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)
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.
" \'
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.
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.
0
\
j 4
5 6
WA
VE
NU
MB
ER
-·~'·1
--1 ·
'-~ .. f:
j::=
--=~
7 8
9 10
11
W
AV
EL
EN
GT
H
(MIC
RO
NS
) 12
·1
3 i i ~ ! I I
-•¥
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pp
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ix v
.
1.
2.
3.
4.
s.
6.
7.
8.
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