T H E S E .N c C I 0 A L K A L 0 I D S

The correlation of structures with particular

reference to senecic acid and tts lsomerso

By

Giovanni. Parazzt, B.Sc.(Gen.Hons.)London.

l\ thesis presented to The Unlversi. ty of Cape Town

tn parttal fulftlment of the requtrements for the

degree of Master of Sci.ence.

Department of Chemtstryp

University of Cape Town,

CoS.IcR. Natural Products Research Uni.tp

C.&.f:.ILJ OWN.

1967.

The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non-commercial research purposes only.

Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author.

The author wtshes to express hts slncere

thanks to~-

Professor F. L. Warren for hls tnvaLuabLe

gui..da:nce and encouragement ln thls work.

Mrs. G. Y. Merchant for the mlcro-analysls.

~~s. J. Oates for typlng and stencllllng

the formulae ln thts thesls.

The C 0 S. I c R. for thelr rGsearch grant wh tch

made thts work posslble.

~-·-Q. .. lLI.J: .. .NJ2

f.. a~§

SU~_N/"RY • • •• •• 0 • ("' t.;

1 0 INTRODUCTION •• • • . . 1.

a) The alkaloid structure 0 • • • 1 •

b) The C 10 adipic or "neci..c 11 acids •• 1.

c) Attempts to correlate the stereo ... chemistry of the acids •• • • 2.

2. DISCUSSION • 0 • • •• • • 10 •

a) Present studi..es •• • • • • 10.

b) Conclusion . . " . • • • • 23 •

3. EXPERIJviEl\ITAL • • 0 • • • •• 28.

1) Extraction of retrorsine from Sene~J .. Q LS.~~-t,.Ldeus ·• . • • • • 28.

2) Hydrolysi..s of retrorsi..ne D 0 • • 29.

3) Preparation of sodium tsa t i..neca te from bari..um is at i..necate • • 0 • 29.

4) Methylati..on of sodi..um lsati..necate wlth methyl Lodi.de ... • • 29

5) Preparatlon of dlmethyl lsati..necate using sU.ver l sat i.. nee ate and methyl.. lodi..de • • . . " . •• 30.

6) Trans-esteriflcation of retrorstne uslng methyl alcohol • • •• 31.

7) Oxi..dation of dimethyl isatinecate using sodium periodate • • •• 32.

8) Reaction of oxidLsed dimethyl isati.necate wtth methyl magnestum iodide • • 32.

9)

10)

Chromatography of the above mixture

Preparation of barium senecate from dimethyl senecate •• ...

Hydrolysis of barium senecate

. .. • •

_!'a g.~ 33.

11)

12) Sublimation of senecic acid and isomers

35.

35.

36.

13)

14)

15)

16)

17)

18)

19)

20)

21)

APPENDIX

APPE.NDIX

/,PPE.NDIX

APPENDIX

Oxidation of senecic acid and isomers with lead tetra-acetate •• ••

Alcoholic potassium hydroxide hydrolysis of retrorsine • • . . Isolation of the retronectc actd

Oxidation of retronecic aicd ...

Reaction of oxidised retronectc acid wtth methyl magnestum lodtde

Oxidation of retrorsine • •

Reaction of cyclic keto ester with methyl magnesium iodide ••

Chromatography of the above reactior:,

The Grignard apparatus • •

L • e • • . . . . .. II. .. I II. 0 •

IV. .. • 0 . . . . . .

. . • e

• •

• •

. .

• •

APPE.!'miX V. • • • • 0 •

BI BLI OGRAPh'Y . . . . . . •• . .

36.

38 •

38

38.

39.

4L

41

46.

47.

48.

49.

so.

5L

SUMMARY

Seneclc and lntegerrlneclc acld have been

asslgned structures (A) and (B) on the basts of

degradation reactions and X-ray studies.

H CH H COOH OH I ~ / 1 ,,-'

CH3C\ C --· C \\ / \

C-CH CH I 2 -3

CH3

CH3

H COOH OH

I ' / ' ,.-·" H-C C---C

\_fH \ I 2 CH3

HOCC HOCC

(A) (B)

Seneclc acid Integerrtnectc actd

Two tsomers artsep namely; platynecic and

usaramoensenectc actd and are reported in the literature.

Thetr structure as tsomers of (A) and (B) have been

speculated.

Thls thesis ts concerned with a study of the

isomers of (A) and (B) and leads to the concluston

that platynecic and usaramoensenecic actd do not

exlst and are probably mixtures.

(t)

The procedure for this study tnvolved the

oxtdatlon of tsatineclc (C) and retroneclc (D) acids

and of their esters to the keto derivative (E) and

a Grtgnard reaction to give (F) whtch can be one

of the isomers of (A) and (B).

CH3

.CH::C .CH2 .CH(CH3

) .C ( OH) .CH3 . I f

COOH COOH

(A) cts form

(B) trans form

CH3.CH4.CH2 .CH(CH3 ).1(0H).CH3 JC-(-· _

COOH COOH

(F)

(C) ill form

(D) trans form

keto acld

(E)

(tt)

I N T R 0 D U C T I 0 N

INTRODUCTION

a) The alkaloid structure.

The Senecio alkaloids, in general, comprise a group

of basic substances which have a methyl-pyrrollzidtne

nucleus with one or more hydroxyl grouptngs estertfted

by organic acids. The acids are obtained from the

1.

alkaloid by hydrolysis or hydrogenolysts and can be

classified tnto three groups, i· ~· : ( 1) c10 adipic or

nneclc" acids.

ti) The c10 adtptc or 11 nectc 11 acids.

(2) Glutaric acids.

{3) c7 actds.

The 11 neci..c 11 acids are terpenic: aci..ds, as was ori..ginally

suggested by Barger in 1936 and later proved by Kropman

and Warren(!) who also showed that four of these acids

had the same t~regular isopreme skeleton:

c·-c-c-c 1 c

c t -c-c-c

J c

(!)

The general formula for these four actds is as

follows:-

CH3-ctLi-cH2-cH(CH3 )i(OH).CH2x- (II)

COOH COOH

where X = OH in Isatinecic acid (ill)

Retronect.c acid (trans)

X: = H in Senecic acid (cis)

Integerrtneci..c acid (trans)

Two more aci..ds have also been claimed to have the

same general structure and formula as senectc acid:

usaramoensenectc( 2 ) and platynecic acid( 3).

These latter acids have not been re-tsolated and

2.

were not reported tn the synthesis of senecic aci..d carried

out by Cutvenor and Geissman( 4 ). A study of the formula

(II) shows that there are two asymmetric carbon centres

and a pair of double bonds within the same carbon skeleton

and this can give rise to eight isomers. The author

;;r has accordingly attempted to correlate the stereo-chemical

relationship of these acids containing this uniform

structure.

c-) Attempts to correlate the stereo-chemistry of these

aci..ds.

Isati..nectc and retronecic acids were shown by Chri..stte,

Kropman and Warren( 5 ) to be~- and trans-1:2-dthydroxy-

3-methylhept-5-ene-2:5-dtcarboxyttc acids respectively,

with the geometric isomerism about the double bond gtvtng

ri..se to the two acids.

Senecic acid, which occurs in a number of alkaloids

as shovm on Table I, was analysed by Kropman and Warren( 6 )

who showed that it was a 2-hydroxy-3-methyl-5-ene-2 :5- •

dtcarboxylic acid. The lactone of senectc actd, as

demonstrated by Kropman and \'larr~n ( 7 ), gave the !f_g_l]§.­

senecic acid whtch was identified as tntegerrinectc acid

obtained by Hanske(s). The geometricaL tsomertsm of

senectc actd and integerrtnectc actd thus parallels that

found for tsatinectc and retroneclc actds.

Table Ic Occurences of Senectc acid.

1 Alkalotd ,______ ------1 Platyphylllne

l Base J----------·-------···--

Seneclc or

Actd IRef._J 25 26 : Platynectne

Platynectc acld 3

Rosmartnlne Rosmartnectne Seneclc actd !27 28

Renardtne Otoneclne Senecic acLd 29

Senecionlne Retronectne SenecLc acid 30 31

? Seneclc acid i 32 I

lNeoptatyphyttlne I Ptatyneclne----~-----­lactone I Isomers of 133

1 s . acid I ! enectc ! _________ ,.... .. __ Culvenor and Geissman( 4 ) synthesized tntegerrinecic

and senecic acid as shown on Chart I, and in dotng so

showed the absolute geometry of the compounds tn the ltght

of X-ray studies recently performed by Fridrtchson( 9).

3.

. C

H3

.CH

(OO

:.C

H3

).C

=C

H

......

CH

3.C

H( 0

0: .

CH

3)

.C (C

OO

H):

=CH

2

t <;:

:H3

.CH

:=C

(C

OO

H)

.CH

2 .C

H(C

H3

) .C

O. C

H3

<

CH

3.C

H:=

C (

CO

OC

H3

) .C

H2

• C{

C0

0: 2

H5

) (C

H3

) .C

O. C

H3

l 'l

H 'c

/ C

H3

/CH

2.C

H(C

H3

) .C

O.C

H3

= c

'-co

oH

(-

)-"cis

"-k

eto

acld

t (-

)-"cts

"-k

eto

acid

H '

/ C

H3

c

i ~H

3 H

/ C

H2

-C

:;-

__ ,

CO

OH

C

H3--

= C

C

-C

H ~

C

"-

I 3~

/ C

OO

H

OH

H

il CH

)i

~-

H~

CH

2-

C~

CO

OH

/

' ,-

c· =

c

c /

CH

~.

'-co

-0

/

""-,.

CH

3

3

......

7

C~3

/CH

2.C

H(C

H3

).C

O.C

H3

c =

c

/ '

H

CO

OH

(±)-

" tr

an

s"-k

eto

acid

!cy

an

hy

dri

n

hy

dro

Ly

sis

reso

Lu

tio

n

. .

CH

3 .,

H

/C

H2-

t(

,,C

OO

H

= c

c,

""-.

CO

-0

/

""-.

CH

3

CH

3....

.._C

H/

H

CH

'-.

.. I

3 C

H2--

C

CH

3 /

'\.

,--

= C

C

"

""-.

/ -..

...._

C O

OH

C

O--

0

Ch

art

I.

Th

e C

ulv

en

or-

Geis

sman

S

yn

thesis

&

In

terc

on

vers

ion

s

of

Sen

ecic

an

d

Inte

gerr

inectc

A

cld

s.

~ .

Further studies of these 11 necic actds 11 have shown

that tn the U.Vo spectra nOt only wasA x for the s::,ts ma •

form (215 ~) less than that of the trans acid (218 ~u),

but the E of the former was approxtmately half that max.

of the latter.

Degradation of isatinecic acid and senecic acid to

(+)-methyl-succtnic acld(lO) established the conftguration

of the asymmetrtc carbon c( 3 ). The fact that lactone

formation does not tnvolve c( 3 ) led Adams to conclude that

this asymmetrlc carbon atom in retronectc and lntegerrl-

necic actds also remained unchanged. Further evldence

of thts was shown by the di lactone of hygrophyll inec ·_c

acid discovered by Richardson, Warren(ll) and Schlosser( 12 )

whtch has the same carbon skeleton as senectc acid and

here again the c 3 is not affected during lactoni.zatio~.

Usaramoenstnectc acld from the Crotolari~ alkalold

discovered by Adams and van Duuren( 13 ) was found to be

lsomeric with senecic and integerrLnecLc acLd and like

senecLc acid gave Lntegerrinecic acid lactone. U. V o stud 'i.. e c

on the acid showed a maxtmum absorption at 215 ~ which

was similar to that of senecic aci.d for which the cis

configuration was assigned.

Since senectc, tntegerrlnectc and usaramoens~necic

aCids give the same lactone, t. ~· tntegerrtnecic acid

lactone, Adams concluded that the isomerism ts not assoctatod

wtth the asymmetry at c( 3 ) but more probably wtth the

c(2 ). Hence Adams and co-workers showed that structure

(II) (page 1.) can exist in three stereoisomeric forms

6.

which can be wrttten showing the absolute configuration at

c( 3) (proved by formation of (+)-methyl-succinic acid).

Another acid found by Danilova and Konolova( 3 ) called

platynecic acld (obtained by alk:1linc hydrolysls of the

alkaloid platyphylllne) has shown to be isomeric wlth

senecic aci..d and lactonized to tntegerrinecic acid lactone

and has been clained to be the fourth member of this group.

Adams and co-workers( 13) suggested that slnce senecic

and usaramoens~necic acids are both £1[ and both undergo

a change in configuration at the double bond to give the

stable trans form of the lactone on treatment with the acid

or alkali~ it was suggested that the difference between

the two acids must be due to the configuration at c( 2 ).

Furthermore Adams stated that in tntegerrinecic acid

the c(2) will have lts hydroxyl group cis to the lactonlzlng

carboxyl since the acid and the lactone are lnterconvertable.

In the other two acids the hydroxyl of the c( 2 ) may be

c~ or trans with inversion taking place tn one of these

acids during lactonization. The author regards these

terms ~ and trans as very misleading and proposes to

name the acids using the absolute configuration method

according to Cahn~ Ingold and Prelog(l 4 ).

7.

The structure of the acids as given by Adams is shown

tn Chart II. Hence, the work of Adams and van Duuren

seems to be the only mention of the asymmetry at c( 2 )

since tt was necessary to use Lt to exptaLn the retationshlp

of usaramoensenectc 9 senecLc, and lntegerrlnectc actd.

a.

OLd nomenclature

New nomencLature

trans-c is·-lntegerrlnec Lc ac Ld

trans-(2R,3R] Lntegerrlnectc acid

O.N. trans,trans~platynecLc acld

N.N. trans [2s ,3R] pta tyneclc acid *

O.N. cls,trans~senecLc acld

N.N. cis [2R,3R] senecLc acld

O.N. cts,cts usaramoensenecic ~cid

N.N. : ill [2S,3R] usaramoensenecic acid *

Chart I I. The StructuraL ReLationship of Integerrt-

neclc, PLatyneclc and Usaramoen-

seneci..c aci..ds.

The term cis and trans refers to angeLic and

tigltc acid nomenclature and has been retained.

It ts acknowledged that the I.U.P.A.C. rules

wouLd dictate the interchange of these terms

cis a_nd trans.

9.

D I S C U S S I 0 N

" \'

DISCUSS I ONo

No attempt has yet been made to conftrm that the

actds shown Ln Chart II dtffer at the c( 2 ) cen~re.

The author has set out to do this by converting

Lsattnectc actd (£1~.) to senecic (c~~) since the

absolute configurations at c( 3 ) in tsattnecic acld and

senec Lc ac Ld are known to be the same.

The investtgatton had as lts objecttve the

converston not only to senecic acid but also the ,., synthests and structure of usaramoensenectc and

platyneci..c acido

The conversion was performedp as shown ln Chart

III 9 by oxidati..on of di..rflethyl i..ss.tinecate (III)

followed by a Grignard reactton on the rc:sulttng keto

acid (IV) produc i..ng dimethyl stnecate and its isomers

(V) and the final hydrolysi..s to yleld a mtxture of

senecic acid and i..ts isomers (VI).

The esters of the acid were used because the

author wtshed to keep the reaction product in solution

during the Gri..gnard reaction si..nce tt was feared that

the magneslum salt of the acid would be Lnsoluble.

Although the Gri..gnard addition should have been

stereochemi..cally di..rected there should be a small

10.

11.

CH3.CH=1•CH2.CH(CH3 ).1( OH).CH2• OH (III)

COOCH3 COOCH3

Na104

CH3

.Cn::C .cH2 .CH(CH3

) .C:O I I

COOCH3 COCCH3

(IV)

Grlgnard

(V)

Hydrolysts

CH3CHl·. CH2 • CH ( CH3 ) ·1 ( OH). CH3 (VI) COOH COOH

Chart III. - Converston of Isatlnectc Actd to Seneclc

Aclcl.

quantlty of the second acid formed, that i.s its

diastereoisomer.

The inttlal problem was to find a method whtch

would give a good yield of dimethyl tsatinecate, as

shown in Chart IV, (VI I; R = CH3) since the known (15)

method according to Reimer and Downes , where a

trans-esterification starttng wtth retrorsi.ne (VIII)

ts done directly on the alkaloid with methyl alcohol,

only gtves a 6o% yield.

(VI I)

12.

(VIII)

Chart IVo - The Preparation of Dimethyl Isattnecate.

13.

Hence sodium isatinecate (VII; R = Na) was

methylated wtth methyl iodide; but the yield was low

approximating to lo%. Attempts to use silver isatinecate

(VII; R = Ag), formed from barium isatinecate and silver

nitrate, had to be carrted out ln the dark and methylation

using methyl iodide gave an oily product which did not

have a definite boiling point. In fact thin layer

chromatography reve:.led a mixtu:t'.J of of stx compounds,

some of the latter probably being decomposition

products brought about by silver oxide. The author

eventually used the Reiner and Downes trans-esteri­

ftca t ton method: (VII) ---=»(VI I; R = CH3 ).

The freshly prepared dimethyl tsatinecate was

treated wtth sodium periodate tn an aliquot mixture

of water and dioxan. This oxidation was instantaneous

and quantitative; but the newly formed keto-ester

had to be extracted within four minutes. Experiments

showed that decomposition took place after four minutes

and after elght JT.lr,utes only a 70% yieJ_d' could be

obtained~ but thls remained constant even after three

hours. The keto-ester was obtained as an optically

active oil indicattoc that no racemlsatlon had yet

taken place.

The Grlgnard reaction which followed was

performed using the apparatus shown on Fig. I, page 44

The Grignard reagent was first prepared nnd added

to an etheral solution of keto-ester 9 in order

to avoid excess of the Grtgnard reagent being present

at any ttme during the reaction. Thi..s procedure

was adopted to avoid excess reagent acting on the

ester groupings.

Thi..n layer chromatography of the product produced

four spots. The mixture was separated by column

chromatography using neutral alumi..na and one of the

four bands yielded a colourless optically inactive

oil which was dimethyl senecate and its isomers.

Crystallisation from benzene yi..elded crystals

which did not have a definite melting point and were

optically inactive. The mixture of isomers could

not be separated with thin layer or paper chromatography.

With paper chromatography a variety of systems were

used but all resulted in streaks being produced.

Slow sublimation under reduced pressure effected

no separation as shown by the infra-red spectrum:

that of the sublimed product was identical with that

of the residue as shown on appendix I~ page 46.

The mixture was then oxidlsed with Lead tetra-

acetate to form a new oily optically inactive keto

acid, as shown on Chart V. (X). Thi..s oxidation was

first carried out by Warren and Kropman(l 6 ) on seneclc

actd and later by Culvenor and Gelssman( 4 ) durtng thetr

synthesis of senectc and tntegerrtnectc actds.

cts(z)-keto acld

J H:l

/

~~~(±)-keto actd

Chart V. - The Lead Tetra-acetate Oxtdatton of

Senectc Aci..d.

15.

The 2,4-dini..trophenylhydrazi..ne derivati..ve of

thts compound had a lower melti..ng potnt than that

quoted by Culvenor and Getssman( 4 ). This led

the author to suspect that some of the tra~ form

of the keto acid might have been present. To test

this assumption the keto acid was then converted to

the trans form by treating it with concentrated

hydrochloric acid when crystals of the !!P~ keto

acid~ m. p. 47 - 50°, were obtained whose 0 2,4-dlnitrophenylhydrazine derivative, m. p. 145 9

had the same melting point as the trans derivative~

m. p. 145°, reported by Culvenor and Geissman( 4 ).

Hence the ottgtnal possibility was confirmed 1 namely

that a mixture of cis and trans dl and d 9 t' of the

acids had been obtalned during converslon.

These results clearly demonstrated that Cram's

rule( 1?) cannot be applied directly to predict the

configuration of the resulting product because

had Cram's rule been applicable then~ as shown on

Chart VI, oxidised dlmethyl isattnecate (XI) should

have given (+)-dimethyl senecate (XII) on reacting

with methyl magnesi..um lodldc.

16.

(XI) (XI I)

Chart VI. Grtgnard Reaction on Di.methyl Isatineaate

It ls also of interest that the oxidatlon of senecic

actd (XIIIa) can~ied out by Schlosser(lS), as shown

on Chart VII, to the keto acid (XIV) and the addition

of hydrogen cyanide to give (XVI) followed by . .

hydrotys is gave integerrlnectc acid (XI IIb) whtch ts

contrary to Cram's rule whtch would predtct (XV).

It is dtfficutt to understand the stereospectfic

addttton to (XIV) not following Cram' rule. The

addition of the Grignard reagent, however, to oxtdtsed

d lmethyl is at lnec ate (XI) gave a mtxture of products

whtch could well have been res1..1.lted from racemisatton

and the more rc:·.ndom adci tion of the carbonyl carbon.

It i.s of s ignL fics,nce that for hts lnvest tga t ions

Cram( 17 ) deliberately chose a system containing no groups

on C( 1 ) capable of gtving complexes wt th the reagent

tnvolved tn the production of asyrrunetry at c( 2 ). In

the presence of such a group, e. g., ln the alumtnlum

alkoxtde reductlon of Ar.CO(.NHR).cH2 .0!-I, ti1e sterlc

17.

18:. CH H "3, /

C. . CH3

H COOH .OH II ~ ,/ \ , .. , .... c c---c

HOCC./ "CH( \ CH3

Senectc acld - (XIIIa) Integerrlneclc aci.d - (XIIIb)

l 1 c~ ,H /.o c~ c./" ----~'

/. """ 7 R . CH

3.

.CH3 .H CN OH " '/, c'-''---c. /. "" R ~CH . 3

(XIV) (XVI)

CH H OH CN 3 ~ ' ~ ,/ "' ,,'

. . ~l.-. __ ...__ c . / .. , '• \

R · (, ..• .,. · ··· CH .3

CH3 ,H OH COOH

~ / "" ~,' c----c R/ \CH

3

, (XIVa) (XV)

Chart VII. - Posstbte modes of addi. tton to the methyL­

ketone ester obtalned from the oxtdatton of

di.methyt senecate: accordtng to Cram's Rute,

(XIV)~(XIVa)~(XV); accordtng to expertment,

(XIV)--+ (XVI) --4 (XIIIb).

course of the reaction appears to be determined by

the free terminal. hydroxyl.. group.

In the exampLe under discussion we undoubtedly

have the keto group flanked on both sides wtth steric

control L i..ng groups$ as shown on (XVI I).

(XVII)

Another attempt was carried out 1 this time on

the actd alone$ wtth the hope that the absence of the

methyl. ester groups would produce a more stgnifi..cant

resuLt.

Retroneci..c aci..d 6 obtained by the alcohoti..c

potasstum hydroxi..de hydl~otysi..s(lg) method from

retrorstne was was oxi..dlsed with sodlum peri..odate to

yteld the (+)-keto acid as an oily product. The

reaction was carrled out ln acldlc conditions slnce

racemi..sati..on took place wi..thin minutes at pH 12 or

13 to produce an optically tnacttve mixture. At

pH 1 no racemtsatlon took place. The (+)-keto actd

19.

20.

was reacted wtth methyl.-magnestum i..odLde to produce

a gum~ whi..ch after a considerable amount of dlffi..cutty

formed ftne whi..te needle ltke crystals of tnte-

gerri..nectc actd. The tnfra-red spectrum of these

crystals was tdenti..cat wtth that of lntegerri..nectc

actd from seneclc acid lactone, as shown ln Appendtx II 1

page 47.

The mother llquors 9 from whtch the lntegerrlnectc

actd had been separated 9 could not be tnduced to

crystatttze and rematned as a clear olt 9 analyslng

to that expected for the Grtgnard reaction product 9

C'10H16°s·

The tnvestlgatton on the aclds reported above

parattels work carrted out by Mattocks( 20) tn these

taboratortes: the oxtdatton of retrorslne to the

cycllc keto-ester and the Grtgnard reaction on this

product. The resultlng compound was either the

expected seneclonLne or tsoseneclonlne accordlng to

the experlmental condlti.ons. Seneclontne and

tsoseneclontne v.rere shown to be the retronectne esters

of (+)-senectc and (-)-senectc actds.

The yteLds obtalned by lvlattocks were small and

a considerable amount of material remained unresolved.

In vtew ~f the expertments wtth the aci..ds themseLves

tt was envisaged that the resi..dual material mtght

be a source of the platynect.c and/or usaramoensenecic

ac 'Lds. Hence the author repeated the above experlments

and tt was observed that dur'Lng the Grignard reaction

a yelLowish insolubLe restn was s.Lso formed. The

gum obtained at the end of the expertment was dissolved

tn some ethyl acetate and passed through a column.

Senectone was obtained but no other alkaloid. Hence

the development of the resln was responstble for

Mattock's low yteld and not, as was hoped 9 the formatton

of new alkalolds.

V!ht le the above expertments were tn progress

Hattocks( 2 l) reported that he had extended hts

studtes, started tn these laboratories 9 {see belnvr)

to tnctude the oxtdatlon and Grtgnard reactlon on

tsattnectc acld. He oxldlsed lsattnectc acld wtth

sodlum metaperiodate, under acldic conditions, to

form the (-)-keto acid. Thts was followed by a

Grtgnard reaction and rather unexpectedly the (+)

dlastereotsomer (XIX) of senecic acld (XVI I I) was

obtained as the maln product, as shown on Chart IX.

The new dlastereotsomer has been call.ed dtasenectc

acid. (see Appendix III, page 48).

Dlaseneclc acld was oxldtsed wtth l.ead tetra-

acetate and tt gave the same keto acid (X) as the

21.

22.

Isatlneci.c acld

(-)-keto acld

Grtgnard

CH3.CH CH3 H II "-/ C ~ C ,COOH

. /" ~ "/ HOOC CH2 /C ~ OH

CH 3

Seneci.c acld. Dlaseneci.c actd.

(XVIII) (XIX)

Chart IX. - The Formatlon of Seneclc and Dlaseneclc Aclds.

one obtained by a similar oxidation on seneclc acid

"' (see Chart V ). Hence the two aclds have the same

configuration at c(3)• Furthermore, U. V. studies

performed by the author on dlaseneclc actd showed . that the tatter has a fl .. ~ configuration whlch ls the

same as senecic acld. This means that the senecic

and dlaseneci..c aclds differ only at c( 2 ) as shown

by formulae (XVI II) and (XIX) on Chart IX.

Racemic diaseneclc acid together with seneclc

acid has also been recently synthesized by Edwards

e~ .~ (22).

b) ~nclusi..o_n.

As has been shown above the properties of

dlasenecic acid do not correspond to those of usara-

moensenecic acid. Thus, the latter cannot be a

stereoisomer of senecic acid. The author ts convinced

that usaramoensenecic aci.d does not exist at alt.

Furthermore, Culvenor and Smith( 23 ) recently carried

out a re-investtgatlon on the alk8.loi.ds of £. usara-

!llQ.§..nsj&. This plant was found to contai..n usaramtne

together with i..ntegerrimtne, seneci..onine and retrorslne,

but.no usaramoensine. They suggest that the latter

was a mixture of i..ntegerrlmlne, senectonlne, and

usaramtne. Retronectc acid (from usarami..ne) wotJ.ld

23.

account for the htgh mo p. of 11 usaramoensenec'Lc actd"~

Fi..nally, platynect.c ac'Ld has not been found tn

any of the syntheses and the onl.y actd whtch would flt

tts stereo-chemtcal structure ts .!]:lill§_-(+)-dlasei1ecic

actd. Furthermore~ Lt would appear~ as suggested

by Leonard( 24 ), that thls acld could be a mixture of

tntegerrtnectc ac'Ld and senectc ac'Ld rather than a

pure chemtcal tndividual. Thts vvould explaln more

sattsfactorily the finding that platynectc actd and t

. .

senec 'Lc acld, after abso:cpt lon of two a toms of hydrogen

catalytlcally, are convert'Lble to the same saturated

lacton'Lc acid as obta'Lned from integerrinectc RCld

lactone by catalyt'Lc hydrogenation. Platyneci..c

acld ls probably senectc acid ln the alkalold

platyphylllne.

The isomers of senectc acld are now all known

as shown on page 25.

24.

25.

Isomers of Senectc Actd.

Rl R 2 R3 R4 Rs .ACID - NO MeCH::C,

C02H

(+) senectc cls Me H OH Me (XX)

(-) senectc cls H Me Me OH (XXI)

(+) lntegerri.neclc trans Me H OH Me (XXII)

(-) lntegerri.nectc trans H Me Me OH (XXI I)

(+) dtaseneci.c cls Me H Me OH (XXIV)

(-) di.aseneclc ci.s H Me OH Me (XXV)

(+) trans-di.aseneclc trans Me H Me OH (XXVI)

(-) trans-di.asenectc trans H Me OH Me (XXVII)

26.

H CH3

H COOH OH H H CH OH COOH I ,,/ ,_,., ,. / '/ 3 '/ I CH-C C' c CH-C c c

3. \. I \ 3 '\ / \ C-CH CH

3 C:-. CH2 CH I 2 / I .3

HOOC HOCC

(XX) (XXI)

(+ )-Senectc actd (-)-Seneclc actd

CH3

CH3 H COOH OH

/ ~ /, ' ..-"'"' CH3 H CH3 OH COOH I . \/ '- /

H-e c·--c -~ / \

c~cH CH I 2 3 . HOOC

H-C c-.....,...._-C" ~ / \

C-CH CH3 / 2 HOOC

(XXI I) (XXIII)

{+)~Integerrlnectc acld (-)-Integerrlnectc acld

. 1:I CH3 H OH COOH

I. "" ,/ ·. ' / cH3-c . c--- c . " / \

C-CH CH I 2 - . 3

HOOC

(XXIV)

(+)•Dlaseneclc acld

CH3 CH3 H OH .,COOH I . ~ ,/ '. /

,H-"~ 1c-- .C\

C-CH2 CH3 I . . HOOC

(XXVI)

(+)-trans-Dlasenecic acld

27 •

H H CH3 COOH OH

/ '/ "- / CH-C C----- C . 3 '\ / \

c-· CH CH / 2 3

HOOC

(XXV)

(-)-Dtasenectc acid

CH3 H CH3 COOH OH I '/ ""- __ ,

H-e c----c '\. / \

0-CH CH3

HOOC/

2

(XXVI I)

(-)-trans-DLaseneclc acld

Chart X. - The Absolute Configuration of Senecic Acld

and lts Isomers.

EX PERI MENTAL

to glve retrorslnej m. Po 216 - 217°. Rtchardson and

,,r • 21 ~0 1'\'etrren g1.. ve mo p. I • Yteld~ 20 g.

2. HYDROLYSIS OF RETRORSINE

Retrorstne (1.0 g.) and hydrated bartum hydroxide

(Ba(OH)2.sH2o) dtssolved Ln water (250 ml.) were refluxed

for 3 - 4 hourso Carbon dioxtde was then passed lnto

the solution untiL all the bartum carbonate was pre-

ctpitated. After filtration the solution was evaporated

to dryness, and the soltd continuously extracted vrith

eth2.nol (5 hours) tn order to remove the base. The

remaining solid was re-crystallised from water to give

barlum isatlnecate as a crystalltne powder.

3. PREPARATION OF SODIUH ISATH~CATE FROl'··l BARIUN

ISATINECATE

To a solutton of barlum tsattnecate (8 g.)~ sodtum

29.

sulphat~ solutton was added ln excess. Sodtu_m tsattnecate

vras formed and bartum sulpll.e.te was precipitated. After

filtration the solutton was evaporated to dryness under

reduced pressure to gtve crystalline sodium isattnecate.

Yield~ 5 g.

4. fviETI--IYLATICJ\; OF SODIUI·Jj. ISATH-::ECATE WITH IvlETHYL IODIDE

Sodium lsattnecate (1 g.) and methyl todlde (1.6 g.)

30 ..

ln absolute methanol (2 ml.) were heated for one hour

in a sealed tube ln a water bath. The solution was

cooled 1 water added and extracted with ether. The etheral.

layer was dried over anhydrous sodium sulphate and the ether

was evaporated off~ leaving a small quantity of oily

substance whtch was dtsttl.led at 125°/ 0.01 mm .. to glve

methyl tsatlnecate as an ott. Yleld: 0. 1 g.

Found: C~ 55.1; H9 7.9%.

Calculated for c 12H20o6 ~ C$ 55.4; H, 7.8%.

5. PREPARATION OF DH£Th"YL ISATI.f\lliCATE US H,JG S ILVE:R.

ISATI1\ECATE A.t\'D t.BTHYL IODIDE

Silver nttrate (20 g.) was added to a solutton of

barium lsatinecate (20 g.), the whole was heated and

stirred on a water bath for 15 mtnutes in the dark.

The preci..pltated silver i..sati..necate was filtered and

dried under reduced pressure. It was then refluxed with

methyl aLcohol (10 ml.) and methyl todtde (13 g.) for

three hours durtng Vlhtch a whi.. te precipt tate of silver

lodlde was formed. After filtration the precipitate

was washed with methanol. The ftltrate was evaporated

to yteld an oily substance~ whtch on dtsttllati..on gave

an oily product at 125 - 130°/ 0.01 mrn.

Found; C , 54. 5; H, 7. 6%.

Thtn layer chromatography uslng ethyl alcohol as

a developer on stltca plates revealed six spots thus

indicating a mixture.

6. TRANS-ESTERIFICATION OF RSTRORSil\lE USI.NG l'IJETHYL

AU:.OHOL

The esterification was carried out following the

Reimer Downes( 15 ) method at room temperature$ with a

modification as to the length of time taken over the

shaking and refluxing of certaln stazes of the method.

Retrorslne (6 g.) in absolute methanol (60 mL.) together

with potassium metal (0.08 g.) was shaken for thirty

31.

minutes then refluxed for three to four hours. Hethanollc

hydrochlorLc acid was added until the solution was neutralo

The solution was flltered and approxlmately four fifths

of the methanol removed under pressureo Iced water

(15 ml.) was added and the resultant mixture was

thoroughly shaken out with ether. ( 4 x 7 5 ml.). The

ether~ dried over anhydrous sodium sulphate and flltered 9

gave dlmethyl lsatinecate as an oll b. p. 135 - 136°/ 0.01 m~,

Found: C, 55.1; H, 7.9%.

7. OXIDATION OF DI~ffiTHYL ISATI~~CATE USING SODIUM

PERIODATE

32.

Dimethyl tsattnecate (2 g.) was dlssol.ved tn a mlxture

of dloxan (12 mt.) and water (4 mt.) at room temperature.

0.3M sodlum pertodate (25.8 ml..) was added and after two

mlnutes water (20 ml.) was added tmmedtately? the new

ketone formed was extracted wtth ether four ttmes. The

ether together wlth smaller quanttttes of dloxan and

water were dtstilled off under reduced pressure to give

dlmethyl 2-methyl-hex-3-ene-1-one-1,4-dlcarboxylate as

an otty llqutd at 105 - 108°/ 0.01 mm. Yield~ 1.2 g.

tJ1 Found: C, 57.1; H, 7.2~.

Calculated for c11 H16o5 : C, 57.9; H, 7.1%.

(ex] ~0 +3. 55°. Therefore t t was not racemtsed.

Addttton of 2?4-dtnttrophenythydraztne to the ott ln

ethanol formed a 2,"~-dtnttrophenylhydrazone dertvattve of

the keto ester as a dark brown ott which could not be

crystal.Ltsed.

Found: C, 49.6; H, 5.6; N, 13.8%.

Calculated for c 17H20N408 : C? 50.0; H, 5.0; Ns 13.1%.

8. REACTION OF OXIDISED DIJVJETHYL ISATINECATE 1'f!TH

METHYL-1'1AGNES I UM IODIDE

The reaction was carrted out ustng the apparatus shown

on page 44. The Grtgnard reagent was ftrst prepared.

MethyL iod'lde ( 1. 7 mL; 2. 5 motes) was s'Low'Ly

added to cLean dry magnesium ribbon (0.7 g.; 2.5 atoms)

in disttlled dry ether (20 mL) at room temperature and

after the addt.tton was compLeted the mtxture was warmed

on a water bath. When alL the magnesium ribbon had

been used up, the resultant mtxture was added drop by

drop to a mixture of the keto ester (6.4 g.; 1 mole)

tn dry ether (20 mt.). Thts reaction was kept below

10°. The new compLex was decomposed by the additton

of cold water (40 ml.) with a Little dttute hydrochloric

acid. The ether layer separated 9 and the aqueous layer

was shaken with four lots of ether. The combtned ether

layers were drLed over anhydrous sodium sulphate~ and

shaken with a little sodium thtosulphate to remove any

lodlne present. Evaporatton of the ether produced an

otl which distilled at 115 - 125°/ 0.01 mm. Thin layer

plates of alu~t.na wtth benzene and ethyl alcohoL (96:4)

mixture as a developer reveaLed four spotso

9. CHRO.t-'JATOGRAPHY OF THE ABOVE MIXTURE

A 3 em. x 27 em. column was prepared from neutral

alumtntum oxtde (150 g.) ( 11 CAf>~.iJ\.G 11 H.F.C.) suspended ln

dry benzene. To thts was added the otly mlxture (6 g.)

dissolved ln a few drops of benzene 9 and a flow of

150 mL./ hour of benzene was matntatned using air

33.

pressure. Fractton (40 ml.) were collected~ and after

560 ml. of benzene had passed ethyl acetate (100 ml.)

was lntroduced and ftnaLly ethyl alcohol (100 ml.).

Four bands were formed on the column.

The results obtalned were as follows:-

Fractton ml. Material

1 - 4 160

5 40 Ftrst band

6 40

34.

7

8

40

40

Part of second band

Rest of second band

Fraction

9 - 10 80

11

17

18

20

- 16 240

40

- 20 80

40

Thtrd band

Part of fourth band

Rest of fourth band

5 on evaporation ytelded a few mtlltgrams of

brown otl whlch was dtscarded.

Fractton 7-8 on evaporation ylelded a clear ott.

Found: c~ 64.3; H~ 8.9% ..

Fracttons 11-16 on evaporation yielded dlmethyt sinecate

as a clear oll. [oc] ;o ;±0°. Yte ld: 5 g.

Found: C , 59. 0 ; H , 8 • S%.

Fracttons 17-19 on evaporatlon yielded an oll.

Found:

10. PREPARA.TI ON OF BARIUH SE.NECATE FROH DH1ETHYL SENECATE

Dtmethyl senecate (1.0 g.) was dissolved in methanol

(8 mt.) and was added to a solution of barium hydroxtde

(2.8 g.) and lt was refluxed for eight hours. Carbon

dtoxtde was passed lnto the hot solution and the barium

carbonate preclpltated was flttered off. The solutlon

35~

was evaporated to dryness and barlum senecate was obtalned.

Yteld: 0.91 g.

11. HYDROLYSIS OF BARIUM SEt-JECATE

Barlum senecate (0.91 g.) was dlssotved in water

(10 ml.) and passed through an ton exchange column

(Regenerated Amberttte Resln- I.R. - 120; column$

1.3 em. x 4.0 em.). The aqueous sotutlon was extracted wlth

ether flve tlmes. The ether was drled over anhydrous sodium

sulphate and ev~porated to produce a gum. Crystalllsatlon

from benzene yletded whlte crystals of seneclc acld and

Found:

12. SUBLIMATIOl'..Y OF SE.l\1ECIC ACID AND ISOi''.lERS

The mtxture of senectc acid and its isomers was

subllmed at 110°/ 0.001 mm. ~ for four hours. A gummy

deposit was obtatned on the cold ftnger whlch was taken

up wtth benzene and the solutton concentrated to yteld

t 1 135 - 147°. crys a~.-s ~ m. p.

Found:

The tnfra-red spectrum of this compound was the same

as the tnfra-red spectrum of the restdue~ as shown tn

Appendtx I~ page 46.

13.. OXIDATION OF SENECIC ACID AND ISONERS \!liTH LEAD

TETRA-ACET/,TE

Lead tetra-acetate (1.2 g.) was added to a solution

of senectc acid (0.5 g.) tn dry benzene (100 ml.). The

sotutton was warmed to 50°P and shaken for one hour.

36.

Excess oxtdant was destroyed with ethylene glycol (2 drops)

the solution filtered and the benzene evaporated off.

The restdue was dissolved tn hot water, and diluted

sulphuric acid was added. After removing the lead

sulphate formed by filtration, the solutton was extracted

four times with ether. The ether dried over anhydrous

sodium sulphate was evaporated to yield (±)-5-methyl-2-

[,..J-J 20 00 (. hepten-6-one-3-carboxyl.ic acid. """. D Ln absolute

alcohol).

Found: (!'!' C, 64.2; H~ 8.7/c.

Calculated for c9H14o3 : c, 63.5; H, 8.3%.

The (.±)-keto acid formed a 2 ,4-cllni tror..>henythydrazone 0 dertvattve, m. p. 160 - 161 • , from ethanol as brown

trregular crystals. Culvenor and Geissman( 4 ) quote

~· p. 189 - 190°. for the 2,4-dinltrophenylhydrazone

derlvattve of (±)-si~-keto acld. The (±)-keto acid was

heated for thirty minutes at 100° tn concentrated

hydrochloric acid and recovered wlth ether after the

addttton of water. The product was taken up ln pentane

cooled to 0° and needles of (±)-~r~~-keto acld m. p. 49

37.

50° were obtained. The 2,4-dlnitrophenylhydrazone crystals

obtained from ethanol melted at 135 - 137°. Purtftcatton

of the crystals by passing them through a small column

of neutral aluminium oxide suspended ln ethanol ytelded

brown crystals, m. p. 144- 146°.

quote m. p. 145 - 146°).

(Culvenor and Getssman

14. ALCOHOLIC POTASSIUH hYDROXIDE HYDROLYSIS OF

RETRORSINE

To retrorsLne (10 g.) dissolved in ethanol (80 ml.)

was added solid potassium hydroxide (4 g.; 1.3 mol.) and

then boiled under reflux. Within five minutes crystals

separated and after ten minutes the content of the flask

38.

was one· mass of crystals. The crystals were filtered off,

thoroughly washed with ethanol and dried to yield potassium

retronecate.

15. ISOL\TION OF THE ACID

The potassium retronecate was dissolved in cold

water (20 ml.) 9 the solution neutraLised with 8N sulphuric

acid untiL just acid to congo red, and filtered. The

filtrate on evaporation gave crystals 9 which, washed

with water 9 yielded crystals of retronectc acid, m. p. 181°.

16. OXID:O,TI ON OF EETR0.[\1ECIC ACID

A solution of sodium pertodate (2.0 g.) in water

(10 mt.) was added to a solution of retronectc acid (2.0 g.)

ln water (10 ml.), at room temperature. A few drops of

dilute hydrochloric ae\d were added to bring the pH to

one. After two minutes the solution was extracted with

six lots of ether. The combined etheral extracts were

/

drled over anhydrous sodtum sulphate and the ether was

evaporated off to yleld the keto actd as an olly product

( 1. 85 g.)~ [1::1(]~ 9 +10.2 0 (ln ethanol).

Found~ c, 53.4; H, 7 0 1%.

Calculated for C 9H12.o5 : c, 53.9; H, 6.0% ..

The 2,4-dlnttrophenyLhydrazlne derlvative of the keto

acld formed from ethanol red brown needles, m. p. 185°.

Found: c~ 42.7; H, 4.9; N, 12.4%.

Calculated for C 15H16N4o8

: c, 43.3; H~ 4.2; 4'-J, 1 'i. Oi·~·.

17. REACT I 01\T OF OXIDI SED RETRONEC IC ACID WITH 1''£THYL-

MA.Gl\TES I U.tvl IODIDE

The reaction was performed using the apparatus as

shown on page 44. The Grlgnard reagent was first

prepared •

.Methyl iodlde (1.7 g.; 2.5 moles) was slowly added

to clean magneslum ribbon (0.3 g.; 2.5 moles) ln

dlstllled dry ether (15 ml.) at room temperature, at

first~ and later the mixture was warmed on a warm bath.

When all the magnesium rlbbon was used up 9 the resultant

mixture was added drop by drop to the keto acld (1.0 g.;

1 mole) in dry ether (10 mt. ). Thts reaction was kept

0 below 10 • On completion, the complex formed, was

decomposed by the addltlon of cold water (30 ml.) and

diluted hydrochloric acid (2- 3 ml.). The ether Layer

39 ..

40.

separated out 9 and the aqueous layer was shaken wlth

four lots of ether. The combi..ned ether layers were

shaken wi..th a little sodium sulphi..te to remove any lodi..ne

present and were then drled over anhydrous sodi..um sulphate.

The ether was evaporated off to yi..eld a llght brown gum.

After vartous attempts to crystalllse the gum failed a

successful crystalllsati..on was obtained by washing the

gum wlth ethyl acetate and evaporating off the ethyl

acetate extracts. These also yi..elded a gum which was.

read'tly soLuble ln a few drops of benzene. Thi..s solutlon

was added to ltght petroleum (b. p. 60- 80°) (10 ml.)

and whtte needle llke crystals of i..ntegerrineclc aci..d

were obtai..ned m. p. 148° (t:ropman and Warren(?) quote

151°)._[ot.];0 +15.8° (ln ethanol).

Found: C, 54.6; H, 7.5%.

The tnfra-red spectrum was ldentical as that of

integerri..neclc acid formed from senectc acld lactone~

as shown on Appendix II, page 47.

Mtxed melting polnt with integerrineclc aci..d was 150°.

Attempts to crystalli..se the resi..dual gum with several

solvents failed.

Found: C, 54.4; H, 7.2%.

18. OXIDATION OF RETRORSINE

A solutlon of retrorsine (4 g.) tn dilute

hydrochloric acld (20 ml.) was neutralLzed wtth sodlum

hydroxide and mtxed wlth sodlum metaperlodate (4 g.)

tn water (24 ml.) at room temperature. After one

minute excess perlodate was destroyed by adding ethylene

glycol (1.2 mL.). 2N hydrochlortc acld (8 ml.) was

added and the solutton was kept~ at room temper~ture 9

for three hours. The pH was then adjusted to etght

41.

wtth a saturated solution of disodtum hydrogen phosphates

and immediately extracted with four lots of chloroform.

The combined extracts were dried for a few minutes and

the chloroform was removed at room temperature under

reduced pressure~ to yield an oily residue which

crystallised on rubbing with a few drops of ether.

Yield 3 g.

19. REACT I ON OF CYCLIC KETO ESTERS vHTH !1ETHYL-

1'1AG.f\1ES I m~i IODIDE

The reaction was carried out using the apparatus

shown on page 44a

prepared.

The Grignard reagent was first

Methyl iodide (2. 0 mL; 3 moles) was slowly

added to clean dry magneslum ribbon (Oe68 g.; 3 moles)

in distilled dry ether (20 ml.) at room temperatures

and after the addition was completed the mixture was

warmed on a water bath. 'Vfhen all the magnesium

ribbon had been used up~ the resultant mtxture was

added drop by drop to a mixture of the Cj'C 1.. i..C keto

ester (3 g.; 1 mole) Ln dry ether (20 ml.). Durtng

the course of the reaction whtch was kept well below

10°, a yeLLow restnous deposit was also formed. The

new complex was decomposed by the addi..ti..on of cold water

(40Jml.) wtth a little dilute hydrochlortc actd. The

ether layer whtch separated was washed wi..th a tittle

dilute hydrochlortc ati..d (5 ml.). and the combined

aqueous Layers were washed with ether, baslfied wi..th

ammonia and extracted wlth stx lots of chloroform.

The combined extracts were dri..ed and concentrated under

reduced pressure to yi..eld a gum. Yield 1 g.

20. CHROH/\TQGRJI.,PHY

A 1 em. x 18 em. column was prepared from

neutral aluminlum oxide (25 g.)("CAMA.G 11 H.F.Co)

suspended ln ethyl acetate. To thi..s was added the

gum (1 g.) dlssolved ln ethyl acetate (2 mt.) and a

flow of 150 mt./ hour of ethyl acetate was maintained.

Fractions (8 mt.) were collected, and after 104 ml.

of ethyl acetate had passed, ethyl alcohol (50 ml.)

42.

d

43.,

was lntroduced and finally water (50 ml.)

The results obtatned were as follows:-

Fractton mlo Matert.a.L

1 - 2 16

3 8 Part of ftrst band

4 8 Rest of first band

5 - 7 24

8 8 Second band

9 - 13 40

14 8 Part of thLrd band

15 8 Rest of tht.rd band

16 - 25 108

Fracttons 3-4 on evaporation yielded a few mtllt.grams

of brown ot l.

Fractton 8 on evaporation yielded a couple of mtlllgrams

of brownish oL L

Fractions 14-15 on evaporation yielded a gum~ which gave

crystals of senectontne~ on addLng a few

drops of ethyl acetate 9 m. p. 230 (decomp)

(c<]~0-so.3° (ln ethanol). The tnfra-red

spectrum of thts com9ound was slmllar to

the spectrum of senectontne (see Appendtx Vs

page 50).

Found: Cs 62.1; Hs 8.3; Ns 3.9%.

Calculated for c18H25o5N: Cs 64.5; Hs 7.5; N9 4.2%.

21. THE GRIGNJ\RD APPAPJi.TUS

The Grtgnard reactions were carrted out using the

apparatus shown on Ftg.I 9 page 45. The Grtgnard

reagent was ftrst prepared tn ftask (D) havtng ftrst

closed taps (A) and (C). Tap (A) was opened untll

a complete vacuum was obtat.ned tn section (B). Tap

(A) was ctosed and tap (C) was opened. The Grlgnard

reagent passed into sectt.on (B) and tap (C) vvas ctosed.

Section (B) was then detached from flask (D) and

attached to ftask (E) whtch contat.ned a sotutlon

of the ketone t.n dry ether. The Grlgnard solutlon

from sectt.on (B) was then passed t.nto ftask (E) drop

by drop.

44.

, ..

45.

To vacuum pump

lt.

B

c

D

Ftg. 1. APPARATUS USED FOR TFIE GRIGN/l.RI> REACTIONS

.J ..

0

\

j 4

5 6

WA

VE

NU

MB

ER

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1.

2.

3.

4.

s.

6.

7.

8.

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