a c e ta te was o b ta in e d w i t h b . p .

1 5 6 ° / 8 mm. in 02% yield from the acid chloride, 1 0 8 -1 1 6 ° / 2 - 3

mm.

in

55$ y ie ld

fro m t h e f r e e

and with b.p.

a c id .

B o ilin g

points previously recorded include, 1 4 6 - 1 4 7 ^ 1 2 mm. 1 9 1 1 ),

141 - 1 4 5 V i 2 mm.

( S m ile s , 1 9 0 5 )

(Christopher and Hilditch, 1912).

(Cohen,

and 1 77-1 7 8 ° / 4 0 mm.

The distillates solidified

and the crude ester was found to crystallise from light p e tr o le u m p ro d u c t [ a ^ 546 l

(b .p .

4 0 -6 0 °)

1 8 .5 -1 9 . 5 ^ . The 25 O 2 o b ta in e d fro m t h e a c id c h lo r i d e had [ a ] ^ y g ^ - 6 8 .ÿ ± 0 . 2 ° 5780'

~ 7 8 .1 ^ i

p a r e d fro m th e

0 .2 °

as n e e d le s , m .p .

(c ,

2 . 5 in

c h lo r o f o r m ) ,

f r e e a c id had

[a ]^ ^ - 7 7 . 4 ° - C i2 ^ ( c , 5461 p. o p r o d u c t had -6 7 .9

and t h a t p r e ­

3^ - 0 .2 *^ ,

2 .5 in

c h lo r o f o r m ) .

- 0 .8 ^

(1 = 0 . 5 d m .).

The fo r m e r T h is v a lu e

s h o u ld be com pared w i t h t h a t r e p o r t e d b y C h r is to p h e r and H ild itc h -

(1 91 2 ) f o r a 2 .5 % s o l u t i o n i n

[a ]^ ° ° -6 3 .2 0 ° .

c h lo r o fo r m

■ III. IHTBRACTIOK OP PHENYL MAGMBSIUM BROMIDE AMD (-)-M S H T H Y L W-AdËTYL PATTY ACID ESTERS

32

IIlZ

INTERACTION OP PHENYL MAGNESi m BROMIDE AND ( - ) -MENTHYL Ü -ACETYL PATTY ACID ESTERS

Ilia .

In tr o d u c tio n B e fo r e

s t u d y in g th e

a s y m m e tric s y n th e s e s r e s u l t i n g

fro m t h e r e a c t i o n b e tw e e n p h e n y l m agnesium b ro m id e and (-)-m e n th y l

O -a c e ty l f a t t y

CHyCOXOHg)^. 002^0^0^1 9

a c id e s t e r s ,

i.e . Ph

---------------------------- > CH,-C-(CH2)^00;u.C^ 0^1 9

(4 w here

n = 0,

2,

Ph I C H ^ -C -(C H 2 )^ C 02 H

'

(-)

3» 4 and 8 Ph I C H ^ -C -(C H 2)^C 02-C ^

^-----------

OH

OH

(-) (o p tic a lly it

a c tiv e ? )

was e s s e n t i a l t o

d e v e lo p a r e p r o d u c ib le m ethod f o r

p r e p a r a t i o n o f p h e n y l m agnesium b ro m id e , th e

and to d e te rm in e

amount o f d ip h e n y l form ed u n d er th e s e c o n d it io n s

th is

lo s s

G r ig n a r d

th e

so t h a t

o f brom obenzene d u r in g th e p r e p a r a t io n o f th e re a g e n t c o u ld be

a llo w e d f o r .

T h is S e c t io n in c lu d e s d e s c r ip t io n s e s t i m a t i o n o f d ip h e n y l and o f th e b a s ic

o f th e method o f c o n d it io n s used f o r

s tu d y in g t h e above ty p e o f a s y m m e tric s y n t h e s is , w i t h th e e x p e r im e n ta l r e s u l t s

o b ta in e d d u r in g th e

to g e th e r in v e s tig a ­

tio n . (+ )

U n le s s o th e r w is e s t a t e d o p t i c a l o b s e r v a tio n s w e re made on e t h a n o l i c s o l u t io n s .

g

33

Illb .

P r e p a r a t io n o f p h e n y l m agnesium 'brom ide P h e n y l m agnesium ‘brom ide was p r e p a r e d i n

o f n itr o g e n , t u r n in g s

u s in g 3 m o le c u la r p r o p o r t io n s

to 1 o f brom obenzene

d ip h e n y l fo r m e d ). r a tio n

( t o re d u c e

The m ethod f i n a l l y

an atm o sp h e re

o f magnesium

th e amount o f

e v o lv e d

fo r th e p re p a ­

o f an e t h e r e a l s o l u t i o n o f p h e n y l magnesium b ro m id e

was as f o l l o w s .

A p o r tio n

(a b o u t

3% ) of

th e m agnesium was

c o v e re d w i t h e t h e r and a fe w d ro p s o f brom obenzene w ere add ed; t h e r e a c t i o n f l a s k was h e a te d i n t h e r e a c t i o n had s t a r t e d .

The r e s t o f th e magnesium was

added and c o v e re d w i t h e t h e r ,

and an e t h e r e a l s o l u t i o n o f

brom obenzene was added a t su ch a r a t e b o ilin g

a b a t h a t 60^ u n t i l

as to m a in t a in g e n t l e

o f th e e t h e r w it h o u t e x t e r n a l c o o lin g o r h e a t in g .

When a l l th e brom obenzene had b een added th e w as h e a te d i n a b a t h a t 6C^ f o r 30 m in s . was s ip h o n e d i n t o n itr o g e n ,

a d ro p p in g f u n n e l i n

re a d y f o r

a d d itio n to

r e a c t i o n m ix tu r e

The s u p e rn a ta n t^ ,

an atm o sp here o f

an e t h e r e a l s o l u t i o n o f th e

( - ) -m e n th y l e s t e r . IIIc .

M ethod o f e s t i m a t io n o f d ip h e n y l A p h e n y l magnesium b ro m id e s o l u t i o n , p r e p a r e d a c c o r d in g

t o t h e above c o n d it io n s , was s e p a r a te d fro m excess magnesium b y s ip h o n in g and was p o u re d on t o i c e . a c i d i f i e d w i t h 5 N - s u lp h u r ic a c id and th e

The m ix tu r e was e t h e r s e p a r a te d

fro m th e aqueous l a y e r w h ic h was th e n e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t ,

combined w it h th e f i r s t

e th e r s o lu tio n .

34

was w ashed w i t h w a t e r and sodium c a rb o n a te d r ie d

o v e r sodium s u lp h a t e .

d is tilla tio n

s o lu tio n ,

and

The r e s id u e r e m a in in g a f t e r

o f th e e t h e r was h e a te d on a b o i l i n g w a te r

b a th a t a p re s s u re

o f a b o u t 20 mm. t o rem ove t r a c e s

of

benzene.

From t h e w e ig h t o f th e r e s id u e

d ip h e n y l)

th e amount o f brom obenzene c o n v e rte d i n t o d ip h e n y l

c o u ld be c a l c u l a t e d .

It

(a ssu m in g i t

was assumed t h a t th e

brom obenzene was c o n v e rte d i n t o

to be

r e s t o f th e

th e G r ig n a r d r e a g e n t .

In

th e m ethod o f p r e p a r a t io n o u t li n e d a b o v e , 95 % o f th e brom o­ b e n ze n e was c o n v e rte d i n t o Illd ,

th e G rig n a r d r e a g e n t ,

C o n d itio n s em ployed f o r t h e G r ig n a r d r e a c t i o n , and i s o l a t i o n o f th e p ro d u c ts An e t h e r e a l

c o n d it io n s t o

s o lu t io n

o f PhMgBr was added under v a r y in g

an e t h e r e a l s o l u t i o n o f th e ( - ) -m e n th y l e s t e r .

The r e a c t i o n m ix tu r e was k e p t th e n decomposed w i t h ic e

under v a r y in g c o n d it io n s

and s u lp h u r ic

o f th e e t h e r e x t r a c t o f t h i s m ix tu r e o f th e d u c ts

( - ) -m e n th y l e s t e r

a c id .

and

C o n c e n t r a t io n

gave an o i l

c o n s is t in g

o f th e h y d ro x y a c i d , n e u t r a l p r o ­

and any unchanged ( - ) - m e n t h y l k e t o e s t e r , p re s u m a b ly

r e g e n e r a t e d fro m t h e p r o d u c t o b ta in e d b y r e a c t i o n o f th e e n o l fo rm o f th e k e to e s t e r , b y th e

A n e u t r a l p r o d u c t c o u ld be fo rm e d

r e a c tio n Ph PhliCgBr

O H yC O , ( CH 2 ) n , C 0 2 0 ^ 1 9 —

(-)

^ ^ Ph

Ph

C H ^ -C -(C H 2 )n -C -P h . CH . 6 . ( C H 2 ) n .C : 0 ^ OH 0-------- ' y - H y d r o x y - y - p h e n y lv a le r ic

a c id

(n = 2 i n

(h = 2 or 3 )

above f o r m u la )

c o u ld be c o n v e rte d i n t o y -p h e n y l -y - v a l e r o l ac t one, w i t h no a p p a re n t r a c e n d s a t io n , b y r e p e a te d d i s t i l l a t i o n s fro m th e

compound.

o f b en zen e

P a r t i a l c o n v e rs io n o f

ÇH, t ^ Ph-C=CH-CHo

I 2

0 = 0 -OMgBr

Ph T h is ty p e o f r e a c t i o n w ou ld he f a c i l e m e th y l e s t e r s in c e

th e

i n th e case o f th e

r e a c t i v i t y o f m e th y l e s t e r s

g e n e r a l l y g r e a t e r th a n t h a t o f th e h ig h e r e s t e r s . a lte r n a tiv e

is

t h a t th e

u n s a tu r a te d

h y in t e r n a l e lim in a tio n in v o lv in g g iv e

is The

a c id w ould he fo rm e d

th e py c a rh o n atom s to

th e u n s a tu r a te d e s t e r , w h ic h m ig h t he h y d ro ly s e d w i t h

ic e -c o ld

h y d r o c h lo r ic a c id d u r in g d e c o m p o s itio n o f th e

G r ig n a r d r e a g e n t .

T h is l a t t e r

o f th e tw o s in c e i t

is

c o u rs e seems th e l e s s l i k e l y

im p ro h a h le t h a t a C-C hond o f

C-OMgX w ou ld he b r o k e n com pared w i t h th e C -0 hond o f an e s t e r g ro u p , f i s s i o n o f w h ic h w o u ld g iv e th e la c t o n e d is c u s s e d a h o ve. shown t h a t

F u r t h e r , C a m p b e ll and Kenyon ( 1 9 4 7 )

te r tia r y

a lc o h o ls ,

as have

o r t h e i r hromomagnesiurn

d e r i v a t i v e s , do n o t undergo d e h y d r a t io n i n th e p re s e n c e

of

84

ex c e s s G rig n a r d r e a g e n t . 4 - p h e n y l - 3 - p e n t e n o ic

It

a c id i n

fo rm e d th ro u g h t h e la c t o n e M o r e o v e r, h ro m id e ,

if

th u s a p p e a rs l i k e l y

th a t

th e

th e s e e x p e r im e n ts w o u ld he

i n th e G r ig n a r d r e a c t i o n m ix t u r e .

e th y l la e v u la te is

t r e a t e d w i t h am yl m agnesium

41% o f y -me n t h y l -y - p e l a r go l a c t one i s

o b t a in e d

d i r e c t fro m th e G r ig n a r d r e a c t i o n m ix t u r e h y d e c o m p o s itio n w it h w a te r

(S o lo w a y and L a F o r g e , 1 9 4 7 ) .

and S l a t e r

(1 941 ) , h y v a r y in g

th e

A ls o , R o h in s o n

c o n d it io n s u n d e r w h ic h

2 - n a p h t h y l m agnesium h ro m id e and e t h y l l a e v u l a t e a c te d ,

succeed ed i n

m ix tu r e v a r y i n g la c to n e . If

is o la tin g

in te r ­

fro m th e G r ig n a r d r e a c t i o n

amounts o f y - h y d r o x y - y - 2 -n a p h t h y l v a l e r o ­

and y - 2 -n a p h t h y l -p -p e n t e n o i c a c id . th e la c t o n e w e re th e p r e c u r s o r o f th e

a c id i n th e

e x p e rim e n ts

u n s a tu r a t e d

u s in g ( - ) -m e n th y l l a e v u l a t e ,

" e s te r"

( b ) s h o u ld have s m e lt s t r o n g ly o f m e n th o l;

w as th e

ca s e .

th e

th is

The s tro n g s m e ll o f m e n th o l c o u ld a ls o have

a r i s e n h y i n t e r a c t i o n o f th e e s t e r g ro u p w i t h th e p h e n y l m agnesium h ro m id e : Ph 1

CH-z. C, (CHq ) y., CO pR !i 2 n ^ 0

PMvIgBr

} CH-2, C, (CHp ) n . COpR ^

OMgBr 2PWÆgBr Ph I

Ph I

CH 3 .C.(CH2 )n*Ç-OMgBr. OMgBr H o w e v e r, a t th e

Ph

a n a lo g o u s s ta g e u s in g ( - ) -m e n th y l

85

a c e ty llD u ty r a te a b ly l e s s ,

(n = 3 ) ,

th e s m e ll o f m e n th o l was c o n s id e r ­

and when ( - ) -m en t h y l ace t y l v a le r a t e

( n = 8 ) w ere used t h e r e was

( - ) - m e n t h y l a c e t y lp e la r g o n a t e no p e r c e p t i b l e

s m e ll o f m e n th o l.

c a r r i e d o u t w i t h th e c o n d it io n s , w e re

m ents w i t h

In

a l l th e e x p e r im e n ts

v a r io u s m e n th y l e s t e r s u n der s i m i l a r

o n ly v e r y s m a ll y i e l d s

o b ta in e d .

( n = 4 ) and

Thus,

it

is

o f n e u t r a l p r o d u c ts

more p r o b a b le

(-)-m e h th y l la e v u la te

th e

th a t in

e x p e r i­

s tro n g s m e ll o f

m e n th o l was due to la c t o n e f o r m a t io n . When th e y - h y d r o x y - y - p h e n y l v a l e r i c a c id ic p r o d u c t(s ),

o b t a in e d a f t e r

p r e c i p i t a t e d fro m a n a l k a l i n e w i t h m in e r a l a c i d , c a s e s a b ro w n o i l

it

A ls o ,

b y w a s h in g th e tio n ,

to

a c id

a c id ,

fr a c tio n

some

b e f o r e th e s e p a r a t i o n a t a pH v e r y l i t t l e (F ),

is o la te d

as a syru p

c ru d e la c t o n e " w i t h sodium c a rb o n a te

was i n s o l u b l e

a tte m p t

s o lu tio n b y a c i d i f i c a t i o n

s e p a r a te d f i r s t ,

th e

h y d r o l y s i s , w ere

w i l l b e rem em bered t h a t i n

o f y -h y d ro x y - y - p h e n y l v a l e r i c b e lo w 7 .

th e

a c id and o t h e r

s e p a ra te

i n w a te r .

Thus th e

an a p p r e c ia b le

fa ilu r e

s o lu ­

o f th e

amount o f a c id b e f o r e

h y d r o ly s is m ig h t have b ee n due e i t h e r t o th e lo w s o l u b i l i t y o f th e

u n d is s o c ia t e d a c id i n w a te r

to i t s

s o lu b ility

c o n s ta n t o f th e

in

e th e r)

a n d /o r t o

r e la tiv e

a lo w d i s s o c i a t i o n

a c id .

4 - P h e n y l - 5 - p e n t e n o ic is o m e r ic fo rm s ,

(e s p e c ia lly )

and i t

a c id

can e x i s t i n two g e o m e t r ic a lly

may be s i g n i f i c a n t

t h a t w hen M ic h a e l

86

and Ross (1 931 ) p r e p a r e d i t a - p h e n y l p r o p io n a ld é h y d e ,

fr o m e t h y l m a lo n a te

t h e y o b t a in e d i t

w h ic h th e y c o u ld n o t in d u c e K lo e tz e l a w h it e

hence i t

fre e

as a s y ru p

c r y s ta llis e ,

a lth o u g h

and M aye r and Stamm ( 1 9 2 3 ) o b t a in e d i t

(1 9 4 0 )

c r y s ta llin e

The

to

and

s o lid .

a c id "

fr a c tio n

e x h ib i t e d o p t i c a l

c o u ld n o t have b ee n e n t i r e l y ,

3 - p e n t e n o ic a c id .

as

It

i s p o s s ib le

if

at a l l ,

a c tiv ity ;

4 -p h e n y l-

t h a t some o p t i c a l l y

a c tiv e

a c i d i c b y -p r o d u c ts m ig h t have been fo rm e d b y r e a c t io n s i n v o l v i n g two m o le c u le s o f

(-)-m e n th y l la e v u la te ,

y ie ld in g

^CH2.C02H compounds such as CH^.CO.CH.C , CH^.CHp.CO^H \ CH3 'OH CO.CH 3

j

C H y CO.CH.CHg.COgH,

d .

th e

and

c a rb o n y l g r o u p (s ) o f w h ic h m ig h t

th e n r e a c t w i t h p h e n y l magnesium b ro m id e . a n t t h a t Solow ay and L a P o rg e

(1 9 4 7 )

o f y - m e t h y l- y - h y d r o x y p e la r g o n ic

It

is

s ig n ific ­

o b t a in e d o n ly 41%

a c id on t r e a t i n g

e th y l

l a e v u l a t e w i t h am yl m agnesium b ro m id e , t o g e t h e r w i t h la r g e

amount o f h ig h b o i l i n g

m ig h t be a t r i k e t o c a p r i c

f r a c t i o n w h ic h t h e y s u g g e s t

a c id such as

C H ^ .C O .(C H ^ ) 2 #CO.CHg.CO. (CH 2 ) 2 * CO2H. in v e s tig a tio n i t p h e n y lh y d ra z o n e

was n o t p o s s ib le o f th e " f r e e

C o m p a ris o n o f th e b e fo re

a

I n th e p r e s e n t

to p re p a re a 2 : 4 - d in i t r o -

a c id " .

s p e c ific

r o ta tio n s

and a f t e r c a r b o n a te w a s h in g

o f th e

in d ic a te s

th a t

la c t o n e a la r g e

87

p r o p o r t io n o f th e " f r e e

a c i d " , w h ic h was d e m o n s tra te d h y

t i t r a t i o n , m ust have been an o p t i c a l l y i n a c t i v e Thus,

it

m ix t u r e ,

a p p e a rs t h a t th e

" fre e

a c o n c lu s io n w h ic h i s

c o n s id e r a t io n s .

a c id " w a s , i n

a c id .

fa c t,

a

s u p p o rte d b y s o l u b i l i t y

The m ix tu r e m ig h t have in c lu d e d 4—p h e n y l-

3 -p e n t e n o ic a c id and compounds r e s u l t i n g fro m th e i n t e r ­ a c t io n o f two o r more m o le c u le s

o f ( - ) -m e n th y l l a e v u l a t e .

The d e g re e o f a s y m m e tric s y n th e s is th e

s p e c ific

o b t a in e d ,

r o t a t i o n o f th e la c t o n e b e f o r e

i.e .

any p ro c e s s o f

f r a c t i o n a t i o n such as p r e c i p i t a t i o n o f th e h y d r o x y a c id fro m an a l k a l i n e

s o l u t i o n w i t h m in e r a l a c id had been

p e r fo r m e d , was dependent G r ig n a r d r e a c t i o n . v a r i e d w i t h th e to

th e

lim its .

c o n d it io n s

used f o r

T h e re was

The d e g re e o f asym m etric s y n t h e s is

( - ) -m e n th y l l a e v u l a t e , w i t h i n c e r t a i n a ls o some dependence on th e

r e a g e n ts d u r in g

r i n g was c o n tin u e d a f t e r b ro m id e was c o m p le te ,

a d d i t i o n o f th e p h e n y l m agnesium

y - P h e n y l - y - v a l e r o l a c to n e to

a p r o d u c t c o n s is t in g

and 9 4 .5 ^ o f ra c e m ic l a c t o n e .

o b ta in e d

( - ) -m e n th y l l a e v u l a t e

o v e r a v e r y s h o r t p e r io d o f tim e had a s p e c i f i c

$agnesiurn b ro m id e t o th e

c o n d it io n s

a d d i t i o n and on w h e th e r s t i r ­

b y a d d in g p h e n y l m agnesium b ro m id e

c o rre s p o n d in g to

th e

tim e o f a d d in g th e p h e n y l m agnesium b ro m id e

s o lu tio n o f

o f m ix in g th e

on th e

r o ta tio n

o f 5 . 5^ ( - ) - la c t o n e

When a d d i t i o n o f th e p h e n y l

e s t e r was p ro lo n g e d ( fr o m 1 t o 4

h o u rs ) w i t h no su b s eq u en t s t i r r i n g

o f the

r e a c t i o n m ix t u r e .

88

th e la c to n e b e in g

c o n t a in e d 9 *5 -1 0 % o f

r a c e m ic la c t o n e .

M ix in g

h o u r fo llo w e d b y s t i r r i n g s p e c ific one.

r o ta tio n s

P r e lim in a r y

fo r

( - ) - la c to n e ,

o f th e

th e

re a c ta n ts

re s t

over &

1 h o u r ga ve p r o d u c t s w i t h

c o r r e s p o n d in g t o

1 1 -1 2 % e x c e s s

( - ) - la c t-

e x p e r im e n ts had show n t h a t th e p r o d u c t-

o b t a in e d b y a d d i t i o n o f th e p h e n y l m a g n e s iu m b r o m id e t o e s te r over i a l p u r ity

h o u r w i t h no s u b s e q u e n t s t i r r i n g

th e

had an o p t i c ­

m id - ^ a y b e tw e e n t h a t o f th e p r o d u c t o b t a in e d b y

m ix in g th e

re a c ta n ts

o v e r a fe w m in u te s

in g o v e r 1 h o u r ( s a y ) . p r e lim in a r y

A ls o

e x p e r im e n ts w i t h

c o m p a r is o n o f r e s u l t s

fr o m

th o s e

s c a le

e x p e r im e n t s in d ic a t e s t h a t s t i r r i n g s h a k in g , w h i l s t

m ix in g th e

and t h a t b y m ix ­

fr o m th e l a r g e r as o p p o s e d t o

re a c ta n ts ,

hand

in c r e a s e d th e

d e g re e

o f a s y m m e tr ic s y n t h e s is . The y i e l d w as c o n s id e r a b ly h ig h e r i n w h e re

m ix in g o f th e

o f tim e ,

and th e

la c to n e "

fro m t h i s

in

lit t le

w ith

s t u d y th e p e r io d

p e r c e n ta g e

o f " fre e

a c id "

y ie ld

and p e r c e n ta g e It

th e

"c ru d e

and th e n

as f a r

as ^cou ld be

o f o th e r a c id ( s )

v a r ie d

w o u ld have b e e n o f i n t e r e s t

e f f e c t o f m ix in g th e

re a c ta n ts

s tir r in g

th e

o b t a in e d b y th e

to

over a v e ry s h o rt

r e a c t io n m ix tu r e .

The d e g re e o f a s y m m e tr ic s y n t h e s is c a p r o la c t o n e ,

in

e x p e r im e n t w as c o n s id e r a b ly lo w e r t h a n

c o n d itio n s .

o f tim e

e x p e r im e n t

r e a c t a n t s was o v e r a v e r y s h o r t p e r i o d

th e . o t h e r e x p e r im e n t s , i n w h ic h ,

d is c e r n e d , th e

th e

of

in t e r a c tio n

^ -p h e n y l-o f phenyl

88 a

m agnesium "bromide and ( - ) -m e n th y l

^ ^ -a c e ty l-n -h u ty r a te ,

was a g a in found to h e dep end ent on th e c o n d it io n s p r e ­ v a ilin g

d u r in g th e G r ig n a r d r e a c t i o n .

d itio n s

a f fe c tin g

th e

th e

In th is

case

con­

d e g re e o f asym m etric s y n t h e s is have

o p p o s ite e f f e c t t o w h a t t h e y have i n e x p e rim e n ts i n ­

v o lv in g

( - ) -m e n th y l l a e v u l a t e .

W ork done h y a c o lle a g u e

(M is s D .M . B o v ey ) i n d i c a t e s t h a t th e

s p e c ific

r o ta tio n of

- p h e n y l - c T -c a p ro la c to n e i n e t h a n o l a t 2 5 ^ i s o rd e r of

^5•5^ f o r

th e la c t o n e

th e m e rc u ry g r e e n l i n e

o b ta in e d fro m th e

( 5461 A ^ ) .

T h u s,

e x p e rim e n t where th e p h e n y l

m agnesium h ro m id e was added t o t h e s h a k in g c o n s is te d o f

o f th e

e s t e r o v e r 1 m in . w i t h

ahout 16 % ( - ) - la c t o n e

and 8 4 ^ r a c e m ic .

By a d d i t i o n o v e r 30 m in s . w i t h no sub sequ ent s t i r r i n g ,

a

p r o d u c t was o b t a in e d c o n s is t in g o f about 9 * 5fo ( - ) - l a c t o n e . B y a d d i t i o n o v e r 30 mins,» w i t h su b sequ ent s t i r r i n g d u c t w i t h o n ly 1 . 5^ excess

a p ro ­

( - ) l a c t o n e m s o b ta in e d .

S in c e th e i n t e r a c t i o n o f ( - ) -m e n th y l ^ '^ - a c e t y l- n - v a le r a t e and p h e n y l magnesium b ro m id e w i t h subsequent h y d r o ly s is gave

5 - h y d r o x y - 5 “p h e n y l- h e x a n - 1 - c a r b o x y l i c s tu d y o f t h i s p ro d u c t was n o t to g iv e

a la c to n e .

c o m p lic a te d b y r i n g

H ow ever, t h i s

t h a t any asym m etric s y n th e s is

a c id , p o l a r i m e t r i e

has the

d is a d v a n ta g e

t h a t m ig h t o ccu r

w % ld . be /

h a r d e r to d e t e c t s in c e r in g

fo r m a t io n (s u c h as th e

s io n o f a h y d r o x y -a c id i n t o

its

la c to n e ),

c lo s u r e

is ,in

c o n v e r­

g e n e r a l,

accom panied b y a n u m e r ic a l in c r e a s e i n o p t i c a l r o t a t o r y

89

pow er ( c f .

Kauzmann, W a lt e r and B y r in g

(l9 4 0 )).

The 5 -h y d r o % y -5 -p h e n y l-h e x a n - 1 - c a r h o x y l l c

a c id

o b t a in ­

u s in g 1 . 2 5 , 2 , 5 and

ed fro m th e p r e l i m i n a r y e x p e r im e n ts ,

4 m o le c u la r p r o p o r t io n s o f p h e n y l magnesium "bromide to

1 m o le c u la r p r o p o r t io n o f ( - ) -m e n th y l

-a c e ty l-n -v a le r a t e ,

had no o"bservahle o p t i c a l r o t a t o r y p o w er; "but a l a r g e r s c a le

e x p e rim e n t c a r r i e d o u t u n d e r s ta n d a r d is e d c o n d it io n s

(m ix in g o f r e a c t a n t s s tir r in g ,

no i n d i c a t i o n

th a t th is

r a tio )

f o llo w e d "by s t i r r i n g

p r o d u c t w h ic h had is

( 1 . 25:1

i

hour w i t h

f o r 1 hour a t 0 ° )

+ 0 .0 9 ^ ( c , as to th e d e g re e

r e p r e s e n ts s in c e

over

gave a

50 i n e t h a n o l ) . of

T h e re

asym m etric s y n t h e s is

5 - h y d r o x y - 5 -p h e n y l-h e x a n H -

c a r" b o x y lic a c id has n o t "been r e s o lv e d . The 9 - h y d r o x y - 9 - p h e n y l-d e c a n -1 -G a r"b o x y lic a c id o b t a i n ­ ed "by th e

i n t e r a c t i o n o f ( - ) - m e n t h y l a c e t y lp e la r g o n a t e

and

p h e n y l magnesium "bromide, w i t h su"bsequent h y d r o ly s is , showed no o p t i c a l r o t a t o r y p o w e r, "but t h i s th e

m ig ht "be due to

o p t i c a l l y p u re h y d ro x y a c id h a v in g a lo w s p e c i f i c

r o ta tio n . The la c t o n e p r e p a r e d fro m y - h y d r o x y ^ - p h e n y l v a l e r ic a c id has o p p o s ite r o t a t o r y power t o one assumes t h a t th e i n th e

£- la c t o n e

t h a t o f the a c id .

has o p t i c a l r o t a t o r y power

o p p o s ite d i r e c t i o n t o t h a t o f th e

p h e n y lc a p r o ic o p tic a lly

a c id ,

a c tiv e

If

fro m w h ic h i t

(f-h y d ro x y -c f-

is p re p a re d ,

a l l th e

h y d ro x y a c id s t h a t w ere p re p a re d h y th e

90

i n t e r a c t i o n o f ( - ) -m e n th y l

6 J -a c e ty l f a t t y

p h e n y l magnesium h ro m id e v/ere

d e x tro ro ta to ry .

h y d r o x y -a c id s p re p a re d o n ly a t r o l a c t i n i c p r e v io u s ly been r e s o lv e d .

a c id e s t e r a and

(±)

a c id

O f the ( n = O) has

- H y d r o x y - y - p h e n y lv a le r ic

a c id has b een p r e p a r e d b y o t h e r w o rk e rs b u t n o t No r e f e r e n c e

to

- h y d r o x y - ^ - p h e n y lc a p r o ic

5 - p h e n y l - h e x a n - i - c a r b o x y li c d e c a n - 1 - c a r b o x y lic

a c id

r e s o lv e d .

a c id ,

5 -h y d ro x y -

a c id , o r 9 - h y d r o x y - 9 - p h e n y l-

can be found i n th e l i t e r a t u r e .

An asym m etric s y n th e s is was a ls o a c c o m p lis h e d th ro u g h th e i n t e r a c t i o n o f ( - ) -m e n th y l b ro m o a c e tic e s t e r , phenone and z in c h y d r o ly s is .

(R e fo rm a ts k y r e a c t i o n )

a c e to -

and subsequent

The s e r ie s o f r e a c t io n s in v o lv e d

CHp. COpC. Zn I ^ Ph.OD.Me+ BrCHp.COpC^O^ 9----------- P h .C -M e (_ ) I OZnBr

Is

in d ic a te d :-

Q ^

HpO

CHm.COpH I ^ ^Ph.Ù .C H z I

O'H and • a lk a lin e h y d r o ly s is

The d e g re e o f a s y m m e tric s y n th e s is

(i.e .

th e s p e c i f i c

r o t a t i o n o f th e g- h y d r o x y - p - p h e n y l- b u t y r ic was in d e p e n d e n t

o f th e e s t e r : ace tophenone r a t i o

in d e p e n d e n t o f th e as m ix in g tim e

c o n d itio n s used f o r

o f th e r e a c t a n t s

a p p a re n t v a r i a t i o n o f th e ( [ a l^ y g o

2.31

a c id o b t a in e d )

- 2 .4 7 ;

r e l a t e d w i t h th e

th e

r e a c t i o n (s u c h

and d i l u t i o n ) .

s p e c ific

and

The

r o t a t i o n o f th e p r o d u c t

2 .5 7 - 2 . 8 9 )

c o n c e n t r a t io n o f th e

c o u ld be c o r -

s o l u t i o n used f o r

the

91

s p e c ific

r o t a t io n ^ a n in c r e a s e

in c r e a s e i n s p e c i f i c

r o ta tio n .

i n c o n c e n t r a t io n c a u s in g an (i)-g -H y d r o x y -p -p h e n y l-

" b u ty ric a c id has p r e v io u s ly h e e n p r e p a r e d b y Ar"busov (1 901 ) b u t has n o t b e e n a d e q u a te ly d e s c r ib e d . i n v e s t i g a t i o n th e

race m ic

I n th e p r e s e n t

a c id was o b ta in e d w i t h a m e lt in g

p o in t 20^ h ig h e r th a n t h a t re c o rd e d b y A rb u s o v . ra c e m ic a c id has n o t b e e n r e s o lv e d .

So f a r

th e

VI. DISCUSSION OP GOMCa^USIOKS IN RELATION TO THBOBIBS OF ASYMMBTRIC SYNTHESIS

92

V I,

DISCUSSION

V ia ,

O FCONCLUSIONS

IN RELATION TO THEORIES OF ASYMMETRIC SYNTHESIS

P r e v io u s work T h is

s e c t io n w i l l g iv e

e x te n d e d f o r

e x p la n a t io n o f th e ty p e o f a s ym m e tric syn ­

th e s e s i n v o l v i n g th e e i t h e r an o p t i c a l l y an a c y l o a r t i n o l .

th e s e

a d d i t i o n o f a G r ig n a r d

re a g e n t

a c t i v e e s t e r o f an a - k e t o A " b r ie f o u t lin e

g iv e n i n S e c t io n I . in th is

a w id e r r e v ie w o f s u g g e s tio n s

The im p o rta n c e

to ,

a c id ,

or to

o f c u r r e n t id e a s was o f th e

in v e s t ig a t io n w ith re s p e c t to

r e s u lts

o b ta in e d

such i d e a ^ and how

r e s u l t s h ave e x te n d e d our know ledge o f t h i s

ty p e o f

as y m m e tric s y n t h e s is ^ w il l th e n he d is c u s s e d , M c K e n zie and c o -w o rk e rs e x p la in e d th e a s y m m e tric s y n ­ th e s e s

O b ta in e d i n t h e i r

a c t iv e

e s te rs o f a -k e to

a s s u m p tio n t h a t the

e a r l i e r e x p e rim e n ts u s in g o p t i c a l l y a c id s

a fte r

o p tic a lly

c o m p le te h y d r o ly s is

an o p t i c a l l y

1930 i t

on th e

a d d i t i o n o f th e G rig n a r d re a g e n t to th e

c a rb o n y l g ro u p was s u b je c t t o e x e r t e d b y th e

(s e e S e c t io n l )

a " d ir e c t in g * *

in f lu e n c e

a c t iv e a lc o h o l r a d i c a l ; o f th e

a c tiv e g l y c o l l ic

r e s u ltin g

g ly c o llic

a c id was o b ta in e d .

was s u g g e s te d by M c K e n z ie , R i t c h i e

th u s , e s te r

About

and c o -w o rk e rs

t h a t a s y m m e tric in d u c t io n m ig h t be an e x p la n a t io n f o r t h e m u t a r o t a t io n o f th e k e t o - e s t e r s i n w as assumed t h a t th e c e n tre o f

a lc o h o l s o lu t io n s .

It

c a rb o n y l group e x is t e d as a l a b i l e

asym m etry and t h a t t h e r e

o c c u rre d i n

s o lu t i o n a

93

change o f " e q u ililD r iu m ’' e . g . (“)

( “*)

(+ )

(-)

Me. CO, C 0 2 ( - ) - m e n t h o l + Me. 0 0 . C 0 2 ( - ) - m e n t h y l (e q u a l a à o u n te )

(-)

(-)

(+)

^

M e . CO. CO ^ ( - ) -m e n t h y l

+

(-)

M e .CO .C O ^ C -)-m e n th y l

(u n e q u a l am ounts) It

was s u g g e s te d t h a t th e

c o n f ig u r a t i o n o f th e

c a rb o n y l

g ro u p was a non p la n a r one such a s : -

As a c o r o l l a r y to th e

above s u g g e s tio n , th e phenomenon

o f a s y m m e tric s y n th e s is w as e x p la in e d on th e t h a t i n th e e t h e r e a l s o l u t i o n th e w ere p r e s e n t i n

a s s u m p tio n

tw o " d ia s t e r e o is o m e r ides **

u n e q u a l amounts ( t h e

c a rb o n y l group

assum ing dissym metric c o n f i g u r a t io n u n der th e in f lu e n c e th e

o p tic a lly

a c t iv e

a lc o h o l r a d i c a l ) .

On r e a c t i n g w i t h th e G -rig n a rd r e a g e n t , th e l a b i l e tio n s

c o n f ig u r a ­

o f each " is o m e r" w ere f i x e d , th u s fo rm in g two

d ia s te r e o is o m e r s i n h y d r o ly s is

of

u n e q u al amounts w h ic h y ie ld e d

an o p t i c a l l y a c t i v e g l y c o l l i c

a c id .

on

94

I n ac c o rd a n c e w i t h t h i s t e n t a t i v e

s u g g e s tio n ,

e x p e r i­

m e n ta l r e s u l t s s u g g e s te d t h a t , when th e m u t a r o t a t io n o f a ke to e s t e r i n a lc o h o l r e s u lt e d th e d e g re e o f r o t a t i o n ,

th e

i n a n u m e r ic a l in c r e a s e

r e s u ltin g g ly c o llic

in

a c id w o u ld

a lw a y s have a r o t a t i o n o f th e same s ig n as th e p a r e n t e s te r.

The a to v e

b e tw e e n th e

s u g g e s tio n r e q u ir e s t h a t an e q u i lib r iu m

two " d ia s t e r e o is o m e r s ” be e s t a b lis h e d i n e t h e r ,

and th e la c k o f o b s e rv e d m u t a r o t a t io n i n e t h e r was a c c o u n te d f o r r a p id

on th e

grounds t h a t e q u i l i b r a t i o n was so

as t o be u n o b s e rv a b le p o l a r i m e t r i c a l l y , w h e re a s i n

a lc o h o lic

s o l u t i o n th e

r e la tiv e ly

e s ta b lis h m e n t o f e q u ilib r iu m was

slow and c o u ld be f o llo w e d p o la r im e t r i à a l l y .

M cK enzie and c o -w o rk e rs assume t h a t r a p id e q u ili b r iu m o c c u rs i n i t i a l l y ; p o in t

it

m u st,

o u t , b e p o s t u la t e d t h a t th e

G r ig n a r d r e a g e n t t o th e ra te

as T u rn e r and H a r r i s

of e q u ilib r a tio n

o f a d d itio n to

ra te

o f a d d it io n o f th e

c a rb o n y l g ro u p i s

( s in c e

it

is

(1 9 4 7 )

f a s t e r t h a n th e

u n l i k e l y t h a t th e

d ia s t e r e o is o m e r id e s w o u ld be

the

sam e),

Jam iso n and T u rn e r ( i 941 ) and T u rn e r and H a r r i s p r e f e r to

(1 9 4 7 )

re g a rd th e m u t a r o t a t io n o f a - k e t o e s t e r s i n a lc o h o l

as a f i r s t

o r d e r t r a n s f o r m a t io n b etw e en th e d i a s t e r e o -

is o m e r ic herniac e t a l s , o r as th e h e m ia c e ta l.

It

slow f o r m a t io n o f th e

has b e e n shown b y G la z e r and T u rn e r ( i 9 4 9 )

t h a t t h e m u t a r o t a t io n w as, i n f o r m a t io n .

ra te

fa c t,

due t o slow h e m ia c e ta l

The l a c k o f m u t a r o t a t io n i n e t h e r was ta k e n t o

95

d is p ro v e

th e e x is te n c e

o f th e h y p o t h e t ic a l d i a s t e r e o ­

is o m e rid e s . As has h e e n shown i n S e c t io n I , was p r e p a r e d h y th e

( - ) -a tr o la c tin ic

i n t e r a c t i o n o f ( - ) -m e n th y l h e n z o y l-

fo r m a te and m e th y l magnesium h ro m id e , h u t SLdid h y th e i n t e r a c t i o n magnesium h ro m id e .

( + ) -a tr o la c tin ic

o f ( - ) -m e n th y l p y r u v a te

On acco u n t o f t h i s ,

c o r r e l a t i o n b e tw e e n th e o f a -k e to e s te rs

a c id

and p h e n y l

and o f th e

a p p a re n t

change o f d i r e c t i o n o f th e

r o ta tio n

d u rin g m u t a r o t a t io n ,

and th e a lg e b r a ic

s ig n o f th e r o t a t i o n o f th e p ro d u c ts o b ta in e d h y a s y m m e tric s y n t h e s is , R i t c h i e " T h is

re m a rk e d :

s u g g e s ts a m echanism i n w h ic h th e

asym m etry o f th e in

(1 9 4 7 )

in d u c e d

two ty p e s o f u - k e t o n i c e s t e r s

( o p p o s it e

sense p e rh a p s owing t o th e v e r y p o w e r f u lly n e g a t iv e

n a tu r e

o f th e p h e n y l group as c o n tr a s te d w i t h th e m e th y l

g ro u p ) i s

r e f l e c t e d h y m u t a r o t a t io n i n

a ls o h y th e f i x a t i o n h y th e G r ig n a r d o p p o s it e ly r o t a t i n g

s e r ie s

o p p o s ite

sense,

re a g e n t to g iv e

o f s u b s titu te d g l y c o l l ic

and

two a c i d s . ’’

T i f f e n e a u , L e v y and D i t z ( l 951 , 1 9 3 5 ) have r e j e c t e d th e e x p la n a t io n o f as ym m etric s y n th e s is p ro p o s e d h y M c K e n z ie , R i t c h i e t i o n t h a t th e

and c o -w o rk e rs i n

fa v o u r o f th e

two bonds o f th e c a rb o n y l g rou p are

d i f f e r e n t i a l l y when t h e r e i s e ls e w h e re i n th e m o le c u le .

sugges­ a tta c k e d

an o p t i c a l l y a c t i v e sys tem L ik e

e a r l i e r in v e s tig a to r s

t h e y had n o te d th e u n i l a t e r a l a t t a c k o f a G rig n a r d

re a g e n t

96

on a c a rb o n y l group w h ic h i s

a d ja c e n t

to a d i^ y m m e tric carb o n

atom when one o f th e groups was e i t h e r -OH o r w o rk on b e n z o in ) .

They a ls o o b s e rv e d t h a t ,

ment o f ( + ) - p h e n y l-d -c a m p h o i en^^l k e to n e groups a re

i n th e

(w here

the

a n tip o d e s a re fo rm e d ,

These w o rk e rs s u g g e s t t h a t ,

as the number o f

o p tic a lly

c a r b o n y l group i s

so w i l l t h e e x te n t

in c r e a s e d ,

a sym m etric s^m th esis

a c t iv e

ac co m p lis h e d d e c re a s e .

group and th e o f th e

T h is s u g g e s tio n

e x te n d e d to a p p ly t o M c K e n z ie ’ s w o rk and i t

t h a t th e

two

one fo rm p re p o n ­

atoms in tr o d u c e d b e tw ee n th e

is

tre a t­

s e p a ra te d b y a m e th y le n e g ro u p ) w i t h a G rig n a r d

re a g e n t b o th o f th e d e r a t in g .

(^cf.

is

p o s t u la t e d

d e g re e o f asym m etric s y n th e s is may be lo w b e c a u s e

o f th e i n t r o d u c t i o n o f th e

-C O O -group.

R itc h ie

s id e r s t h a t h is h y p o th e s is and T i f f e n e a u ’ s a re

(1 94?)

con­

com p lem en tary

r a t h e r th a n opposed. R o ger ( l 9 3 9 ) G r ig n a r d

d is c u s s e d the

u n ila te r a l

a d d it i o n o f a

re a g e n t t o b e n z o in and p h e n y l p r o p io n y l c a r b in o l

w here i n v e r s i o n o f th e o r d e r o f i n t r o d u c t i o n o f two groups le a d s

to i n v e r s i o n o f c o n f ig u r a t io n o f th e p r o d u c t ,

f

H Ph—C—C—S t

Ml

Ph - Ç — C — P h j

I

OHO He e x p la in s t h e s is

on th e

I

OH (~ )

OH^ (+ )

th is

ty p e

i.e .

f f P Ph — C - C — Ph «*«4Ph—C - G -

I

II

I

OH

0

OH K t ( - ) (~ )

I

o f " u n i l a t e r a l ” asy m m etric syn­

grounds t h a t th e

c a rb o n y l group assumes a

97

dissyim netric c o n f i g u r a t i o n , o f th e

u n d er th e d i r e c t i n g

a s y m m e tric g ro u p , w h ic h i s

re a g e n t.

in f l u e n c e

f i x e d h y th e G r ig n a r d

A t th e same tim e he s u g g e s ts :

" S in c e cases, i t

th e in d u c in g c e n tr e i s

o f th e same s ig n i n h o th

m ig h t r e a s o n a b ly he e x p e c te d t h a t th e d i r e c t i o n

o f in d u c t i o n i n

th e in d u c e d c e n t r e s w ou ld he th e same.

Y e t , when th e s e

two in d u c e d c e n tr e s he come f i x e d ,

o f o p p o s ite

s ig n , i . e .

th e

same n e g a tiv e

has a p p a r e n t ly caused a n e g a tiv e case and a p o s i t i v e t o he i l l o g i c a l . r a d ic a l d ir e c t ly

e f f e c t i n th e

o th e r:

t o th e

th e

t h i s w o u ld a p p e a r

a t ta c h e d t o th e in d u c e d c e n tr e s

a r e la tiv e ly

(th e

a re v e r y d i f f e r e n t i n

d iffe r e n t

a rra n g e m e n t i n

two c e n tr e s o f in d u c e d asym m etry w i t h r e g a r d

c e n tre o f fix e d

each c a s e ).

From th e s e

c o n f ig u r a t io n s

asym m etry ( t h e m a n d e ly l com plex i n c o n s id e r a tio n s i t

o f th e new c e n tr e s

w o u ld seem t h a t

o f asym m etry i n th e

two fo rm s o f e th y lh y d r o h e n z o in a re d e f i n i t e l y f i x e d moment o f a d d i t i o n

S in c e

th e fu n d a m e n ta l a c tio n s

tw o G rig n a r d r e a g e n ts must he s i m i l a r , f i g u r a t i o n o f th e

th e

o f th e

r e s p e c t iv e con­

two new c e n tr e s must depend on t h e n a tu r e

o f h o th th e e n t r a n t r a d i c a l s and a ls o th e

a r y l r a d ic a ls

a t th e

o f th e G rig n a r d r e a g e n ts t o th e ke t o n ic

g rou ps o f th e k e t o l s .

o r s iz e

one

The f a c t t h a t th e p h e n y l and th e e t h y l

c h a r a c t e r may cajise o f th e

in d u c in g c e n tr e

in d u c t io n e f f e c t i n

c a r h o n y l g ro u p s ) i n t h e two k e t o ls

space

t h e y are

a lk y l or

a tta c h e d t o th e k e t o n ic groups o f th e k e t o l s .

98

No d e f i n i t e

la w can t e

P a r t r id g e

(1 9 3 9 )

fo r m u la te d o ffe rs

r e g a r d in g

th is p o in t .. . "

an e x p la n a t io n o f th e

a to v e

r e s u l t s h y assum ing t h a t a d d it io n t o th e

d o ub le bond ta k e s

p la c e b y " the d o u b le bond o p enin g i n

same sense i n

each c a s e ” , v/hen ” th e d if f e r e n c e th e

o f c o n f ig u r a t io n b e tw e e n

e t h y l b e n z o in s p ro d u c ed by th e

n e c e s s a ry consequence

th e

two r o u te s i s

a

o f th e o r d e r i n w h ic h th e p h e n y l and

e t h y l g ro u p s have b e e n i n t r o d u c e d .” W ith r e s p e c t to th e

asy m m etric s y n th e s e s e f f e c t e d i n

th e a - k e t o e s te r /G -r ig n a r d r e a g e n t s e r i e s , w here d i a s t e r e o is o m e rid e s

o f th e

a lc o h o l r a d i c a l ) to o k th e v ie w

R* * t * (R = o p t ic a lly a c tiv e R— Ç— OMgX a re fo rm e d , Kenyon and P a r t r id g e (1 9 3 6 ) ty p e

t h a t c o l l i s i o n s b e tw e e n G r ig n a r d r e a g e n t and

k e t o - e s t e r w h ic h l e d t o one d ia s t e r e o is o m e r ic in t e r m e d ia t e w ere more l i k e l y

t o o c c u r th an th o s e le a d in g

They add t h a t ” i t

is

a d iffe r e n c e

in

R itc h ie s y n th e s is

p ro d u c ts w h ic h i s

th e o n e -s id e d r e a c t i o n ” .

( 1 9 4 7 ) su g g es ts t h a t th e la c k o f as ym m etric

o b ta in e d b y th e

a d d it io n o f

m e th y l e t h y l ke t e n ( g E H £ t X e ^ [ ^ used i n e v id e n c e a g a in s t th e P a r tr id g e .

o th e r.

e n e rg y a s s o c ia te d

w i t h th e d ia s t e r e o is o m e r ic in t e r m e d ia t e r e s p o n s ib le f o r

t o th e

H o w ever, th e

( - ) -m e n th o l t o 1 9 3 4 ) may be

h y p o th e s is o f Kenyon and

two r e a c t io n s a re n o t s t r i c t l y

a n a lo g o u s . Brokaw and Brode

(1 948)

have in v e s t ig a t e d

th e " in d u c t iv e

99

e ffe c t"

o f th e

a c t i v e -a m y l r a d i c a l h y s tu d y in g th e i n t e r ­

a c t i o n o f a l k y l - a c t i v e - a m i k e to n e s w i t h G rig n a rd r e a g e n t s , i.e .

w here

group a re

th e o p t i c a l l y

a c t iv e

s e p a r a te d hy a m e th y le n e

s y n th e s is was o b s e rv e d , in d u c t iv e

g ro u p .

No a s y m m e tric

e ffe c t:

r e la te d w ith r e s u lts in te r p r e ta tio n

o f R oger and M cK enzie

c e n tr e

in g s t r u c t u r e s a re l i s t e d in flu e n c e :

These a u th o rs

e f f e c t n o te d h e r e i n was

acknow ledge

o f in d u c t i v e

to r e a c t i o n c e n t r e .

i n d e c r e a s in g a b i l i t y ^

)) t h a t th e

c o r­

to p r o v id e an

o f t r a n s m is s io n o r i n s u l a t i o n

power fro m d i r e c t i n g

v io u s

and th e u n s a tu r a te d

and th e y comment on th e l a c k o f

"The la c k o f in d u c t iv e

th e

c e n tr e

The f o l l o w ­ t o t r a n s m it

R -C -G H 2 -C ^

compounds used i n p r e ­

a s y m m e tric s y n th e s e s i n v o lv in g G rig n a r d r e a g e n ts

p o ssess s t r u c t u r e s w h ic h p e r m it G r ig n a r d In

o f c o - o r d in a t i o n o f th e

r e a g e n t. c o n n e c tio n w i t h th e w o rk o f Brokaw and B rode

th e l a c k o f

(1 9 4 8 ) ,

asym m etric s y n t h e s is o b s e rv e d m ig h t n o t have

b een due t o th e e f f e c t o f th e i n t e r v e n i n g m e th y le n e grou p b e tw e e n th e

c a rb o n y l and o p t i c a l l y a c t i v e

m ig h t be in h e r e n t i n w h ic h ,

t h e low d e g ree o f as ym m etric s y n th e s is

under any c irc u m s ta n c e s , m ig h t be a s s o c ia te d w i t h

th e g ro u p .

It

is

i n t e r e s t i n g t h a t i n v e s t i g a t i o n o f th e

r e a c t i o n b e tw e e n ( - ) - § - o c t y l a - k e t o a g e n ts

g ro u p s , b u t

e s te r s

and G r ig n a r d r e ­

(M cK en zie and R i t c h i e , 1 931 ) showed t h a t o n ly a v e r y

100

low d e g re e o f a s y m m e tric s y n th e s is T a r h e ll

and P a u ls o n ( 1 9 4 2 ) , i n

o f a s y m m e tric s y n th e s is

u s in g

.

d is c u s s in g t h e i r l a c k

( + ) - m e t h y l - s - h u t y l e t h e r as

a s o lv e n t f o r th e i n t e r a c t i o n magnesium h ro m id e

had o c c u rre d .

o f h e n z a ld e h y d e

(s e e S e c t io n I ) ,

and m e th y l

suggest t h a t:

th e organo magnesium compound i s

c o - o r d in a t e d

w i t h two m o le c u le s o f e t h e r i n such a way t h a t th e com plex has a p la n e

o f sym m etry” .

Vavon, R iv ie r e m e t r ic

and A n g e lo

s y n th e s is o b se rv ed i n

(1 9 4 6 ) e x p l a i n th e

th e r e d u c t io n o f acetophenone

w i t h i s o - h o r n y l magnesium c h lo r id e ” a 1 * in s ta n t

asym­

q u i p ré c è d e l a

as f o l l o w s : -

r e a c tio n ,

la

m o le c u le de

m ag n é s ie n e s t au c o n ta c t de 1 * a c é to p h é n o n e , H -C -M g C l é t a n t v o is in

de 1 ' une des deux v a le n c e s 0 = 0 , v a le n c e s

s y m é triq u e s p a r r a p p o r t v a le n c e s

au p la n d é te rm in é p a r l e s deux

C e t e n s e m b le,

e s t d iffé r e n t

e t non

m ag n ésien acé to p hé n o n e ,

s y m é triq u e de l ’ ensem ble

où H -C -M gC l s e r a i t v o i s i n de l ’ a u t r e v a le n c e a pas s u i t e

aucune r a is o n p o u r qu’ i l s

même f a c i l i t é p a r r u p tu r e

e t é v o lu e n t

c o rre s p o n d a n t

de 0 = 0 ; i l

se fo rm e n t

avec l a même v i t e s s e .

de l ’ une des v a le n c e s 0 = 0 ,

n’y

avec l a O r l ’ un,

c o n d u it a l ’ is o m è re

d r o i t ; l ’ a u t r e , p a r r u p t u r e de l ’ a u t r e v a le n c e , l ’ is o m è re gau che.

q u i so n t

c o n d u it à

L e s deux is o m è re s p e u v e n t donc se fo r m e r

en q u a n t it é s in é g a l e s . ” T u rn e r and H a r r i s

( l 947)

have r e c e n t l y commented on

101

th e ty p e

o f a s y m m e tric s y n th e s is

under d is c u s s io n as

f o llo w s " In o rd e r t h a t a f ix e d in f lu e n c e

th e s t e r i c

u n s a tu r a te d s y n t h e s is , s e le c tiv e fir s t

c e n tre th e r e

th e

p ro c e s s or

o rd e r a s y m m e tric t r a n s f o r m a t io n ta k e s p la c e o f argum ent can he fo r e s e e n .

a d d i t i o n o f XY t o

fir s t

X

R I C==0 I R'

c e n t r e o f asym m etry ( i n

ap p ro ach o f X ”

a rra n g e m e n ts r e p r e s e n te d hy th e p la n e and

X a r e p o s s ib le b e f o r e

th e

R

R

c-

'< / \ - / X

a d d it io n o f

concerned i n th e f o r m a t io n o f th e s e

If

th e e n e rg y changes

two s t r u c t u r e s a r e

no im m e d ia te asym m etric a d d it i o n .

a re unequal ( i . e .

group R ) ,

end o f th e p o l a r i z e d c a rh o n y l g ro u p :

R

th e re is

in

R , _ ♦ ----------------- > x ------- 0 I R*

The two t e t r a h e d r a l d ia g ra m s

Thus,

a c a rh o n y l g ro u p o f a m o le c u le

s ta g e may he re g a rd e d as th e

to w a rd s th e p o s i t i v e

e q u a l,

a t w h ic h e i t h e r s t e r e o ­

occurs as an i r r e v e r s i b l e

a lr e a d y c o n t a in in g a f i x e d th e

same m o le c u le i n an a s y m m e tric

must he some s tag e

a d d it io n

o f asym m etry s h a l l

course o f an a d d it io n r e a c t i o n a t an

in

some g e n e r a l l i n e s th e

c e n tr e

in f lu e n c e d h y e x i s t i n g

If

th e y

a s y m m e try ), t h e n

we have a s y m m e tric a d d i t i o n , w h ic h a p p e ars to ta k e p la c e

102

e ven i n n o n - r e v e r B ib le (e .g .,

a sy m m e tric r e a c t io n s

G r ig n a r d r e a c t i o n s ) .

w h ic h i s

On th e

of th is

o t h e r h an d, a d d it io n

known to b e c h e m ic a lly r e v e r s i b l e

i s ON ) c o u ld be accom panied b y f i r s t

( e . g . when X~

o r d e r a sy m m e tric

t r a n s f o r m a t io n o f th e n e w ly fo rm e d m o le c u le and i t

V lb .

at th is

s ta g e ,

w ould be ra s h to s a y w it h o u t f u r t h e r e x p e r im e n t,

w h e th e r th e new asym m etry i s fir s t

ty p e

in tr o d u c e d d u r in g o r a f t e r

th e

a d d it io n o r a t b o th s t a g e s . ” P re s e n t i n v e s t i g a t i o n O b s e r v a tio n s made d u r in g th e p r e s e n t i n v e s t i g a t i o n ,

a s y m m e tric s y n th e s is i n r e l a t i o n compounds in v o lv e d ,

to th e

s tru c tu re

a re sum m arised b e lo w

(c f.

o f th e

S e c t io n V ) .

(1 ) A sym m etric s y n th e s e s have b e e n o b s e rv e d i n th e a c tio n o f o p t ic a lly a c id s th e

a c t iv e

and a G r ig n a r d

h y d r o x y -a c id .

e s te rs

o f p y r u v ic

and a c e t y l v a l e r i c

e s te r s

of a - ,

-

and

in te r ­

^

-k e to

r e a g e n t w i t h su b seq u en t h y d r o ly s is

The k e to e s te r s a c id , l a e v u l i c a c id .

used w ere th e

a c id ,

on

to

( - ) -m e n th y l

a c e ty lb u ty r ic

a c id

No asy m m etric s y n th e s is was

o b s e rv e d when ( - ) -m e n th y l a c e t y lp e la r g o n a t e

(a 9 -k e to e s te r )

was used. (2 )

The d e g re e o f asym m etric s y n th e s is

( - ) -m e n th y l l a e v u l a t e

and ( - ) -m e n th y l a c e t y lb u t y r a t e was

fou nd t o be dependent on th e tio n

o b ta in e d u s in g

r e a c t i o n c o n d it io n s .

o f c o n d itio n s le a d in g t o an in c r e a s e

V a r ia ­

i n th e d e g re e o f

a s y m m e tric s y n th e s is u s in g ( - ) -m e n th y lla e v t u ia t e ,

had th e

103

o p p o s ite e f f e c t when ( - ) -m e n th y l a c e t y lh u t y r a t e was used. (3 )

An a sym m etric s y n th e s is was acc o m p lis h e d h y th e

i n t e r a c t i o n o f ( - ) -m e n th y l h r o m o a c e ta te , and z i n c , w i t h

sub séqu ent h y d r o ly s is o f th e p r o d u c t.

I n th e s e e x p e rim e n ts o f th e

acetophenone

th e f o r m a t io n o f u n e q u a l amounts

two d ia s t e r e o is o m e r id e s Ph

(

C H ^-Ç -(C H2)^_C 02C 0 (-)

)

IZn^ a t th e i n i t i a l

s ta g e

(i.e .

an asym m etric r e a c t i o n ) was

p ro v e d h y c o m p le te h y d r o ly s is a lly

a c t iv e

h y d ro x y a c id s

o f th e

(i.e .

e s te rs

to g iv e

o p tic ­

an asy m m e tric s y n t h e s is ) .

E x p la n a tio n s o f asym m etric s y n th e s is

h ith e r to

advanced

have had to accommodate a sy m m e tric s y n th e s e s r e s u l t i n g fro m th e

a d d it io n o f a a r ig n a r d

a m o le c u le w h ic h i t s e l f

re a g e n t to

a c a rh o n y l group i n

c o n ta in s an asy m m etric c e n t r e .

Any

t h e o r y o f asym m etric s y n th e s is must now accommodate the fa c t th e

th a t

an asym m etric s y n th e s is can a ls o he e f f e c t e d when

asy m m e tric c e n tr e i s

m e ta llic

i n th e same m o le c u le as th e

group and a s y m m e tric a l k e to n e i s

I n th e l i g h t c h e m is tr y , th e

o f c u rre n t e le c tr o n ic

t h e o r ie s

c o n f ig u r a t i o n , p r i o r

ap p ro ach o f th e G rig n a rd r e a g e n t , is

used. o f o r g a n ic

s u g g e s tio n t h a t a c a rh o n y l group c o u ld

assume a " d is s y m m e tric "

It

organo*

now th o u g h t

t h a t th e

TT

to th e

c o u ld n o t he a c c e p te d .

e le c t r o n s

( o f a ch ro m o p h o ric

1C4

g ro u p ) m oving i n th e

u n s y m m e tric a l fo r c e f i e l d

a s y m m e tric c e n tr e g iv e a c tiv ity ;

is

th e

to an e f f e c t

and Kenyon ( 1 9 4 2 ) ,

It

the TT m o le c u la r wave f u n c t io n s

a d d i t i o n r e a c t io n s

and H a r r i s

any r a t e

a t the

c o r r e la tin g

a ls o known t h a t

th a t

a re c o n c ern ed i n

th e y f u n c t i o n i n th e

as p a r t o f th e

c h e m ic a l s p h e re ,

a c t i v a t i o n o f th e d o ub le hond p r i o r

s a tu r a tio n .

It

seems p ro h a h le

th e c h e m ic a l r e a c t i v i t y

fro m

(" a s y m m e tric in d u c t io n " )

r o t a t o r y d is p e r s io n e f f e c t s U n t i l th e

two

can he d ra w n ."

A p a r t fro m th e

ahove c o n s id e r a t io n s ,

r e s u l t s w h ic h have heen o b ta in e d i n ju s tify

h e e n used to

w ith

at

have h e e n more c lo s e ly in v e s t i g a t e d no u s e f u l con­

c lu s io n s

i n th e

th a t,

moment, o n ly c o n fu s io n w i l l r e s u l t

(" in d u c e d asym m etry") a s s o c ia te d w i t h i t .

can n o t

fo r

c o n t r a r y , th e y p l a y t h e i r n o rm a l p a r t i n

o f a c a rh o n y l group w i t h th e

e ffe c ts

as T u rn e r

o u t:

sphere

p e r m ittin g e le c tr o n ic tw o -s ta g e

is

c a rh o n y l g ro u p ,

s t a t e o f th e m o le c u le ;

a l l we know to th e

to i t s

o f th e

0947) p o in t

" I n th e o p t i c a l perm an ent

o f o p tic a l

t h i s phenomenon has t e e n te rm ed in d u c e d a n is o ­

t r o p y h y B a lf e it

r is e

o f an

th e id e a o f

th is

e x p e r im e n ta l in v e s tig a tio n

asym m etric in d u c t io n ,

e x p l a i n asym m etric s y n t h e s is .

case o f th e

as i t

has

P re s u m a b ly ,

tr e a tm e n t o f ( - ) - m e n t h y l h ro m o a c e ta te

a c e to p h e n o n e , th e

asym m etric s y n th e s is o b served w o u ld

have to he e x p la in e d on th e b a s is o f an in t e r m o le c u la r

105

in d u c t iv e e f f e c t .

If

t h i s w e re th e

u n l i k e l y t h a t such c o n s is t e n t

case, i t

r e s u lts

fo r

is

th e d eg ree o f

as y m m e tric s y n th e s is w ould have heen o b t a in e d , o f r e a c t i o n c o n d it io n s ,

e x tr e m e ly

ir r e s p e c tiv e

e s p e c i a l l y c o n c e n tr a tio n s

of

re a c ta n ts . The a d d i t i o n o f an o r g a n o m e t a llic compound to a c a rb o n y l group i s th e s e g ro u p s i s asym m etry,

an i r r e v e r s i b l e

i n t e r a c t i o n w i l l le a d

o f asym m etry, th e

If,

to th e

compound i s

o p tic a lly

c o n v e rt o b le

f o r th e

e q u il ib r iu m ,

an asym­

d ia s t e r e o is o m e r ­

u n e q u a l am ounts.

d ia s t e r e o is o m e r id e s

and th u s to be i n

o r i g i n a l c e n tr e

a c tiv e ,

r e a c t i o n w i l l have o c c u rre d and the

im p o s s ib le

of

fo r m a t io n o f

on rem o vin g th e

id e s w i l l have b e e n p r e s e n t i n is

When one o f

i n a m o le c u le w h ic h has a n o th e r c e n tr e

d ia s t e r e o is o m e r id e s .

m e t r ic

r e a c t io n .

S in c e i t

to be i n t e r ­ i.e .

no f i r s t

o r d e r a s y m m e tric t r a n s f o r m a t io n can ta k e p l a c e , m e c h a n is tic d i f f e r e n t i a t i o n must be sought a t the c o rre s p o n d in g t r a n s i t i o n is o m e rid e s

two

s t a t e s fro m w h ic h th e d i a s t e r e o ­

are fo rm e d i r r e v e r s i b l y .

The i n t e r a c t i o n o f an a - k e t o re a g e n t

s ta g e o f th e

e s t e r and a G -rig n ard

can be r e p r e s e n te d as belo w

r e a c t io n s i n v o l v i n g o t h e r k e to

(a s can th e

e s te rs ).

an alo g o u s

106

R 'M fX + RCOCO.R'

The two t r a n s i t i o n d iffe r e n t

e n e r g ie s ,

is o m e r id e s , ¥e

and

(2 )

s t a t e s , A ’ and B * , s in c e a re

( l ) m ust have

th e y a re o f th e n a tu r e

o f d ia s t e r e o ­

form ed r e v e r s i b l v fro m th e

thu s have a m echanism w h ere b y th e

r o u te w i t h th e lo w e r

a c t i v a t i o n e n e rg y can be f o llo w e d p r e f e r e n t i a l l y " a s y m m e tric

r e a c t io n "

i s p o s s ib le .

b e tw e e n th e

two t r a n s i t i o n

s ta te s

re a c ta n ts .

and an

The " e q u ilib r iu m " b e a rs a fo r m a l res e m b la n ce

t o t h a t b e tw e e n two d ia s t e r e o is o m e r id e s

u n d e rg o in g f i r s t

107

o r d e r a s y m m e tric t r a n s f o r m â t ! on. (Ow ing to s t e r i c G rig n a r d

e ffe c ts

it

seems p r o b a b le t h a t th e

re a g e n t w i l l a t t a c k th e k e to n e

a t an a n g le t o

p la n e i n w h ic h th e two g ro u p s a t ta c h e d to th e

th e

c a rb o n y l

g ro u p s l i e ) . A s im ila r s ta te ly

a c tiv e

o p tic a lly s ta te s

of a ffa ir s

w ill

o r g a n o m e t a llic compound i s a c t i v e k e to n e .

In th is

e x i s t when an o p t i c a l ­ used as opposed t o an

case the

two t r a n s i t i o n

and th e r e s u l t a n t p r o d u c t can be e x p re s s e d a s : -

Me

Me

I-

s -

CH.CO.C.H,,

C.HiO.CCH,.......

CS

ZnBr

ZnBr

Me

Me

Ph. .cAo.ccHr

'O Z n B r

BrZnO'

'C H .C O .C .H .

108

S in c e

th is

ty p e

of r e a c t i o n

th e m echanism cannot he e n t i r e l y

p ro c e e d s a s y m m e t r ic a lly , th r o u g h an in t e r m e d ia t e

+

c a tio n

[ R -C -R *

]

; if

it

w e re ,

it

is

e x tr e m e ly u n l i k e l y

&MgX th a t

a s y m m e tric a d d it io n w o u ld ta k e p la c e * It

has he en s u g g e s te d h y v a r io u s

a s y m m e tric r e a c t i o n m ig ht

s till

tru e ,

in

t h a t such an

ta k e p la c e h y th e p r e f e r e n t i a l

o p e n in g o f one o f th e honds o f th e is

a u th o rs

a sense,

m echanism s u g g e s te d

ahove.

W it h r e f e r e n c e

t o th e

and i s

c a rh o n y l g ro u p .

c o m p a tib le w i t h th e

asym m etric s y n t h e s is o f

c a r h in o ls ,

a c c o m p lis h e d h y Vavon and c o -w o rk e rs

S e c t io n I ,

and th e

f i r s t p a r t o f th is

o f syHimesrt'ficplketones w i t h is

d iffic u lt

th e th is

ahove ty p e

to

o f r e d u c t io n .

(s e e

S e c t io n ) hy r e d u c t io n

ty p e o f s y n t h e s is f i t s

more i s It

it

in to

known o f th e m echanism o f

seems l i k e l y ,

h o w e v e r, t h a t th e

r e a c t i o n m ig h t t a k e p la c e th ro u g h a t r a n s i t i o n

s ta te

, i n w h ic h case

such as

" d ia s te re o is o m e ric ^ * argum ent s i m i l a r

s e c o n d a ry

i s o - h o r n y l m agnesium c h l o r i d e ,

say how t h i s

th e o ry u n t il

T h is

t r a n s i t i o n s t a t e s w o u ld e x i s t

to th e

ahove w o u ld he a p p l i c a b l e .

and an Vavon’ s

e x p la n a t io n assumed t h a t two ^'di as te re o i some r id e s " are fo rm e d ow ing t o th e th e

-M g - b e in g

c a rh o n y l h o n d s ;th e

a d ja c e n t to

f o r m a t io n o f th e

one o r o t h e r o f

two d ia s t e r e o is o m e r -

id e s w ou ld th u s p ro c e e d a t d i f f e r e n t r a t e s ,

as w o u ld t h e i r

109

d e c o m p o s itio n .

Thus an a s y m m e tric s y n th e s is

w o u ld he o b t a in e d . v/ould in v o lv e a

e th y le n ic e x is t is

fo r

the t r a n s

d o u b le bond. d iffic u lt

o r d in a tio n o f th e

s u b seq u en t r e a c t i o n such a d d it i o n o f b ro m in e to

i n v ie w

o f the

fa c t

asym m etric s y n th e s e s u s in g b e n z o in

o r o th e r a c y l c a r b i n o l s , w here o n ly one o f th e d ia s t e r e o is o m e r id e s was o b ta in e d

d iffe r e n c e

and f i r s t

It

seems

o f f r e e e n e rg y o f th e

d ia s t e r e o is o m e r id e s w o u ld be so la r g e s u g g e s tio n i s

o xy g e n o f th e

c a rb o n y l i s

fo r

Ph » H - C----------------C-CgH^ .

example

two p o s s ib le

(s e e S e c t io n I ,

S e c t i o n ) , must now be d is c u s s e d .

The a l t e r n a t i v e

p o s s ib le ,

o f e le c t r o n s .

The q u e s tio n o f th e

th is .

t h a t co­

oxygen atom on to magnesium i s

u n l i k e l y t h a t th e

an

W h e th e r such a com plex w o u ld

to s a y ,

ow ing to th e lo n e p a i r

p a r t o f th is

c a r h in o l

P re s u m a b ly , a mechanism such as t h i s

TT -c o m p le x w i t h

as t h a t p r e d ic t e d

o f th e

two

as to acco u n t f o r th a t in th is

case th e

c o - o r d in a t e d on t o th e m agnesium , In

o r d e r to

X accommodate the magnesium atom , i t \

fo r

th e

r in g

q

w o u ld no t be p o s s ib le

_________

(

^

) to be p l a n a r .

It

is lik e ly

Mg ii th a t

an e t h e r m o le c u le w i l l

a ls o be c o - o r d in a t e d on t o

th e

m agnesium . I n p u b lis h e d exam ples o f such a s y m m e tric r e a c t i o n s , one o f th e

groups o f

th e

c a r b in o l has been a la r g e

group

110

such as an a r o m a tic r a d i c a l . h in d r a n c e ,

I n th e

absence

of

s te r ic

th e magnesium atom c o u ld occupy e i t h e r o f two

p o s itio n s w it h

r e fe r e n c e

T h u s , fro m s t e r i c

to th e

o t h e r atoms i n th e r i n g .

c o n s id e r a t io n s ,

it

is p r o b a b le

t h a t o n ly

one o f th e s e two c o n f ig u r a t io n s w o u ld be p o s s ib le case. th e

If

so,

c a rb o n o f th e

c a rb o n y l group w o u ld be h in d e r e d fro m

th u s o n ly one o f th e

w o u ld be p ro d u c e d . th a t

th e

two d ia s t e r e o is o m e r id e s

T h is w o u ld be c o m p a tib le w i t h th e f i n d ­

c o n f i g u r a t io n a t th e new a s ym m e tric c a rb o n

atom depends on th e to t h i s

th is

a t t a c k o f a m o le c u le o f G r ig n a r d r e a c t i o n a t

one d i r e c t i o n ;

in g

in

o r d e r i n w h ic h th e

two groups a tta c h e d

atom are in t r o d u c e d .

The e x p e rim e n ts w i t h G r ig n a r d re a g e n ts i n th e p r e s e n t i n v e s t i g a t i o n w ere c a r r i e d out w i t h a s e r ie s fa tty

a c id e s t e r s .

w e ig h t o f th e d e g re e o f to th e th e

One m ig h t e x p e c t t h a t

re a c ta n ts

asym m etric

d if f e r e n c e

two d ia s t e r e o is o m e r ic

deg ree o f

im p o s s ib le t o

on d e g re e o f

m o le c u la r so. th e

s lo w ly d e c re a s e owing

in fre e

fo rm s .

a sym m etric s y n t h e s is ,

to such a w id e e x te n t w i t h is

as the

and p r o d u c ts in c r e a s e d ,

s y n th e s is m ig h t

d e c re a s e o f th e

of 6 3 -a c e ty l

e n e rg y b e tw ee n

In a c tu a l f a c t , usiiqg th e

th e

same e s t e r ,

v a r ie d

e x p e r im e n ta l c o n d it io n s t h a t i t

say w hat i s

th e

a c tu a l e f f e c t o f

a s y m m e tric s y n t h e s is /

t h e s i s w e re due to some type

of

If

th e

s tru c tu re

asym m etric syn­

asym m etric in d u c t io n ,

i n v o lv in g an e l e c t r o n i c m echanism ,

it

is

h ig h l y im p ro b a b le

t h a t th e e f f e c t w ould be o b s e rv e d e v e n w i t h a compound

111

such as ( - ) - m e n t h y l l a e v u l a t e , w here o n ly two m e th y le n e g ro u p s in t e r v e n e b e tw e e n th e g ro u p .

c a rh o n y l grou p and th e

A n o th e r d i f f i c u l t y v /h ic h a ro s e i n

s tru c tu re fa ilu r e

c o r r e la tin g

and d e g re e o f asy m m e tric s y n th e s is wafe t h a t

to o b s e rv e a s y m m e tric s y n th e s is

u s in g th e

e s t e r s m ig h t have b ee n due m e r e ly t o th e lo w r o ta tio n lo w

e s te r

o f th e o p t i c a l l y p u re h y d ro x y a c id s ,

or n e g l i g i b l e

d e g re e o f

h ig h e r

s p e c ific and n o t to

asy m m e tric s y n t h e s is .

a

The

o p t i c a l r o t a t o r y power o f h y d ro x y f a t t y a c id s o f th e Ph fo r m u la C H ^- 6 _(C H 2 )n -C 0 2 H be e x p e c te d to

g e n e ra l

OH d e c re a s e

as n i s

in c r e a s e d .

When n = 2 or

th e s tu d y

o f th e

o p t i c a l r o t a t o r y power o f th e p ro d u c t was f a c i l i t a t e d

b y th e

fa c t th a t y -

v e r tib le

to th e

S-h y d r o x y

and

a c id s a re e a s i l y

con­

c o rre s p o n d in g la c t o n e s w h ic h , i n g e n e r a l,

have n u m e r ic a lly a h ig h e r r o t a t o r y pow er th a n th e

h y d ro x y

a c id s . The v a r i a t i o n

o f d e g re e o f a s y m m e tric s y n th e s is w i t h

c o n d it io n s m ig h t p o s s ib ly be due t o ta k in g p la c e . in v o l v i n g o f th e

T h is i s

s e c o n d a ry r e a c t io n s

e s p e c ia lly tru e

(-)-m e n th y l la e v u la te ,

d ia s t e r e o is o m e r ic

o f th e e x p e rim e n ts

i n w h ic h d e c o m p o s itio n

p ro d u c ts o f th e G rig n a r d

rea g e n t

Ph (C H ^ -C ------- (^ ^ 2 ^ 2 '^ ^ 2 ^ ) ÔMgX

d iffe r e n t

l a c t o n e was a c o m p lic a tin g f a c t o r .

r a t e s to g iv e th e If

no s e c o n d a ry r e a c t i o n

112

w ere th e

o c c u r r in g , t h i s r a tio

o f th e

d e c o m p o s itio n w o u ld n o t have a f f e c t e d

two h y d r o x y -a c id s f i n a l l y

e a c h o f th e la c t o n e s ,

as w e l l

b e h y d ro ly s e d to g iv e th e if

th e la c t o n e

m ig h t be a l t e r e d .

s in c e

as any unchanged e s t e r , w o u ld

c o rre s p o n d in g h y d ro xy a c id .

underw ent a s e c o n d a ry r e a c t i o n , th e

th e two s t e r e o is o m e r ic

But

r a tio

of

h y d ro x y a c id s form ed on h y d r o ly s is

A s i m i l a r type

a p p ly to a c e r t a i n e x te n t to th e a c e ty lb u ty r a te

o b t a in e d ,

(n = 3 ) .

o f argum ent m ig h t a ls o e x p e rim e n ts w i t h

(-)-m e n th y l

I t w o u ld have b een i n t e r e s t i n g t o

exam ine th e

r e a c t i o n in v o lv in g

(-)-m e n th y l

e s te r of

a compound such as th e

a lo n g c h a in f a t t y

CH^.CO. (CH^)^ 2^. CO^H, w here once

a c id such as

a g a in th e

r e s u l t i n g h y d ro x y

a c id can fo rm a l a c t o n e . The v a r i a t i o n i n be,

in p a r t,

due to

agen t w i t h th e w ill

in v o lv e

degree o f

asym m etric s y n th e s is m ig h t

the i n t e r a c t i o n o f th e G r ig n a r d r e ­

e s te r group t o

g iv e

a d i-a lc o h o l.

T h is

the i n t e r a c t i o n o f each o f two d ia s t e r e o is o ­

m e rid e s w i t h th e G r ig n a r d r e a g e n t , - r e a c t io n s w h ic h w i l l p r o b a b ly p ro c e e d a t

d iffe r e n t

ra te s .

d e g re e s ,

If

th is

p ro c e e d e d to

d iffe r in g

em p lo y e d , i t

w o u ld , t h e o r e t i c a l l y be p o s s ib le

r e a c t io n

a c c o rd in g to th e to

c o n d itio n s account

f o r th e v a r i a t i o n i n but i t

d eg ree o f asy m m e tric s y n th e s is o b s e rv e d ; \ must be n o te d t h a t i n many cases th e y i e l d o f d i ­

a lc o h o l was e x tr e m e ly low and had no a p p r e c ia b le The l a c k o f v a r i a t i o n o f

a c tiv ity .

asym m etric s y n th e s is w i t h

113

c o n d it io n s i n th e case o f th e R e fo rm a ts k y r e a c t i o n m ig h t "be a s s o c ia te d w i t h th e was o b ta in e d .

I n th e

f a c t t h a t a c l e a r r e a c t io n s o l u t i o n case o f th e G r ig n a r d r e a c t i o n ,

soon as th e G r ig n a r d r e a g e n t was added t o th e o f th e k e to

e s t e r , th e

as

s o lu tio n

system became h e te ro g e n e o u s ; i t

is

s i g n i f i c a n t t h a t re p la c e m e n t o f hand s h a k in g b y m e c h a n ic a l s tir r in g

had some e f f e c t on th e

g e n e it y o f the

system m ig h t be p a r t i a l l y

cause o f th e v a r i a b i l i t y If

th e

s y n th e s is

on th e

mechanism o f a sy m m e tric

a c tiv ity ,

as to w h e th e r

o r d e r o f i n t r o d u c t i o n o f th e groups o f

th e new a s y m m e tric c e n tre w i l l le a d

a re d i f f e r e n t

o r w h o lly th e

c o r r e c t , t h e r e w i l l b e no r u le

a r e v e r s a l o f th e

o p tic a l

The h e t e r o ­

o f asym m etric s y n t h e s is .

above h y p o th e s is

is

r e a c t io n .

s in c e

i n th e

th e

to p ro d u c ts o f o p p o s ite

t r a n s i t i o n s t a t e s in v o lv e d

two cases.

M o re o v e r, t h e r e i s

re a s o n why th e s ig n o f the o p t i c a l r o t a t i o n o f th e p r o d u c t s h o u ld be th e ed w i t h d i f f e r e n t

same i f

th e

same k e to

G rig n a r d r e a g e n ts ,

th e

r e s u ltin g

e s te r is

tre a t­

as had been su g g es ted

i n th e t h e o r y o f M cK enzie and c o -w o rk e rs is

ho

s ig n o f r o t a t i o n

c o r r e l a t e d w i t h th e n u m e ric a l in c r e a s e o r d e c re a s e o f s p e c ific

m u t a r o t a t io n .

r o t a t i o n o f th e

e s te r i n

a lc o h o l owing to

R e s u lts o f some e x p e rim e n ts

accordan ce w i t h t h i s

s u g g e s tio n ,

e .g .

are n o t i n

th e i n t e r a c t i o n o f

I

(-) -m e n t h y l £ -to lu y lfo r m a te

and m e th y l magnesium brom ide

and p h e n y l magnesium b ro m id e r e s p e c t i v e l y , when p ro d u c ts

114

o f dp.p:0 8 ± tê o p t i c a l r o t a t o r y pow er w e re olD tained (M cK en zie and C h r i s t i e , 1 9 3 5 ) .

If

a m e n th y l e s t e r i s

V a r io u s G rig n a r d r e a g e n ts ,

and i f

it

is

tr e a te d w ith

assumed t h a t con­

f i g u r a t i o n and s ig n o f r o t a t i o n go hand i n hand, i t

is

p ro b a b le t h a t p ro d u c ts o f th e

same s ig n w i l l be o b t a in e d ,

s in c e

tr a n s itio n

th e " d ia s t e r e o is o m e r ic "

same c o n f i g u r a t i o n must be the le s s case.

s t a t e s w i t h th e

o r more s t a b le

in

each

V II. PREPARATION AMD RESOLUTION OF ( - ) - / -HYDBOXY-y-PHENYLVALERIC ACID (3-HYDR0XÏ-3-PHBNŸL-BUTAN-1 -CARBOXYLIC -------------------------------------------------

115

V II.

PBBP.ABATIOH AMD EBSOLDTION OP (-)-V -H Y D R O X Y -^ -P H B im iVALERIC " a c id 3-HYDR0XY-3-PEBMYL-BUTAN-1 -CAEEOXYL IC

(

S c m l --------------------------------------------------------

V ila ,

In tr o d u c tio n The r e a c t i o n s t u d ie d most e x t e n s i v e l y d u r in g th e

i n v e s t i g a t i o n o f th e

asym m etric s y n th e s e s o f h y d r o x y - a c id s ,

fro m p h e n y l magnesium h ro m id e and ( - ) -m e n th y l fa tty

a c id e s t e r s , was t h a t u s in g ( - ) - m e n t h y l l a e v u l a t e .

I n o rd e r t o d e te rm in e the o c c u r r in g i n t h i s v a le r ic V llh .

^ -a c e ty l

d e g re e o f asym m etric s y n th e s is

r e a c t i o n th e ra c e m ic y - h y d r o x y - y - p h e n y l-

a c id was p r e p a r e d and re s o lv e d .

P r e p a r a t io n o f ( - ) - v - h y d r o x y - v - n h e n y lv a le r ic

CH^. CO. CHg. GÏÏ2. COOC^H^

a c id

CgHgMgBr --- ^ C. CH^. CH^. COOH and subsequent h y d r o ly s is

CH^

oh

The i n t e r a c t i o n o f p h e n y l magnesium hrom ide and e t h y l la e v u la te

( 1 . 2 5 g.

a lk a lin e

h y d r o ly s is

p h e n y lv a le r ic

m ol.

: 1 g. m o l . ) , w i t h subsequent

o f the p r o d u c t , g ave crude h y d ro x y -

a c id w h ic h was im m e d ia te ly c o n v e rte d i n t o

y - p h e n y l - y - v a l e r o l a c t o n e b y r e p e a te d d i s t i l l a t i o n s ben zene fro m th e y ie ld

a c id .

of

The crude la c to n e was o b ta in e d i n

as a d a rk brow n o i l .

An e t h e r e a l s o lu t i o n o f

th e la c to n e was washed r e p e a t e d ly w i t h sodium c a rb o n a te s o lu tio n .

The la c t o n e o b ta in e d fro m th e

was d is s o lv e d i n

e th e re a l s o lu tio n

hot 2 . 5N -p o ta s s iu m h y d ro x id e

s o lu t io n .

11 6

A c id if ic a tio n o f th is s o lid

s o lu t io n and c r y s t a l l i s a t i o n

o f th e

thus o b ta in e d fro m benzene gave y -h y d ro x y - y - p h e n y l-

v a le r ic

a c id ,

m .p .

1 0 5 . 5 - 1 0 6 ° , i n 27% y i e l d .

N argund (l 9 4 l ) r e c o rd e d m .p.

T r i v e d i and

1 0 4 - 1 0 6 ° and Johnson, P e te r s e n

and S c h n e id e r (1 9 4 7 ) m .p. 1 0 5 -5 -1 0 6 ® . V IIc .

R e s o lu tio n - p r e l i m i n a r y It

e x p e rim e n ts

was p ro p o s e d to a tte m p t th e

y - p h e n y lv a le r ic

a c id by f r a c t i o n a l

r e s o lu t io n o f y - h y d r o x y c r y s t a l l is a t i o n o f th e

d ia s t e r e o is o m e r id e s form ed b y c o m b in a tio n o f th e an o p t i c a l l y

a c t iv e b a s e .

a c id w i t h

P r e lim in a r y e x p e rim e n ts w ere

c a r r i e d out u s in g e q u im o le c u la r p r o p o r t io n s o f th e and th e base ( s t r y c h n in e v a r io u s s o lv e n t s . in

or b r u c in e )

( O .l

g.

A tte m p ts to p r e p a r e th e

e th a n o l and a c e to n e l e d to th e

a c id

o f a c id )

and

s tr y c h n in e s a l t

s e p a r a t io n o f s t r y c h n in e ;

when c h lo ro fo rm and c h lo r o f o r m - lig h t p e tr o le u m m ix tu r e w ere used no c r y s t a l l i s a t i o n o c c u rr e d , b u t v/hen w a te r was used an o i l

s e p a ra te d w h ich c o u ld n o t be in d u c e d t o

The use o f b ru c in e r e s u lts .

c r y s ta llis e .

as the base gave r a t h e r more p r o m is in g

A s m a ll amount o f th e

s a l t s e p a r a te d fro m a some­

w h at c o n c e n tr a te d s o l u t i o n i n a c e to n e , b u t th e r e was no c r y s ta llis a tio n

fro m e t h a n o l.

A good y i e l d

o f n e e d le s , m ,p,

1 0 0 - 1 0 8 ° (d e c o m p .) was o b ta in e d when w a te r was used as the s o lv e n t ; th e s e

c r y s t a ls

decomposed to

when t r e a t e d w i t h sodium c arb o n a te

g iv e a w h ite

s o lid

and an o p a le s c e n t

^ ♦ s o lu tio n ” when t r e a t e d w i t h h y d r o c h lo r ic a c id ,

and i t

was

117

c o n c lu d e d fro m th e s e o b s e r v a tio n s t h a t i t

was th e s a l t

t h a t had s e p a r a te d . V lld .

C o n d itio n s f o r I s o l a t i o n o f y - h y d r o x y - y - p h e n y lv a le r ic a c id and y -p h e n y l - v a l e r o la c t one fro m th e b r u c in e s a l t o f th e a c id The s a l t was suspended i n

s o l u t i o n and v/armed.

The b r u c in e w h ic h had s e p a ra te d was

e x t r a c t e d w i t h c h lo ro fo rm . d is s o lv e d i n th e and th e

T ra c e s o f c h lo r o fo r m w h ic h had

aqueous l a y e r w e re e x p e lle d b y warm ing

a c id vms th e n p r e c i p i t a t e d

t i o n w i t h m in e r a l v a le r ic

a c id .

fro m th e

a c id was e x t r a c t e d v /i t h e t h e r ,

r e s id u e e i t h e r

d is tilla tio n ,

c f.

s o lu ­

s in c e th e volume o f

The e t h e r was e x p e l le d ,

c o n v e rte d to th e la c t o n e S e c t io n

a lk a lin e

I n g e n e r a l, th e h y d ro x y p h e n y l-

th e aqueous l a y e r was l a r g e . th e

excess sodium h y d ro x id e

and

(b y benzene

I I I ) or e ls e d is s o lv e d i n th e

minimum amount o f 2 . 5 N -p o ta s s iu m h y d ro x id e h y d ro x y a c id p r e c i p i t a t e d w i t h

a c id .

s o l u t i o n and the

The s o l i d was f i l t e r ­

ed o f f and v/ashed th o r o u g h ly w i t h w a t e r . V ile .

R e s o lu t io n u s in g b r u c in e From th e

above e x p e rim e n ts i t

c r y s ta llis a tio n v a le r ic fir s t le d

o f th e b r u c in e

a p p ea re d t h a t th e

s a lt

o f y - h y d r o x y - y - p h e n y l-

a c id fro m w a te r m ight le a d t o

a tte m p t t o

to th e

c r y s ta llis e

r e s o lu t io n .

the b r u c in e

s e p a r a t io n o f b r u c in e ;

( 0 . 0 2 5 g. m o l.)

in th is

o f h y d r o x y - p h e n y lv a le r ic

350 m l. o f w a te r . m ol.

i n aqueous medium

s a lt

fro m w a te r

e x p e rim e n t 4 .8 5 g, a c id was used and

I n a f u r t h e r e x p e r im e n t,

o f hydro x y -p h e n y lv a l er i c a c id

The

u s in g 0 .0 0 2 5 g.

and 1 0 m l.

o f w a te r ,

11 8

C . 88 g. T h is

of s a lt

(m .p .

s a l t had

c h lo r o fo r m )

-5 0 .0 ° ,

e th a n o l).

^°^^546l

-2 1 .5 ° ,

“ 5 8 . 8 ° ( c , 1 .0 0 0 i n

“* 2 4 .0 ° ( c , 0 .6 4 0

[^']^jq q£ê .»- 5 0 ^ ,

- 60°

p r e c ip it a t io n o f hydro x y -p h e n y lv a l e r i c

S e c t io n I I I ) ,

it

a p p e a re d t h a t a f a i r

had b een e f f e c t e d . liq u o r at

CH, \

a c id . ,

d e g re e o f s e p a r a t io n

C o n c e n tr a tio n o f the

aqueous m other

a tm o s p h e ric p re s s u re caused a brown o i l t o

s e p a r a t e , p re s u m a b ly p h e n y lv a le r o la c t o n e . the

in

S in c e the o p t i c a l l y p u re y - p h e n y l- v a le r o la c t o n e

was e x p e c te d to have

th a t

c r y s ta llis e d .

and on d e c o m p o s itio n gave y - p h e n y l - y - v a le r o ~

la c t o n e w i t h

(c f.

1 0 5 -1 C6^ (decom p. ) )

fo llo v ^ in g e q u ili b r iu m

e x is t s

in

It

i s p r o b a b le

s o lu tio n :-

CH. \ C-CH^-CHg .1 X 2 ^ V--------

B ru c in e C-CH^-CHo /

C6H5'

B ru c in e

"6^5

0 --------- 0=0

OH

COOH

Such an e q u i l i b r i u m w ould a cc o u n t f o r the b r u c in e

s a lt.

2

s e p a r a tio n o f

i n some cases.

I n th e n e x t e x p e rim e n t more w a te r was used i n th e hope o f e f f e c t i n g ( 0 .0 2 5 g.

m o l.)

a more com plete s e p a r a tio n .

o f hydr ox y -p h e n y lv a l e r i c a c id was t r e a t e d

w i t h b r u c in e i n 250 m l. w ith

4 . 85G.

" 5 3 .0 °

o f w a te r .

[«•35461

5 - 4 9g .

of s a lt

- 6 3 . cP ( c , 1 .0 0 0 i n c h lo r o fo r m ).

C o n c e n tr a tio n o f th e m other l i q u o r fro m w h ic h t h i s o b ta in e d gave b r u c in e ,

s e p a ra te d

crop was

and f u r t h e r c o n c e n t r a t io n gave a

119

s m a l l amount o f t h e o f th e

T h re e f u r t h e r c r y s t a l l i s a t i o n s

m a in c r o p g a v e a p r o d u c t o f c o n s t a n t r o t a t i o n

hut

s a lt.

-6 6 /6 ^ ,

""77 . 8 °

[c(']^2*.6l

th e p h e n y lv a le r o la c t o n e

[ct]{z;r^,30

- 0 . 4^,

[O

(c,

1 .0 0 0 i n

c h lo r o fo r m )

is o la te d

fro m th e

s a lt

'

had o n l y

- 48 . 4 ° ~ C . 4 ^ ( ^ ,

]

0.640

i n e th a n o l). The m a in e x p e r i m e n t , s h e d , was c a r r i e d p h e n y lv a le ric is

o u t u s in g 9 . 7g.

a c id

re co rd e d i n

i n w h i c h r e s o l u t i o n was a c c o m p l i ­

and w a t e r

d e ta il in

(200 m l. )

S e c tio n V I I I .

o f ( + ) - v - h y d ro x y - y -p h e n y lv a le r ic ( d e c o m p .) of

a c id ,

s e p a ra te d fro m w a te r w i t h

c r y s ta llis a tio n

h y d ro x y -

e x p e r im e n t

The h r u c i n e m .p .

it

+ 4 . 8° ± 0 . 2 ° ,

2 .5 4 4 i n e t h a n o l ) .

c h lo ro -

a c i d had m .p .

[ a l ^ ^ g ^ + 5. 7 ° ± 0 . 2 °

( -) -y - P h e n y l- y -v a le ro la c to n e

t^ ^ 5 7 8 C - 5^ ' 8 ° ± 0 . 4 ° ,

o f w a te r

had

- 75 . 9° - 0 . 5 ° ( c , 0 .9 9 5 i n

[ 0.]

s a lt

1 0 7 -1 0 8 ®

2 ^ m o le c u l e s

(+) - y -h y d r o x y ^ - p h e n y lv a le ric

122 : 122 . 5° ,

m o l.)

T h is

as s h e a v e s o f n e e d l e s ;

- 64 . 9 ° - 0 . 5 ° , fo rm ).

(0 .0 5 g .

(c ,

had

- 6l . 9 ° - 0 . 4 ° ( c , 1.214 i n

e th a n o l). The h r u c i n e s e p a ra te d w a te r i t

s a lt

of

( - ) -y -h y d r o x y -y - p h e n y lv a le r ic

fro m w a te r i n p l a t e s ; s e p a ra te d w i t h h r u c in e .

y - p h e n y lv a le ric

o n re c r y s t a l l i s a t i o n In s u ffic ie n t

( + ) _ y -p h e n y l-y - v a le r o la c to n e , [a ]5 4 g i

fro m

( - ) -y -h y d ro x y -

a c i d , m .p . 1 21 -1 2 2 ° , was o b t a i n e d f o r

o p t ic a l r o t a t i o n d e te rm in a tio n h u t i t

+ 6 1 . 8 ^ t 0 . 5° ( c ,

a c id

an

was c o n v e r t e d t o

w h ic h had [ a ] ^ ^ g ^ + 5 3 . 9® ± 0 . 5 ®

0.955 i n e t h a n o l ) .

VIII. EXPERIMENTAL

120

VIII. EXPERIMENTAL V illa .

P r e p a r a t io n o f ( - ) -m e n th y l p y r u v a te

P y r u v ic a c id .

- A m ix tu r e

of ta r ta r ic

a c id

(4 0 0 g . ;

and p o ta s s iu m hydrogen s u lp h a te ( 600 g . ;

2 . 6 6 g.

m o l.)

4 .4 2 g.

m o l.) was h e a te d a t 2 0 0 -2 1 0 ^ i n

a d is tilla tio n

a p p a ra tu s u n t i l t h e r e was no f u r t h e r d i s t i l l a t e . o b ta in e d g ave 9 0 . 5 g .

o f p a le y e llo w l i q u i d p y r u v ic

a c id , h . p .

5 8 ° / 7 mm., a f t e r

( -) -M e n t h y l p y ru v a te . (4 4 g . ; 0 . 5

g. m o l.)

The 2 2 5 g.

(39% ) o f

two f u r t h e r d i s t i l l a t i o n s .

A m ix tu r e

o f p y r u v ic

a c id

and m e n th o l (3 1 2 g. ; 2 g. m o l.) was

h e a te d a t 1 0 0 ^ f o r 7 h o u rs w h i l s t a strea m o f h y d ro g e n c h lo r id e was b u b b le d th ro u g h i n t e r m i t t e n t l y . kept

A f t e r b e in g

o v e r n ig h t th e m ix tu r e was shaken w it h e t h e r and th e

e t h e r e a l s o l u t i o n washed w i t h sodium c a rb o n a te s o lu t i o n ( 1 0%)

and w a t e r .

fro m th e

It

was prop osed to s e p a r a te th e m e n th o l

e s t e r by steam d i s t i l l a t i o n

th e steam d i s t i l l a t i o n

o f th e m e n th o l.

had been p ro c e e d in g f o r

o i l was o b served to be d i s t i l l i n g

A fte r

8 hours an

t o g e th e r w i t h th e m e n th o l.

The steam d i s t i l l a t i o n was stopped and th e r e s id u e i n th e d is tillin g t io n

f la s k e x tra c te d w ith e th e r.

The e t h e r e a l s o lu ­

o f m e n th y l p y r u v a te and m e n th o l was d r ie d o v e r sodium

s u lp h a te

and c o n c e n tr a te d ;

g ave 2 6 . 5 g.

( 24 %) o f

66 g . o f o i l was o b ta in e d w h ic h

crude ( - ) - m e n t h y l p y r u v a t e , b .p .

1 28-1 3 0 ^ /8 mm. , on d i s t i l l a t i o n

i n vacuum; a la r g e

p o ly m e ris e d m a t e r i a l re m ain e d u n d i s t i l l e d .

amount o f

The p r o d u c t was

1 21

d is tille d r e q u ir e d

t e c o n s ta n t r o t a t i o n ; to g iv e

10 mm., o

V lllb .

( - ) - m e n t h y l p y r u v a te

1 .4 5 6 5 ,

-4 6 .6 4 ° ,

DO93

o f b .p .

1 3 2 .5 -1 3 3 . 5 V

-4 8 .7 5 ° ,

5780

P r e p a r a t io n o f ( - ) - iâ e n t h .y l l a e v u l a t e

( - ) -M e n th y l l a e v u l a t e . (il6

two r e d i s t i l l a t i o n s w ere

g . ; 1 g . m o l.)

- A m ix tu r e

o f la e v u lic

and ( - ) -m ent h o i (6 2 4

h e a te d a t 1 GO^C f o r

a c id

4 g. m o l . ) was

7 hours and h y d ro g e n c h lo r id e b u b b le d

th ro u g h i n t e r m i t t e n t l y .

The r e a c t i o n m ix tu r e was th e n

e x t r a c t e d w i t h e t h e r and th e e x t r a c t washed v /it h sodium c a rb o n a te s o l u t i o n sodium s u lp h a te

(10% ) and w a te r .

A f t e r d r y in g o v e r

th e e t h e r was d i s t i l l e d

fro m th e

s o lu tio n

and th e

r e s id u e ^ ( - ) -m e n th o l and ( - ) -m e n th y l l a e v u l a t e ] / d i s t i l l e d i n v a cuo. Two f r a c t i o n s o f ( - ) -m e n th y l l a e v u l a t e w e re c o l l e c t e d h a v in g th e

same r o t a t i o n ;

o f each th e m id d le f r a c t i o n s p r e v io u s ly . o b ta in e d I n

had th e

same r o t a t i o n s

( - ) -M e n th y l l a e v u l a t e , b . p .

71 %y i e l d

0 .9 7 6 5 ,

d^^°

-6 3 .6 2 ° ,

'■‘^^5461 - 7 1 . 8 4 ° .

on r e d i s t i l l a t i o n

l 51 ^ /2 mm. , was

(1 8 0 g. ) w i t h n^^* ^ 0 .9 7 1 ,

1 .4 5 7 3 ,

-6 1 .1 4 °.

- 7 2 .0 1 °.

- 6 3 . 1 ,9 ° ,

Pound: 0 , 7 0 . 7 ; H ,1 0 .3 % . C a lc ,

^ 15 ^ 26 ^ 3 ’ ^^ 7 0 . 8 ; H , 1 0 .3 % .

as

The sem icarb azo n e

fro m e th a n o l i n p r i s m a t i c n e e d le s , m .p .

fo r

c r y s t a llis e d c 1 5 6 -1 5 6 .3 * '.

1 22

VIIIc.

Preparation of (~)-menthyl

6) - A c e t y l - n - b u t y r l c ( 56 g* ; 0 . 5

1 ;3 ~ d io n e s o lu tio n

g.

a c id .

8 . 6 4 ) d is s o lv e d i n KOH ( c a .6 0 m l . ) and a c i d i f i e d i n s ta g e s J ------------------------

P p t. ” a ” : K R l . l 1 .9 3 g . ; m .p .i 1 6-11 7 . 5 [ Cl 3^= + 4. 20 j [ ct 1cp— 4. 60 ^ ( c , 5.1 2 r 1 g . d is s o lv e d i n KOH & r e p p td . "by a c id } pH a t f i l t n . 5 .2 - 5 .5 K E f T ll 0 . 4 8 g . ; m . p . 1 1 9 .5 - 1 2 0 . 5 5 } [ a ] = + 4 .81 y (0, 2o29f

------------------ Î P p t. " b " : K R 1.2 2 . 3 5 g . ; m . p .1 1 9 .5 - 1 2 0 . 5 ° [ a ] = - 4 . 7 3 5[ a ] = - 5 .3 0 ^ ( c , 5 .2 2 ) ® C .7 5 g . r e p p t d .} pH at f ilt n . 3 - 4 jjfci a c id ­ i f i e d to pH < 1

P p t . " c " : K R 1.3 1 . 53g. ; m .p .i 1 6 .5 -1 1 7^ [ a ] = + 4 . 3 2 ; [ ^ ]^ = + 5 .3 0 ^ (c , 5 .1 0 ) ^ il g . r e - p p t d . ; |pH a t f i l t n . ,5 .2

r

KR1.31 0 .2 4 g . ; m .p .l 2 1 - 1 2 1 . 5 °

KR1.12

0 .2 5 g . m .p .1 1 9 . 5-1 20 . 5^ sP K E 1.21 0 .5 4 g . ^ m. p . 1 1 6 - 1 1 9 °

I

P p t. " d " : K R 1 .4 * 1 .1 8g. jm. p . 1 05 -1 0 8 . 5^ • 7 6 ; [ a ] „ = - l . 94 ^ ( c , 5 .6 9 ^ ^

a c id ifie d pH 2 - 3

KR 1 .3 2 0 . 55g. m .p .1 1 8-11 90

a c id ifie d to pH < 1

K H l. 2'2® 0 .0 9 g .^ m .p .1 16-11 8 °

(#•) The aqueous m other l i q u o r , a f t e r re m o v a l o f K R 1 .4 , was e t h e r e x t r a c t e d . The la c t o n e is o la t e d fro m t h i s e x t r a c t w eigh ed 0 . 9 0 2 g. and had no d e f i n i t e r o t a t i o n (& « - 0 .0 1 , ac- - 0 . 0 2 ; o,4.~315 ) . ( e ) The aqueous m o th er l i q u o r a f t e r f i l t r a t i o n o f K E 1 .2 1 was a c i d i f i e d to pH < 1 , h u t no c r y s t a l s s e p a r a te d d u r in g the f i r s t h o u r; i t was k e p t o v e r n ig h t and th e h y d ro x y a c id c r y s t a l l i s e d i n l a r g e n e e d le s .

^

142

steam v o l a t i l e

( n e u t r a l p ro d u c ts

e s t e r g rou p w i t h

th e G rig n a rd

form ed “by r e a c t i o n o f th e

re a g e n t).

An e t h a n o l / c h l o r o -

fo rm s o l u t i o n o f t h i s m a t e r i a l was o p t i c a l l y i n a c t i v e ; s o l u b i l i t y o f th e n e u t r a l aqueous l a y e r , w ith

th e

compound was lo w i n e t h a n o l.

The

a f t e r th e e t h e r e x t r a c t i o n s , was a c i d i f i e d

5 N -s u lp h u r ic a c id and th e

^ - h y d r o x y -( T - p h e n y lc a p r o ic

a c id , v /h ic h s e p a r a te d , was e x t r a c t e d w i t h e t h e r .

The

e t h e r e a l s o l u t i o n was d r ie d o v e r sodium s u lp h a te and con­ c e n t r a t e d to d ry n e s s .

Benzene (3 p o r t io n s ,

was a llo w e d to d i s t i l fro m th e tra c e s

r e s id u e ;

fin a lly ,

ea c h )

la s t

o f b en zene w e re rem oved b y h e a t in g un der re d u c e d

p re s s u re

a t 1 0 0 ^.

1 0 . 260 .

o f y e llo w

on s ta n d in g , p a r t i a l l y s o l i d i f i e d . had th is

100 m l.

—0 . 0 4

, ^3461

O.0 3

o i l was o b ta in e d , w h ic h ,

An e t h a n o lic s o l u t i o n

( ^ , 1 5 « 4 5 5 ) j when 2 m l.

of

needed 7 . 38 m l.

of

s o l u t i o n was d i l u t e d w i t h w a te r i t

0 .1 N -so d iu m h y d ro x id e s o lu t io n f o r n e u t r a l i s a t i o n p h t h a le in )

( p h e n o l-

and a f t e r h y d r o ly s is o f th e la c t o n e p r e s e n t

r e q u ir e d a f u r t h e r 7 .7 1 abo ut 47 % l a c t o n e ,

m l.

c a lc u la t e d

These f ig u r e s from th e

c o rre s p o n d t o

e x p r e s s io n : -

VoL o f N-NaOH needed to neutralise hydrolysed la c to n e x M.W. x 1 0 0 , W e ig h t o f m a t e r i a l known to be p re s e n t 1 0 00 R e tre a tm e n t o f t h i s p r o d u c t w it h b e n z e n e ,

as abo ve, f o llo w e d

3 hours a t lO O ° /5 mm. gave a p ro d u c t c o n 0 ^o B is t in g o f 78% la c t o n e w h ic h had -O .O 6 , 0,^ 24.61

b y h e a tin g f o r

(c , 1 3. 238).

T h is m a t e r i a l t h e n had t o lu e n e s lo w ly d i s ­

tille d

and was s u b s e q u e n tly k e p t a t 1 0 0 ° / 3 ram. f o r

fro m i t

143

8 h o u rs;

s l i g h t d a r k e n in g had o c c u rre d .

o b ta in e d c o n s is te d o f about 90% la c to n e ^5780

The p ro d u c t th u s and had

( c , 1 5 . 4 1 8 ) i n e th a n o l s o l u t i o n . An e t h e r e a l s o l u t i o n o f th e

im pure

-p h e n y l--c a p r o -

la c t o n e was washed w i t h sodium c a rb o n a te s o l u t i o n and d r ie d o v e r sodium s u lp h a t e . tilla tio n

Removal o f th e e t h e r b y d i s ­

and d r y in g i n vacuo

o v e r c a lc iu m c h lo r id e

p a r a f f i n wax gave ^ - p h e n y l- c ? -c a p ro la c to n e , m .p. e t h a n o lic

s o l u t i o n o f w h ic h had

(c , 12. 033).

T i t r a t i o n o f 2 m l.

and

52^,

- 0 . 0 5 ° , ^5if6 l

an

-0 .0 6 ^

o f th e s o l u t i o n used f o r

o p t i c a l o b s e r v a t io n w i t h 0.1 N -sod iu m h y d ro x id e s o l u t i o n showed lh a t 0.11

m l. was r e q u ir e d f o r n e u t r a l i s a t i o n ,

h y d r o ly s in g the la c t o n e f u r t h e r 1 2 .3 4 m l.

to th e h y d r o x y -a c id ,

of a lk a li.

b e fo re

and th e n a

Pound: C , 7 5 . 2 ; H , 7 .5 % .

C12 H14 O2 r e q u i r e s : C , 7 5 . 8 ; H , 7.4% . A c i d i f i c a t i o n o f th e

sodium c a rb o n a te e x t r a c t , w i t h

subsequent e t h e r e x t r a c t i o n , a lly

gave a s m a ll amount o f o p t i c ­

in a c tiv e m a te r ia l.

S m a ll s c a le

e x p e rim e n t

An e t h e r e a l

s o l u t i o n o f p h e n y l magnesium brom ide ( 0 .0 2 5

g. m o l.) was added, w i t h s h a k in g , t o

a s o lu tio n o f

( - ) - m e n t h y l a c e t y lb u t y r a t e w h ic h was c o o le d i n i c e - w a t e r , over i

h o u r.

The r e a c t io n m ix tu r e was k e p t

and th e n decomposed w i t h ic e

and s u lp h u r ic

a t 0 ° o v e r n ig h t , a c id and sub­

s e q u e n tly w orked up as i n t h e p r e v io u s e xa m p le .

By

144

c o n c e n tr a tio n o f th e e t h e r e x t r a c t 6 .8 4 g .

o f o i l was

o b ta in e d w h ic h was h y d ro ly s e d and th e n t r e a t e d g iv e an a l k a l i n e a c id

s o lu tio n o f

é- h y d r o x y - /

as d e s c r ib e d p r e v io u s ly .

and e th e r e x t r a c t e d . w a te r,

T h is

s o l u t i o n was a c i d i f i e d

The e t h e r e x t r a c t was washed w i t h

ed b y d i s t i l l a t i o n .

T h re e p o r t io n s

e a c h ) w ere

fro m th e

a t 1 0 0 ° / 5 mm. f o r 5 h o u rs , e t h a n o lic 2 m l.

-p h e n y lc a p r o ic

d r ie d o v e r sodium s u lp h a te and th e n th e

d is tille d

so as to

s o l u t i o n had

o f benzene

e t h e r rem ov­ (5 0 m l.

re s id u e w h ic h was th e n k e p t

and f i n a l l y

w eighed 2.7 1

- 0 . 27 ° ,

“ 0 . 29°

g.

An

( c , l 5 . 295 );

o f t h i s s o l u t i o n r e q u ir e d 2 .8 3 m l. 0 ,1 N -sod iu m

h y d ro x id e

s o lu tio n f o r n e u t r a lis a t io n

and a f u r t h e r 1 0 . 9 8 m l, opened.

( p he n o lp h t h a le i n )

a f t e r th e la c t o n e

An e t h e r e a l s o lu t i o n o f th e

r in g had b e e n

above m a t e r i a l was

e x t r a c t e d w i t h sodium c a rb o n a te s o l u t i o n and

S- c a p r o la c to n e

o b ta in e d fro m th e

d r ie d s o lu t io n

s u lp h a te ) b y e v a p o r a tio n o f th e e t h e r . on c o o lin g ,

gave a s o l i d , m .p .

cT - p h e n y l-

The p a le

(sodiu m y e llo w

o il,

GS^T'I ° w h ic h had V

-1 ,3 2 ° ,

2 15Q..

o f th is

n e u tr a lis a tio n la c t o n e r i n g .

[ a ] ^2^61 “^ •^ '7 ° - 0 . 0 8 ° ( c ,

s o l u t i o n r e q u ir e d 0 . 1 0 m l.

anà a

f u r t h e r 9 . 8 7 m l.

6 .4 6 6 i n e th a n o l);

a lk a li fo r

a f t e r o p en in g o f th e

145

(v )

I n t e r a c t i o n o f (~ )~ m e n th y l ^ - a c e t y l - n - v a i e r a t e and phényl magnesium "bromide

B x p e rim e n t (s m a ll s c a le ) G rig n a rd re a g e n t

using; 1 . 2 5 m o le c u la r p r o p o r tio n s

of

An e t h e r e a l s o lu t io n o f p h e n y l magnesium h ro m id e (C .C 2 5 g. m o l.) was added t o a s o lu t io n a c e ty lv a le r a te

10 m in s.

( 5 . 65 g. ; 0 . 0 2 g. m o l.)

a t room te m p e r a tu r e ; th e

a c t io n m ix tu r e ro s e t o 30^.

o f (-)-m e n th y l

(20 m l . )

in e th e r

over

te m p e ra tu re o f th e r e ­

The r e a c t io n m ix t u r e was k e p t

a t room te m p e r a tu re f o r 30 m in s. , and was th e n h e a te d i n h a t h a t 60^ f o r 90 m in s.

The r e a c t io n m ix t u r e ,

had s e p a r a te d a s t ic k y w h ite

was e x t r a c t e d w i t h e t h e r (3 % 25 m l . )

The aqueous l a y e r

a t th e end o f w h ic h i t

The o r i g i n a l e t h e r l a y e r

e x t r a c t s w ere combined and washed w it h w a t e r , a te

s o l u t i o n and a g a in w it h w a te r .

had no o p t i c a l a c t i v i t y .

fro m w h ic h

s o l i d , was t r e a t e d w i t h i c e

( 50 g . ) and 53^T-sulphuri c a c id (2 5 m l . ) .

was o p t i c a l l y i n a c t i v e .

a

sodium c a rb o n ­

The aqueous w ashin gs

The d r ie d e t h e r e a l

s u lp h a te ) was c o n c e n tra te d t o

and e t h e r

d ry n e s s ,

s o lu t i o n (sodiu m

and th e

re s id u e

( 7 . 4 3 g . ) was h y d ro ly s e d by b o i l i n g under r e f l u x w i t h 5N sodium h y d ro x id e

s o lu t io n

(5 m l . ) and e t h a n o l (4 0 m l. ) f o r

h o u rs . A lc o h o l was removed b y d i s t i l l a t i o n b a t h and a s m a ll amount o f w a te r was added t o w h ic h was th e n e x t r a c t e d w i t h e th e r e t h e r e x t r a c t had no o p t i c a l tra c ts

r e fe r r e d to

as " A " ).

fro m a s te a m th e r e s id u e

( 4 x 1 5 m l.);

a c tiv ity

th e f i n a l

(com bined e t h e r e x ­

The a l k a l i n e

aqueous l a y e r was

146

w i t h 5N - s u lp h u r ic a c id ;

a c id ifie d

(3 t im e s ) ;

was e x t r a c t e d w i t h e t h e r in a c t iv e .

The e t h e r e a l

th e

th e

o v e r sodium s u lp h a t e .

by d i s t i l l a t i o n

and th e

re s id u e

3 . i 7g .

vacua

( 72 ^ ) ,

o b ta in e d w h ic h was o p t i c a l l y C^ 3 H^q0 3 has M.W.

219.

v o la tile o f th is

The e th e r was rem oved

d r ie d

o v e r c a lc iu m

o f a p a le

y e llo w

i n a c t i v e ; M.W.

L a r g e s c a le

(b y t i t r a t i o n ) :

and th e n o n -s te a m

m a t e r i a l was e x t r a c t e d w i t h e t h e r .

w h ic h h a d ,

o i l was

w ere steam d i s t i l l e d ,

fro m m en th o l and d ip h e n y l,

d r ie d e th e r

c h lo r id e

222.

The com bined e t h e r e x t r a c t s u n til fr e e

aqueous l a y e r was

e x t r a c t s w e re c o m b in ed , washed w i t h

w a t e r and d r ie d

and wax i n

o i l w h ic h s e p a r a te d

C o n c e n t r a t io n

e x t r a c t gave a s m a ll amount o f m a t e r i a l - 0 . 0 5 ^.

i n e th a n o lic s o lu tio n , e x p e rim e n t

An e t h e r e a l s o l u t i o n o f p h e n y l m agnesium bro m id e ( 0.10

g. m o l . ) was added to

v a le r a te

( 2 2 . 6 g . ; 0 . 0 8 g.

a s o lu tio n o f m o l. ) i n

e th e r

m in s . w i t h i c e - c o o l i n g and s t i r r i n g . w ith

c o o lin g f o r

Was k e p t • ic e

at 0 °.

(8 0 m l . )

S tir r in g

a f u r t h e r h o u r and th e

o v e r n ig h t

( - ) - m e n t h y l ace t y l ­

r e a c t i o n m ix t u r e

( 1 00 m l . ) .

l a y e r was e x t r a c t e d w i t h e t h e r ( 4 x 50 m l . ) e t h e r e x t r a c t s w ere washed w i t h w a te r

and th e n d r ie d o v e r

was c o n tin u e d

The m ix tu r e was decomposed w i t h

(50 g . ) and 5N - s u lp h u r ic a c id

sodium c a rb o n a te s o l u t i o n

o v e r 30

(3 x 25 m l . )

sodium s u lp h a t e .

The aqueous and th e

(3 x 50 m l . ) , and w a te r

com bined

10 ^ -

( 3 x 25 m l . )

C o n c e n t r a t io n o f t h i s

147

s o l u t i o n to

d ryness gave a y e llo w o i l

( 2 9 . 3 g, ) w h ic h was

h y d ro ly s e d "by " b o ilin g u n d er r e f l u x w i t h 2 . 5N -p o ta s s iu m h y d ro x id e s o l u t i o n (4 0 m l . ) h o u rs .

and e th a n o l

(8 0 m l . ) f o r 4

E th a n o l was removed "by d i s t i l l a t i o n

b a t h and th e

fro m a s te a m -

r e s id u e was e x t r a c t e d w i t h e t h e r (2 x 75 m l. ,

5 X 50 m l . ) ; no s m e ll o f m e n th o l was p e r c e p t i b l e when th e la s t

e th e r e x t r a c t was c o n c e n tr a te d .

w ere steam d i s t i l l e d

and Ce06g.

The e t h e r e x t r a c t s

o f n o n -s te a m v o l a t i l e *

m a t e r i a l was i s o l a t e d by e t h e r e x t r a c t i o n . a lly

in a c tiv e .

The a l k a l i n e

with 5 N -s u lp h u r ic

w as o p t i c ­

T h is

aqueous l a y e r was a c i d i f i e d

a c id and th e n e t h e r e x t r a c t e d .

e x t r a c t was washed w i t h w a t e r ,

The e t h e r

d r ie d o v e r sodium s u lp h a te

and th e e t h e r e x p e lle d b y h e a t in g on a s te a m -b a th . ( £ 4%) o f 5 - h y d r o x y - 5 - p h e n y l- h e x a n e - l- c a r b o 3^ 1 i c

1 4 . 8 6 g.

a c id was

o b ta in e d as a y e llo w v is c o u s o i l w h ic h w ould n o t c r y s t a l ­ lis e .

Pound: C , 7 0 . 3 ; H , 8 .2 ^ .

C , 7 0 . 2 ; H , 8 .2 ^ . The y e llo w

had

p il d is tille d

d is tilla tio n o b ta in e d .

It

a p a le

r e q u ir e s : + 0 .0 9 ^

(c ,

4 9 .9 5 i n

a t 1 6 0 - I 9 2 ^ /3 mm. and on r e ­

y e llo w l i q u i d ,

Pound: G, 7 1 . 1 ; H 8 . 8%.

b .p .

150-1 7 8 / 3 mm. was

A d e h y d r a tio n o f p r o ­

d u c t o f 5 - h y d r o x y - 5 - p h e n y lh e x a n - l- c a r b o x y lic (C -l 2H^g 0 2 ) w ou ld r e q u ir e :

e t h a n o l) .

0,

7 6 .4 ; H , 7*9% .

a c id

148

( v i ) I n t e r a c t i o n o f ( - ) - m e n t h y l O - a c e t y lp e la r g o n a t e and p h e n y l ma.ecnesimn 'bromide An e t h e r e a l s o l u t i o n o f p h e n y l magnesium hro m id e

i

(0 .1

g. m o l.) was added o v e r

tio n

o f ( - ) - m e n t h y l 6J - a c e t y lp e la r g o n a t e

m o l.) w i t h s t i r r i n g . p re v e n te d e f f i c i e n t

hour to an ic e - c o o le d

A t h ic k s t ic k y o i l s tir r in g ,

( 27 . 04.g 4 0 . 0 8 g. s e p a ra te d w h ich

a lth o u g h a tte m p ts to c o n tin u e

s tir r in g

f o r a f u r t h e r h o u r w ere made.

was k e p t

a t 0 ^ o v e r n ig h t ,

The r e a c t i o n m ix tu r e

and th e n decomposed w i t h ic e

(50 g. ) and 5 N -s u lp h u r ic a c id

(iC O m l . ) .

The aqueous l a y e r

was e x t r a c t e d w i t h e t h e r (4- x 50 m l. ) and th e e t h e r e a l s o l u t i o n s , a f t e r w ashing w i t h w a te r

1 0$ - 8 odium c a rb o n a te

s o lu t io n ( 3 x 25 m l . )

25 m l . ) , w ere d r ie d o v e r sodium s u lp h a te . c o n c e n tr a te d to

d ryness and th e

d is tilla tio n

fo r

8 h o u rs .

and w a te r ( 3 x The s o l u t i o n was

s o l u t i o n (4 0 m l . )

and

fro m a steam b a t h and th e r e s id u e was e x ­

6 x 50 m l , ) .

l a y e r was a c i d i f i e d w i t h 5 N -s u lp h u r ic a c id s e x t r a c t e d w i t h e t h e r . washed w i t h w a te r

The aqueous

a c id and th e

o rg a n ic

The e t h e r e a l s o l u t i o n was

(3 x 25 m l . ) and a f t e r d r y in g o v e r sodium

c o n c e n tr a te d to

d ryn ess to g iv e 22.14- g.

im pure g - h y d r o x y - g - p h e n y l- d e c a n e - l- c a r b o x y lic y e llo w

(3 x 50 m l . ) ,

The a lc o h o l was removed b y

t r a c t e d w i t h e t h e r (2 x 75 m l . ,

s u lp h a t e ,

combined

re s id u e h y d ro ly s e d b y b o i l ­

in g w i t h 2 . 5N -p o t assium h y d ro x id e e th a n o l (8 0 m l . )

s o lu ­

o i l w h ic h p a r t l y

Pound: C, 70 .1 ; H , 9 .9 % .

s o lid ifie d

of

a c id as a

on p ro lo n g e d s ta n d in g .

^ 17 ^ 26^3 re q u ir e s : C , 7 3 . 3 ;

149

H, 9.4% , d e fin ite

An e t h a n o lic o p t ic a l

s o lu tio n

(a p p ro x .

a c tiv ity

2^)

and

e x h ib it e d no

-C .O i^ ),

th u s

no a tte m p t was made to p u r i f y th e 9 -h y d r o x y - 9 -p h e n y l-d e c a n e 1 -c a r b o x y lic

a c id ;

have a c c o u n te d f o r V lllh .

th e lo w c a rb o n c o n te n t.

R e fo rm a ts k y r e a c t io n s

(i)

P a r t i a l a sym m etric s y n th e s is o f B -h y d r o x y -B -p h e n y lb u t y r i c a c id

A s o lu tio n o f 0 .1 1

unchanged a c e t y lp e la r g o n i c a c id w ou ld

g. m o l.)

m e c h a n ic a l

( - ) - m e n t h y l b ro m o a c e ta te

i n benzene

s tir r in g ,

(1 0 m l . )

over

( 30.47 g . ;

w as added d ro p w is e w i t h

h rs . , to a b o ilin g

(l3 .2

t h i op he ne f r e e )

i n th e p re s e n c e o f z in c n e e d le s B o ili n g

g. m o l .) i n

benzene (50 m l. ;

o f acetophenone

0 . 1 6 5 g. m o l . ) .

g. ; 0.11

and s t i r r i n g

a f u r t h e r f o u r h o urs a f t e r

s o lu tio n

(IC .8 g. ;

w ere c o n tin u e d f o r

a d d i t i o n was c o m p le te .

The r e ­

a c t i o n m ix tu r e was k e p t o v e r n ig h t a t room te m p e ra tu re and f i n a l l y th e l i q u i d was d e c a n te d fro m u n re a c te d z in c ( 3 . 6 8 g . ; e t h e r and 0 . 0 5 6 4 g. m o l.) w h ich was washed w it lr ^ w a t e r . The combined l i q u i d s w ere t r e a t e d w i t h ic e a c id

(100 m l . ) .

(2 5 g. ) and 5 1^ -G u lp h u ric

The aqueous l a y e r was e x t r a c t e d w i t h e t h e r

(1 X 1 0 0 , 2 X 50 m l . ) ; th e com bined e t h e r b en zen e s o l u t i o n w ere washed w it h w a te r d r ie d

o v e r sodium s u lp h a t e .

to d ry n e s s , f i n a l l y o f a y e llo w

and

( 3 x 25 m l . )

C o n c e n t r a t io n o f t h i s

and

s o lu tio n

under red u ced p r e s s u r e , gave 33 *3 2 g.

o i l w h ic h s o l i d i f i e d

had a brom ine

e x tra c ts

c o n te n t o f 1 .7 1 % ,

on s ta n d in g .

T h is p ro d u c t

c o rre s p o n d in g to 1 .9 8 g.

of

150

urrîhanged ( - ) - m e n t h y l ‘b ro m o a c e ta te . ly s e d i n 2 p o r t i o n s ,

The p ro d u c t was h y d ro ­

each u s in g 1 5 .1 5 g.

o f " e s te r"

(c o r­

re s p o n d in g to th e p r o d u c t o 'b ta in e d fro m 0 . 0 5 g. m o l.

of

( - ) - m e n t h y l ‘b r o m o a c e ta te ). (a )

-

The p ro d u c t ( 1 5 .1 5 g. ) was ‘b o ile d

under r e f l u x w i t h

2 . 5 N -p o ta s s iu m h y d ro x id e s o lu t i o n ( 2 5 m l. ; 0 .0 6 2 5 g. m o l. KOH) and e t h y l a lc o h o l

(5 0 m l . )

f o r 4 h o u rs ,

p - p h e n y l- ‘b u t y r i c a c id was i s o l a t e d an o i l

+ 3.01

s ta n d in g , w i t h (c ,

* 2.64 - 0 . 0 5 ^ (c ,

fo u n d b y t i t r a t i o n : (b ) -

1 8 l.

s o lid ifie d

+ 2 .3 4 - 0 . 0 5 ° , 9 .1

in

C a lc ,

e t h a n o l) .

M o l.

w e ig h t

f o r C -|cH i2^3* 1 8 0 .

. r e f l u x w i t h N -p o ta s s iu m h y d ro x id e

s o lu t io n

end o f th e

w h e re a s i n

(a )

h y d r o ly s is

(a ) w ith

th e r e w e re s t i l l tw o la y e r s p -H y d ro x y -

( 4 .3 6 5 g. ; 49^ y i e l d ) was o b ta in e d as + 2 .7 3 - 0.05*^. [a }^ 2 f6 l

( c , 1 5 . 7 5 i n e t h a n o l) . C>io^l 2^3

f o r 17 h o u rs ;

a c l e a r s o l u t i o n had been o b ta in e d .

P - p h e n y lb u t y r ic a c id

u n der

( 6 2 . 3 m l. ;

0 . 0 6 2 5 g . m o l. KOH) and e t h y l a lc o h o l (3 0 m l . )

in

on p r o lo n g e d

The c o n d e n s a tio n p ro d u c t ( 1 5 .1 5 g. ) was b o i l e d

a t th e

as

+3.38 ± 0 . 0 5 °

-

2 2 . 0 5 i n e t h a n o l ) , and

[^35461

(a s d e s c rib e d b e lo w )

53% )^w h ich

( y i e l d 4 .7 3 5 g . ;

p -H y d ro x y -

Found: 0 ,

+ 3 .0 6 - 0 .0 5 ^

6 6 . 4 ; H , 7.04% .

6 6 .7 ; H, 6 . 71 %.

A s y s te m a tic e x a m in a tio n was made o f th e p r o d u c ts o f h y d r o ly s is .

The p ro d u c t fro m 0 . 0 5 g. m o l.

( - ) -m e n th y l

b ro m o a c e ta te was b o i l e d w i t h aqueous a lc o h o lic p o ta s s iu m

151

h y d ro x id e

(s ee a h o v e ); f i n a l l y

d is tilla tio n ,

th e r e s id u e

(1 X 50 , 5 X 25 m l . )

th e a lc o h o l was removed hy

th e n h e in g e x t r a c t e d w it h e t h e r

to remove n e u t r a l

compounds.

The

e t h e r e a l e x t r a c t was c o n c e n tra te d to d ry n e s s and th e 9 .7 3 g. of o il le f t

was steam d i s t i l l e d .

A s m a ll amount (O .C 4 g . )

o f non s t e a m - v o l a t i l e r e s id u e was e x t r a c t e d h y means o f e t h e r and gave on d is s o lv in g i n e th a n o l ( i 5 m l . ) - 0.Q7®, a lk a li,

- 0 .0 8 ^ .

n o r was i t

The steam v o l a t i l e aceto p h e n o n e .

T h is o i l was no t

s o lu b le i n

h y d ro ly s e d f u r t h e r hy h o i l i n g w i t h a l k a l i . m a t e r ia l was a m ix tu r e

From 4 .8 7 g.

o f m en thol and

o f n e u t r a l p ro d u c ts 2.1

g.

of

th e 2 : 4 “ d in itr o p h e n y lh y d r a z o n e o f acetophenone was O b ta in e d , m .p .

23 9 - 2 4 0 ^; c r y s t a l l i s e d

had m .p .

from aqueous a c e t i c

a c id t h i s

2 4 2 - 3 ° (d e c o m p .).

The aqueous s lk a lin e

s o lu t io n ( a f t e r rem o v al o f th e

n e u t r a l p ro d u c ts as ahove) was a c i d i f i e d w i t h 5 N - s u lp h u r ic a c id and th e (3 -h y d ro x y -p -p h e n y l h u t y r i c w ith e th e r

(1 x 50 , 3 x 20 m l . ) .

washed w it h w a te r (3 % 20 m l . ) ,

a c id e x t r a c t e d

The e t h e r e x t r a c t e d was d r ie d o v e r NaaSO^^

and c o n c e n tra te d t o d ry n e s s , th e r e b y g iv in g th e p ro d u c ts d e s c r ib e d above.

The a c id aqueous l a y e r

( a f t e r e x tr a c tio n

o f { 3 -h y d r o x y -p -p h e n y lh u ty r ic a c id ) was o p t i c a l l y i n a c t i v e . Steam d i s t i l l a t i o n

gave a c e t ic a c id ,

N KDH f o r n e u t r a l i s a t i o n

7

r e q u ir in g 1 1 .8 m l.

( t o thym ol b l u e ) ;

152 (il)

P r e p a r a t io n o f (1 ) - 6 -h y d r o x y -( 3 - p h e n y l-b u t y r ic a c id

A s o lu t io n o f e t h y l b ro ra o -a c e ta te and acetophenone

(2.88 g . ; 0.024 g. m o l.) i n benzene

( ^ 5 n il. ) was b o ile d u n d e r r e f l u x (1 .3 1

g . ; 0 . 0 2 g. m o l. ) f o r

p ro d u c t

( 3 .3 4 g . ; 0 . 0 2 g. mol.)

( 4.365 g . ) ,

o b ta in e d

li

i n th e p re se n ce o f z in c

h o u rs .

The c o n d e n s a tio n

as i n th e above e x a m p le , was

h y d ro ly s e d by b o i l i n g u n d e r r e f l u x w i t h 2 . 5 N -p o ta s s iu m h y d ro x id e s o lu t io n a lc o h o l

(10 m l. ; O.025 g, m o l. KOH) and e t h y l

(25 m l . ) .

The p ro d u c t o f h y d r o ly s is was worked up

as in th e above e x p e rim e n t and 0 - h y d r o x y - 6 - p h e n y l- b u t y r ic a c id

s o lid ifie d p e tro le u m 7 1 -7 2 ^ . C,

2 .3 5 5 g . ; 65%) was o b ta in e d as an o i l w hich

(y ie ld

on s ta n d in g .

On c r y s t a l l i s a t i o n fro m l i g h t

( b . p . 100 - 120 ° ) n e e d le s w ere o b ta in e d , m .p . Found: G, 6 6 .7 ^ ; H, 6 . 85%.

66.7fo; H , (iii)

‘^10^^12^3 r e q u ir e s :

6 . 71 %.

P r e p a r a t io n o f 2 - h y d r o x y - 2 - i s o - b u t y l- 4 - m e t h y lh e x a n o ic a c id

A s o lu t io n o f ( - ) -m e n th y l b ro m o a c e ta te 0 .0 1 m o l.) z in c

g . m o l.)

( 2 .7 7

g .;

and d i - i s o - b u t y l k eto n e

( 1 .7 0 g . ; 0 .0 1 2 g .

i n ben zene ( l 5 m l . ) was b o i l e d ,

i n th e p re s e n c e o f

( 0 . 6 5 4 g . ; 0 .0 1

g.

a to m s ), u n d e r r e f l u x f o r 5 h o u rs .

The r e a c t i o n m ix tu r e was worked up and h y d ro ly s e d as u s u a l.

3 . 4 8 5 . o f c o n d e n s a tio n p ro d u c t was o b ta in e d w h ich on h y d r o ly s is gave a p a le y e llo w o i l w hich d id n o t d e c o lo u r is e

( y i e l d 0 .7 5 g . ;

37% )

a c id p o ta s s iu m perm anganate

s o lu t io n .

(Found: G, 6 4 . 8 ; H,

G, 6 5 . 3 , H,

1 1 .0 ^ ).

I O . 85S.

^ ilH 2 2 ^ 3 r e q u ir e s :

153

V llln .

( ~ ) - v - H y d r o x y - y - p h e n y lv a le r ic a c id

(i)

P r e p a r a t io n

E th y l la e v u la te .

-

A s o lu t io n

5 g. m o l. ) i n e t h a n o l (1^150 m l . ) s o l u t i o n o f hyd ro gen c h lo r id e r e f l u x f o r 24 h o u rs .

As m a ll

of la e v u lic

a c id

and a s a tu r a t e d

(6 0 m l. ) was h o ile d

(5 8 0 g . ;

a l c o h o lic u n d er

volume o f e t h e r was added and

th e e t h e r e a l s o l u t i o n was washed w i t h 1 0 $ -s o d iu m c a rb o n a te s o lu t io n and w a te r and f i n a l l y and sodium c a rb o n a te . e th y l la e v u la t e , b .p . b .p .

d r ie d

D is tilla tio n 9 8 ^ / l 5 mm.

o v er sodium s u lp h a te gave 586g.

(81% ) o f

R u z ic k a (1 9 1 7 ) re c o rd s

9 S V l 5 mm. ( - ) “V - H y d r o x y - y - p h e n y lv a le r ic a c id . -

s o l u t i o n o f p h e n y l magnesium brom ide added t o e t h y l l a e v u l a t e

( l 44 g. ; 1 . 0

An e t h e r e a l

( l . 2 5 g. m o l.) was g. m o l.) i n e t h e r

( l 000 m l . ) , w i t h ic e - c o o lin g and s t i r r i n g

o v e r 20 m in s .

S t i r r i n g was c o n tin u e d f o r a f u r t h e r 10 m in s . w i t h i c e c o o lin g , a t 0 °.

and th e r e a c t io n m ix tu r e was th e n k e p t o v e r n ig h t A h a rd s o lid mass had s e p a r a te d fro m th e e t h e r .

The r e a c t i o n m ix tu r e was t r e a t e d w i t h ic e 5 N - s u lp h u r ic a c id

( l 000 m l . ) .

(5 0 0 g. ) and

The aqueous l a y e r was ex­

t r a c t e d w i t h e t h e r ( 4 x 500 m l . )

and th e combined e t h e r e a l

s o lu t io n s w ere washed w i t h w a te r

( 3 x 300 m l. ), 1 0% -sodium

c a rb o n a te s o l u t i o n ( 3 x 300 m l . )

and w a te r ( 3 x 300 m l . ) .

D is tilla tio n

o f th e e t h e r fro m th e d r ie d s o lu t io n

s u lp h a t e ) gave 1 80 g.

o f y e llo w

(sodiu m

o i l w h ic h was h y d ro ly s e d b y

154

■ b o ilin g under r e f l u x w i t h e th a n o l (1 0 0 0 m l . )

and 2 . 5N-

p o tasB iu m h y d ro x id e s o l u t io n

(5 0 0 m l.)

d a rk brow n s o lu t io n was k e p t

o v e r n ig h t and was e x t r a c t e d

w ith e th e r.

f o r 5 h o u rs .

The aqueous l a y e r was a c i d i f i e d w it h

5 N -S u lp h u r ic a c id and e t h e r e x t r a c t e d . t i o n was washed w i t h w a te r and d r ie d The e t h e r was d i s t i l l e d p o r t io n s

The

The e t h e r e a l s o lu ­

o ve r sodium s u lp h a te .

and th e r e s id u e ,

o f benzene (2 5 0 m l.

o b ta in e d as a d a rk brown o i l

h a v in g had t h r e e

each) d i s t i l l e d ( 8 3 g. ; 47% ).

fro m i t ,

was

Crude y - p h e n y l -

y - v a l e r o l a c t o n e , o b ta in e d as a b o ve , was d is s o lv e d i n e t h e r and th e s o l u t i o n was washed w i t h 10% -sodium c a rb o n a te s o lu tio n

( 6 X 50 m l . ) .

The e t h e r was d i s t i l l e d

fro m th e

e t h e r e a l s o l u t i o n and th e re s id u e d is s o lv e d i n h o t 2 . 5 N -p o ta s s iu m h y d ro x id e s o l u t io n . w i t h c h a r c o a l,

c o o le d and f i l t e r e d .

The s o lu t i o n was t r e a t e d Slow a c i d i f i c a t i o n o f

th e a l k a l i n e s o l u t i o n w i t h g ^ T -s u lp h u ric a c id gave y -h y d r o x y -y -p h e n y l v a l e r ic

a c id as m ic r o c r y s t a ls

(48g.; 27% ).

C r y s ta l­

l i s a t i o n fro m benzene gave p l a t e s , m .p . 1 0 5 .5 - 1 0 6 ^ . Found: C, 6 8 .2 ; H, 7 .4 % . (ii)

C a lc ,

fo r

C, 6 8 .0 ; H , 7 .3 % .

R e s o lu tio n

y -H y d r o x y -y -p h e n j'l v a l e r i c a c id

( 9 . 7 g. ; 0 . 0 5 g. m o l.)

was d is s o lv e d i n w a te r (2 0 0 m l. ) w i t h t h e minimum amount o f h e a t in g .

B ru c in e

(+ 4 H 2O)

(23 g. ; O. 0 5 g. m o l.) was

added i n one b a tc h w i t h s t i r r i n g u n t i l s o l u t i o n was o b t a in e d .

and w arm ing c o n tin u e d

The s o l u t i o n was f i l t e r e d

155

and a llo w e d

to c o o l.

R o s e tte a o f n e e d le s s e p a ra te d

( l 5# 47 g . ) w h ic h had m .p. 1 0 5 - 1 1 0 ^ (d e com p.) and [O 'Î 57 g 0 - 4 9 . 6 ° ,

[0 ']5 4 6 i

-5 8 .2 °

(M o th e r l i q u o r fro m t h i s liq u o r " ).

A fte r fiv e

“b r u c in e s a l t

(c ,

0 .9 9 8 i n c h lo r o fo r m ).

term ed "M a in aqueous m o th e r-

c r y s ta llis a tio n s

fro m w a te r th e

o f ( + ) - y - h y d r o x y - y - n he n y l v a l e r i c

a c id was

o b ta in e d as sheaves o f n e e d le s , m .p . 1 0 7 - 1 0 8 ° (decomp. ) and [ a ] 3780 - 6 4 . 9 °

- 0.5°,

[ a ] 546 ,

- 7 5 .9 ° - 0 . 5 ° ( c , 0 .9 9 5 i n

c h lo ro fo rm ^ . Pound: C, 6 4 .5 ; H, 7.3% . O34 H40 O 7 N2 , 2& H 2O r e q u ir e s : C, 6 4 . 4 ; H 7.1% . The s a l t was t r e a t e d w i t h warm e x c e s s sodium h y d ro x id e s o l u t i o n and th e b ru c in e w h ic h had s e p a r a te d v/as e x t r a c t e d w i t h c h lo ro fo rm (3 t im e s ) . w h ic h t r a c e s

The a l k a l i n e

s o l u t i o n , fro m

o f d is s o lv e d c h lo ro fo rm had b e e n e x p e lle d b y

w arm ing was a c i d i f i e d w i t h h y d r o c h lo r ic a c id w i t h i c e c o o lin g

and e t h e r e x t r a c t e d .

The e t h e r e x t r a c t was washed

w i t h w a te r and d r ie d o v e r sodium s u lp h a t e . d is tille d

The e t h e r was

and th e r e s id u e d is s o lv e d i n th e minimum amount

o f hot 2 . 5 N -p o ta s s iu m h y d ro x id e s o l u t i o n . was a c i d i f i e d

w i t h ic e

The s o lu t io n

c o o lin g and k e p t a t 0 ° f o r

( + ) _ y _ h y d r o x y - y - p h e n y lv a le r ic a c id f i l t e r e d th o ro u g h ly w it h ic e d w a te r . [ a ] ^ 73 Q + 4 . 8 ° ± 0 . 2 ° , e t h a n o l) .

It

h o u r, and

o f f and washed

had m .p . 1 2 2 - 1 2 2 . 5 ° ,

5 .7 °

- 0 .2 °

R e p r e c i p i t a t i o n fro m a l k a l i n e

m in e r a l a c id d id n o t a f f e c t

i

th e s p e c i f i c

(c ,

2 .5 4 4 i n

s o lu t io n w i t h r o ta tio n .

c r y s t a l l i s a t i o n fro m benzene d id no t a f f e c t th e

Re­

r o ta tio n

1 56

and a c id o b ta in e d fro m th e m o th er l i q u o r had th e same r o ta tio n . la tio n s

The la c t o n e was p re p a re d b y sub sequent d i s t i l ­

o f benzene from t h e

and , f i n a l l y ,

a c id

(a s d e s c rib e d e a r l i e r )

th e o i l was h e a te d a t 1 0 0 ^ .

y - v a l e r o l a c t o n e was o b ta in e d w i t h [°'^ 5 4 6 i

- 0 . 4 ° ( c , 1 .2 1 4 i n

C , 6 7 . 9 ; H, 7 .3 % .

C a lc ,

( -)-y -P h e n y l-54-. 8 - 0 . 4 ° ,

e t h a n o l) .

fo r

0,

Found :

6 8 . 0 , H , 7.3 % .

The " m ain aqueous m other l i q u o r ’* was c o n c e n tra te d t o 35 m l. in itia l

S m a ll amounts o f s o l i d , w h ic h had s e p a r a te d i n th e s ta g e s o f th e c o n c e n t r a t io n , w ere rem oved b y

filtr a tio n . and p la t e s

On c o o lin g t h i s s e p a ra te d w it h

m ix tu re

a m ix tu r e

-2 2 .4 ^ ,

( c , 1 .0 0 2 i n c h lo r o fo r m ). m a t e r i a l gave f i r s t

s o lu tio n ,

I^^^546l

o f n e e d le s - 27 . 5 °

R e c r y s t a l l i s a t i o n o f t h is

a s m a ll amount o f b r u c in e and t h e n a

o f n e e d le s and p la t e s w h ic h had

C15461 "0 .0 1 ° ( c , 1.0 11

in

+ 0 .0 3 ° ,

c h lo r o fo r m ).

y - H y d r o x y - y - p h e n y lv a le r ic a c id was o b ta in e d fro m t h i s m a te r ia l,

as d e s c rib e d

b r u c in e s a l t

abo ve, and th e n re c o n v e r te d to th e

( s in c e b r u c in e had b e en s e p a r a t in g d u rin g th e

c r y s ta llis a tio n ).

The b r u c in e s a l t th u s o b ta in e d s e p a ra te d

fro m w a te r i n p l a t e s , m .p . [a j^ y g o + 7 . 1 ° - 0 . 1 ° . c h lo r o fo r m ).

9 5 . 5 - 9 8 ° (d e c o m p .) + 6 .5 ° ± 0 . 1 ° (c ,

and had 5 .0 6 2 i n

R e c r y s t a l l i s a t io n o f t h i s s a l t gave a p ro d u c t

w ith [a ]jY 8 0

^ *5 ° " 0 .1 ° ,

i n c h lo ro fo rm )

(it

+ 5 .8 ° t 0 . 1 °

ap p eared fro m th e s e f ig u r e s

was c r y s t a l l i s i n g o u t as w e l l as th e

(c ,

3 .4 4 1

t h a t b r u c in e

s a l t ) , y -H y d r o x y -

157

y -p h e n y lv a le r ic

a c id was i s o l a t e d b o th fro m t h e s a l t

and th e m o t h e r - liq u o r *

B o th crops w ere c o n v e rte d i n t o

la c to n e s w h ic h had i n e t h a n o l)

+ 5 9 .6 ® ( c , 0 , 7 5 2

+ 5 3 .4 ^ ,

and [aJpygQ + 5 3 . 2 ° ,

and

( c , 0 . 8 5 4 i n e t h a n o l) r e s p e c t i v e l y .

th e

+ 5 9 .9 ° These crops w ere com-

h in e d and d is s o lv e d i n hot p o ta s s iu m h y d ro x id e s o l u t i o n . ( - ) - y - h y d r o x y - y - p h e n y lv a le r ic a c id was p r e c i p i t a t e d filte r e d

fro m t h i s

v e r t e d to

s o lu t io n ,

as d e s c rib e d b e f o r e ,

( 4 ) ^ -p h e n y l-y -v a le r o la c to n e .

th e la c to n e

to t h e a c id and th e a c id b ac k t o th e la c t o n e

( - ) - y - H y d r o x y - y - p h e n y lv a le r ic

a c id , m .p .

( + )-y -p H e n y l-y -v a le r o la c to n e w ith

C a lc , f o r

r o ta tio n .

1 2 1 -1 2 2 ® , gave + 5 3 .9 ° - 0 . 5

+ 6 i . 8 ° - 0 . 5 ° ( c , 0 .9 5 5 i n e t h a n o l ) .

C , 6 7 .3 ; H , 7.1% .

(+)

and con­

R e c o n v e rs io n o f

as p r e v io u s ly caused no change i n th e s p e c i f i c

[ a ] ^ 46 i

and

,

Pound:

C , 6 8 . 0 ; H, 7 .3 % .+

P r e p a r a t io n o f th e s o lu t io n o f v - p h e n y l-v -^v a le r o la c t o n e f o r o p t ic a l m easurem ents. S in ce o n ly s m a ll amounts o f th e la c to n e w ere a v a i l a b l e th e p ro c e d u re used f o r th e p r e p a r a t io n o f th e s o lu t io n was as f o ll o w s . The la c t o n e ( d r ie d a t 1 0 0 ° , and a llo w e d to c o o l i n a vacuum d e s ic c a to r )w a s d is s o lv e d i n e th a n o l and t r a n s ­ f e r r e d to a s ta n d a rd f l a s k ; th e o r i g i n a l f l a s k was th e n d r ie d under th e c o n d itio n s used p r e v io u s ly and r e ­ w e ig h e d .

SUMMARY

158 rX.

1.

SUIviï'Æ ARY

( - ) - M e n t h y l e s te r s o f O - a c e t y l f a t t y

a c id s

[CH 3 .CO. (CH 2 )n * ^ 0 2 .C'|QH-|g] w ere p r e p a r e d , w it h n = 0 , 2 , 3 , 4 and 8 . 2.

These e s t e r s were t r e a t e d w it h p h e n y l magnesium b ro m id e .

By h y d r o ly s is o f th e r e s u l t i n g h y d r o x y -e s te r

and e x a m in a tio n o f th e p ro d u c t f o r o p t ic a l a c t i v i t y ,

an

asym m etric r e a c t i o n was shown t o occu r when n = 0 , 2 , 3 o r 4.

When n = 0 ,

was o b ta in e d

2 o r 4 a d e x t r o - r o t a t o r y h y d ro x y -a c id

and when n = 2 o r 3 a l a e v o - r o t a t o r y la c to n e

(c o rre s p o n d in g t o t h e h y d r o x y -a c id ) was o b ta in e d . asym m etric s y n th e s is was o b served u s in g ^ -a c e ty lp e la r g o n a te 3.

No

(-)-m e n th y l

(n = 8 ) .

The d eg ree o f asym m etric s y n th e s is o b ta in e d u s in g th e e s te r s w it h n = 2 or 3 v a r ie d w it h th e e x p e r im e n ta l c o n d itio n s em ployed. la e v u la te

The r e a c t io n u s in g

(-)-m e n th y l

(n = 2 ) was s tu d ie d e x t e n s iv e ly .

The y i e l d ,

as

w e l l as th e d eg ree o f asym m etric s y n t h e s is , was fo u n d to v a r y w ith r e a c t i o n c o n d it io n s .

A na tte m p t

was made t o

a s c e r t a in th e n a tu r e o f th e b y -p ro d u c ts fro m t h i s 4.

r e a c tio n .

The p ro d u c t o b ta in e d fro m th e r e a c t io n w i t h n = 2 ( y - h y d r o x y - y - p h e n y l- n - v a l e r ic a c id ) was s e p a ra te d ( + ) and ( - ) a lk a lin e

isom ers by c o n t r o lle d

a c id ific a tio n

s o lu t io n w it h m in e r a l a c id .

in t o

o f an

The p ro d u c ts

( a c id s

and th e c o rre s p o n d in g la c t o n e s ) w ere a lm o s t o p t i c a l l y p u r e .

1 59

as shown h y com parison o f t h e i r s p e c i f i c r o t a t i o n w i t h those o f the o p t i c a l l y p u re specimens.

The l a t t e r w e re

o b ta in e d by r e s o lu t io n o f ( ± ) - y - h y d r o x y - / - p h e n y l - n v a l e r i c a c id . 5.

( - ) - M e n t h y l b ro m o a c e ta te was p r e p a r e d . m e t r ic r e a c t i o n o c c u rre d when i t

was t r e a t e d w i t h a c e to -

phenone and z in c (R e fo rm a ts k y r e a c t i o n ) . p u r ity

o f th e p - h y d r o x y -a c id ,

An asym­

The o p t ic a l

o b ta in e d by h y d r o ly s is o f

th e h y d r o x y - e s t e r , was found t o be re m a rk a b ly c o n s ta n t and in d e p e n d e n t o f th e c o n d itio n s used f o r th e

r e a c t io n .

C o n tr o l e x p e rim e n ts u s in g th e same e s t e r and d i - i s o b u t y l k e to n e , or th e same k e to n e and e t h y l b ro m o a c e ta te r e s p e c tiv e ly ,

gave p ro d u c ts w h ic h ,

n o t e x h ib it o p tic a l 6.

T h e o rie s

a f t e r h y d r o ly s is d id

a c tiv ity .

o f asym m etric s y n th e s is

an e x p la n a t io n o f th e r e s u lt s t i o n s u g g e s te d .

a re d is c u s s e d and

o b ta in e d i n t h i s

in v e s tig a ­

REPERSNC3S

160

X . RBFERHNCBS Abraham , E .P . , M owat, S .L .R . , and S m ith , J .C * J . Chem. Soc. , 9 4 8 . A lb e r t s o n , N .P .

( 1901) .

A rb u s o v , A. Aschan, 0 .

(1 9 4 8 ).

(1 9 1 3 ).

B a l f e , M .P .

J . Amer. Chem. S e e ., JgO, 66 9 .

J. p r a k t.

B ergm ann, B.

Chem .,

(ii),

54 6.

B e r . , 4 6 ,' 21 6 2.

and Kenyon, J .

B e n t le y , W.H.

(1 9 3 7 ).

( 1 9 4 2 ).

Anru

(1 896) .

and P e r k in , ¥ .H . and H a r t r o t t , R .J .

J.

(1 9 3 5 ).

126.

Rep. ,

J.

Chem. Soc. , 6^ 1 510. Chem. Soc. ,1 218 .

B e t t i , M. and Luc c h i , E . ( 1 9 4 0 ) , B o l l . s c i . , f a c o l t a in d . B o lo g n a , No 1 - 2 , 2. c f . Chem. A b s tra c ts , 1940, 2354 . B l a i s e , B .B .

and K o e h le r , A.

( l 9 1 0 ).

B o n n e r, W.A. ,

( 1947) ,

Boorman, B .J .

and L in s te a d , R .P .

B ro kaw , G .Y .

andB ro d e , ¥ .R .

C a m p b e ll, A .

and Kenyon, J . (l 9 4 7 ).

J. Amer.

C aso n , J .

(1947).

C ason , J.

and P r o u t, P .S .

B u ll.

Soc.

Chem. Soc. ,

chim . ( i v ) , I , 215. 183.

( l 9 3 3 ) . J. Chem. Soc. , 577 , ( 1 9 3 5 ) . J . Chem. Soc. , 258 ,

(1 9 4 8 ).

J. J.

O rg. Chem ., 1_^, 1 94 , Chem. S o c ., 4 3 6 .

Chem. Rev. , W , 1 5 . (1 9 4 4 ).

C h r is t o p h e r , H. and H i l d i t c h , T .P .

J . Am er. (l 9 1 2 ).

Chem. S o c ., 6 6 , 46. J.

Chem. Soc. , 101 , 2 0 2 .

C h u i t , P . , B o e ls in g , P . , H a u s s e r, J . and M a le t , G. H e lv . Chim. A c ta . 10 7 4 . C ia m ic ia n , G .L .

Cohen, J.B.

chim .

and S i l b a , P.

(l 9 1 3 ),

( 1926) ,

B e r . , 4 6 , 3 0 77 .

(19H ). J. Chem. Soc. , 2 2 f 1058 .

161

D e r ic k , C .G .

and H es s, R.W.

(1 9 1 8 ).

J . Amer. Chem, S o c ., W , 537.

R ic h te r , P.

and G u l l y , S . ( 1 8 9 7 ) . B e r . , J O , 2 0 4 7 .

F is c h e r , E.

( 18 9 4 ).

B e r. , 2 J , 31 89.

F is c h e r , E .

(1901 ) .

B e r . , J 4 , 629 .

F i t t i n g , R. and W o l f f , L . ( 1 8 8 3 ) . A n n a le n , 2 1 6 . 127. ^ G l'^ z e r , J and T 'lr n e r , F .E . ( 1 9 4 9 ) , -J. Chem. 9oo, 3169. ( G la s s to n e , 8 . ( l 9 4 0 ). T e x t-b o o k o f P h y s ic a l C h e m is try . ^ M a c M illa n & Co. L t d . , p. 1 3 8 . G r ig n a r d , V. ( 1 9 0 2 ) . C o m p t.ren d . 3 3 5 , 627 . H a rra d e n o e , R .H . and L io n s , F . ( 1 9 3 9 ) . J . P ro c . Roy. Soc. N .S . W a le s , %2, 2 3 3 . o f . Chem. A b s t r a c t s , 1 9 3 9 , J l , 58 55 . H a w o rth , W .N. H e n r i, V. H ill, H ills ,

J.W .

and P e r k in , W .H.

and F ro m ag eo t, C. ( 1930 ) .

(l 9 0 8 ).

J.

(1 9 2 5 ). B u ll.

21>

Soc.

chim . 845.

U,

J . Amer. Chem. Soc. , J 2 , 4 1 1 0 .

H . J .W ., Kenyon, J . and P h i l l i p s , J . Chem. Soc. 576.

H o p f f, H.

Chem. Soc. 5 7 3.

H.

(1 9 3 6 ).

and Rapp. W. ( 1 9 4 2 ) . U .S .? . 2 ,2 6 5 ,1 65 . A b s tra c ts , 1 942, 1 6l 4.

H u ssey, A ,S .

and Newman, M .S .

( l 9 4 8 ).

c f.

J . Amer. Chem. S o c ., 2 0 , 3 0 24 .

I d d l e s , H .A . , Low , A.W. , R osen, B .D . and H a r t , R .T . In d . Bng. Chem. [ A n a l. ] , 1_1_, 1 0 2 . J a m is o n , M.M.

and T u r n e r , 3 .E .

(l 941 ) .

6^,

and D r ik o s , G.

(1 9 3 3 ).

(1 9 3 9 ) .

J . Chem. Soc. , 53 8.

Johnson, W .S. , P e te r s e n , J.W . and S c h n e id e r, W .P. J . Amer. Chem. Soc. , 74. K a ra g u n is , C.

Chem.

(1 9 4 7 ).

N a tu r e , 1 J 2 , 3 5 4 ,

Kauzmann, W .J . , W a lt e r , J .S . and B y r in g , H. Rev. , 2 6 , 339 .

(1 9 4 0 ).

Chem.

Kenyon, J. and Partridge, S.M. (1936), J. Chem. Soc. , 1313.

162

K L o e tz e l, M .C .

( 1 9 4 0 ).

J . Amer. Chem. S o c .,

( 1 9 3 4 ) . A nna^en, 5 0 9 . 2 59 .

Komppa, G-. and R o h m a n n , ¥ . Kon, G .A .R . K o rtlim , G.

and M ay, 0 . J . ,

1708.

(1927).

J.

Chem. Soc. , 1 5 4 9 .

( 1 9 3 2 ) . *^Neaere Porschungen uher d ie o p tis c h e A k t i v i t a t chem ischer M o le k u le n ’*, S t u t t g a r t .

K b tz , A . , B lend erm ann , K. , M a h n e rt, P. and Rosenhusch, R. ( 19 1 3 ) . A n n a le n , 4 0 0 . 7 2 . K ra fft,

( 1896) .

P.

B e r. ,

2232.

( 1929).

Kuhn, W.

and B rau n , E.

Kuhn, W.

and K n o p f, E." ( l 9 3 0 ). N a tu r w is s . , 1_8, 1 8 3 . p h y s ik . Chem. J B , 29 2,

L e a s e , E .J .

N a t u r w is s .,

and M c E lv a in , S .M .

(1 9 3 3 ).

227.

J . Amer.

Z.

Chem. Soc. ,

806 L ip k in ,

D.

and S t e w a r t ,

T .D .

( l 9 3 9 ).

J . A m er.

.

Chem. S o c . ,

6i, 3295. L i p p , A. L u k e s , R.

( 1896) .

A n n a le n , 2 8 9 . 1 7 3 .

and Go ro c h o l in s k y , J . ( l 9 3 6 ) . C o ll e c t i o n C z e c h o s la v . chem. C o m m u n ic a tio n s , 8 , c f . Chem. A b s t r a c t s , _20, 5989.

J . Amer. Chem. Soc. , 6 8 , 832 .

M cK en n is, H.

and V ig n e a u d , V.

(1 9 4 6 ).

M c K e n z ie , A.

(1904).

J.

Chem.

Soc. , 8 5 , 1 2 4 9 .

M c K e n zie , A.

( 1905) .

J.

Chem.

Soc. , 8%, 1 3 7 3 .

M c K e n z ie , A.

(1906 ) . J .

M c K e n zie , A.

and W ren, H. (19 06 ) .

M c K e n zie , A.

and C lo u g h , G.W.

M c K e n z ie , A.

and C h r is t i^ .W ( 1 9 3 4 ). J?Ch,em. Soq . , . 1070 .

M c K e n zie , A.

and C h ris tie ,E .W .

M c K e n z ie , â .

and M i t c h e l l ,

8^,

Chem. SÔC. , J.

( 191 0 ) .

A .G .

223 .

36 5 .

Chem. Soc. , 8 2 , 6 8 8 . J.

Chem.

Biochem .

Soc. , 11 7 , 1016.

Z. , 2 7 7 , 4 2 6 .

( 1 9 2 9 ) . Biochem .

Z. , 208, 476.

163

M c K e n zie , A .

and M u l l e r , H .A .

(1 9 C 9 ).

J.

Chem. S o c ., 9 5 , 544.

M c K e n z ie , A.

and R i t c h i e , P .D .

(l9 3 la ).

Biochem.

Z. , 2^1, 412.

M c K e n z ie , A / and R i t c h i e , P .D .

(l9 3 ll> ).

Biochem.

Z. ,

. .

232 1 M c K e n z ie , A. M a n n ic h , C.

and R i t c h i e , P .D .

(1 9 3 2 ).

and F o u rn eau , J .P .

(1 9 3 8 ).

M a rc k w a ld , W.

( 1 9 0 4 ) . B e r. ,

M a y e r, F .

and Stamm, G.

M e y e r, H.

( l 901 ) .

M ic h a e l, A.

Biochem . B e r. ,

Z. , 2 3 0 > 376. 209 0 .

349.

( l 9 2 3 ).

B e r. , _^6, 1 4 2 4 .

Monatsch. , 2 2 , 4l 5.

and R o s s , J.

( 1 931 ) .

J . Amer.

Chem. S o c ., 5 3 , 11 5 0.

M i l a s , N .A . , M acD on ald , N .S . and B la c k , D.M . ( l 9 4 8 ). J . Amer. Chem. Soc. , %0, 1 8 2 9 . M ü l l e r , A.

and K ra u s s , P.

M y d d le tc n , ¥ ,W . N a v e s , Y.

and B a r r e t t , A.\T. Soc. 42^ 2 2 5 8 .

( l 9 4 8 ).

P a r t r i d g e , S .M , P e r k in , W .H . P o l g a r , N.

(1 9 3 2 ). M o n a ts c h ., ( l9 2 ? ).

H e lv . Chim. A c ta .

(l 9 3 9 ).

( 1890).

J.

J.

Chem.

J . Amer.

Chem.

151.

Soc. 1 2 0 1 .

Chem. S o c . , ^ ,

and R o h in so n , R.

206.

(1 9 4 5 ).

J.

204. Chem.

Soc. , 389 .

R i t c h i e , P .D .

( l9 3 3 a ) . A sym m etric S y n th e s is and A sym m etric In d u c t io n ; O x fo rd U n iv e r s i t y P r e s s , p . 1 1 0 .

R itc h ie * , P .D .

(l9 3 3 t).

R itc h ie ,

(l 9 4 7 ). Advances i n S n zym o log y, V I I . 6 5 .

P .D .

R o h in s o n , R.

- " -

and S l a t e r , 8 .N .

R o g e r , R. ( 1 9 3 7 ) .

J.

Chem.

( l 941 ) .

Soc. , 1048 .

p. 1 2 6

J.

Chem. Soc. ,3 7 6 .

164-

R o g e r, R.

(1 9 3 9 ).

R o g e r, R.

and R i t c h i e ,

R u z ic k a , L .

J.

Chenu S o c ., 1 0 8 .

(l 91 7 ) .

P .D .

( 1 9 3 2 ) . Biochem.

Z. , 2 5 3 > 2 3 9.

B e r. , ^ 0 , 1 3 6 2 .

R u z ic k a , L . , S e id e l, O .P. , S c h in z , H. and P f e i f f e r , M. (1 9 4 -8 ). H e lv . Chim. A ct a , j l , 4 2 2 . R u z ic k a , L .

and S t o l l ,

van R y s s e lB e rg e , M.

M.

(l 9 2 7 ).

(1 9 2 6 ).

B u ll .

S h e r r i l l , M .L . and S m ith , J .C . S m ile a , S.

(l9 0 5 ).

J.

H e lv .

Soc. Chim. B e lg .

( l9 3 7 ) .

Chenu Soc. ,

Chinu A c ta , 1 0 ,6 9 1 .

Q J,

J.

3 11 .

Chenu S o c ., 1 5 0 1 .

450.

S o lo w ay, S .B .

a n d L a P o r g e , P .B .

(l 9 4 7 ) , J . Amer. Chem. Soc. , 2 24 4.

T a r b e l l , D .S .

and P a u ls o n , M .C .

(l 9 4 2 ).

J . Amer. Chem. Soc. 6 4 , 28 42 .

u.

T a te v o s y k , G .T . , M e lik y a n , M. I . and T u te r y a n , M. G. ^ ( 1 9 4 6 ) . B u l l . A rm enian B ranch Acad. Sc. U .S .S .R . 1 9 4 4 , No. 3 7 . c f . Chem. A b s t r a c t s , 1 9 4 6 , 4 g , 3398. T if f e n e a u , M. and L e v y , J .

( l 9 2 7 ).

B u ll.

Soc.

chim . , 41 ,1 3 5 1 .

T iffe n e a u , M ., L e v y , J.

and D i t z , B.

( 1 931 ) .

Compt. re n d . 1 9 2 , 955.

T i f f e n e a u , M. , L e v y , J . chim. ,

and D i t z , B. 1848, 1855.

( l 9 3 5 ). B u l l .

Soc.

T r ie b s , W ., 1 9 4 4 . A n n a le n , 5 5 6 , 1 0 . T r iv e d i,

J .J .

T u rn e r, B .B .

and N argund, K .S . and H a r r i s , M.M.

V a v o n , G. , R i v i e r e , C . , V avo n , G.

and A n g e lo , B.

V b r la n d e r , D.

(l9 4 l).

(l9 4 7 ).

and A n g e lo , B. (1 9 4 7 ).

( l 8 9 7 ) , A n n a le n ,

J.

U n iv . Bombay, IQ , 102.

29 9 .

Q u a rt. Rev. , 1 ,

( 1 9 4 6 ) , Compt. re n d . , 2 2 2 959

Compt.

2 9 4 , 253 ,

,

ren d. , 2 2 4 , 1 4 3 5 .

.

165

V /a lla c h , 0 ,

( 1 9 0 5 ) . A nnalen, 3 2 9 . 368. (1 9 0 8 ). " 152» 287.

28, 1 4A8.

W e la n d e r, E .

(1 8 9 5 ). B e r . ,

de W ild e , P .

( l 86 A ) , A n n a le n , 1 J 2 , 1 71 .