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tSCOPE AND hECHANISM OF THE IAENGEKAL,
MICHAELIS-BI,JCIM REACTION'
A Thesis presented by
Paul Anthony Worthington, B.Sc., A.R.C.S.,
in partial fulfilment of the requirements for
the degree of
DOCTOR OF PHILOSOPHY
of the
ITJ OF LONDON
Thorpe-Whiteley Laboratory, August 1974
Department of Chemistry,
imperial College,
London. S.W.7.
ACKNOWLF,DGEIETITS
I wish to thank my supervisors, Dr. Laurie Phillips
(Imperial College) and Dr. Clive B.C. Boyce (Shell Research), for
their help, guidance and friendship during the course of this work.
my sincere thanks to Professor Sir Derek H.R. Barton for the privilege of working in his department.
I am grateful to my colleagues in the Thorpe-Whiteley
Laboratory, (Soss, Bob, Mansoor, Pete, Martin, Mike and Vic) and
C.O.D., Shell Research, Sittingbourne, Kent (Jack, Roger, John,
Nike, Shirley and others too numerous to mention) for their help,
often useful comments and friendship over the past three years. I thank the college technical staff for their assistance
4 particularly Mrs. J. Lee for her excellent mass spectral service,
Mr. K. I. Jones and his staff for the accurate analytical data at
all times and Mr. M.H. Pend.lebury and Mr. S.J. Roberts for shimming
of the XL 100 and HA 100 spectrometers respectively.
I should like to thank Mrs. Carol Stark who typed this
thesis and corrected my mistakes in the process. Lastly, thanks are due to the Science Research Council
and Shell Research Limited for the award of a CAPS scholarship.
TO NY PARENTS
FOR IdAKING EVERYTHING POSSIBLE
ABSTRACT
The reaction of dimethyl Phosphenate with a range of m-halo
carbonyl compounds has been studied. Various products have been isolated
including vinyl phosphatesI keto phospnonatesand epoxy phosehonates, and
their formation has been related to the structure of the ac-halo carbonyl
compound.
Reaction of dimethyl phosphonate with a series of 2,2-dichloro
2f-substituted acetophenones gives exclusive vinyl phosphate formation
where the E/Z isomer ratio obtained is dependent upon the nature of the
ortho-substituent in the aromatic ring. This variation in the E/Z isomer
ratio has been shown to be independent upon the nature of substituents in
the meta- and para- positions of the aromatic ring. The E/Z isomer ratios
obtained from 2,2-dichloro 2'-substituted acetophenones has been related
to the conformation properties of ortho-substituted para-f]uoro-a,a-dimethyl
benzyl alcohols in solution. Variations in the nature of the phosphorus
reagent used in the reaction with 2,2-dichloro 2'-substituted ecetoehenonee
have been shown to affect the EA isomer ratio of vinyl phosphates obtained.
A mechanism for the 'abnormal' Michaelis-Becker reaction has been
proposed which accounts for the variation of products obtained with the
nature of the at-halo carbonyl compound and the phosphorus reagent. The E- and
2-vinyl phosphates obtained from 2,2-dichloro 2'-substituted acetophenones
are formed by a stereospecific trans elimination from two different
transition states which are determined by the nature of the ortho-substituent.
1H nmr studies on a series of diethyl 2-substituted vinyl phosehates
and diethyl 1-phenyl 2-substituted vinyl phosphates had led to a method for
determining the stereochemistry of the olefinic double bond by .means of
proton chemical shift measurements. For a pair of geometric isomers of
type RIR"P(X)01-.CHW the proton cis to the phosshoryl group (:S-isomer)
Y
absorbs to low field of the corresuonding trans proton (Z-isomer) for a wide
range of substituents. Subsequently, it has been shown that observations
of the magnitude of 4,Ipp. coupling constants are unreliable in determining
the geometry of vinyl phosphates. The Presence of a substituent at
carbon-1 in the vinyl phosphate changes the conformational preferences for
the molecule and hence the magnitude of these coupling constants•
13C nmr studies for a series of dimethyl 1-substituted vinyl
phosphates, diethyl 2-substituted vinyl phosphates and dimethyl 1-phenyl
2-substituted vinyl phosphates have been carried out. The substituent
effects observed on carbon-i and carbon-2 of the olefinic bond are
similar to those already established for the simple mono-substituted
ethylenes.
3IP nthr chemical shifts for the E- and Z-isomers of diethyl
2-substituted vinyl phosphates and dimethyl 1-phenyl 2-substituted vinyl
phosphates have been recorded and been shown to relate to the conformational
properties of these molecules in solution.
An off-resonance decoupling experiment (1H decoupled
has been developed to determine the absolute signs of 4J andand
vinyl phosphates in general.
from 13C) 2J for PC
CONTENTS
Page
CHAPTER 1 - The 'Abnormal/ Michelis-Becker Reaction
- Reaction of dialkylphosohonates with
p[-halo carbonyl compounds
1. Introduction 11
2. Structure of yhosyhorus compounds 33
3. Nomenclature 34
4. Results and Discussion 36
5. Experimental 45
CHATTER 2-- The Geometry of Vinyl Phosphates as Determined
by Nuclear Magnetic Resonance
1. Introduction - The geometry of tri- 55 substituted ethylenes
2. Nomenclature of vinyl phosphates 57
3. 1H nmr of 2-substituted and 1,2- 59 disubstituted vinyl phosphates -
Use of chemical shifts to determine
the stereochemistry of vinyl phosphates
4. 130 nmr of 1-substituted 2-substituted 76
and 1,2-disubstituted vinyl pros,-hates -
Use of 13C-P coupling constants in
determining the stereochemistry of
vinyl phosphates
5. 31P near of 2-substituted an1_121:disub- 105
stituted vinyl phosphates
6. Experimental 114
• CONTENTS continued
Page
CF"IPTER 3 - Effect of Varying the Nature cf the Leaving Group upon the Course of the Perkcw and 'Abnormal' Michaelis-Becker Reactions
1. Reaction of trialkyl phosphite with at-halo carbonyl compounds - Perkow
reacton
2. Reaction of dialkyl phosphonate with
QC-halo carbonyl compounds -
'Abnormal' Michaelis-Becker reaction
3. Luerimental
CHAPTER 4 - The Effect of Aromatic Substituents unon the CO') Isomer Ratio of Vinyl Phosphates Formed in the Reaction of 2,2-Dichloro Substituted Acetophenones with Dimethyl Phosphonate in the
Presence of Base
1. Arollailaringtituted 2 2-dichloro
acetophenones
2. Reaction of dimethyl phosphonate with ring substituted 2 2-dichloro
acetophenones
3. Experimental
CITAPTER 5 - The Effect of Varying the Nature cf the Phosphorus Rear'ent on the Course of the 'Abnormal' Michaelis-
Becker Reaction
1. Results and Discussion
2. Experimental 206
121
129
142
158
162
173
187
8
COI\TTENTS continued
Page
•
CHAPTER 6 - The Mechanism of the 'Abnormal/ Michaelis-Becker
Reaction
1. Discussion and Conclusions 214
APPEBDIX I - TO CHAPTER 2
238
REFERENCES 245
•
!Weird scenes inside the gold mine!
Jim Norrison
- 10
CHAPTER 1
•
CHAPTER 1
The 'Abnormal' Michaelis--Becker Reaction - reaction of dialkyl phosphonates
with cr-halocarbonyl compcunds
1. Introduction
It has long been known that alkyl halides (I) react with sodium
or potassium dialkyl phosphonates (Michaelis-Becker reaction, Scheme 1)1'2
\ and with trialkyl phosphites (Michaelis-Arbueov reaction, Scheme 2i39 95 to give alkyl phosphonaLes (II).
0 0 " Scheme 1 RX + MP(0R1 )2 --+ R-P(OR
I )2 + MX
0 " N Scheme 2 RX + P(0R1)
3 R-P(OR1 ;2 + R
1X
I II
The mechanism of the reaction leading to the formation of a new carbon-
phosphorus bond involves a nucleophilic attack by the phosphorus on the
cc-carbon of the alkyl halide6'7 to give the alkyl phosphonate directly
in the M ichaelis-Becker reaction, or in the case of the Michaelis-Arbuzov
reaction an intermediary trialkoxylalkylphosphonium halide (III) which
is dealkylated by an SN2 displacement reaction of X to give the dialkyl
alkylphosphonate and a new alkyl halide.
rr RX + P(0R1)3
----b- Ljt1 o)3r-R_ix- (R I 0)213-R + R1X
I This latter mechanism is supported by the isolation of stable intermediates
(III, R1=Ph) from triaryl phosphites and alkyl halides4'8.
The reaction is not limited to alkyl halides and trialkyl phosphites
react with aromatic and aliphatic acid chlorides for example to give
ketophosphonates (IV)9,10.
- 12 -
R-C-Cl + P(OR1)3 2Th'0)3 -g-R2C1- (R 0)2Pg-C-R+R Cl
IV
Although halogen has been the group most commonly displaced by
phosphorus, leaving groups such as amino11, alkoxy12, and acetate15 have
also been used. The Michaelis-Arbuzov reaction has been investigated with
a number of other halides including choro ethers14,cx-bromo silanes and
trichloromethylamines16. Similarly, the salts of dialkyl phosphonates
have been reacted with chlorosilanes17 and 2-chloroethyldiphenylphosphine18
to give the expected phosphonates. The reaction of diethyl phosphonte with
1,2-dibromoethyloyanide19 gave diethyl 2-cyanoethyl phoaphonate probably via
a debromination and addition mechanism.
9e 0 (Et0)2P + BrCH2CHBrON (Et0)2kH2CH2CN
It was therefore originally assumed thatex-haloaldehydes20 cc-halo ketones21,22,25,24
and cc-halo esters25'26 gave the corresponding phosphonates of the type
expected from the normal course of the Michaelis-Arbuzov reaction with
trialkyl phosphites, Razumov and Petrov27 obtained two isomeric products
from triethyl phosphite and bromoacetone which analysed for the 2-oxopropyl
phosphonate and concluded they were tautomeric forms of the phosphonate.
The probability of tautomerism of this kind had been pointed out by Arbuzov
and Razumov as early as 1934 by an analogy with acetoacetic ester28•
Q Q9H (C2H50)3P + BrCH2-00CH3 (C2H50)2P-CH2-C-CH3 (C2H50)2P-CH=O-CH3
In 1952 however Perkow discovered thatcx-halo aldehydes did not react with
trialkyl phosphites according to the Michaelis-Arbuzov reaction but gave
instead the isomeric vinyl phosphate29.
- 13 -
I Scheme 3 (R0)3P + 0=g-C-X (R0)2P-0-
V04- + RX
, g (R0)2P-C-CHO + RX
Pudovik and Lebedeva subsequently found an analogous reaction between
M-halogeno-ketones and trialkyl phosphites30.
In general a-halo aldehydes are more reactive than ac-halo
ketones and ac-halo esters and give only vinyl phosphate while with some
a-halo ketones both the Michaelis-Arbuzov reaction (formation of 2-oxoalkyl
phosphonate) and the Perkow reaction (formation of vinyl phosphate) can
take place31.
The Perkow reaction Scheme 3, has been the subject of a great
number of reviews and reports32-38 In general trialkyl phosphites
undergo the Perkow reaction with an organic halide in which the halogen
atom is a good leaving group and is also to an aldehyde, keto, or in
some cases, ester carbonyl group. The smaller the number of (x-halogen atoms
the less the reactivity e.g. chloroacetaldehyde requires a temperature of
1100 to initiate the reaction whereas chloral and bromal react exothermically.
With cc-haloketones there is a predominance of vinyl phosphate formation
at lower temperature and for the halogen substituents in the order
01> Br). I e.g. iodoacetone gives exclusively ketophosphonate even at
low temperatures"' 40,41 . Them-halo ketones which have the halogen
on a secondary carbon atom react to a significantly greater extent
according to the Perkow reaction than those having the halogen on a
primary carbon atom.42 With more than one halogen atom in them-position
of the halo-ketone the reaction is found to proceed almost exclusively
- 14 -
via the Perkow route to give the vinyl phosphate35,43,44,45. The cc-halo
esters are considerably less reactive than haloaldehydes or haloketones:
trichloroacetates react according to the Perkow reaction to give 1-alkoXY-
2,2-dichlorovinyl phosphates46'47 while monohalo-esters react exclusively
according to the Michaelis-Arbuzov reaction e.g. ethyl chloroacetate gives
a good yield of diethyl carbethoxymethylphosphonate upon reaction with
triethyl phosphite23,47
These results are summarised in Scheme 4 and
Table 1.
Scheme 4 cc-Ealoaldehydes
9 0 (Ro)
3P + (Ro)2P-o-y.C.
cc-Ealoketones
(i) 9 0 9 1 (R0)3P + R (R0)2P-CH2-C-R + (HO)2 P-O-C=CH2 ,
See Table 1 for variation of product ratios as a function of variation
in R1 and X (R=Et), and reaction conditions.
Table 1
% (R0)2P(0)-0H2-COR1 % (R0)2P(0)-0-CR1=CH2 Conditions: Temp./Solvent
14 86 CH3
Cl 160-170°
20 80 CH3
Br Ether/Reflux
70 30 CH3 Br 1600
90 10 CH3
I Ether/Reflux
- 100 Ph Cl 130-140°
64 36 Ph Br Ether/Reflux
85 15 Ph Br 150°
76 24 Ph 1 Ether/Reflux
15
(ii) (R0)3P ------* (RO2P-oticHR2 + RX
where R2 = alkyl or halogen
oc-Haloesters
(1) 0
(Ro)3p + 9 13 ( RO)2 P-O-C.CC12 + RC1
R1 OR
• (Ro)2P9 -cH2-c9 woc2H5 + RC1
3 (ii) CRO)P + g -CH Cl
c g2 2 5
The scope of the abnormal Michaelis-Becker reaction
A necessary condition for the Perkow reaction to occur is
that the trivalent phosphorus carries at least one alkoxy group46,48.
0 04
1 -6
1 -x >-0- C=C- +
OR
However if the trivalent phosphorus carries a hydroxy grouping the reaction
with x-halo carbonyl compounds apparently takes a different course from
either the Michaelis-Becker or Perkow reactions and dialkyl phosphonates
generally behave like the other highly basic nucleophiles e.g. RO-, OR,
RHE2 in that they tend to react preferentially at the carbonly carbon atom.33
Thus when dimethyl phosphonate is added to chloral a vigorous reaction takes
place and dimethyl 2,2,2-trichloro-l-hydroxyethylphosphonate is obtained as
a crystalline solid in 54% yield49 5°
(CH30)2P-H + Cl3CCE0 (CH30)2P1-0C13
11 (CH50)2P-OR
This product is relatively stable at room temperature in aqueous solution
but in alkaline medium an interesting rearrangement takes place with the
formation of the same vinyl phosphate50,51 as occurs in the Perkow
- 16 -
reaction between trimethylphosphite and chloral.
OH 9
(cH 3 .0)2 1 P-C-CC1 3 H
NaOH (cH 0) P-O-C=CC1 3 2 2
H
Dichloroacetaldehyde reacts with diethyl phosphonate at 40-50° to give
a quantitative yield of diethyl 2,2-dichloro-l-hydroxyethylphosphonate
which is more stable than the trichloroethyl phosphonate in aqueous
sodium hydroxide affordirg only a very small portion of impure vinyl
phosphate51. Recently, monochloroacetaldehyde has been shown to react
with diethyl phosphonate in the presence of triethylamine to give good
yields of diethyl 2-chloro 1-hydroxyethyl phosphonate.When diethyl 2-chloro
1-hydroxyethyl phosphonate was treated with sodium ethoxide in ethanol
the corresponding diethyl epoxyethyl phosphonate was produced52.
(Et0)2?-H + C1CH2CHO Et3N 9 ) C1CH2CH(OH)P(OEt)2
Etd9NO/EtoH 9 oR, (Eto)2p-i_cH2--ci
H
dP\ ---* (Eto)2p
9 - --cH2
However acid chlorides react with dialkyl phosphonate in typical
Michaelis-Becker fashion to give a ketophosphonate which can then react with
more dialkyl phosphonate at carbonyl carbon to give diphosphinates21.
9 9 cH3coci + (c2H50)2P.o cH3-c-p(oc2H5)2 + ci
)- CH I-P(OC2H (C H 0) P0 2 5 2 =
3 5) 2 0=P(OC2H5)2
CH3COC1 010CH3
) cH3-- (0C2H5)2 + Cl-
0=k0C2H5
)2
17
If the sodium salt of a dialkyl phosphonate is added to
chloroacetone at low temperatures the sodium salt of the Ilydroxy phosphonate
can be detected. This has been reported to rearrange to the isopropenyl
esters as shown in the following scheme40.
-50° 0 ONa (C2 H5 ' 0)2 P-ONa + CH5ICH2Cl ----> (C2H50)2II- -CH2C1
H3
(stable at 20°C)
44M.24
(c2H50)2?-0-7=CB2 OH 3
Arbuzov and his co-workers have since made a somewhat incomplete study
of the 'abnormal/ Michaelis-Becker reaction. They reacted the sodium salt
of diethyl phosphonate with the a-halocarbonyl compoundin ether at refluxing
temperature and observed a number of products depending on the nature of
the carbonyl compound. The three main compounds observed were
ketophosphonates (Iv), epoxyphosphonates (V), and vinyl phosphates (VI)
- Scheme - of which the epoxyphosphonate has never been detected in the
Perkow reaction: 9
Scheme 5 9
IV
(C2H50)2Plie + R-C-C-X
(C2H50)2P-y-C2Cc
- V
R
( E 0)2?-0-T1- VI
When they repeated Kreutzkamp and Kayser's condensation of ohloroacetone
with sodium diethyl phosphonate they obtained, not the isopropenyl ester
- 18 -
which had been reported40 but diethyl 1,2-epoxy-l-methylethylphosphonate
as the main product with a small amount of diethyl aceto4ylphosphonate
(the structural assignments were supported by Raman spectra and infra red
spectra, epoxy band at 11.80-11.98 p53'54). The same products resulted
using bromoacetone, instead of chloroacetone55,56
a-Halo ketones which'have a halogen on a secondary carbon atom
give more of the 'abnormal' products than those having the halogen on a
primary carbon atom, for example ax-bromo ethyl methyl ketone reacts with
sodium diethyl phosphonate to give exclusively the epoxyphosphonate55,56
The methyl substituent makes attack at the Cc-carbon atom sterically
unfavourable but probably activates the carbonyl carbon atom to nucleophilic
addition. Further substitution at them-carbor atom results in the exclusive
formation of vinyl phosphate since them-carbon is probably now too
sterically crowded to allow for epoxide formation55'56'57. Similar
observations were found when monohalo acetophenone was successively
substituted with a methyl group in the CC-position. Both phenacyl chloride
and phenacyl bromide gave 'abnormal' products when reacted with sodium
diethyl phosphonate. Phenacyl chloride gave only vinyl phosphate whereas
phenacyl bromide gave a mixture of vinyl phosphate and epoxide because the
weakness of the C-Br bond favours attack at the cc-carbon atom. When the
effect of substitution at theex-carbon atom was studied it was found that
m-bromoprepiophenone gave only the epoxide whilst ce-bromoisobutyrophenone gave
only the vinyl phosphate58 Abramov concluded that m-haloketones with a
halogen atom on a tertiary carbon atom yield vinyl phosphates in reaction
with either trialkyl phosphites or sodium dialkyl phosphites59. These
regUlts are summarised in Scheme 6.
— 19
Scheme 6
0H3- C H2 X + ( 02 350 Et 20
refl (C2H50 ux , (c2H5o)2p
9 -cH21cH3
major product X = Cl or Br
Et20 C-CH2C1 + (C21150)2PNa refit= (C2H50)2P-
9 c-CE2Br + (C2H5o)2 Et20
(C 2H 5 2 0) P-O-C=CH2 + (021150)2 reflux
C 3 , 9 Et 20 R- C4Br + (C2H50)2PNa reflux ) (021150
H
R = methyl or phenyl
g 3 g 11t2o 3 R-C- -Br + (02H50)2PNa reflux (C2H50)2 -0-C=u-CH3
3 R - methyl or phenyl
Similar substituent effects have been observed in the earbocyclic series
where oc-chlorocyclohexanone and sodium diethyl phosphcnate gives only
the epoxide whereas the methyl-substituted compound gives only the
vinyl phosphate55.
ether + (C2H50)2PNa --------* reflux
- 20
1 Q ether + (C2H50)2PNa reflux
Variation in the acyl group OR = H, Me, Ph or part of carbocyclic ring
- see EshsIne) appears therefore to have little or no effect on
the course of the reaction.
Meisters and Swan60 have indicated that it is possible to effect
a change in the product distribution of the 'abnormal* Michaelis-Becker
reaction by variations in the solvent polarity. Arbuzov58 had
reported that the reaction of sodium diethyl phosphonate with phenacyl
chloride gives exclusively diethyl 1-phenyl vinyl phosphate. However,
the reaction of phenacyl chloride with sodium Ikthyl phosphonate
in liquid ammonia yielded a mixture of diethyl 1-phenylcpoxyethyl
phosphonate and diethyl 1-phenyl vinyl phosphate in a molar ratio
of 7:3. When diethyl phosphonate and phenacyl chloride were treated with
triethylamine in refluxing benzene only the vinyl phosphate was produced
with no trace of epoxide.
(C2H2O)2P9
H Cl (C2H50 liquid NH
3
- 21 -
Na
3 7
(c211502LH 9 H2C1 ) (C2H50)2P-0 =CH2 Et3N/Benzene
No work has been published on the reactions of dialkyl
phosphonates with di-halogenated ketones in particular the di-halogenated
derivatives of acetone and acetophenone. These are particularly
interesting substrates since their expected reaction products can
exist as geometric isomers and they could therefore provide .an
opportunity to investigate the hitherto neglected subject of the
stereochemistry of the 'abnormal' Michaelis-Becker reaction.
Very little is known about the limitations of the 'abnormal'
Michaelis-Becker reaction with respect to the phosphorus species
Pelchowicz61 has shown that dialkyl thiophosphonate reacts with chloral
to give 0,0-dialkoxy-S-2,2-dichlorovinlylphosphorothiolate and not
vinyl phosphorothionate as expected by analogy with the reaction
between dialkylphosphite and chloral.
80 (R0)2LH + ClC.CHO. --------* (RO)2 ?-S-C.CC1 2
H
-0-C=CC1 i 2 (Ho)
(RO)2PPtx -X (RO) - 3 21r. r 12 9 R0143
0 R1 0.,- R1
(R0)2P0 -0-C.02.3
- 22 -
Mechanism
Several mechanisms have been proposed for aCC-halogenated.
carbonyl compound undergoing the 'abnormal* Michaelis-Becker reaction62.
These correspond to nucleophilic attack of the dialkyl phosphonate
anion on:
1. Saturated carbon atom
2. Carbonyl carbon atom
3. Carbonyl oxygen atom
4. Halogen atom
Moreover the dialkyl phosphonate anion is itself an ambident nucleophile
with the possibility of attack by phosphorus or oxygen since in basic
solution the following equilibria exist:
(R0)2111H
(R0)2P-OH
base
11 base
(R021)_ (R0)2P-0-
However the phosphorus atom is believed to be the effective
nucleophile because of the isolation of cx-hydrovphosphonates49,50,65,64
Attack on saturated carbon atom
This mechanism proposed by Cramer65 and Perkow66 involves
an SN2 displacement of halogen by the dialkyl phosphonate anion to
(c2H50)2P-olmcH2 Ph
15%
Q + (c2H5cp-cH2-c-ph
A
85%
23
give the expected Michaelis-Becker ketophosphonate1'2 which
subsequently rearranges to vinyl phosphate by means of a 4-centre
mechanism analogous to the Wittig reaction°. However, the analogy
with the Wittig reaction is not a very good one since the negatively
charged oxygen atom of the ketaine intermediate in the Wittig
reaction is highly nucleophilic compared with the carbonyl oxygen
atom of the ketophosphonate33. In fact the ketophosphonate obtained
from the reaction of ec-bromoacetophenone and triethyl phosphite at
1500 68
resisted all attempts to rearrange it to the isomeric vinyl
phosphate°.
+ P(OC2H5)3 -CH2Br
0 OH
(C2H50)211.-CH=O-Ph
It would therefore seem very unlikely that attack on the a-carbon atom
is involved in the initial step of the 'abnormal' Michaelis-Becker.
2. Attack on carbonyl carbon atom
(R0)2P---
/03
This mechanism originally proposed by Bengelsdorf70,71 involves
addition of the dialkyl phosphonate anion to the carbonyl carbon atom
which is usually the most electrophilic centre in the molecule as the
first step. Bengelsdorf71 stated that if -X is an atom, or group of
"` 24 ••
atoms, capable of leaving as an anion, then rearrangement to vinyl
phosphate should take place:
0 R2 (RO)
1 R3
A 2 (110)2t x (R0)2?-0-T.CR2R3 + X-
Ri R3
If -X is not such a group, then thea-hydroxyphosphonate should revert
to the original starting materials, i.e. carbonyl compound and dialkyl
phosphonate. However, an electron withdrawing substituent on the
a.-carbon atom is sufficient to cause rearrangement e.g. dialkyl 1-hydroxy-
2-oxoalkylphosphonates will, when treated with sodium ethoxide in ethanol
rearrange to the corresponding trialkyl phosphate72 .
00H0 0 C H 0
(RO IL6-6-CH (R°)2 RHan3
3 C2H5OH 3
3
g ? H+ -30 (R0)2P-0-C=C-CH3 (R0)2P-0- -C-CH3
CH
Considerable support for a mechanism of this type which is directly
analogous to that generally accepted for the Perkow reaction" (Scheme 1)
has come from the isolation of hydror phosphonates from a variety of
aldehydes and ketones73)74 and from studies on their subsequent 9 50,51,63,64 rearrangement to vinyl phosphates4-,-
3 OR3
4
25
Scheme - Perkow Reaction
R2 (RO)3P I -X
1R5
> (R0)
-0-C.CR R ; 2 3 ) (110)2F9 -0-14R2R5 + RR (RO)
Phenacyl chloride has been shown to react with dimethyl
phosphonate in the presence of piperidine to give dimethyl 1-chloromethyl
1-hydroxybenzyl phosphonate along witha-piperidylacetophenone75. This
illustrates not only the different preferences of the N and P
nucleophiles but that phosphorus can attack the carbonyl carbon of
tics-halogenated carbonyl compound
Ph-00CH2C1 + (CH50)2P
9H H
R al-E(005)2
CH2Cl
PhCOCH2
A recent review on the reactions of tervalent phosphorus
compounds76 has discussed the possibility of the Michaelis-Arbuzov
and Perkow reactions taking place from a common intermediate involving
26
the attack of phosphorus at the saturated carbon atom - Scheme 8.
However, the involvement of a hydroxyphoaphonate anion
from an attack of dialkyl phosphonate anion at carbonyl carbon
explains very well the formation of epoxide from several ketones55,56,59,60
/R2 eei)( (R0)2
R3
Scheme 8
R 0
X P(0111)3 OSIMES•••••••1). 0.0•St111.÷
-RIX
,OH'
0R!
/OR'
(!)R 113
R—E)F---- "OR
The absence of epoxide formation in the Perkow reaction may be attributed
to the greater eleotrophilic properties of the P centre as compared to
the saturated carbon atom24.
27 NM
3. Attack on carbonyl oxygen atom
(Ro)2Prk (110)2P -0-C.CR2R3
This mechanism has the merit of being the simplest in that
it leads to vinyl phosphate formation directly. It is however extremely
difficult to envisgae any epoxide being formed from an attack of the
dialkyl phosphonate anion on the carbonyl oxygen atom. This need not
eliminate a mechanism of this type since epoxide and vinyl phosphate
are not necessarily produced from a common intermediate. Several
workers71.78,79 have proposed a mechanism of this type for the
analogous Perkow reaction but no real compelling evidence has been
produced. Certainly the addition of trialkyl phosphites to carbonyl
oxygen is by no means unprecedented and a number of papers have appeared
describing the reaction of cyclopentadienones with these phosphite estersSO'81
Dialkyl phosphonate reacts with tetracyclone in aqueous methanol to give
cyclopentenone. The mechanism is thought to involve initial attack by
phosphorus on the carbonyl oxygen followed by a proton shift and
hydrolysis to the required cyclopentenone82.
(R0)2P-H
H Ph _ CH_3 OR Ph h
_-H'20 \
Phi Ph
i(0n)2
Ph
An attack of phosphorus on carbonyl carbon followed by a rearrangement
might equally well explain the formation of cyclopentenone.
- 28 -
(R0)2P9 -H +
Ph Ph (,g(0R)2
MI I I= OMNI 40
Ph -
H
Ph
NaHCO HO OCH3
20o 3
Ph
Ph
+ (CH30)2P-H
160° Ph
H
(now Ph k3,) 2 (OH)2
The reaction has been reinvestigated by Miller83'84 who has
shown that reactions at 70° in sodium bicarbonate leads to products with
phosphorus situated at carbon rather than oxygen. At 165° quite different
products were obtained, one of which contained phosphorus bonded to
oxygen.
Some Russian workers85 have also obtained the hydroxyphosphonate
from a similar reaction of tetracyclone with dimethylphosphonate in the
presence of triethylamine as a catalyst. Their observations of the
rearrangement to phosphate over a period of several days suggest that
phosphorylation of oxygen probably involves an initial attack at
carbonyl carbon rather than carbonyl oxygen, followed by a rearrangement.
- 29 -
Ph Et-N P Ph
h catalyst Ph Ph HO (OCH
3)2
,Q (CH
30)P-11
several days
The addition of phosphorus to carbonyl oxygen has also been
claimed in the reaction of diallgi phosphites withhexaf/uoroacetone86.
An isomeric mixture of phosphate and hydroxyphosphonate is observed
as a result of what is thought to be phosphorus addition to the
carbonyl function in both senses. Dimethyl and diethyl phosphonate
give prediminantly the phosphate by addition at carbonyl oxygen while
di n-butylphosphite gives nearly all hydroxy phosphonate by addition
H 0 (RO )2iS-0-t (cF3 )2
(CF3)2CO
OH
(R0)2P-1(CP3)2
S- The change in polarity of the P-H bond from P---E (for 110- = Me0 or Et0-)
S S+ to P (for HO- = n-Bu0-) has been used to explain the variation in
the mode of addition. Subsequently it has been shown87 that the base
t: catalysed hydroxyphosphonate to phosphate rearrangement occurs very
readily in this case (e.g. in dichoromethane at 330 in the presence of
pyridine).
to carbonyl carbon.
(RO2V-H
At
30 -
0R02,,l(c,3 )2 0.02,0„(.3),
However this rearrangement does not occur under the preparative
conditions so that in this special case attack on oxygen appears valid.
In a similar way dialkyl phosphonates and dialkyl thiophosphonates
have been shown to react exothermically with benzophenone in the presence
of base to give phosphates88 At room temperature and low base
concentration the ec-hydroxyphosphonate has been isolated for the
dialkyl phosphonate ease
Xs base (Ro)2P-H Ar2co Ar
2CH0P(0R)2
<30° trace of base
OH Q
(RO)2P-CAr2
4. Attack on haloamate
_ The attack of phosphites on positive halogen is well known
e.g. in the preparation of phosphorohalidates89 and the reaction with
penta- and hexachlorocyclopentadiene90.
(R0)3P + SO2C12 (R0)2P-C1 + SO2 + Cl ----* (R0)2P-C1 110)
ci jpi (Roy + (Roy-c1
C11 Cl a cl CI Cl
(Ro)216-ci
Q 1H
31
Similarly attack of the phosphonate anion on the halogen atom
of anoc-halocarbonyl compound should produce an enolate anion which can
then react with phosphorohalidate formed to give a vinyl phosphate:
C1 :(0R)2 (R0)2P----%'"0-C.CR2R ----i-(R0)2 ? -0 -C.CR2R3
3 It,
In fact phenacyl bromide reacts with trivalent phosphorus compouns
such as triphenyl phosphine to give a bromophosphonium ion pair and
acetophenone on treatment with acid91
0-
Ph-C-CH2Br PP 2Tia3hi7LTh-LcH2.7
3P-O-C4H21 H3
or 0
Ph3PBr Ph-LCH
3 gh3P-CH2-C-Pg
However when phenacyl bromide was reacted with diethyl phosphonate
in the presence of ammonia almost quantitative yields of acetophenone
and diethyl amino phosphate were obtained69. This is analogous to
the reaction of carbon tetrachloride with diethyl phosphonate and
ammonia92 but contrary to the observations of Arbuzov who obtained
a mixture of epoxide and vinyl phosphate with a trace of keto
phosphonate58. Arbuzov was treating the sodium salt of diethyl
phosphonate with phenacyl bromide which might account for the difference
in the products observed.
It is possible to generate the enolate anion of a ketone by
treatment with sodium hydride. Subsequent treatment of the enolate
anion with dialkyl ohlorophosphate will give the vinyl phosphate.
11÷
Br-
(Schrader reaction76.) When dichloroacetophenones were converted into
vinyl phosphates by the Schrader and 'abnormal' Michaelis-Becker reaction
different ratios of geometric isomers were obtained69 indicating that the
initial attack on positive chlorine is not a realistic mechanistic
pathway for the 'abnormal' Michaelis-Becker reaction.
R-?-CH2X NaH ). HO\=cpix
R /
(RI0)21-C1
'Schrader reaction'
The reaction of trichloroacetylthiourea and triethyl
phosphite to diethylphosphorochloridate demonstrates that the Perkow
reaction can take place with attack of phosphorus on positive halogen94.
This example is probably an exception since the halogen atoms have
considerable positive character and attack on the carbonyl function is
sterically hindered.
Stereochemistry
No mention has been made in the literature of the geometry
of vinyl phosphates obtained by the 'abnormal' Michaelis-Becker reaction.
Pudovik has shown that treatment of diethyl phosphonate with M-chloroethyl
acetoacetate in the presence of triethylamine gives one epoxide
stereospecifically. It is suggested that the angular dependence of
P-CC-H coupling constants may be used to distinguish between cis and
trans isomers of the oxiran ring95.
Et (Et0)2KH CH3-C-CHC1C02Et
3N
* (Et0)2 ?-d2bHCO2Et
6113
- 33 -
2. Structure of Phosphorus Compounds
The structure of and the type of bonding that exists in
phosphorus compounds is well known°. Phosphorus is a group V
element with electronic structure for the isolated atom of
(1132282463823p3) and can form a variety of covalent compounds of
differing stereochemistry. The type of compound of particular interest
in this work is best illustrated by considering the structures of (VII)
and (viii)97.
VII
Phosphine (VII) is an example where phosphorus is covalently
bonded to three other atoms in a pyramidal arrangement and also possesses
a lone-pair of electrons. These compounds behave as donors due to the
presence of the lone-pairs and acceptors because the phosphorus has
empty d-orbitals of favourable energy available. In orthophosphonic
acid (VIII) the phosphorus is covalently bound to four other atoms in
a tetrahedral arrangement. The phosphorus atom exhibits 5p3-type
hybridisation and a double bond to the oxygen atom is formed by means
of dlY -pl.,' overlap using the low energy empty d-orbitals on the
phosphorus.
- 34 -
IL Nomenclature
The lower, pIII, and higher, PV, acids of phosphorus are well
understood. The lower acid has the phosphorus atom bound as in P(OH)3,
while the higher acid is derived from 0.P(OH)3. There are a variety of
lower PIII i acids of differing basicities, all having with the exception
of the triesters P(OR)3
e.g. trimethyl phosphite P(OCH3)3 - has a
structure of type (VII)] at least one P-H bond with four bonds (51)3)
to phosphorus - type (VIII). The common lower P/II acids are given in
Table 2. They are distinguished from the higher PV acids by the
ending -ous instead of -ice
Table 2
Some common P I acids
H PO 3 2
H3PO3
RPO2H2
R2FOH
▪ Hypophosphorous aicd
▪ Phosphorous acid
▪ Phosphonous acid
• Phosphinous acid
The nomenclature for compounds containing a free acid function
has been complicated to some extent because they can either be considered
derivatives cfhosizuontaisacid (IX) or of phosphinie acid (X).
(H0)2PH HOP(0)H2
iR
X
The evidence" (see introduction where the hydrogen atom
transfer in dialkyl phosphonate is thought to be similar to keto-enol
- 35 -
shift in carbonyl compounds) seems to favour a structure of type (IC)%
e.g.
CH3
-H
CH3
phosphite phosphonate
It will be the policy for the remainder of this work to
consider the esters of these PIII acids as derivatives of the compounds
according to the form in which they usually exist99.
e.g. (cH30)2P(0)H is dimethyl phosphonate rather than dimethyl phosphite
CH3PH(0)0CH3 is dimethyl phosphinate rather than dimethyl phosphonate
The sulphur analogues are named by using the thio- prefix.
e.g. (CH30)2P(S)H is dimethyl thiophosphonate
CH3PH(s)0cH3 is dimethyl thiophosphinate
This nomenclature can also be used for the vinyl phosphates
which are of particular interest to this work - Table
Table 3
vigil (thio)phnsehate ziulLthicapLicazhojate yial....(thio)phosphinate
-1 A R2 alkyl
X = 0, S
X The hydrogen phosphites show a clear evidence for phosphonate
structure -31P chemical shift is in the region 0-12 ppm and a
large 'tipH coupling of about 700 H.100,
CH3
CH3
-OH
- 36 -
0
4. Results and Discussion
The reaction ef dimethyl phosphonate with various ee-chlorinated
carbonyl compounds has been studied using a variety of bases. Dimethyl
phosphonate was thought to be most convenient because not only was it
readily available in large quantities but the products of the reaction
could be readily identified by 'H nmr. The methoxy signals in the 'H nmr
were easier to locate than would be.the ethoxy signals for the diethyl
analogue. This was particularly important when isomeric mixtures of
vinyl phosphates (VI), epoxy phosphonates (V), and ketophosphonates (IV)
were obtained. The isomer ratios of the products obtained in these
reactions were calculated directly by 1H nmr integration of convenient
signals in the 'H nmr of the crude reaction mixtures (e.g. nmr
integration of methoxy resonances). It is possible to use a variety
of phosphorylating agents (see Chapter 5) and also to vary the nature
of the leaving group e.g. changing chlorine for bromine but this will
be considered in more detail in a later section (see Chapter ).
When phenacyl chloride was treated with dimethyl phosphonate
in the presence of a variety of bases such as ammonia, triethylamine,
methoxide, or hydride ion using a suitable solvent such as methanol or
acetonitrile, the only product that could be detected was dimethyl
1-phenyl vinyl phosphate (XI). Using thin layer chromatography (tic)
and 'H nmr it was impossible to. detect the presence of any dimethyl
1-phenyl epoxyethyl phosphonate (XII). Dimethyl epoxyethyl phosphonates (V)
are more polar than the corresponding dimethyl vinyl phosphates (V1)
and can be very easily observed in the 111 nmr since the methoxy groups
are non-equivalent being next to an asymmetric centre with J R/ . 11.0 He
- 37 -
The methoxy resonances in dimethyl vinyl phosphates are equivalent
and show a coupling to phosphorus of the order of 11.0 Hz,
H Cl 1.NH3/CH3OH/10o (CH30)2Kg =CH2
a
2. ° Et3N/CH3CN/10
XI
(cH30)2LH 3eNs0CH /CH OH/10°
/ 3 / 3 4 .NaB/ TIT/ 10o
0
XII
Dim'thyl 1-phenyl vinyl phosphate (XI) was identified by means - 1 ,
of I.R. -.‘1 max = 1640s cm - kC=C strething frequency) and 'H nmr
6 5.20 ppm (2H, m) - (vinylic resonances).
Initially the reaction conditions used were the ones that
had been developed by Shell Research Limited for the synthesis of the
insecticide IBirlane'll. Ammonia was bubbled through a methanolic
solution of dimethyl phosphonate and phenacyl chloride until one
equivalent had been taken up. It was necessary to use methanol as
solvent and not ethanol when using dimethyl phosphonate since any
transesterification which might occur will not interfere with the final
products. There was a problem that methanol, being nucleophilic, might
D.E. Poel, N. Fekkes, D. Medema, "Birlane Synthesis: Route starting
from M-dichlorobenzene and using diethyl phosphite as phosphorylating
agent", K.S.L.A. Research Report No. R 1416/67
CH3CH2
=CHC1 CH3CH2CY Cl
'Birlanel
• 1
ether CH3CH2
CH3CH2O
OM 38 O.
hydrolyse the vinyl phosphate to the acetophenone and these products
were detected on several occasions.
CH 1 3 :0 -H
CH30.44_,/
// -‘134 CH30 2
(CH30)3P.0
Also it was found inconvenient to use ammonia as the base
since it was impossible to add accurately an equivalent amount.
Instead it was thought better to carry out the reactions in acetonitrile
using triethylamine as the base. Acetonitrile is a non-nucleophilic
solvent with a dielectric constant similar to methanol and triethylamine
is a good base but a very poor nucleophile.
•
Dimethyl l-phenyl vinyl phosphate (XI) was the only product
isolated when sodium dimethyl phosphonate was treated with phenacyl
chloride using THF as solvent. This was again confirmed by both the
tic and 'H nmr. Meisters and Swan60 had already reported a similar
observation when treating sodium diethyl phosphonate with phenacyl
chloride using ether as the solvent.
- 39 -
When monochloroacetone was treated with dimethyl phosphonate
in the presence of triethylamine using acetonitrile as the solvent,
no product of phosphorylation could be detected by chromatography
or by nmr after normal work-up even after stirring at room temperature
for several days. However, when monochloroacetone was added to sodium
dimethyl phosphonate in acetonitrile solution a mixture of dimethyl
1-methyl vinyl phosphate (XIII) - 39% and dimethyl 1-methyl epoxyethyl
phosphonate (XIV) - 615 was produced. The isomer ratio was determined
by integration of the methyl region in the 'H nmr of the crude reaction
mixture.
3 /2k
3
THF (CH 0\ NaE) + CH -Cg -CH2Cl (CH 0)2 J,C=CH2
CHt 3
XIII - 39%
(CH30)
XIV - It was possible to separate these isomers by column chromatography
and to analyse them individually. Dimethyl 1-methyl vinyl phosphate (XIII)
was identified by I.R.>) max 1670s (fC=d,stretch). 1295vs (P=0 stretch),
1190 (P-C-methyl), 1040 (P-0-alkyl) cm -1 and 'H nmr 6 1.93 (methyl),
3.74 (methoxy), 4.48, 4.69 (vinylic protons)ppm. Dimethyl 1-methyl
epoxyethyl phosphonate (XIV) was the more polar compound and identified
by I.R. V max 1270vs (13=0 stretch), 1185 (P-0-methyl), 1030 vs (P-0-alkyl),
835s (oxiran ring) cm-1 and 'H nmr 6 1.52 (methyl), 2.73, 313 (methylene
- two triplets JII-H = JH-P), 3.75 (methoxy)ppm.
- 40
The dimethyl 1-methyl epoxyethyl phosphonate (XIV) reacts
with hydrogen chloride gas to give a hydroxy phosphonate as a crystalline
compound, the expected product of an epoxide-ring opening reaction.
Two possible hydroxy phosphonates may be produced eitherdimethyl 1-methyl,
1-hydroxy, 2-chloroethyl phosphonate (XV) or dimethyl 1-methyl, 1-chloro,
2-hydroxy ethyl phosphonate (XVI) depending on the mechanism of epoxide
ring opening.
(CH 0) ?-011 3 2 -' 2
CH3
HC1
0 H (CH30) -CH Cl '2 2
CH3
XV
or
` (O1130)2P- -CH2OH
CH3
XVI
1H nmr showed resonances at 6 1.53 (methyl doublet, JP-H..
15.0 Hz), 3.77 (methylene multiplet), 3.89 (methoxy), 4.72 (broad hydroXY
- exchangeable with D20)ppm. The absence of aay coupling of phosphorus
to the hydroxy proton suggests that the hydroxy group is attached to
carbon-2, making the structure (XVI) most probable. These two compounds
may be distinguished chemicalbrsince when treated with base (XV) should
give a mixture of dimethyl 1-methyl vinyl phosphate (XIII) and dimethyl
1-methyl epoxy ethyl phosphonate (XIV) while (XVI) can only form
dimethyl 1-methyl epoxyethyl phosphonate (XIV). This assumes that vinyl
phosphate is produced from the hydroxy phosphonate intermediate derived
from the attack of dimethyl phosphonate at carbonyl carbon (see Chapter 6),
No attempt has been made to rearrange the hydroxyphosphonate and so
differentiate between structures (XV) and (XVI).
- 41 -
OH (CH o) 3 20
2ol
CH3
Base? (030)2?-0-?-02 XIII
ell3
XV
(cH3o XIV
ci (030) P -CH2OH
Ai3
Base? (CH30)2?-162
OH3
XIV
When 2,2-dichloro acetophenone was reacted with dimethyl
phosphonate in either ammonia/methanol or triethylamine/acetonitrile
an isomeric mixture of dimethyl 1-phenyl 2-ohloro vinyl phosphate.(XVII)
was produced - 95= E, go No formation of the corresponding dimethyl
1-phenyl 2-chloro epoxy ethyl phosphonate could be detected either by
floornmr. The dimethyl 1-phenyl 7-chloro vinyl phosphate was
identified by I.R.).max 1640s( `A=C stretch), 1290vs (P=0 stretch),
1185 m (P-0-methyl), 1040 vs (P-0-alkyl) cm-1 and 111 nmr 6 6.45 (vinylic proton in E-isomer), & 6.15 (vinylic proton in Z-isomer)ppm. The
assignments of the stereochemistry are based on the observations that
the proton which is cis to phosphorus in a pair of geometric isomers
resonates to low field of the proton which is.trans to phosphorus,
(this rule will be fully established in Chapter Isomer ratios were
determined by integration using 211 and 31P nmr and glc analysis.
9 1.NH /CH. OH (CH3o)2P-H CH3CN (CH
3 0)3 ",c
+ (CH30))-OK „ :c=
(I)
95% E-isomer Z-isomer
XVII
Treatment of sodium dimethyl phosphonate with 212-dichlorophenone
in a similar manner gave the same vinyl phosphate (XVII) in good yield as
the only product but only the E-isomer could be detected.
In a similar reaction 2,2-dichioroacetone when treated with
dimethyl phosphonate in the presence of triethylamine gave the expected
dimethyl 1-methyl-2-chloro vinyl phosphate (XVIII) along with a trace of
epoxide which could not be isolated. Unfortunately, only one isomer
could be detected by 'H nmr making it impossible to assign the geometry
of the product directly using the rules already established (see Chapter 2).
1.Et3N/cH
3CN/100
(CH3 0)2 + CH3COCHC12 > (ONO)2 P-OTCHC1 2.NaH/THP/10° 3 H3
XVIII
This same isomer was produced when sodium dimethyl phosphonate
was treated with 2,2-dichioroacetone. The dimethyl 1-methyl 2-chloro
vinyl phosphate was identified by I.R.Lx 1660m(>4 stretch), 1300 vs
(P=0 stretch), 1170s (1)-0-methyl), 1050 vs (P-0-alkyl cm-1 and 'H nmr
& 2.10 (methyl, 3.86 (methoxy), 6.15 (vinylic proton) ppm.
It is possible to calculate the chemical shifts of the vinylic
protons in dimethyl 1-methyl 2-chloro vinyl Phosphate using the method
of Tobey101. The resonance position of the vinylic proton depends upon
the additivity of the individual symmetrical substituents - equation 1.
Y// Z gem trans
6H ppm = -5.27 + creis-X + o*trans-Y crgem-Z
- 43 -
In this equation -5.27 ppm represents the resonance position
of ethylene and otis-X, atrans-Y, and o'gemeZ are the shielding constants
of X, Y, and Z from the cis, trans and gem substituent locations. Tobey
has emphasised. that this additivity approach only holds well for small
substituent groups of symmetry greater than or equal to C. It is
assumed that for this example that the substituents are small enough
to allow an additivity relationship to apply. Also it is possible to
make use of values for the substituent shielding parameters that have
appeared in the literature - Table 4.
Table 4 Substituent Shieldin Parameters
Substituent cis ppm
trans ppm
gem ppm
-0P(0)(OCH3)2 -0.08102
+0.36102 -
-CH3
+0.26101 +0.29101 _0.44101
-Cl 101 -0.19 101 -0.03 101 -1.00
The calculated chemical shifts for the protons in the two isomers
are therefore SHE - -6.06 ppm and SHz = -5.65 ppm. The experimental value
determined for the isomer of dimethyl 1-methyl 2-chioro vinyl phosphate
(XVIII) was S 6.15 ppm which agrees very well with the calculated value
S 6,05 ppm for the isomer where the proton is cis to the phosphorus -
the E-isomer.
Therefore in the case of the two vinyl phosphates studied where
,the possibility of geometric isomerism exists a stereospecific formation
of the E-isomer occurs.
Base R-,,-CHC12 (CH30)2V-H "(CH
3o (cH 0
Cl
- 44 -
R E-isomer
005 95
Z-isomer
5
•
1 CH3
00
- 45 -
Infra-red spectra were recorded using a Peskin-Elmer 157
grating spectrometer or a Perkin-Elmer 257 grating spectrometer when
otherwise stated, liquid as thin films and solids as mulls. near were
recorded in carbon tetrachloride using a Varian Associates HA 100
spectrometer operating at 100 M Hz using field frequency lock or a
Varian Associates T60 spectrometer when otherwise stated. 31P nmr
were recorded in d-chloroform using a Varian Associates XL 100-12
spectrometer with proton noise decoupling and deuterium lock operating at
40.505 X Hz. Gas liquid chromatography (glc) was carried out using either
a Perkin-Elmer Fll or Pye-Unicam 104 gas chromatograph fitted with
0.9m x 3mm ID column packed with Gas Chrom 1 supporting yif, w cyclohexane
dimethanol succinate as stationary phase and operating at 2000. Flame
ionisation detection was employed and the product ratios determined
using a disc integrator. This column was efficient for separating vinyl
phosphate isomers but for vinyl thiophosphates and vinyl (thio)phosphonates
other packings were used. Thin layer chromatography (tic) was carried
out using Merck pre-coated silica gel F254
plates. Column chromatography
(cc) was carried out using Hopkin and Williams silica gel M.F.C. (about
100 to 200 mesh). The p-nitrobenzyl pyridine/tetraethylenepentamine
spray reagent developed for organophosphate pesticides103 was used to
detect the presence of P=0 containing compounds (organophosphates react
to give blue spots).
All mass spectral analysis were made using an A.E.I. M.S.902
or Perkin-Elmer MS 270 mass spectrometer.
- 46 -
All solvents were dried and redistilled before use. Tetrahydro-
furan (T.H.F.) was dried over lithium aluminium hydride (L.A.H.). Triethyl-
amine and acetonitrile were dried over 4A molecular sieves. Methanol was
distilled before use from magnesium methylate.
Melting points were recorded on a Kofler hot stage and all
distillations were carried out under nitrogen.
Phenac 1 Chloride
Monochloroacetyl chloride (79.1 g,(53 ma), 0.7 mol) was added
dropwise to a solution of sodium-dried benzene (234 g,(265 ml), 3 mol.) and
powdered anhydrous aluminium chloride (103 g, 0.77 mol). Hydrogen chloride
was evolved and some cooling was necessary to control the vigorous reaction.
After the addition (about one hour) the mixture was warmed at 500 for a
further one hour to complete reaction. The solution was cooled to room
temperature and water (500 ml) added dropwise 'to destroy the complex and
generate the phenacyl chloride - C.HC1 (50 ml) was also added to destroy
any remaining solid. The organic layer was sc-esrated off, washed with
saturated sodium bicarbonate (2 x 100 ml), water (2 x 100 ml) and dried
over powdered calcium chloride. The benzene solution was concentrated
at the pump to give an orange liquid which crystallied on standing.
The product was taken up in hot ethanol (300m1), decclourised with animal
charcoal and allowed to crystallise. Phenacyl chloride (65.4 g, 60%) was
obtained as colourless plates m.p. 540-550 (Lit." m.p. 56°-57°).
'H rmy & 4.73 (2H,$), 7.57 (311,m), 7.98 (2E,m)ppm.
Dimethyl 1.-phenyl vinyl phosphate
A. Ammonian procedure
A stirred solution of dimethyl phosphonate (5.5 g, 0.05 mol.),
phenacyl chloride (7.8 g, 0.05 mol.) in methanol (150 ml) were saturated
- 47 -
with dry ammonia at room temperature and allowed to stir at room
temperature for twenty-four hours. A white precipitate of ammonium
chloride was produced and tic indicated the presence of a new compound
with complete disappearance of phenacyl chloride. The methanol was taken
off at the pump and the residue taken up in ether (200 ml), washed with
water (4 x 100 ml) and dried over anhydrous sulphate. Removal of the
solvent gave a yellow liquid (8.72 g, rig) which was purified by column
chromatography (silica gel eluted with ethyl acetate/benzene, 1:1) to
give dimethyl 172henyl vinyl phosphate as a colourless liquid.
(Found: C, 52.53; H, 5.77; P, 13.45%. C101113PO4 requires: C, 52.63;
H, 5.74; P.13.57%.). max 3050 w, 2950 w, 2850 w, 1640 a, 1580 w,
1490 m, 1450 m, 1290 vs, 1190 m, 1110 w, 1060 vs, 1020 s, 860 vs,
780 s, 760 w, 720 m, 700 w, cm-1.
1/1 niar S 3.75 (6H, d; JH-P 11.3 Hz), 5.20 (2H, m), 7.28 (3H, m), 7.53 (2H, m)
ppm.
B. Triethylaminl_procedure
Dimethyl phosphonate (5.5 g, 50 mmol.) and phenacyl chloride
(7.73 g, 50 mmol.) in CH3CN (20.0 ml) were stirred together at 0°. A
solution of triethylamine (5.05 g, 50 mmol.) in CH3CN (30.0 ml) was
added dropwise over a period of thirty minutes so that the temperature
didn't rise above 5° - some cooling was required. The solution was
stirred for twenty-four hours at room temperature when tic indicated
the absence of phenacyl chloride and formation of vinyl phosphate.
After removing CH3CN at the pump, the residue was taken up in ether
(200 ml), washed with water (3 x 150 ml), and dried over anhydrous
sodium sulphate. The ether was removed at the pump to give a pale yellow
liquid (7.7 g, 66%) which was purified by column chromatography to
- 48 -
to produce a colourless liquid with identical ?H nmr and I.R. as
dimethyl 1-phenyl vinyl phosphate.
C. Sodium methoxide in methanol procedure
Dimethyl phosphonate (2.75 g, 25 mmol.) and phenacyl chloride
(3.9 g, 25 mmol.) were stirred together at 5-10° in a nitrogen atmosphere.
A solution of sodium methoxide in methanol (25 ml of 1.0 M solution
standardised with 1.014 HC1) was added dropwise at such a rate that
the temperature didn't rise above 100 - cooling was required. After
stirring at room temperature for twenty-four hours the reaction was
worked 1.11) in the usual way - see 217222111],a13.1 to give - a colourless liquid
(4.5 g, 79%) which was identical in all respects with dimethyl 1-phenyl
vinyl phosphate
D. Sodium hydride procedure,
Dimethyl phosphonate (la g, 10 mmole.) was added dropwise to
a stirred suspension of sodium hydride (0.5 g - 100% excess since sodium
hydride is 50% suspension in oil) in dry T.H.F. (20.0 ml) at 0-5°. The
solution was stirred until no further evolution of hydrogen was detected
and a further portion of dimethyl phosphonate added if necessary to
neutralise any remaining sodium hydride.
Phenacyl chloride (1.54 g, 10 mmol.) in dry T.H.F. (5.0 ml)
was added dropwise over thirty minutes so that the temperature did not
rise above 0° and the solution stirred at room temperature for twenty-four
hours - tic indicated the absence of phenacyl chloride with formation of
vinyl phosphate. Work up in the usual way - see Procedure B, afforded
cLatt ztisrai vinyl phosphate (1.86 g, 82%) identical in all respects
nmr and I.R.) with an authentic sample.
49 -
Monochloroacetone105
Sulphuryl chloride (80.0 g, 0.593 nol.) was added dropwise to
acetone (580 g, 10 mol.) over a period of five and a half hours, taking
care to exclude moisture and keeping the flask in an ice-bath. After
removing the excess acetone at the pump the residue was washed with
K2003 solution (10.0 ml of 50% solution) and dried over Ne2SO4. The
crude product was distilled at reduced pressure to give monochloroacetone
(20.1 g, 37%) as a colourless liquid b.p. 39-40°/20 mm Hg. 1
Lit.05 b.p. 118-120°.
III rem t 2.31 (3H, 0, 4.16 (2H, s) ppm*
Dimethyl 1-methyl vinxy?! phosphate
Dimethyl phosphonate (2.75 g, 25 mmol.) was added dropwise
to a stirred suspension of sodium hydride (1.20 g, 25 mmol. since NaH
is 50Tie suspension in oil) in dry T.H.F. (25.0 ml) at 0°. The mixture was
stirred until no further evolution of hydrogen was detected and a further
portion of dimethyl phosphonate added to neutralise any excess sodium
hydride.
Monochloroacetone (2.31 g, 25 mmol.) was added dropwise to the
brown solution at 0-5 - the solution went red in colour. The solution
was stirred at room temperature in a nitrogen atmosphere for twenty-four
hours to produce a white precipitate of sodium chloride and finally
refluxed for two hours. The solution was filtered, dried and the T.H.F.
removed at the pump to give a yellow liquid (3.0 g, 72%). Tle (silica
eluted with ethyl acetate) and 'H nmr (integration of the methyl signals)
showed what looked like a mixture of dimethyl 1-methyl vinyl phosphate (39%)
and dimethyl 1-methyl epoxyethyl phosphonate (61%). Column chromatography
(silica eluted with ethyl acetate) gave a fast moving compound dirithlia.
1-methyl vinyl thosthite (0.95 g, (Found : C, 35.97; H, 6.37;
PI 18.82: 051111PO4 requires : C, H, 6.67; P, 18.65,').
lmax 3000 m, 2850 w, 1670 s, 1450 m, 1375 w, 1295 vs, 1240 m, 1190 m,
1040 vs, 990 s, 915 m, 860 s, 810 m, cm-I.
1H nmr ft. 1.95 (5H, s), 3.74 (6H, d; JII_p 11.3 Hz), 4.48 (1H, m), 4.69 (1H. m)
PPm.
31P nMr.+4.8 ppm (from H3PO4).
The slower moving compound was din12:th.11-nlero.-ethlz_.
phosphonate (1.98 g, 48). (Found : C, 35.72; H, 6.63; P, 18.09:
C5H11PO4 requires : C, 36.15; H, 6.67; P, 18.65,1).
imax 2950 m, 2850 w, 1450 s, 1270 vs, 1210 s, 1185 m, 1030 vs, 855 s,
835 s, 810 m, 760 u, cm-1.
1H nmr 6 1.52 (3H, d; 311,..p 11.8 Hz), 2.73 (1H, t; 4111.4D 541 Hz,' JEI_H 5.1 Hz),
3.13 (1H, t; Jil_p 5.1 Hz, 311-H 5.1 Hz), 3.75 (6H, d; J11.0, 11.3 Hz) ppm.
P nmr -23.0 ppm (from H3PO4).
Treatment of dimethyl 1-methyl epoxy ethylshosphonate with hydrogen chloride
as
- Dimethyl 1-methyl epoxy ethyl phosphonate (0.166 g, 0.001 mol.)
was dissolved in a mixture of 40/60 petroleum ether (10.0 ml) and ether
(2.0 m1). Dry hydrogen chloride gas was passed as a slow stream through
the solution for four hours and the reaction allowed to stir at room
temperature for fifteen hours. After removing the solvent at the pump
the residue was taken up in chloroform (50.0 ml), waned with water
(3 x 20.0 ml), and dried over anhydrous sodium sulphate. Removal of the
chloroform at the pump gave a solid which recrystallised from 40/60
petroleum ether as colourless prisms m.p. 74-750. This was thought
to be dimethyl 1-methyl, 1-hydrovi 2-chlorof1122_111ovhonate.
31
51 ONO
(Found: C, 29.11; H, 6.01; Cl, 15.60%4 C5H17PO4C1 requires: C, 29.641
H, 5.97; Cl, 17.50M
1 H nmr 6 1.55 (3H, d; JR-P 15.2 Hz), 3.77 (2H, m), 3.89 (611, d; JH-P 10.1 Hz),
4.72 (1H, be) ppm.
2.2-Dichloro acetophenone
Dichloro acetyl chloride (14.8 a, 0.1 mol.) - prepared by
treatment of dichloroacetic acid with thionyl chloride was added dropwise
to a stirred suspension of powdered aluminium chloride (14.7 g, 0.11 ma.)
in sodium-dried benzene (38.0 ml). Hydrogen chloride gas was evolved
and some cooling was necessary to control the reaction. After the
addition (about one hour) the mixture was stirred at room temperature
for four hours and then warmed at 50o for a further one hour. The
solution was cooled to room temperature and water (70.0 ml) was added
dropwise to destroy the complex, generating the dichloroacetophenone
c HCI (7.0 ml) was added to dissolve any remaining solid.
The organic layer was separated washed with saturated sodium.
bicarbonate (20.0 ml), water (2 x 20 ml) and dried over powdered calcium
chloride. Removal of benzene in vacuo gave a dark yellow liquid (15.84 g)
which distilled at reduced pressure to give pure 2 2-dichloro acetophenone,
(12.8 g, 68%) b.p. 82-83°/0.6 mm Hg as a colourless liquid.
9H nmr 6 6.60(1H, a), 7.43 (3H, m), 7.93 (2H, m) ppm.
Dimetty.11:2122 o7co vinzlphosohate
A slow stream of ammonia was passed into a stirred solution of
diriethyl phosphonate (5.5 g, 0.05 mol.) and 2,2-dichloro acetophenone
(9.45 g, 0.05 mole in methanol (60.0 ml) at room temperature until
saturation. The solution was stirred at room temperature for
twenty-four hours. After removing the methanol at the pump, the oil
52
was taken up in ether (200.0 ml), washed with water (2 x 150m1) and dried
over magnesium sulphate. Removal of the ether gave a pale yellow liquid
(11.9 g, 84%) which was an isomeric mixture of dimethyl 1-phenyl
2-chloro vinyl phosphate (95% Et 5% Z by 'H nmr integration of vinylic
region). No trace of epoxide formation could be detected by tic or 'H nmr.
Column chromatography gave dineth;11-hen12-01ovilhosphate
as a colourless liquid (Found: Ct 45.5; H, 4.7; P, 11.7; Cl, 14.7%:
C10H11F04 Cl requires: C, 45.7; H9 4.6; Pt 11.8; Cl, 13.91.). Nimax 3070 mt 2950 m, 2850 mt 1630 w, 1495 m, 1445 s, 1330 m, 1290 s,
1185 st 1095 s, 1040 vs, 925 st 910 st 855 st 770 m, 760 m, 695 s, om-1.
'H nmr a-isomer & 3.68 (3H, d; JH-P 11.2 Hz), 6.45 (1H, d; NH-P 2.8 Hz),
7.30 (3H, m), 7.58 (2H, m) ppm.
'H nmr Z-isomer 6 3.70 (3H, d; JE-P 11.4 Hz), 6.15 (1H, d; JH-P 2.1 Hz).
7.30 (3H, m), 7.58 (2H, m) ppm.
222:14c111927"....--106
Suiphuryl chloride (67.5 g, 0.5 mol.) was added dropwise to
Analar acetone (14.5 g, 0.25 mol) at 30°-45° with stirring over a period
of one hour. After complete addition the reaction was stirred at room
temperature for twenty-four hours. The crude material was distilled
at atmospheric pressure to give pure 2117Lichleroacetone (26.5 g, 83%)
as a colourless liquid b.p. 90-92° (Litl06b. p. 117-118(3).
'H nmr i 2.46 (3H, s), 5.83 (IH, s)
Dimethyl 1-methjl 2-chlorovinyl
2,2-Dichloro acetone (3.18 g, 25 mmol.) and dimethyl phosphonate
(2.75 g, 25 mmol.) were stirred in CH3CN (10.0 ml) at 10° in a nitrogen
atmosphere. Triethylamine (2.53 g, 25 mmol.) in CH3CN (15.0 ml) was
added dropwise to the solution over a period of thirty minutes. The
- 53 -
mixture was heated at 300 for one hour and then stirred at room temperature
for twelve hours. After filtering off the triethylamine hydrochloride
the solvent was removed in vacuo to give a pale yellow liquid (2.7 g, 50)
which was purified by column chromatography (silica ethyl acetate/benzene
1:1) giving dimethyl 1-methyl 2-chlorovinyi phosphate, as a colourless
a liquid (Found: C, 30.18; H, 5.06; Cl, 17.78; P, 15.44%: C5H10PO4C1
requires: C, 29.94; H, 5.03; Cl, 17.68; P, 15.40.).
-;) max 3100 w, 2950 m, 2850 w, 1660 m, 1460 m, 1395 m, 1300 vs, 1170 s,
1050 vs, 970 s, 860 s, 790 m, 850 w, cm 1.
1H nmr 6 2.10 (3H, d; JH-P 0.9 Hz), 3.86 (611, d; 41-P 11.5 Hz), 6.15 (1H, m)
- only E-isomer present.
r
rt*
- 54 -
S
CHAPTER 2
- 55 -
CHAPTER 2
The Geometry of Vinyl Phosphates as Determined byEmlearliamais
Resonance
1. 'Introduction
The Geometry of trisubstituted ethlenes
The stereochemistry of symmetrically and unsymmetrically
I,2-disubstituted ethylenes, type (XIX) (trans-isomer) and type (XX)
(cis-isomer) is determined by making use of the fact that Piall trans/ >himi .
107 cis/•
H H
XIX XX
• trans-isomer cis-isomer
For the trisubstituted ethylenes, type (XXI) it is no longer
possible to make use of the magnitude of the H-H coupling constants for
assigning the geometry.
A H
XXI
In the trisubstituted ethylene (XXI) geometric isomerism exists
when the proton may be cis or trans to the substituents A and B respectively,
Several attempts have been made101408,109 to use an additive
substituent chemical shift (S.C.S.) approach in providing corroborative
evidence for the assignment of stereochemistry. In this treatment the
chemical shift of the vinylic proton is calculated from the empirical
relationship - 1.
6 (ppm) = -5.27 + °l-cis + od + 1 e-trans C-gem
- 56 -
In this equation, -5.27 ppm is the chemical shift of ethylene (from Me
4Si internal reference; positive shift to high field), and
ce, 0', ce, are the S.C.S. of tne substituent groups in their appropriate
locations (with respect to H). These values, are average values for
the S.C.S. obtained in a variety of situations (e.g. 1-substituted and
1,2-disbustituted ethylenes) where the geometry is unambiguous. It is
possible to tabulate the functional group shielding parameters for
an endless variety of vinylic substituents102.
This additivity approach completely ignores any interactions
between the substituents and can only be expected to hold for small
substituents of symmetry greater than or equal to C3v (especially for single
atoms). It might be expected to fall down for large substituents for lower
symmetry because of the long-range interactions which may depend upon
the conformational properties of the substituents. Pascual, Meier,
and Simon108 have attempted to overcome this difficulty by recognising
that conjugative-type interactions between vinyl substitutions will
profoundly alter their effective o'values. It is possible to obtain two
sets of yvalues. One set. is used when substituents are present alone
on the double bond (solo). The other is used when two or more groups
capable of conjugation are present together (conj). This approach is
probably too over-simplified because the cooperative shielding properties
of, two functional groups capable of mitigative interaction will depend
to a large extent on the relative geometries of the two substituents.
Tobey101 has discussed this problem in some detail and concludes that
in order to predict the resonance positions of vinylic protons in
trisubstituted ethylenes bearing two asymmetric (Cs or lesser symmetry)
substituents a 'model compound' approach is necessary. A compound is
selected from the literature which bears the asymmetric substituents
in the appropriate geometry and environment, and in ehich the vinyl
resonance positions can be unambiguously assigned by means of chemical
shifts or coupling constants. This 'model compound' can then be
transformed into the desired trisubstituted ethylene by applying the
appropriate & value in the usual way. This treatment automatically
takes into account most of the interactions between asymmetric groups.
- 57 -
2. Nomenclature of Vinyl Phosphates
Vinyl phosphates (XXII) can be considered as being substituted
ethylenes.
R1 X
=CWH (X = 0,S)
XXII
The stereochemistry of 2-substituted vinyl phosphates (XXII,
Y = H) has been assigned either cis or trans depending upon the
relationship of the hydrogen atoms about the double bond. For the
1,2-disubstituted vinyl phosphates (XXII, Y,W H) the problem of
nomenclature is not so straightforward. PhosdrinR insecticide is a
mixture of the two geometrical isomers of dimethyl 1-methyl 2-carboxy
methyl vinyl phosphate which were assigned cis (XXIII) and trans (XXIV)
by virtue of the relationship of the proton with respect to the
phosphoryl group110.
(CH ON __e//H (C1130)2P-ON //CO2CR3
CH/C LNCO2CH3 3 CH" 3 XXIII
XXIV
cis-isomer trans-isomer
This problem has been'turther complicated by Casida 111, 112
designating the isomers ec- and V7 corresponding to cis (XXIII) amd trans (XXIV) - thee&-isomer being more toxic to insects and mammals.
Recently, the prefixes cis- and trans- to describe geometric
isomerism around a double bond have been replaced by the IUPAC descriptions
E and 2115 In order to use this nomenclature it is necessary to
establish a set of operating conditions114:
io For each double bond to be described configurationally
- determine which of the two groups attached to the
doubly bound atoms has the highest priority accoraing
to the sequence of rules by Cahn, Ingold, Prelog115
.
H
R A.R. Stiles, U.S. Pat. 2,685,552, to Shell Development Co.
- 58 MID
ii. That configuration in which the two groups of higher
priority are on the same side of the reference plane
(in the plane of the ifsystem) is assigned the stereochemical
descriptor Z (German-Zusammen). That configuration in
which these two groups arc on opposite sides is assigned the descriptor E (German-Entgegen).
On this basis the 1,2-disubstituted vinyl phosphates cis-(XXIII) and trans-(XXIV) are assigned E and Z respectively. Similarly the trans and cis isomers of 2-substituted vinyl phosphates can be assigned to be
of either E or z configuration. By using this nomenclature it is found as a general rule that
the vinyl phosphate with the proton cis to phosphorus is the E-isomer and the vinyl phosphate having the proton trans to phosphorus is the
Z isomer.
h/Ph2C0 (Et0)2?' -0\ ), (Et0)2 -0e,\t
117
- 59 -
11 1HEErg2-2212etituted and 112aistihstitun ates -
use of chemical shifts to determine the stereochemistry of
vinyl phosphates
A series of diethyl 2-substituted vinyl phosphates ( (XXII);
R1 = R2 = EtO, X =2 0, Y = H, W = Ph, CH3, Br, or C1) were made by
treating the appropriate halogenated aldehyde withiniethyl phosphite
in a Perkow type reaction29.
(Et0)3P + CICHWCRO ) (Et0)2?-0-CH=CHW
Except for the case when W = Ph, a mixture of both E and Z isomers was
obtained from which all the required nmr parameters were measured
directly by a first order analysis. When W = Ph, only the E-isomer was formed, but this was readily photo-isomerised to the Z-isomer using
benzophenone as a triplet sensitiser.
E -isomer
Z-isomer
The observed chemical shifts and coupling constants for diethyl
2-substituted vinyl phosphates are given in Table 5. It was possible to distinguish. the E-isomer from the Z-isomer because PHHtre:11.3/ (in the order of 12.0 - 2.0 Hz) > /JHH cis/ (in the order of 5.0 I 1.0 Hz) which
has already been well establiedned for 1,2-disubstituted ethylenesi073 There is some justification in using first order spectral analysis for the Z-isomers where the chemical shift difference between the coupled
protons is large (5.0 ± 1.0 fiz). greater than 0.1
(>1.0 ppm) compared with the small coupling constant
A very rough estimate is that As should not be
for a first order analysis to apply 116. The E-isomer
(J 12.0 t 2.0 Hz,66 <1.0 ppm) might be expected to show more
considerable second order effects and the first order enalysis may not be fully justified. It can be seen for all pairs of isomers of diethyl 2-substituted vinyl phosphates that the proton in the isomer which is cis to phosphorus resonates to low field of the proton in the one trans
to phosphorus. Also the trans phosphorus-proton coupling constant is
J/H.
bo
Table 5
Nmr arameters of dieth 1 2-substituted vinyl phosphates
(Et0)2?-0>
S (ppm rel. to Me4Si)a
A B 6H GA SB HP AP BP HA Hs A!3
H Br 6.79 6.00 7.50 1.40 11.40
Br H 7.02 5.52 5.50 2.20 4.10
H Cl 6.76 6.08. 7.45 I.50 11.05
Cl H 6.80 5.52 5.6 1.90 4.10
H CH3 6.33 5.28 5.80 1.30 1.50 11.75 1.70 6.90
CH H b 4.75 b b 2.20 6.00 6.90
H Ph 7.00 6.25 6.40 1.20 12.40
Ph H 6.52 5.50 5.30 2.80 6.55
H117 R. 6.55 4.60 4.51 6.8 1.2 207 13.6 6.0 1.7
a Positive shift to low field. Nmr spectra were determined
for 0.3-0.5 M solutions in CC14 (Me4Si internal reference).
b Buried under H resonance of trans isomer
61 eta
greater in magnitude than the cis phosphorus-proton coupling constant. In general JFH cis 1.3 - 0.2 Hz and jPH trans = 2.4 ± 0.4 H * z*
Diethyl 1-phenyl 2-substituted vinyl phosphates ( (XXII); R1 = R2 = EtO, X . 0, Y = Ph, W = Ph, CH
3 Br, or C1) have been made by
treating the appropriate halogenated-phenove with triethyl phosphite
in the normal Terkow type reaction35.
(Et0)3P + C1CHW-C-PH (Et0)2F-o-y.mw
Later (see Chapter 3) it will be shown that the analogous dimethyl
1-phenyl 2-substituted vinyl phosphates ( (XXII); Rli = R2 = MeO, X = 0, Y = Ph, W = Ph, CH
3, Br, or C1) can be obtained by treating the appropriate
halogenated-phenone with dimethyl phosphonate in the presence of base
- 'abnormal' Michaelis-Becker reaction.
(Ae0)2P-H + C1CHWIPh (Me0)ti-O-C.CHW
11
The observed chemical shifts and coupling constants for diethyl
1-phenyl 2-substituted vinyl phosphates are given in Table 6. These
1,2-disubstituted vinyl phosphates can be considered as being trisubstituted ethylenes and so the geometry cf the double bond cannot be assigned
unambiguously from coupling constant considerations. In an earlier example
(see Chapter 1) the stereochemistry of the double bonds in the isomers of dimethyl 1-methyl 2-chloro vinyl phosphate ( (XXII); R1 = R2 = MeO, X Y = CH
3' W = C1) were established by 1H nmr using the additivity approach
developed by Tobey1010 Unfortunately, this treatment tends to fall down
when large substituents have to be considered which will interact with
each other. In fact Borowitz35 used this method to confirm his assignments,
which had been made on the basis of BF3
shifts, and then showed how
unreliable it is when his assignments had to be reversed after further experiments'7 (using lanthanide shift reagents and nuclear Overhauser effects (NOE)).
A more realistic method of calculating proton chemical shifts
in trisubstituted ethylenes is to select a /model compound/ from the
- 62 -
literature which contains some of the unfavourable interactions and where the geometry of the double bond is not in dispute. Diethyl 1-phenyl vinyl phosphate (XXV) provides a particularly convenient model for calculating
the effect of a phenyl substituent geminal to a phosphoryl function on
the proton resonance positions, since fortuitously both vinylic protons
have the same chemical shift35 (-5.21 ppm from Me4 Si - this was reconfirmed)
and there is no problem of assignment. From the available data for diethyl
XXVI)117 vinyl phosphate ( see Table 5, it is possible to calculate
the effect of substituting a phenyl group at carbon-1 on the protons at
carbon-2 in diethyl vinyl phosphate.
(Et0)2?-5=
C6H5
-5.21
xxv
(Eto)2P-oN rn -4.80
,c1-"c■ -6.55 H' `H -4.51
XXVI
Figures are the 1H
chemical shifts in
ppm from Me4Si.
The values of 04Ph cis = -0.70 ppm and &'Ph trans ra.0.41 ppm
(where & represents the substituent chemical shift (S.C.S.) for the phenyl
group relative to a hydrogen in diethyl vinyl phosphates) can be deduced.
It is possible to 'transform' the E and Z isomers of diethyl 2-substituted
vinyl phosphates of known stereochemistry (using H-H coupling constants)
into the E and Z isomers of diethyl 1-phenyl 2-substituted vinyl phosphates
by applying the necessary value of 0'1 for the phenyl group. The
calculated and observed chemical shifts and coupling constants for the
protons in diethyl 1-phenyl 2-substituted vinyl phosphate are shown in Table 6.
IE
Diethyl vinyl phosphate and dimethyl vinyl phosphate were Obtained in good
yield by treating chloromercuriacetaldehyde withiriethyl"phosphite and
timethyl phosphite respectively. Chloroacetaldehyde the normal starting
material is difficult to obtain in a pure state.
, 0 (Ro3p C1HgCH2CHO 010)2 -
R = Et or Me
- 63 -
•
Table 6
jimr parameters for diethyl 1-phenyl 2-substituted vinyl phosphates
0 (Et0)2P-
Ph'
B 6A (ppm) °ale.
6B (ppm) (calc.)8.
6 (ppm) (obs.)a b
JpH(obs.)/H;"1
H Br 6.41 6.49 2.8
Br H 6.22 6.14 1.6 H Cl 6.49 6.45 2,8
Cl H 6.22 6.13 2.3
H CH3 5.69 5.77 2.8
CH. H 5.45 5.60 2.5
H Ph 6.66 6.69 2.5
Ph H 6.20 6.33 1.0
a Positive shifts to low field (Me4 Si internal reference).
•
Nmr spectra determined for 0.3-0.5 M solution in 0014 (ft
4Si internal reference).
- 64 -
From the results it can be seen that there is very good agreement between the calculated and observed chemical shifts in diethyl 1-phenyl
2-substituted vinyl phosphate. Also, in any pair of isomers with structures
of type (XXII) the proton cis to the phosphoryl group resonates to low field of the corresponding trans proton irrespective of the nature of the
substituent Y (Y = Ph, CH3 or H).
The insecticide Gardona R (XXVII) falls within the scope of vinyl phosphates defined by (XXII) and on the basis of the above results it might
be concluded that the isomer in which the vinylic proton resonates at 6.0 ppm to low field of Me
4Si is the Z-isomer (XXVIIa).
An X-ray analysis of (XXVIIa) performed by Professor F. Korte (Technisches Universitat, Mtinchen) has confirmed the original assignments.
(Me0)2P (Me0)2P-O\
Cl Cl
•
XXVII a XXVII b
(JrH 0.7 Hz)
(Jpil 2.5 Hz)
A stereospecific synthesis of diethyl 1-phenyl 2-carboxyethyl
vinyl phosphate (Z-isomer) has been reported in the literature1180 The geometrical assignment was made by virtue of the relative ease with which
the Z-isomer eliminates (in preference to the E-isomer) to give phenyl
acetylene. This observation assumes that the reaction has the
characteristics of an E-2 type elimination; the fact that the elimination is retarded by aqueous media but accelerated by using an alcoholic solution
and a stronger base (such as ethoxide) suggests this to be the (lase119
(Et0)2?-0„.„. H Nat0Et- ------------+ c6 11-5 02Et C6H5-caa-EcH
- 65 -
Dimethyl 1-phenyl 2-carbomethoxy vinyl phosphate (Z-isomer) was prepared by treating the enolate anion of ethyl benzoyl acetate with dimethyl phosphorochloridate in benzene. 1H nmr showed only one vinylic resonance at 6 5.90 ppm. This is the expected product from phosphorylation
of the most stable enolate which has the )anger groups trans to each other and is also stabilised by hydrogen bonding.
Na oEt Ph-C-CH2CO2Et ---+ Et
Benzene Ph
(11e0)P-Cl (Me0)2P-> <CO2Et
Z -isomer
When 2-chloro ethyl benzoyl acetate was treated with trimethyl
phosphite in a normal Perkow reaction an isomer mixture of dimethyl 1-phenyl 2-carboxymethyl vinyl phosphate was obtained. These were
separated by column chromatography and 1H nmr showed vinylic resonances
at & 5.90 ppm - Z-isomer and d 6.02 ppm - E isomer.
(CH50)211-ON (CH
50)2
-01.„\ ,C02Et Ph-g-CH(C1)C02Et + (Ne0)3P--+ C=C4,
Ph' CO2Et Ph/ •Ef
E-isomer Z-isomer
These results provide some useful chemical evidence to suggest that the assignments of geometry using 1H nmr chemical shifts are correct.
From the observations so fax it does-not appear that values of JPH coupling constants can be used to determine the stereochemistry of the double bond in vinyl phosphates. For the 2-substituted vinyl phosphates studied
/4J />/4 PH cis J / whereas in the 1-phenyl 2-substituted PH trans
vinyl phosphates /4jPH cis/ >/4jPH trans/. A study by Gaydou120suggests
that for dimethyl vinyl phosphates (Fig.1, R s H) both planar and gauche type conformations exist. The most stable conformation will be the planar
- 66 -
form havirgthe phosphate group trans to the double bond and where the
contribution of the JPH coupling constant due to the if electron density
is of little importance. As the temperature is increased the population
of the gauche conformations increase changing the value of the 4JPH and
giving information about the signs of these coupling constants. The relative signs of 4JPH cis and have been shown to be opposite
from spin-tickling experiments1420JPH trans . When the temperature was increased
decreased and the 4J increased. Since 4JPH is a the 4JPH trans 4PH Ole function of (thellscontributiontoiH is negative) this indicates that
• is positive and 4JPH cis is negative. When a large substituent 4JPH trans is placed on carbon-1 (Fig.l, R CHI or Ph) the gauche conformations
might be expected to become more favoured. This would explain the
o
bservations that for all 1-phenyl 2-substituted vinyl phosphates studied 4̀JPH PH cis// > /
/ 4JPH trans/. Maybe the absolute signs 4J
PH trans ve and
- ve remain the same and all that is happening is that the value 4JPH cis of the coupling constant decreases with increase 'I' contribution.
A series of dimethyl 1-21 substituted phenyl 2-chloro vinyl phosphates
(XXVIII) have been obtained as isomeric mixtures by treating the
corresponding 2,2 dichloro 21 substituted acetophenone with dimethyl
phosphonate in the presence of base - see Chapter 4.
-CHC12
0
Base (CH30)2 -H
(CH30)2K0 NatCHC1
rsssi
XXVIII
Their nmr parameters (chemical shifts and coupling constants are
shown in LaIlst.1). The assignments were based on the reasonable assumption
that for a pair of isomers the proton which is cis to phosphorus will
resonate to low field of the proton which is trans to phosphorus,
For all the dimethyl 1-21 substituted 2-chloro vinyl phosphates
studied the 4JPH cis for the E-isomer is always greater in magnitude
4- than the corresponding 4JPH trans for the Z-isomer. There is also a
a
6
a 0 f
- 67
)7. le
= H, CH3, Ph
Figure 1 - Stable conformations of dieth 1 1-substituted vinyl phosphates
- 68 -
Table 7
Nmr parameters of 1_21 substituted phenyl 2-chloro vinyl phosphates
:
Substituent X
H I F
C1 I
---
Br
OR l€ 3
OCH s 3
NO 2
-
CH3~Q I CFf (l
CH3~~ =~1 E-isomer
6~ f>CH~O 4~ 3~ I ppm pp Z I
6.450 3.681 2.8 11.2
6.529 3.699 2.6 11.2
6.499 3.685 2.6 11.2
6.485 I 3.680 2.5 11.3 I I 2.6 6.421 3.592 11.2
6.383 3.632 2.5 11.2 I 6.486 3.691 2.3 11.3 I
o CH3E 2.357, S CH3Z 2.315 ppm
b CH30Z 3.819 ppm
Ox .?--isomer
b HZ I OcH~O ppm. pp
6.146 3.704
6.263 3.734
5.932 3.660
5.902 3.645
5·752 3.545
6.206 3.655
5.974 1 3.644
4J-PH HZ
2.1
2.0
1.5
1e4
1.3
1.5
1.1
*
3~H
11.4
11.4
11.3
11.3
11.3 1--
11.3
11.3 1
Recorded on Vzrian XL 100 Spectrometer - 5%M/M solution in
C014
using T.M.S. lock •.
Chemical shifts measured using a frequency counter.
- 69 -
general decrease in the size of both coupling constants with the increase
in size of the ortho substituent. This is probably due to a change in
conformation from a trans co-planar arrangement to a more favourable gauche-
type relationship.
Bother-By and Trautwein121 have already shown that there is a
Karplus type relationship122 between the 3JpocH coupling constant and
the dihedral angle formed by the four atoms P, 0, C and H. It is
interesting to note that both 4s -PH trans and & HZ show a marked decrease in magnitude with increase in size of the ortho substituent. Presumably
this isomer shows the greater change in conformation, adopting a gauche
type arrangement with the hydrogen in the shielding region of the aromatic
ring.
A series of dimethyl 1-41 substituted phenyl 2-chioro vinyl phosphates
were prepared as isomeric mixtures by treating the appropriate 2,2-dichloro
41 substituted acetophenone with dimethyl phosphonate in the presence of base - see Chapter 4. The nmr parameters (chemical shifts and coupling
constants) are shown in Table 8. All spectra recorded were for isomeric
mixtures of vinyl phosphatest.and the assignments were made on the basis
that the proton in the isomer which is cis to phosphorus resonates to
low field of the
phosphorus. For
and 4.7PH trans(2.
corresponding isomer where the proton is trans to
all pairs of isomers studied both 4.7PH cis (2.8 Hz)
2 - 0.1 Hz) remain constant and independent of the nature
of the para substituent. This is reasonable since as already discussed
4JPH is very much influenced by the conformational properties of the
molecule which should not be effected by the para-substituent.
For vinyl phosphates with large substituents attached to carbon-I
gauche-type conformations will be more favoured. In the case of dimethyl
1-21 substituted phenyl vinyl phosphate these conformations will be
modified by changing the nature - of the ortho substituent,(see Table I.
for variation of 43pH). However, substitution in the para position
of the aromatic ring does not change the conformational properties of
the molecule. Any variation in the chemical Shifts of the vinylic protons,
in vinyl phosphates, are due to changes in the electronic nature of the
para substituent.
70 60
Table 8.
Nmr parameters of 1-41 substituted phenyl 2-chloro vinyl phosphates
. CH
CH30.."
CH30 CH
CH30
q
X E-isomer X Z-isomer
Substituent 6E 6CH 0 4JPH 33.7211 u Hz 6CH40 4jPH 3.1PH X PPm Pp Hz Hz i PP m PP th Hz Hz
H 6.450 3.681 2.8 11.2 6.146 3.704 2.1 11.4
P 6.442 3.728 2.8 11.2 6.123 3.745 2.2 11.4
Cl 6.470 3.726 2.8 11.2 6.209 3.749 2.2 11.4
Br 6.468 3.735 2.8 11.2 6.145 3.753 2.2 11.4
Oc113 6.344 3.705 2.8 11.2 5.992 3.732 2.2 11.4
NO2 6.611 3.781 2.8 11.3 6.516 3.817 2.3 11.4
6 CH30E 3.791 ppm
Recorded on Varian XL 100 Spectrometer - 5,7/0 0 solutions in
CC14 using T.M.S. lock.
Chemical shifts measured using a frequency counter.
As well as the magnetic shielding of nearby protons by the
aromatic ring (conformationally dependent) there is the shielding arising
from electronic interaction between the ring and the C=C ('systems
(depends on the nature of the pars substituent). The data for dimethyl
1-41 substituted phenyl vinyl phosphates (Table 8.) show clearly that electron withdrawing groups (e.g. p-Cl, p-Br and p- C2)on the benzene
ring lead to an enhanced deshielding of all the vinylic protons, and
that electron-donating groups (e.g. p-OCH3) cause net shielding. There
is a good correlation between chemical shifts of the E and Z vinylic
protons and the corresponding proton chemical shifts in p-substituted
syrenes125 - see Fig.2. This clearly indicates that the variations in chemical shift are being caused by the change in the electronic nature
of the p-substituents in the aromatic ring. Similar effects are seen for
the dimethyl 1-21 substituted phenyl vinyl phosphates in that electron
withdrawing substituents (e.g. o-F, o-C1, 0-Br and o-NO2) on the benzene
ring lead to an enhanced deshielding of the vinylic protons in the
E-isomer, and electron donating groups (e.g. o-C8:32 and 0-0CH3) cause net
shielding. The situation is complicated for the Z-isomer and there is no
reasonable correlation between chemical shift and electronic nature of
the ortho-substituent. Presumably the chemical shift of the vinylic proton in
the Z-isomer is dominated by the magnetic shielding of the aromatic ring
which will depend on the conformation of thenolecule determined by the nature of the ortho-substituent.
A series of dimethyl 1-21 substituted 2-chloro vinyl (thio)
phosphates and (thio) phosphonates have been prepared (see Chapter 5). The nmr parameters for the ortho-substituents (Y H, and F) are given in qa22122. All the spectra were recorded for isomeric mixtures of vinyl
phosphates (except for dimethyl 1-phenyl 2-chloro vinyl thiophosphate -
only the E-isomer available) and assignment of geometry made in the usual way. An assumption that the proton in the isomer cis to phosphorus
resonates to low field of the proton which is trans to phosphorus,
irrespective of the nature of the substituents on phosphorus, is
justified because the P-O-C bond is present in all cases. It is
probably the presence of oxygen atom which causes the vinylic proton
in the E-isomer to be deshielded. Table 10 shows a series of 2-chloro
- 72 -
Figure 2
- 6 H vs trans 1H on carbon-2 in p-substituted syrenes - see Ref.123 ---Z 1 - 6 H vs cis H on carbon-2 in p-substituted syrenes - see Ref.123
Table 9. ND= arameters of 1-21 substituted. phenyl..210s
CH3ONX
C.. /H R e -° N01
Y=H
E-isomer
30, CH _
Cl R./
H
43
Z-isomer
Substituent SR 6cR40 6R , 3Jm jPR 6 H7 60Rx0 6 R - 3J Jim X R ppi ppi ppm Jz" Et" Hz ppm ppth ppm Hz Hr HV
o CH3
6.478 3.630 1.439 2.9 11.1 17.6 6.157 3.569 1.548 205 11.3 I69
s 0E3 6.235 3.444 1.767 4.0 14.2 15.5 6.116 3.504 1.913 3.3 11.4 15.6
OCH3 6.450 3.681 - 2.8 11.2 - 6.146 3.704 - 2.1 17.4 -
OCH 6306 3.634 - 3.7 13.8 s a a - a a -
Y=F
6 R M SCH0 i) Substituent 6 HE E.CH70 1 ;31H I
117 R JPH X R ppm ppi ppm Hz P ;ppm- ppi ppm Hz Hz g z
0 0113 6.519 3.588 1.398 2.6 11.2 17.6 6.195 3.549 1.489 2.3 11.3 17.8
CH3 6.283 3.487 1.756 3.7 14.2 15.5 6.244 3.545 1.902 3.2 14.4 15.6
0 OCH3 6.529 3.699 - 2.6 11.2 6.263 3.734 - 2.0 11.4
s OCH 6.386 3.648 - 3.5 13.7 6.279 3.710 - 2.7 33.9 -
a - only E isomer available
Recorded on Varian XL 100 nmr spectrometer. 5cAM/M solution in CC14 using T.M.S. lodc.
Chemical shifts measured using a frequency counter.
- 74 -
vinyl phosphates (XXII, Y = H, W = C1) where the geometry is unambiguously
assigned from the magnitude of the vicinal J. In all cases (X = 0 or S)
tne signal. for the vinylic proton cis to the phosphoryl group always occurs
to low field
magnitude of
X = 0, while
of that of the corresponding trans proton. However, the
4jEpsinconsistent and / /4 Jap cis/ when P i i itt d4J BP trans' ''
/4jHP cis/ >14j HP trans/ when X = S.
Table 10
Nmr parameters of 2-chloro vinyl phosphates
at
Ex 01
ii 01
sacs Hp
E-isomer Z-isomer
R1 8Fixa bra J-Fe, Jrup J-Fama 8r.a 8 a Jiixp JR13/, Ja613 ppm ppm Hz Hz Hz ppm Hz Hz Hz
Me0 Me0 0 6.78 6.16 7.2 1.5 11.15 6.84 5.61 5.4 1.8 4.1
i'leO Me° s 6.81 6.05 7.8 2.1 11.1 6.83 5.54 7.6 1.0 4.2
Et0 Et0 0 6.76 6.08 7.45 1.5 11.05 6.80 5.52 5.6 1.9 4.1
Et0 Et0 S 6.82 6.04 7.9 2.1 11.1 6.80 5.54 1.3 4.1
a Relative to Me4si'
positive shifts to low field.
Recorded using HA 100 nmr spectrometer 0.3-0.5 M solutions
in col4.
The chemical shifts of the vinylic protons and the 4JpH coupling
constants for dimethyl 1-21 substituted phenyl 2-chloro vinyl phosphates
OR . OCH3, X . 0, Y = H or F) are very similar to those in the
corresponding dimethyl 1-21 substituted phenyl 2-chloro vinyl phosphonates
(R = CH3' X = 0, Y = H or F). Also, the chemical shifts of the vinylic
protons and the 4JpH coupling constants for dimethyl 1-21 substituted
phenyl 2-chloro vinyl thiophosphates OR = OCH3 , X = St Y = H or F) are 1 similar to those in the corresponding dimethyl 1-2 substituted phenyl
- 75 -
2-chloro vinyl thiophosphonates = CH7, X = S, Y = H or F) but
significantly different from the values for phosphates and phosphonates.
There is some consistency in the magnitude of the 4JPE coupling constant
in that /4JPE cis (E-isomer) > / '43. PH Lears(Z-isemer) ./ irrespective of
the nature of the substituents on the phosphoryl groupo
It is interesting to note that Borowitz35 has used the fact
that for 2-substituted vinyl phosphates /4jPH trans/ )./4JFH cis/ in the
same way that /3JEH trans/ )'/3.3EH cis/
to the 1,2 disubstituted vinyl phosphates recorded that /4JPH trans/ >
/4JpH cid, and concluded that the larger coupling is consistent with the
'zig-zag path' of the trans isomer (Z.-isomer). We have shown that in
the absence of knowledge of the signs of the coupljng constants, JFH values cannot be used reliably to determine stereochemistry and that proton.
chemical shifts are more informative. We have illustrated the dangers of
using an additivity approach to determine proton chemical shifts in
olefins with similar substituent shielding parameters. The values for
the shielding constants of the phosphoryl substituent cc, culated from a
series of vinyl phosphates of known geometry are cis 0- (0R)2, + 0.29; trans, + 0.75 ppm. When these are compared with those obtained by
y for Tobe 101 the phenyl substituent cis Ph, - 0,37; trans Ph, + 0.10 ppm,
the difference in the shielding effect of phenyl and phosphoryl substituent
on the cis and trans protons are seen to be comparable (i.e. - 0.47 for Ph
-0- O compared with - 0.46 for 9. R) . ). Using an additivity approach it is 2 impossible to differentiate between isomeric olefins bearing substituents
with similar shielding coefficients and a 'model compound' approach is more acceptable.
0 He extended this observation
- 76 -
4. 13c nmr of 1-Substituted 2-Substituted and 1 2-Disubstituted Vinyl Phosphates - use of 13C-P coupling constants in determining
the stereochemistry of vinyl phosphates.
From observations of the 4JPH coupling constants of substituted vinyl phosphates it has been possible to make assignments of conformations of these compounds in solution. These couiding constants are significantly
different and so it is to be hoped that the 13CH and 13CP coupling constants will also show significant differences. Further information about the conformations of these molecules in solution should be available from
obserVing the magnitude of these J130 and J13cp coupling constants.
A series of dimethyl 1-substituted vinyl phosphates (XXII;
R1, R2 . MeO, X = 0, W = H, Y = H, CH3, Ph, CN or CO2CH3) were obtained
by a variety of methods. Dimethyl 1-methyl vinyl phosphate and dimethyl
1-phenyl vinyl phosphate were obtained by treating monochloroacetone and
phenacyl chloride with dimethyl phosphonate in the presence of base
('abnormal' Michaelis-Becker reaction - see Chapter 1). Dimethyl 1-cyan
vinyl phosphate and dimethyl 1-carbomethoxy vinyl phosphate were obtained by dehydrochlorination of the corresponding dimethyl 1-cyan-2-chloroethyl phosphate and dimethyl 1-carbomethoxy-2-chloroethyl phosphate. Using
triethylamine as the necessary base.
EtzN (CH30)2?-0-CH-CH2C1 (CH30)2?-0-C=CH,
Ether 1 ' X
Et3Wil.C]?1
X . -CN or --CO2CH3
Dimethyl vinyl phosphate was prepared as already described by
treating chloromercuriacetaldehyde with trimethyl phosphite - Perkow
reaction.
The 13C nmr parameters of the dimethyl 1-substituted vinyl
phosphates are shown in Table 11.
Spectral assignments of the carbon chemical shifts (obtained
by 1H 'noise' decoupling124) to the carbon atoms in the dimethy3al-substituted
vinyl phosphates were made from gated.-decoupled experiments'.
In the Pourer Transform (FT) experiment, if wide-band 1H decoupling
is utilised but the decoupling power is turned off immediately before each •
carbon excitation pulse and then turned back on after each data acquisition
period, then a high resolution spectrum is obtained with substantial nuclear
Table 11. 13
C Nmr parameters of dimethyl 1-substituted vinyl phosphates
01\2
CH D=CH2
3 X'''
Substituent
X
C1
ppm
C2
ppm COCH
3 ppm
2
jC1-P
Hz
C2-P
Hz
2JC -P
Hz
Other Substituents C - ppm, J - Hz
H 142.40 98.58 5.5 10.5 6.0 1JCH30 148.7; ,JcH2 160.7; 'Jai 191. 5
c115 151.67 98.88 53.71 8.2 5.0 6.2 CcH 21.49 (3./pc 5.0); J. 113
0 148.1; 1 3 -JCH3
128.1.9 IJCH2
160.2
C6H5b
152.02 96.69 54.04 8.0 3.9 6.0 Cit 134.34 (3JPC 6.0); 04, 128.59;
C3,,5, 127.95; 021,6i 125.000; 1JoH30 148 • 1J
0112 161.9
ON° 127.94 114.71 cCH2 64.44 CCH 16.88
3
6.9 5.3 JCH2
-
6.0 JCI-I -P
6'.5
CCN
112.22 (3J 7.1); 1JCH3CH20
M 149.1; PC
m
1J CH3CH20 127.4; IJCH2 167.3
CO2CE3
143.48 6.6 GCVO 161.05 (3Jpc 6.0); Cch.::.49.: ( JCR3 3
1 147.8); 3CE
30 148'7; 1417
"42
a the carbon atoms in the double bond assigned C-1 and C-2 b the carbon atoms in the aromatic ring are assigned
only the diethyl 1-cyan vinyl phosphate available 61
5 0 21 4 4,3'
All chemical shifts recorded at infinite dilution in 0014. Positive shifts down'field from T.M.S. Coupling constants
determined for 40°/a M/M solution.
aCH3ON9
•
78
Overhauser enhancement. This is a gated-decoupled experiment125126127
Complete spin-spin coupling is restored immediately the decoupling power
is turned off (C-H coupling constants can be obtained), whereas the population
of the carbon nuclear energy levels return from their "polarised state"
(due to saturation of the 1H nuclei) only as fast as the carbon nuclei
can undergo spin-lattice relaxation. The use of this interrupted 1H
decoupling should increase the sensitivity in the FT high resolution nmr experiment by two- to three-fold128.
1 For example, the terminal methylene shows a jCH coupling of the
order 'of 160 Hz129 (this is general for 13C-H coupling constants with sp2
carbon hybridisation) and the methoxy groups attached to the phosphorus show a 13cH coupling of about 148 Hz130 (
1JCH for sP
3 hybridised carbon is 125 Hz129).
As might be expected the chemical shift of carbon-I is down field of carbon-2
in all the examples studied. Also the intensity of the carbon-2 resonance is
much greater than the carbon-1 resonance because of the directly attached
protons which will favour a 13C-1H dipole-dipole relaxation mechanism. For
most organic molecules the 13C-1H dipole-dipole relaxation mechanism will
dominate the 13C spin-lattice relaxation allowing the nuclei to re-establish
a Boltzmann population distribution131.
The olefin carbon chemical shifts of a variety of mono-substituted
ethylenes have been assembled by Stothers132 and some useful values are
given in Table 12. Substitutent chemical shifts (S.C.S.) have been
calculated using ethylene as the reference compound.
From the carbon chemical shifts of the dimethyl 1-substituted vinyl
phosphates in Table 11 it is possible to calculate S.C.S. for the substituents
at carbon-I on the carbon atom of the olefinic double bond by using dimethyl
vinyl phosphate as the reference compound. These S.C.S. are given in Table 13.
When the S.C.S. at carbon-1 and Carbon-2 ire substituted ethylenes
were plotted against the corresponding S.C.S. in the dimethyl 1-sUbstituted
vinyl phosphates there was a very good correlation for both sets of data -
Fig. 3. Unfortunately the dimethyl 1-substituted vinyl phosphates with X = C1 or Br which would have been interesting to study were not available.
It is possible, using the S.C.S. for
(by comparing dimethyl vinyl phosphate
chemical shifts of the olefinic carbon
phosphate - see 121_2124,
(CH30)2 of C-1 +19.6, C-2 -24.2
with ethylene)) to predict the carbon
atoms in dimethyl 1-substituted vinyl
- 79 -
Table 12
13C Chemical shifts of mono substituted ethylenes132
E2
Substituent X
C-1 ppma
C-2 ppma
S.C.S. at C-lb
S.C.S. at C-2b
H 122.8 122.8 0 0 Cl 126.1 117.4 43.3 -5.4 Br 115.6 122.1 -7.2 -0.7 CH3 133.1 115.1 +10.3 -7.8
C6H5 135.8 112.3 +13.0 -10.5 CO2CH3 128.7 129.9 +5.9 +7.1 CO202H5 129.8 130.5 +7.0 +7.7 CN 107.7 137.8 -15.1 +15.0
a Chemical shifts from T.M.S. Positive shifts to low field
Positive shifts to low field of ethylene, negative shifts to • high field.
Table 13
13C Substituent chemical shifts in dimeth 1 1-substituted vinyl phosphates, GRA 0
Q\';C.CH2 X/
Substituent X
C-1 ppma
C-2 ppma
S.C.S. at C-lb
S.C.S. at C-2b
H 142.40 98458 0 0
CE3
151.67 98.88 +9.27 +0.30
06H5 152.02 96.89 +9.62 -1.69
CO2CH3 143.48 10909 +1.08 +11.41 ON° 127.94 114.71 -14.46 +16.13
aChemical shifts from T.M.S. Positive shifts to low field
bPositive shifts to low field of dimethyl vinyl phosphate,
negative shifts to high field. cOnly diethyl 1-.cyan vinyl phosphate available.
CH30
- 80 -
Table 14
Calculated and observed 13C chemical shifts of 1-substituted vinyl phosphates
Substituent Calculated chemical
C-1 ppm
shifts
C-2 ppm
Observed chemical
C-1 ppm
shifts
C-2 ppm
0113 152.7 90.8 151.67 98.88
06H5 155.4 88.1 152.02 96.89
0020113 148.3 105.7 143.48 109.99 ON 127.3 113.6 127.94 114.71
There is some degree of similarity between the calculated chemical
shifts using an additivity approach and the ones actually observed. Any
difference in the two sets of values results from interaction between
the two geminal substituents.
In all the dimethyl I-substituted vinyl phosphates studied the
magnitudeof2J-ul-P
is greater than the magnitude of 3..TC2-P except for
the unsubstituted case when this observation is reversed. This suggests that
placing a substituent, other than hydrogen, at carbon-1 is changing the
conformational properties of the molecule and hence the magnitude of the
P-C coupling constants. A similar phenomenon for Jim: in the 1H spectra of
diethyl 1-phenyl 2-substituted vinyl phosphatee.has.already - beersediecueSd
earlier in the chapter.
The 13C nmr parameters for a series of diethyl 2-substituted vinyl
phosphates have been recorded and are shown in Table .. These compounds
were previously prepared by the Perkow reaction. of the appropriate
halogenated acetaldehyde with triethyl phosphite. For all cases (except for diethyl 2-phenyl vinyl phosphate when only the F-isomer was available)
the spectra were recorded for isomeric mixtures of the vinyl phosphates. Assignment of C-1 as being down field of C-2 was made on the basis of results
obtained for the dimethyl 1-substituted vinyl phosphate series where C-1
bonded to phosphorus through an oxygen resonates to low field of C-2. These assignments of the dimethyl 1-substituted vinyl phosphates were
unambiguously determined from an off-resonance experimentx when the
carbon atoms directly bonded to hydrogens show residual C-H couplings.
•
0- S.C.S. of C-1 in dimeth,yl 1-substituted vinyl phosphates
plotted a7ainst S.C.S. of C-1 in corresrondinKl-substituted
ethylenes
+ - S.C.S. of C-2 in dimethyl 1-substituted vinyl phosphates
lotted --ainst S.C.S. 0-2 in corresponding 1-substituted
- 82
In an off-resonance experiment, the 1H irradiation is kept at
high power levels, but the centre frequency is moved 500-1000 Hz away
from the protons to be irradiated, and the frequency band width is
switched off. In this experiment, the one-bond C-H coupling patterns
remain, allowing the spectral assignment of non-protonated carbons, CH,
CH2, and CH3 carbons observed a singlets, doublets, triplets and quartets,
respectively. This coupling in an off-resonance decoupled experiment
is not equal to the actual one-bond coupling constant but is a reduced
or residual coupling. This residual coupling JCrH is proportional to
the direct coupling constant Jo, the frquency offset Af from resonance, and inversely proportional to the power level 1112/2Tr124
JCH Af JCrH
)32/21r
An off-resonance experiment for the diethyl 2-substituted
vinyl phosphates is not very helpful since it only indicates that both
C-1 and C-2 are directly bonded to hydrogen atoms. Some justification
for the assignment that C-1 is down field of C-2 in diethyl 2-substituted
vinyl phosphates is obtained by comparing the S.C.S. for both isomers of
this series - Table 16, with the ones already reported for mono-substituted
ethylenes132- Table 12.
For a series of mono-substituted ethylenes CH2=CHX (X = Br, Cl,
CH31- C6H5) there is a down field shift of C-1, when X = Br is replaced
by X = Cl, CH3t C6H5, and a corresponding upfield shift of 0-2. This
is in agreement with the series of 2-substituted vinyl phosphates studied
- see Pig. 4 and Fi.ff25 where the S.C.S. for the E and Z isomers of diethyl
2-substituted vinyl phosphates have been plotted against the S.C.S. of the
corresponding mono-substituted ethylenes. There is a good correlation
between the S.C.S. for both sets of isomers. It is possible using diethyl
vinyl phosphate as a model and the S.C.S. from mono-substituted ethylenes
to predict what the chemical shifts of C-1 and C-2 in diethyl 2-substituted,
vinyl phosphates should be. The observed and calculated chemical shifts
e a the olefinic carbons in diethyl 2-substituted vinyl phosphates are
given in T.22.11.7..
• Table 15. 13 ___rgp tsofdisLt12,Vubstitu-CNmra.ramete tedvilhoshates
CH3CH20 p
CH3CH20 E-isomer H,
,C C1,,X
x ScH a 3 SCH a 2 8 c1a 6 C a 2 2J P Jp 1 lj
H C 1 lj
C Other Substituents
H 15.96 63.14 142.48 98.28 5.6 6.2 5.2 10.4 191.0 160.2 1JOlizelD,0 147.9; 1 H
H
"/ 4- 127.0
C1 15.79 62.62 139.17 108.85 6.1 5.8 5.5 12.9 196.0 196.0 j.TCCH3220
:H20 1- 148.6; JN5'cti 20 127.5
Br 15.90 64.35 140.25 95.35 6.o 6.2 5.4 12.0. 198.2 194.2 Jc/T3K ,, r, 149.0;
1Am. TT2%., 1
1TH 127.0 uCH3CH20
CH3 15.65 63.52 136.41 110.54 6.0 6.5
6.7
6.0
5.2
10.2
10.9
187.4
191.2
154.0
1 53.0
JCH36H20 1_
148.0
J6H3cH20 127.0 C 11. CH3 37(13CH 3 125.7)
m ] .JCH3CH20 148.6; 1
Jj110H20 127.1 Cl, 133.67;C2, 6t 125.80; C31,5,
128.31;C4, 126.91
06H5
15,84 63985 137.30 116.85 5.3
continued
•
Table 12. 13c Nmr arameters of dieth 1 2-substituted vinyl continued CH3CH2ONQ
CH3CH2
41\0. Z-isomer
H,/u
X SCH3
6 CH2 C1 5 C2 2JPC JPC 2JPC1 JPC2
2 Other Substituents
Cl 15.79 62.62 136.71 103.58 6.1 5.8 3.3 12.0 194.6 198.6 1JoH3le1120
C 148,6; 1Jlf 127.5 ll3CH20
Br 15.90 64.35 138.80 91.38 6.0 6.2 3.8 12.0 197.0 199.1 , 1 ocH,N20 149.0; 1 2 JH3CH2
0 127.0 C
CH3 15.65 63.52 135.62 108.93 6.0 6.5 5.6 10.9 187.8 15440 H JC73 1 CF2 0 148,0; 1 JtCHCH20 127.0 0CH311.37 ('JcH3125. 7)
C6H5c
_ - - - - - - - - _ _
a Chemical shifts in ppm from T.M.S. (positive shift to low field) coupling constants in Hz, recorded for 40% 0 solution in C04.
H
b Chemical shifts Cll, C2„ 03,, 04,, Cs,, C6' are posi.%ions in the aromatic ring.
Only E-isomer available.
•
Table 16. 13C Substituent chemical shifts in diethylbstituted vinyl
Substituent
X
E-isomer Z-isomer
C-1 ma
C-1 ma
S.C.S. 0_113
S.C.S. 0-213
0-1a sun
C-1a 'Ism
S.C.S, 0-1 b
S.C. C-2
H 142.48 98.28 0 0 142.48 98.28 0 0
Cl 139.17 108.85 -3.31 +10.57 136.71 103.58 -5.77 +5.30
Br 140.25 95.35 -2.23 -2.93 138.80 91.38 -3.68 -6.90
CH 136.41 110.54 -6.07 +12.26 135.62 108.93 -6.86 +10.65
6H5 137.30 116.85 -5.18 +18.57 c c c c
trN a Go Chemical shifts from T.M.S. Positive shifts to low field. Positive shifts to ].ow field of diethyl vinyl phosphate, negative shifts to high field.
Only E-isomer available.
Table 17. Calculated and observed 13C chemical shifts of 2-substituted alsyLOossi-ia,tes
CH3 CH2 0 0 2
CH3CH20/ =CHX
Substituent
X
Calculated Chemical Shiftsa Observed Chemical Shiftsa
C. PPm C2 ppm C1 -E ppm C2-E ppm C1-Z ppm C2-Z ppm
Cl 137.08 101.58 139.17 108.85 136.71 103.58
Br 141.78 91.08 140.25 95.35 138.80 91.38
CH3
134.68 108.58 136.41 110.54 135.62 108.93
C6H5 131.98 111.28 137.30 116.85 b b
a Chemical shifts in ppm from T.M.S. (positive shifts to low field).
Only the E-isomer was available.
•
- 87
Figure 4
CO - S.C.S. of C-2 in dieth,r1 2-substituted vinyl phosphates
Llmifomer plotted against S.C.S. of C-1 in corresponding
1-substituted ethylenes
_1H S.C.S. of C-I in diethyl 2-substituted vinyl phosphates
L17.1122eT.0 plotted against S.C.S. of C-2 in correspondins.
1-substituted ethylenes
- 88
Figure 5
S.C.S. of C-2 in diethyl 2-substituted vinyl phosphates
CZ-isomer) plotted against S.C.S. of C-1 in corresponding
1-substituted ethylenes
S.C.S. of C-1 in dietLly1 2-substituted vinyl phosphates
(Z-isomer) plotted er'ainst S.C.S. of C-2 in corresponding
1-substituted ethylenes
H 156.2
Cl 194.9 Br 196.6 C 157.4
156.2 160.9 160.3 160.6
- 89 -
There is reasonable agreement between the observed and predicted
values for the carbon chemical shifts. As stated previously these observed
chemical shifts were recorded for isomeric mixtures of the diethyl
2-substituted vinyl phosphates where the isomeric ratios could be
determined by 1H nmr integration. It was assumed, for a given diethyl
2-substituted vinyl phosphate, that the relaxation tiales of the olefinic
carbons were independent of the stereochemistry of the double bond. The
peak height of a carbon resonance was proportional to the amount of that
isomer present, therefore enabling the carbon resonances to be assigned
to either the E- or Z-isomer - see Lis.6.
Observations of JC2H in diethyl 2-substituted vinyl phosphates
show that there is a variation in the magnitude of this coupling with
change in the nature of the substituent for both isomers. Whereas the
(kill seems to be independent of the nature of the substituent on C-2.
A similar effect was seen for dimethyl 1-substituted vinyl phosphates where
the magnitude of Jc2H remains fairly constant (i.e. 164.0 ±3.0 Hz) as the
substituent changes. These changes in Jc2H for diethyl 2-substituted vinyl
phosphates are comparable with those in a series of mono-substituted
ethylenes133 which are given in Table 18.
Table 18. One-band 13C-1H couplin5 constants in
mono-substituted ethylenes
For substituent X = Cl and Br the values of 13C-H gem are comparable
(JC2H 196 1: 3 Hz for diethyl 2-substituted vinyl phosphates and Jog 195 ± 1 Hz. for mono-substituted ethylenes) but for the substituent X = CH
3 and H there
is marked decrease in the coupling constant (Jc2H 156 t 4 Hz for diethyl 2-substituted vinyl phosphates and JcHg 156 I 1 Hz for mono-substituted
ethylenes).
\-0 0
0 •
Sweep width 4096 Hz
C2 Z
rivet\-11J jrip%vfitYkkitgANtviaoa.athdovNivo,brvikfwc evort#4,,ww.skt, Ate.
13C Nmr spectrum of diethyl 2-chloro vinyl phosphate 407to E,.J.22LEI_shollIps_aaignmenteof C-1 and C-2 for each isomer
•
91
In all the 2-substituted vinyl phosphates studied it has been
shown that the C-1 and C-2 carbon atoms of the E-isomer resonate to low
field of the corresponding carbon atoms in the Z-isomer. Also, for all
2-substituted vinyl phosphates /3Jc2p/>/2Jc1p/ in contrast to the 1-substituted vinyl phosphates where /2jcip/I>J3Jc2p/ (except when
1-substituent is hydrogen). This phenomenon is explained by changing the
planar conformation of diethyl 2-substituted vinyl phosphate to a gauche-type
conformation, with the introduction of a substituent at C-1,for dimethyl
1-substituted vinyl phosphates. There is very little change in the
magnitude of the 3.3"pc2 with variation in the substituent at C-2, 7
34C2 110 2 Hz. However, ilJpcii for the E-isomer >/3Jp01/ for the
Z-isomer and this probably reflects a change in conformation with increased
interaction-between vicinal substituents.
A series of dimethyl 1-phenyl 2-substituted vinyl phosphates
((XXII); R1s R2 = MeO, X = 0, Y = Ph, W = Cl, Br, CH3' C6H5, CO2C2H5)
have been prepared by a variety of methods. The compounds ((XXII);
R1 R2 = Me0, X = 0, Y = Ph, W = Cl, Br, CH3, C6H5) were obtained by
treating the appropriate halogenated phenone with dimethyl phosphonate
in the presence of base - 'abnormal' Michaelis-Becker reaction - see
Chapter 3, and ((XXII) R1 = R2 = Me0, X = 0, Y = Ph, W = CO2C2H5) obtained
by treating 2-chloro ethyl benzoyl acetate with trimethyl phosphite -
Perkow reaction.
C6H5
In all cases the dimethyl 1-phenyl 2-substituted vinyl phosphates
were obtained as mixtures of E- and Z-isomers and the 130 nmr parameters
shown in Table 19 were recorded on these isomeric mixtures
The 13C nmr spectra for all vinyl phosphates studied in this chapter were
recorded to infinite dilution in CC14 unless otherwise stated in the tables.
CC14 was a convenient solvent for the study since all 1H nmr had been
recorded under these conditions, when solvent interactions would be minimal,
and also the compounds were sufficiently soluble. In general the dilution
shifts (on average 0.5 ppm for 40% M/1 solution) were significant for
comparative studies.
C6H5C-CH(C1)CO2C2H5 (CH50)3P (CH30)2P-
=CHCO2C2H5
Table 19. 13C Nmr parameters of dimeJlizl ituted vinyl phosphates
CH3 CH3o
5 E-isomer
C2a C11 21 3%5' c4'a
COCHa 3 2J b c P
. b jCg
9 b - jCOCH3P
1 b jC2H
• Other Substituents
H 152.02 96.89 134.34 125.00 127.95 128.59 54.04 8.0 3.9 6.0 6.0 161.9 1JCH30 148.3
Cl 149.08 107.97 131.77 129.03 54.15 9.0 5.2 4.2 6.o 196.6
Brc.
CH
-
'46.1446.14 111.01 134.03 125.11 -
127.83 MS 128.01 53.72
- 8.9 IM
4.9 -
-
4,3 6.0 156.0 13-CH30 148.4;cCH, 12.77 1 )
(4J- -1.4,j-J,_ 126.1) un3r un3
06H5 46.79 116.84 134.23 53.95 8.8 4.9 2.7
5.3
6.0
6.0
156.1
162.8
1 ., 148.6 3
jCH30 148.7,c0.0 163.66 : ca, 59•421JcH2147.0)
n,3 13.99 (1JCH3126.9) _
44 559.41
.
107.12 133.11 127.23 129.10
., ..
129.64 54.15 8,1 4.0
continued
H CH
5
21 3'
2-isomer
Table 19. 13C Nmr parametersethl 1-phenyl 2-84stituti,:62Lisaphospllatfta continued
CH
X C1a C2a C1'4 a
C2211 a c
3V c_4'
a COCH3
2 JCiP 3J -C2P 3 "JCIT
2 JCOCH3i"
6.0
1J
161.9
OtherOther Substituents
H 152.02 96.89 134.34 125.0o 127.95 128.59 54.04 8.0 3.9 6.0
Cl 148.13 105.85 133.36 129.01 54.15 8.4 8.1 1.5 6.0 196.6 1JcH30 148.7
1JCH30 148.6 Br 150.12 93.85 133.82 126.12 128.13 129.06 54.21 7.7 8.4 1.5 6.0 195.8
cH3
146.6o 111.34 135.59 125.11 127.70 128.45 53.88 8.8 6.4 1.8 5.9 155.2 lj c1g 14 : ;c
m
ii.5(4J%1 1.4, ljcH3 126.4)
C6115 146.27 115.55 135.98 53.84 8.9 7.2 - 1.5 5.9 154.0 1Jc130 148.6
CO2C2H5 156.47 206.09 134.27 126.74 128.10 130.12 54.33 8.0 6.2 1.8 5.7 162.1 1JcH 30 148.7 C . 1-C=0
162.55(4Jpc 1.8) .
ccH2 59•21k1JcH2 147.0)CCH3 14.22 (1.701/3 127.0)
aChemical shifts recorded:at infinite dilution in CC14* Positive, shifts to low field of T.M.S.
b cOnly 2-isomer available.
Coupling constants recorded for 40% M/M solution with 1000 Hz sweep width.
I
- 94 -
For any dimethyl 1-phenyl 2-substituted vinyl phosphate C-1
and C-2 were distinguished by an off-resonance experiment (see earlier
for explanation) since C-2 shows residual proton coupling being directly
bonded to a hydrogen atom. The magnitude of this directly bonded 13C-1H coupling constant was determined as before by a gated-decoupled experiment.
Assuming that the relaxation times for the olefinic carbon atoms are
independent of the stereochemistry of the double bond, and knowing the
isomer distribution in a mixture of dimethyl 1-phenyl 2-substituted vinyl
phosphates (1H nmr integration of vinylic region where the proton cis to
phosphorus in the E-isomer resonates to low field of that trans to
phosphorus in the Z-isomer), it is possible to assign C-1 and C-2 for
each isomer - see It is also possible using this approach to
establish small differences in the chemical shifts for the methoxy group
directly bonded to phosphorus.
Using dimethyl 1-phenyl vinyl phosphate as a model compound,
the S.C.S. for substituents at C-2 were calculated and these are given
in Table,20. For substituents other than X = Br, there is a down field
shift of 0-2 (the carbon directly bonded to the substituent) and for
substituents other than carboethoxy there is an up-field shift of C-1.
This is in agreement with the results already obtained for mono-substituted
ethylenes - see Table 12132. There is a very good correlation between
S.C.S. of C-1 and C-2 in mono-substituted ethylenes and the corresponding S.C.S.'sfor the corresponding carbon atoms in both isomers of dimethyl
1-phenyl 2-substituted vinyl phosphates - see 11E48 and Fig. Using the S.C.S. for the phenyl substituent in dimethyl 1-phenyl
vinyl phosphate at C-1 +9.62 and C-2 = -1.69 (see S.C.S. of dimethyl 1-
substituted
vinyl phosphates in Table 12.), and the carbon chemical shifts
for C-1 and 0-2 in the E- and Z-isomers of diethyl 2-substituted vinyl
phosphates (Table 15), the carbon chemical shifts of C-1 and C-2 for
both isomers of dimethyl 1-phenyl 2-substituted vinyl phosphates can be calculated. There is a certain amount of agreement between the observed
and calculated values for the olefinic carbon shifts in dimethyl 1-phenyl 2-substituted vinyl phosphates (Table 21) but this is not sufficient to
enable the stereochemistry of the double bond to be determined by this
C Z C C2E
r, 1.E IZ ! 1
n
C
• PI j
Sweep width 1200 Hz
"44444v*ipow,..*:4g1,4,4A44444-4e4.4,o-t410)
Sweep width 3075 Hz
I
13C Nmr spectra of dimethyl 1-.phenyl 2-chloro vinyl phosphate (43% showingassinments of C-1 and C-2 for each isomer
r4 tZ
ciz
- 96 -
O - S.C.S. of C-2 in dimethyl 1-phenyl 2-substituted vinyl yhos hates (E-isozer) Plotted Egainst S.C.S. of C-1 in corresponding 1-substituted ethylenes
S.C.S. of C-1 in dimethrl 1-nhe2y1 2-substituted vinyl ,,hosT:hates
SEZisomerLIg-9II2Lf-'L"st S.C.S. of f.2:12 1122-11mmaliaa 1-substituted ethylenes
10 CO C 2 CO2C2H5
0 4 ')
- 97 -
Figure 9
-10 Br 10 20
r O - S.C.S. of C-2 in dimethyl l-phenyl 2-substituted vinyl phos211212
K71s20_121otted against S.C.S. of C-1 in
1-substituted ethylenes
- S,C.S. of C-1 in dirnGthrl 1-phenyl 2-substitutedzial_Etosphate
L-isor,.e72) .,_lotted a-ainst S.C.S. of C-2 in cc_respoillaa
1-substituted ethylenes
Table 20. 13C Substituent chemical shifts in d 2-substituted
vinyl phosphates
Sub; tituent X
E-isomer Z--isomer
C-1 ppm C-2 ppma S.C.S. C-lb S.C.S. C-2b C-1 ppma C-2 ppma S.C.S. C-1 S.C.S. C-2b
152.02 96.89 0 0 152.02 96.89 0 0
C1 149.08 107.97 -2.94 +7.08 148.13 105.85 -3.89 +8.96
Br c 0 c c 150.12 93.85 -1.90 -3.04
CIT3
146.14 111.01 -5.88 +14.12 146.60 111.34 -5.42 +14.45
06115 146.79 116.84 -5.23 +19.95 146.27 115.55 -5.75 +18.66
CO2C2H5 159.41 107.12 +7.39 +10.23 156.47 106.09 +4.45 +9.20
aChemical shifts from T.M.S. Positive shifts to low field bPositive shifts to low field of dimethyl 1-phenyl vinyl phosphate,
negative shifts to high field.
°Only Z-iscmer available.
- 99 -
method. For example this approach predicts the wrong stereochemistry
of the double bond in dimethyl 1-phenyl 2-methyl vinyl phosphate
(i,e. C2 calculated 108.85 for E-isomer resembles C2 observed 111.32
observed for Z-isomer). It is unreasonable to expect this simple
additivity approach to predict carbon chemical shifts of stereo-isomers
which only differ by 0.33 ppm.
Table 21. Calculated and observed 1 3C chemical shifts of dimethyl ltplral
2-substituted vinyl phosphates
2 =CBX
Substituent X
Calculated chemical shiftsa Observed chemical sniftsa
C - 1 E C2-E C1-Z C2-Z -E C - -Z
Cl 148.7,9 107.16 146,33 101.89 149.08 107.97 148015 105.85
Br 149.87 93.66 148.42 89.69 b b 150.12 93.85
• CH3
146.03 108.85 145.24 107.24 146,14 111.01 146.60 111.34
C6H5 146.92 115.16 0 c 146.79 116.84 146.27 115.55
a Chemical shifts in ppm from T.M.S. Positive shifts to
low field.
b Only Z-isomer available.
Only E-isomer available.
We have already stated that the 15C-1H coupling constant for C-2
in diethyl 2-substituted vinyl phosphates (i.e. the carbon directly bonded
to the substituent) is a function of the nature of the substituent. The
variations in 1JC2H for the dimethyl 1-phenyl 2-substituted vinyl phosphates
are directly analogous to those observed for the simpler vinyl derivatives
In general the magnitude of 2JClp (8.0 ± 1.0 Hz) is greater than the
'magnitude of 3Jc2p (6.0 t 2.0 Hz). This has already been recognised, for
any dimethyl 1-substituted vinyl phosphate - see Table 11 and is contrary
to the observations in diethyl 2-substituted vinyl phosphates - see Table 15,.
Variations in the magnitude of these coupling constants has been attributed
- 100 -
to changes in conformational preferences of the molecules with the
introduction of a substituent at carbon -1.
For any dimethyl 1-phenyl 2-substituted vinyl phosphate /3Jc2p/ for the Z-isomer is always greater than /3Jc2p/ in the E-isomer. This is
the case whatever the nature of the substituent on carbon-2 and is
independent of the nature of the ortho substituent for a series of dimethyl
1-21-substituted phenyl 2-chloro vinyl phosphates - Table 22. Generally,
/3,7 c2p/ is 7.0 - 1.0 Hz for the Z-isomer and /3Jc p/ is 5.0 1.0 Hz for 2
the E-isomer.
The S.C.S. for the ortho substituents in the aromatic ring have
been calculated using dimethyl 1-phenyl 2-chloro vinyl phoshate as the
model. These are given in Table 23.
If these S.C.S. at C1 and C2 in the E-isomer are each plotted
against the S.C.S. at C1 and C2 in the corresponding Z-isomer there is
found to be an approximately linear correlation of substituent effects
Fig.10 and Fiz....11. This suggests that changing the geometry from
E- to Z- does not affect the conformation of the molecule and probably indicates that a conformation similar to (XXIX) is important where the ortho substituent is cisoid to the phosphoryl group.
J(ocH3)2
Table 22. 13C par parameters of dimeIlal_1:21-sUbstituted phenyl 2-chloro vinyl phosphates
-3'2,- 0H3cr
1 2,/H c.c,
'01
E-isomer
,„3„,1_0,..q. ,ci.
CH30""
H
Z-isomer 0 X 0
Substituent 1 ppma 2 ppma 23011) Hz 3 a C1 PPm a
2 PPm cip Hz 3,102p Hz
H 147.08 107.97 9.0 5.2. 148.13 105.85 8.4 8.1
F 143.38 110.85 8.7 6.1 142.58 109.72 8.3 8.5
Cl 145.96 110.61 8.2 6.2 145.38 109.06 7.5 8.8
Br 147.183 110.40 6.7 6.6 146.55 108.99 8.0 8.8
CH3 148.2o 109.28 9.0 6.8 147.80 106.91 7.0 9.3
NO2 144.96 109.44 9.6 6.2 145.01 108.20 7.4 8.8
00H3
146.19 109.22 8.2 6.3 144.85 108.39 7.7 8.3
a Chemical shifts in ppm from T.M.S. Positive shifts to low field. Recorded for 20% MAI solution in CC140
CH fl
Table 23. 13C Substituent chemical shifts indimptial_1=21-substituted thesy12-chl s
Substituent E-isomer _ Z-isomer
C-1 ppma C-2 ppma S.C.S. C -lb S.C.S. C-2 b' C-1 ppma C-2 ppma S.C.S. 0-1b S.C.S. C-2
H 147.08 107.97 0 0 148.13 105.85 0 0
F 143.38 110.85 -3.70 +2.88 142.58 109.72 -5.55 +3.87
C1 145.96 110.61 -1.12 +2.64 145.38 109.06 -2.75 +3.21
Br 147.18 110.40 +0.10 +2.43 146.55 108.99 -1.58 +3.14 CH3
148.20 109.28 +1.12 +1.31 147.80 106.91 -0.33 +1.06
NO2 144.96 109.44 -2.12 +1.47 145.01 108.20 -3.12 +2.35
00113 146.19 109.22 +0,89 +1.25 144.85 108.39 -3.28 +2.54
a Chemical shifts from T.M.S. Positive shifts to low field.
b Positive shifts to low field of dimethyl 1-phenyl 2-chloro vinyl phosphate, negative shifts to highfield.
• •
- 103 -
azure 10
CH 00CH3
4r. Br 0
Cl
0 NO2
H 0
-5.0
S.C.S. of in dimethyl 1-2'-substituted phenyl 2-chloro vinyl phosphat_.(7,-isomer)E,LaLttlainst S.C.S. of C-1 in dimethvl 1-2I-substituted 7::heny1 2-cbioro vinyl rhosphate
1_1.'3:isomer)
- 104 -
Figure 11
S.C.S. of 0-2 in dimeth71 1-2'-substituted phenyl 2-chloro
vinyl nhosni-iate (Z-isomer) plotted afminst S.C.S. of C-2
in dimeti2LL1a2t-substituted phenyl 2-chloro vinyl phosphate
.(,7isomer)
- 105 -
5. 31P Nmr of 2-Substituted and I 2-Disubstituted Vin,1 Phos hates
7;1 , The 'al) (noise-decoupled from 1H) chemical shifts for the series of
diethyl 2-substituTsd vinyl phosphates have been recorded to infinite
dilution in CDC13
solution. These were referenced against trimethyl
phosphite whose chemical shift from lock 95640.2 Hz was also determined
at infinite dilution. Since the chemical shift of trimethyl phosphite
with respect to 80% phosphoric acid solution is known -141.0 PPm136
(negative sign represents a down field shift), it was possible to
reference all the 31P chemical shifts relative to phosphoric acid
solution - Table 24.
It is possible to resolve the 31P resonances for the E- and
Z-isomers of diethyl 2-substituted vinyl phosphates - Fig. 12. For
all the substituents studied it has been found that the 31P resonance of
the Z-isomer is to low field of the 31P resonance in the corresponding
E-isomer.
Table 24. 31
P Nmr parameters of diethz11 tedy es.
CH3CH20.1
CH3CH20// -a‘ C=CHX
Substituent X Shifta- E Hz Shifta- Z Hz S E P bpm S Z ppmb
Cl 89709.2 89720.5 +5.4 +5.1
Br 89693.6 89716.5 +5.8 +5.2
CH ' 3 89732.2 89751.2 +4.9 +4.4
C6H5 39739.5 c +4.7 c
a Down field shift in Hz from lock. Recorded to
infinite dilution in CDC13
solution.
Shift in ppm from 80% H3PO4 solution. Positive
shifts to high field.
Only E-isomer available.
Figure 12
- 106 - i Z-isomer
* c e
Ii Ir 31P Nmr spectrum of 0
I
diethyl 2-ohloro vinyl 4 11
'phosphate (JW E, 60 Z) 0
showing assignment of E- 4: I
and Z-isomers
E-isomer
i t
I
I'
4
i t
1
Swccp width 30 Hz
I
I
1 1
1 ill
I 1\
I c
I
\ 1‘-.0
- 107 -
However, when the 31P chemical shifts for the dimethyl 1-phenyl
2-substituted vinyl phosphates were recorded in a similar manner -
it was found that the chemical shift of the E-isomer resonates to low field
of that for the Z-isomer - Fig. 13. This illustrates that 31P chemical
shifts are conformationally dependent since it has been established
earlier that the introduction of a substituent at C-1 changes the
conformational properties of vinyl phosphates. With substituent X = CH3 at C-2 it was impossible to resolve the resonances of the E- and Z-isomers
and a broadened signal was obtained. Similar observations were made in
the IH and 13C nmr for dimethyl 1-phenyl 2-methyl vinyl phosphate.
Table 25. 31 pN.I...nra.rp.2.1221dinpl2enr12-sul hoshateE
Substituent X Shift- E Hz Shifts' - Z H ppmb 6Zppmb
Cl 89774.4 89742.5 +3.8 +4.6
Br 89751.8 89728.0 +4.4 +5.0
CH3 89787.2 89785.8 +3.5 +3.5 C6H5 89770.2 89760.6 +3.9 +4.2
002C2H5 89708.3 89705.1 +5.4 +5.5
a Down field shift in Hz from lock. Recorded to
infinite dilution in 0013 solution.
b Shift in ppm from 80% H3PO4 solution. Positive shift to high field.
The3 1P chemical shifts of a series of dimethyl 1-21-substituted' phenyl 2-chloro vinyl phosphates were recorded and these are given in
Table 26. In all cases the 31P chemical shift for the E-isomer was
found to low field for that of the Z-isomer. This has already been
observed for the more general dimethyl 1-phenyl 2-substituted vinyl
phosphates. There is a variation of the 31P chemical shift with the
- 108 -
Z-isomer
Figure 13
E-isomer
1 Sweep width 60 Hz
1
1
31P Nmr sPectrum of dimethyl 1-phenvl 2-chloro vinyl _phosphate (4311, 57‘co Z)
showing assignment of E- and Z-isomers
- 109 -
with the nature of the ortho-substituent. For a series of dimethyl
1-41-substituted phenyl 2-chloro vinyl phosphates, the 31P chemical
shifts - Table 27 were found to' be almost completely independent on
the nature of the para-substituent. This was unexpected since the 1H nmr fcr these compounds had shown a substituent effect that could
be related to similar effects in p-substituted styrenes. The 31P
chemical shifts are probably more dependent upon the conformational
properties of the molecules than the electronic nature of the substituents. We might anticipate substituent effects in the 1H nmr of dimethyl
1-41-substituted phenyl 2-chloro vinyl phosphates because the proton is conjugated to the para-substituent through the Trsystem.
The 31P chemical shifts of dimethyl 1-21-substituted vinyl phosphate
- E-isomer have been plotted against those of the Z-isomer - see F15. 14. There is a good correlation, and the slope of unity indicates that
substituent effects for the E- and Z-isomers are very similar. Comparable
effects have already been shown in the 13C spectra of these compounds.
It was then stated that this indicates a favoured conformation for the
molecules with the substituent cisoid to the phosphoryl group.
These effects in the 31P spectra may confirm this observation.
Using 31P chemical shifts it is possible to differentiate
between the E- and Z-isomers of dimethyl 1-21-substituted phenyl 2-chloro
vinyl (thio) phosphates and (thio) phosphonates. In all cases the 31P
resonance of the E-isomer is found to low field from that of the Z-isomer - Table 23.
- 110 -
Table 26. 31P Nmr arameters of dimethyl 1-21-substituted 2-chloro vinyl phosphates
CH 0 \■"0 3
CH3e/P-N =CHC1 Rf
Substituent X Shift-Ea Hz Shift-e Hz E ppmb r o z ppmb
H 89774.2 89742.5 +3.8 +4.6
P 89754.7 89730.7 +4.3 +4.9
Cl 89745.2 89720.5 +4.5 +5.1
Br 89741.8 89719.5 +4.6 +5.2
CH3
89757.6 89740.2 +4.2 4-4.7
00H3 89751.6 89730.2 +4.4 +4.9
NO2 89733.5 89706.4 +4,8 +5.5
a Down field shift in Hz from lock. Recorded to infinite dilution
in CDC13 solution.
Shift in ppm from 80% H3PO4
solution. Positive shift to high field.
Table 270 aLmIl_parameters of dimethvi 1- 1-substituted 2-chloro vinyl phosphates
CR3 CH30//r .CHC1
Substituent X Shift-Ea Hz Shift-Za Hz S E ppmb 6 Z ppmb
H 89774.4 89742.5 +3.8 +4.6
F 89775.4 89741.2 +3.8 +4.6
ci 89776.1 89742.2 +3.8 +4.6 Br 89777.0 89743.7 +3.8 +4.6
00113 89776.3 89742.7 +3,8 +4.6
NO2 89781.2 89745.3 +3.6 +4.5
a Down field shift in Hz from lock. Recorded to
infinite dilution in CDCI3
solution. b Shift in ppm from 80% 11
3PO
4 solution. Positive
shift to high field.
- 112 -
31P Of dimeth 1 1-2f-substituted phenyl 2-chloro vinyl phosphate
(Z-isomer) -clotted 2.:17ainst 31P of dimethyl 1-2f-substituted
phenyl 2-chloro vinyl phosphate CE-isomer)
5.15
- 113 -
Table 28. 31P Nmr parameters ofdLgtILly1 1-21-substituted Ltanyi 2-chioro vinyl (thio_Lpioshatesa._indlhiol phostihonates
CHOP
R .CHC1
= H
Shift-E Hz Shift-Z Hza 6 E ppmb S Z ppmb
CH3
91118.4 91102.8 -29.4 -29.0
CH3 93855.8 93820.3 -96.9 -96.1
OCH3 89774.4 89742.5 +3.8 +4.6
OCH3 S 92656.6 c -67.3 0
Y =
Shift-E Hza Shift-Z Hza 6 E ppmb E Z ppm
CH3
91125.9 91113.0 -29.5 -29.2
CH3
93851.5 93825.9 -96.8 -96.2
00H3 0 89754.7 89730.7 + 4.2 + 4.9
OCH3 S 92627.4 92610.1 -66.6 -66.2
a Down field shift in Hz from lock. Recorded to infinite dilution in CDC1 3. Shift in ppm from 6O H3PO4 solution. Positive shift to high field, negative shift to low field.
0 Only E-isomer available.
- 114 -
6. Experimental Dibromoacetaldehyde1371138
Bromine (320 g (102.5 ml), 2.0 mol.) was added dropwise to
purified acetaldehyde (44.0 g, 1.0 mol.) in two equal portions. The first portion was added with stirring at 5° over a period of three hours - this gave the mono-brominated compound. The second portion was added at 30° + - 5o over a period of four hours and stirred at 35o overnight. The solution was purged of any hydrogen bromide with nitrogen, dried over P205, and distilled at atmospheric pressure. Pure dibromoacetaldehyde (63.4 g,
31%) b.p. 138-140°/760 mm Hg (Lit.138 b.p. 137-140°/760 mm Hg) was obtained
as a colourless liquid.
Diethyl 2-bromovinyl phosphate
Freshly distilled dibromoacetaldehyde (5.0 g, 0.025 mol.) was added
dropwise to a stirred solution of triethyl phosphite (4.15 g, 0.025 mol.) in. ether (10.0 ml) at 0-5°. The solution was stirred for twenty-four hours at
room temperature. Ether was removed in vacuo and the residue was distilled.
Diethyl 2-bromo vinyl phosphite was isolated (4.3 g, 66%) as a colourless liquid, b.p. 90-95°/0.3 mm Hg (Found: C, 27.8; H, 4.5; Br, 29.1; P, 11.8: C6H12Br04P requires: C, 27.8; H, 4.7; Br, 30.85; P, 11.9%.); isomer ratio (E:Z) ca 9:1.
imax 3100 m, 3050 m,•1650 m, 1480 w, 1450 w1.1400 w, 1380- w, 1280 s, 1210 my
1170 m; 1140 s, 1050 vs, 1000 s, 900 s, 820 ra, 680 m, cm-10 IH nmr - see Table 5. 2-ChloroprolkailLhalt139
6.5 N Hydrochloric acid (125 ml) was cooled and maintained at or below 10° whilst freshly distilled propionaldehyde (36.3 ml, 0.5 mol.) was added dropwise. Chlorine gas was introduced below the surface at suche a rate ,so as to maintain the temperature between 10° and 15°, and the
solution diluted with water accordingly to maintain the total acid
concentration at 6.0 N. When chlorine gas ceased to be absorbed, the
reaction mixture was diluted to 300 ml with distilled water and distilled
at reduced pressure. The crude fraction b.p. 48-52°/160 mm Hg (20.0 ml)
was azeotropically dried with diethyl ether (20.0 ml) and xylene (10.0 ml)
- extra xylene added to form a heterogeneous ether/water mixture with a
liquid temperature at 65-70°. When no more water was being given off
- 115 -
the liquid was distilled and then redistilled to give 2-chloroprepionaldehyde
(10.6 g, 23%) as a colourless liquid b.p. 86-87° (Lit.129 b.p. 86°). Diethyl 2-methyl vinyl phosphate
Freshly prepared 2-chloropropionaldehyde (3.7 g, 0.04 mol.)
was added dropwise to stirred triethyl phosphite (6.64 g, 0.04 mol.) in a nitrogen atmosphere at 20°. The solution was stirred at room temperature for twenty-four hours and distilled under reduced pressure (removing
traces of triethyl phosphite) to give diethyl 2-methyl vinyl phosehate
(5.4 g, 705) as a colourless liquid b.p. 50-5470.15 mm Hg (Found: C, 43.5;
H, 7.7; P, 15.6: C7H1504F requires: C, 43.3; H, 7.8; P, 15.95%.), isomer ratio (E:Z) ca 6:1.
e) max 3050 in, 2950 m, 1680 m, 1490 w, 1450 w, 1400 w, 1370 w, 1280 st 1170 mt 1140 st 1050 vst 980 s, 940 Int 890 m, 820 w, 760 w, cm-1.
IH nmr - see Table 5. Phenyl chloroacetaldehyde140,141
Sulphuryl chloride (33.75 g, 0.25 mol.) in methylene chloride
(4.0 ml) was added dropwise to a stirred solution of phenyl acetaldehyde
(30.0 g, 0.25 mol.) in methylene chloride (10.0 ml) at 10°. The solution
was allowed to warm up and the. rate of addition adjusted so that the
temperature was kept between 150-40° - care was taken to avoid any
accumulation of sulphuryl chloride in the reaction mixture. After complete
addition the solution was stirred for half an hour and finally refluxed
for a further half an hour. The product was distilled under reduced
pressure in a nitrogen atmosphere (to prevent polymerisation) to give
phenyl chloroacetaldehyde (15.8 g, 41.0%) as a colourless liquid b.p. 69-71° /0.3 mm Hg (Lit.141 b.p. 98-100°).
Diethyl 2-phenyl vinIze._ph'Latee eeerl Phenyl chloroacetaldehyde (4.64 g, 0.03 mol.) was added dropwise
with stirring to triethyl phosphite (4.98 g, 0.03 mol.) in a nitrogen
atmosphere at room temperature. The reaction was exothermic - temperature
rising to about 80°. After complete addition the solution was stirred
for twenty-four hours under nitrogen at room temperature. The crude
reaction mixture distilled at reduced pressure to give diethyl ?_-phen,
e:vinyl phosphate (4.2 g, 55%) as a pale green liquid b.p. 145-146°/0.3 mm Ego This was further purified by column chromatograhy (silica gel eluted with
ethyl acetate) for analysis. (Found: C, 56.3; H. 6.6; PI 12.4: C12H1704P requires: C, 56.25; H, 6.7; P, 12.1%), Pure E-isomer.
- 116 -
- )max 3100 Iry 3050 m, 2950 w, 1670 m, 1500 w, 1490 w, 1450 m, 1400 w, 1380 w, 1280 s, 1220 m, 1180 m, 1130 s, 1050 vs, 980 s, 950 m, 930 m,
840 m, 770 m, 710 m, cm-1. 1H nmr - see Table 5. Diethyl 2henl vinyl phosphate (Z-isomer)142
A solution of the E-isomer (200 mg) in sodium dried benzene
(150 ml) was irradiated using benzophenone (250 mg) - as triplet sensitizer,
through Pyrex with a medium pressure mercury lamp for half an hour. A nitrogen bubbler was used to agitate the solution. The product, isolated by
preparative tic (silica gel eluted with ethyl acetatebenzene 1:1), was predominantly the Z-isomer of 112112,y te. Isomer ratio, (E:Z) ca 1:3.
1H nmr - see Table 5. Direct irradiation of the E-isomer in the absence of a triplet
sensitiser resulted in the attainment of the photo-stationary state
after thirty-six hours with isomer ratio (E:Z) ca 1;3. Irradiation for
a further twenty-four hours did not increase the amount of Z-isomer.
Diethyl 2-chlorovinyl phosphate
72kLthv12-chlo.rov- yinlphosthate., 143 was donated by Shell Development Company as a mixture of isomers. Isomer ratio (E:Z) ca 2:3. 1Lmax 3100 w, 3000 m, 2950 w, 1650 m, 1480 w, 1450 w, 1400 w, 1380 w$ 1290 e$ 1240 m, 1170 m, 1150 s, 1100 s, 1050 vs, 990 s $ 920 s, 830 m, 780 m, 750 la, - cm 1
1H nmr see Ta22e_5., Chloromercuri acetaldehyde144 Vinyl acetate (4.3 g, 0.05 mcl.) was added to a solution of
mercuric acetate (16.0 g, 0.05 mol.) in water (75 ml) with shaking. After filtration, potassium chloride (3.8 g, 0.05 mol.) was added in small portions to precipitate chloromercuri acetaldehyde (100%) as a white solid
m.p. 129-130° (with decomposition) (Lit.144 m.p. 129-130°). Diethyl vinyl phosphate145
A solution of chloromercuri acetaldehyde (3.55 g, 0.013 mol.) and triethyl phosphite (2.10 g, 0.013 mol.) in benzene (25.0 ml) was stirred at
room temperature for twenty four hours. The benzene solution was separated off and the mercury washed several times with benzene. Removal of the
117 -
benzene at the pump gave a colourless licuid which distilled at reduced
pressure to give diethyl vinyl phosphate (1.58 g, 69%) as a colourless
liquid b.p. 74-75°/500 mm Hg (Lit.146 b.p. 79°/6.0 mm Hg).
nmr - see 12.1)112...2. Dimethyl 1-carbomethoxy vinyl phosphate
A stirred solution of dimethyl 1-carbomethoxy-2-chloroethyl / phosphate' 47 (3.85 g, 0.0156 mol.) in dry ether (40 ml) was treated with
a solution of triethylamine (5.0 g) in dry ether (10.0 ml). The mixture
was heated under reflux for half an hour, then stirred at room temperature
overnight - white precipitate of triethylamine hydrochloride was produced.
The solution was filtered and the solvent removed at the pump to give a
colourless liquid (3.04 g, 93%) which was purified by column chromatography
(silica eluted with ether) giving dimeth1 1-carbomet .
(2.62 g, 80%) as a colourless liquid b.p. 86-88°/0.3 mm Hg (Found: C, 34.3;
H, 5.2; P, 15.00 C61111P06 requires: C, 34.3; H, 5.2; P, 14.8%). \hoax 3140 w, 3000 w, 2950 m, 2850 m, 2850 w, 1750 vs, 16405 s, 1440 mt
1380 wt 1330 a, 1300 vs, 1210 s, 1170 vs, 1050 vs, 920 w, 870 s, 830 s,
800 w, 770 wt 710 w, cm-1.
IH nmr 6 3.81 (3H, s), 3.82 (6H, d; JE...p 110 Hz), 5.57 (1H, t; 2.2Hz, J1/..p. 2.2 Hz), 5.87 (1H,
Diethyl 1-cyan ,vinyl Phosphate
Diethyl 1-cyano 2-chloro ethyl phosphate148 (2.73 g, 0.0113 mol.)
was stirred in sodium-dried ether (25.0 ml). Dry triethylamine (5.0 g)
in sodium-dried ether (10.0 ml) was added in one portion at 00 and the
solution refluxed for half an hour, then stirred overnight at room
temperature. After filtration, to remove the precipitate of triethylamine
hydrochloride, the ether was removed in vacuo to give a reddish liquid.
Purification by column chromatography (silica eluted with ether) gave
diethyl 1-cyanvi e (1.69 g, 73%) as a ,-,..olourless liquid
b.p. 78°/0.3 mm Hg (Lit.149 b.p. 60/0.001 mm Hg). (Found: 0,40.9; H, 5.0;
P, 14.7; N, 6.8: C71112POIN requires: C, 41.0; Hp 4.85, P, 15.1; N, 6.8cA,
1) max 3140 wt 3000 m, 2950 w, 2900 wt 2250 w, 1635 s, 1480 w, 1450 w, 1395
1375 wt 1290 vs, 1250 s, 1170 in 1105 m, 1030 vs, 970 m, 925 w, 870 m, 830 w,
810 w, 790 w, 710 w, cm-I.
t; JE_H 2.2 Hz, J/i_p 2.2 Hz) ppm.
- 118 -
nmr S 1.39 (6H, dt), 4.20 (4H, m), 5.58 (1H, dd;JH-P 1.85, ..71141 3.0 Hz), 5.75 (1H, del; J/1.4) 2.2, J11.41 3.0 Hz) ppm.
Dimethyl ximlahosthate
Trimethyl phosphite (3.72 g, 0.03 mol.) was added dropwise to a
stirred suspension of chloromercuri acetaldehyde (8.37 g, 0.03 mol.) in
benzene (50.0 ml) at room temperature. After addition the solution
was stirred at room temperature overnight. The solution was filtered
and the mercury washed several times with benzene. Removal of the benzene
in vacuo gave a colourless liquid which distilled at reduced pressure as
pure dimethyl vinyl phosphate (2.72 g, 60%) b.p. 59-60°/0.4 mm Hg.
Desyl chloride (4.6 g, 0.02 mol.) - for preparation see
Chapter 3, was added to trimethyl phosphite (3.1 g, 0.025 mol.) and
the mixture heated at 1000 for sixteen hours. Distillation at reduced pressure gave ydimethil e (4,5 g, 74%) as a
pale yellow liquid b.p. 150-152°/0.05 mm Hg. Isomer ratio (E:Z) ea 2:3,
1H nmr Z-isomer 6 3.49 (6H, d; 3H.4) 11.3 Hz), 6.33 (1Ht d; JH.4)
1.4 Hz), 7.22 (3H, m), 7.47 (2H, m) ppm. IH nmr E-isomer 5 3.70 (6H, d; .34/_p 11.2 Hz), 6.65 (1H, d; J//..p
2.7 Hz), 7.22 (3H, m), 7.47 (2H, m) ppm.
Dimethyl phosphonate (22.0 g, 0.2 mol.) was stirred in chloroform
(44.0 ml) and the solution cooled to 5-10°. Sulphuryl chloride (32.5 g,
0.24 mol.) was added dropwise to the stirred solution keeping the
temperature below 100. After stirring for fifteen minutes, thionyl
chloride (3.8 g, 0.02 mol.) was added and the chloroform distilled off
at atmospheric pressure. The residue was distilled at reduced pressure
to give dimethyl phoaphorochloridate (20.4 g, 71%) as a colourless
liquid b.p. 100-104°/50 mm Hg.
Dimethyl 1-phenyl 2-carboethoxv vinyl ph6sphate (ELs2222s1 Sodium ethoxide (3.4 g, 0.05 mol.) - prepared by dissolving clean
metallic sodium (1.15 g, 0.05 g atoms) in absolute ethanol (50.0 ml)
and removing the excess ethanol at the pump with ether, was suspended in sodium-dried benzene (500 ml). Ethyl benzoyl acetate (9.6 g, 0.05 mol.)
was added dropwise to the stirred solution and solution refluxed overnight.
after removing about half of the benzene, dimethyl phosphorochloridate
- 119 -
(7.2 g, 0.05 mol.) was added drop wise to the stirred solution which
was finally refluxed for two hours. The benzene solution was cooled
to 0°, washed with 55 NaOH (100 ml), water (3 x 70 ml), and dried over
anhydrous sodium sulphate. Removal of the ether at the pump gave
dimethyl 1-phenyl 2-carboethoxy vinyl phosphate (11.8 g, 78%) as an
orange liquid which was purified by column chromatography (silica eluted
with ethyl acetate/benzene 1:1) as a pale yellow liquid.
')max 2950 m, 2850 w, 1730 vs, 1645 a, 1445 my 1365 my 1330 m, 1280 vs, 1180 vs, 1050 vs, 980 m, 920 w, 860 s, 780 m, 700 n, cm 1.
IH neer indicated pure Z-isomer S 1.28 (3H, t; JHer/ 7.1 Hz),
3.72 (6H, d; J.Tiep 11.4 Hz), 4.12 (2H, q; JH_H 7.1 Hz), 5.90 (1H, d; „TH..") 1.6 Hz), 7.30 (5H, m) ppm..
2-Chloro eth- 1 benzo 1 acetate150' 151
Sulphuryl chloride (13.5 g, 0.1 mol.) wan added dropwise to
ethyl benzoyl acetate (19.2 g, 0.1 mol.) with stirring at 0-5°. After
complete addition (three hours) the solution was stirred at room
temperature for twenty-four hours and the UCI and SO2 removed at 40°-50°
by the water pump. Distillation at reduced pressure gave 2-chloro ethyl
bei:ezal222 (15.04 g, 66,T,1) as a pale yellow liquid b.p. 98-99°/
0.05 mm Hg (Lit. b.p. 175-177°/10 mm Hg).
Dimethvl 1-phenyl 2-c 1211-111Eg2-0222112._.(§A:kaREE1 Trimethyl phosphite (3.1 g, 0.025 men.) was added dropwise to
2-chloro ethyl benzoyl acetate (4.54 g, 0.02 mol.) with stirring and the
solution refluxed for two hours, then stirred for twenty-four hours
at room temperature. Distillation at reduced rressure gave pure
dimeth22,yjoeth=rEisimphate (5.35 g, 87%) as a colourless liquid, b.p. 150-1510/0.05 mm Hg. Isomer ratio (E:Z) ca 1:1.
1 nmr Z-isomer - see earlier preparation.
111 nmr E-isomer t.) 1.13 (311 t; J1/...H 7.0 Hz), 3.70 (6H, d;
Jim, 11.3 Hz), 4.00 (2H, q; JH_H 7.0 Hz), 6.02 (IH, d; JH..10 2.0 Hz),
7.30 (5H, m) ppm. The preparation of any other vinyl phosphate mentioned in this
chapter will be included later in the relevant chaptero
120 -
- 121 -
Effect of Varying the Nature of thsLeavirsp .t.1.pon the Course of the Perkow and lAbnormall Michaelis-Becker Reactions
1. Reaction of trialkyl phosithite with or-halo carbonyl compounds -
Perkow reaction
The simplest trialkyl phosphite, trimethyl phosphite, was
reacted with a variety of it-halo carbonyl compounds in order to study not only the effect of varying the nature of the leaving group but to
compare the products formed, with those obtained on reacting dialkyl
phosphonates with oC.-haio carbonyl compounds in the presence of a convenient base.
When trimethyl phosphite was reacted with monochloroacetone at elevated temperature, an isomeric mixture of dimethyl 1-methyl vinyl
phosphate (XIII) - W. and dimethyl acetonyl phoachonate (XXX) - 9-% was
produced along with a small amount of a phosphorus-containing compound
(XXXI) which could not be isolated- by any classical technique. The
isomer ratios were determined by integration of the methyl resonances in
the IH nmr spectra
110-1200 , (CH30)3I' + CH3COCH2C1 ----> (Cile0) t1-0 + (CH 0) P-CH --CH- , 12 '''-- _,,C=CH2 3 2 2 ,
CH. 3
XIII XXX
910
90
(CH30)2 -CH3
XXXI
The dimethyl 1-methyl vinyl phosphate (XIII) and dimethyl acetonyl
phosphonate (XXX) were separated by column chromatography. The faster
eluting component was assigned as a vinyl phosphate on the basis of I.R.
110-120o , (CH30)2P-CH2-C-CH3
2
(cH30)3P f CH
3COCH2Br
- 122 -
-Jmax 1670 s cm-1 Co=0 and 1H nmr spectroscopy 6 4.48 (111, m), 4.69 (111, m) - corresponding to the resonance positions for the vinylic protons. Identification of theother isomer as a ketophosphonate
was based on IRI)max 1710 s cm-1 (0=0) and 1H nmr spectroscopy 6 3.07 (2H, d; JHep 22 Hz) - consistent for a methylene group directly bonded to a phosphoryl substituent.
Treatment of bromo-acetone with trimethyl phosphite under the
same conditions again gave a mixture of (XIII) - 30% and (XXX) - 70%, but
in differing proportions, as well as a larger amount of the unknown (XXXI)
- about three times as much as for chioroacetone reaction.
XIII
XXX
30%
70%
CH OCR (---- 3 3)2
XXXI
When this reaction was repeated at room temperature a larger
percentage of the vinyl phosphate (XIII) - 4e, with respect to the
ketophosphonate (XXX) - 56% was produced along with a much smaller amount
of the unknown (XXXI) - about half as much as when the reaction was
carried out at devated temperatures. Gle analysis of the crude reaction
mixture using Flame ionisation Detection (F.I.D.) - sensistive to
phosphorus, showed the presence of five phosphorus-containing species.
Three of the traces were much larger in intensity than the other two
and were the major products of the reaction (XIII), (XXX) and (XXXI)
which could be clearly seen in the 1H nmr spectrum. The two minor
components were thought to be dimethyl phosphonate- and trimethyl phosphate
contaminants in the starting trimethyl phosphite. An F.T. 31P nmr
- 123 -
spectrum (noise-decoupled from proton) of the crude mixture showed three
sharp resonance lines at 6 +4.8, -22.3, -33.0 ppm relative to 8010 H3PO4
(positive shifts to high field of H3 PO4.). Two of these at E. 4.8 and
-22.3 ppm correspond to the resonance positions for authentic samples of dimethyl 1-methyl vinyl phosphate (XIII) and dimethyl acetonyl phosphonate
, (XXX). W 31P When an undecoupled spectrum was recorded the resonance at
S -33.0 ppm produced a complicated multiplet with two phosphorus-proton couplings of 17.5 Hz and 11.0 Hz. The corresponding resonance in the IH nmr 6 1.45 (3H, d; JE_p 17.5 Hz) is consistent for a methyl group
directly bonded to a phosphorus atom. A .TH-1, = 11.0 Hz can be assigned
to methoxy signals attached to phosphorus and indeed it is possible to
identify these signals in the 1H nmr spectrum at & 3.73 (3H-I, 11.0 Hz) and
& 3.69 (J/3_1, 11.0 Hz). The unknown (XXXI) was thought to be dimethyl methyl phosphonate and the 31P chemical shift of -33.0 ppm agrees favourably
with the reported value of -32.5 ppm136 - the undecoupled spectra were
almost superimposable.
CH 3-0CH 3 1 3 oc H3
XXXI
Trimethyl phosphite is a very good nucleophile and will react
with W-halocarbonyl compounds in a variety of different ways. Keto-
phosphonates (XXXIII) are formed by direct displacement of the halogen
on the a-carbon atom by the trialkyl phosphite in a normal Michaelis-
Arbuzov type reaction followed by dealkylation of the intermediate
trialkoxyketonyl phosphonium halide (XXXII) - Schemej.
The vinyl phosphates (XXXV) are formed by attack of the
trialkyl phosphite at the carbonyl carbon atom of a ec-halo carbonyl
compound followed by dealkylation of the intermediate (XXXIV) as
before - Scheme 10.
This type of mechanism explains very well why different
isomeric ratios of vinyl phosphate/ketophosphonate are obtained when
chloroacetone and bromoacetone react with trimethyl phosphite. More
ketophosphonate is obtained from bromoacetone because bromine is a
better leaving group than chlorine and nucleophilic attack at C-2
-RX (no) -0-C=CH 2 1 .1 2
- 124 -
Scheme 9
+ ] - (R0)3P + R3. -9C-CH2X —5, (R0)3P-CH2-9 C-R1 X
XXXII
R R0-CH 9-R • .— /. 2-C R=Of --.1""
-RX )1. (R0)2P-CH -R1
BSI
Scheme 10
0 (R0)1' R1-g-CH2X [(R0) 3P1 I -CH2X]
1 +
XXXIV
R
XXXV
- 125
would be more favoured for bromoacetone in an SN-2 type process. At
lower temperatures there is greater percentage of attack at carbonyl
carbon than at carbon-2 with a greater proportion of vinyl phosphate
formation -see Table 22, When bromoacetone was reacted with trimethyl
phosphite at 20° a mixture of (XIII) - 44% and (XXX) - 56% was obtained as well as a small amount of (XXXI) - much less than was observed when
the reaction was carried out at 110°. Diethyl methyl phosphonate (XXXI) is formed from a rearrangement of trimethyl phosphite by an.alkylation/
dealkylation reaction. Trimethyl phosphite can be alkylated by methyl
halide formed in the Perkow or Michaelis-Arbuzov reaction to give a
pentavalent-type phosphorus species (XXXVI) which can then dealkylate
to give dimethyl methyl phosphonate (XXXI).
CH- CH3- CH
H30--- -.)-CH3-.67 CH 0-11
( 3
3 \Mt. CH3 CH
3o X
Xxxv' OH30. 0
/ 3 CH3X-
CH36
XXXI
- The larger percentage of dimethyl methyl phosphonate formed when
bromoacetone was used (ca three times as much as for chloro acetone reaction)
reflects the greater alkylating ability of methyl bromide with respect to-
methyl chloride.
When l,l-dichlcro acetone was treated with trimethyl phosphite
at 110420° an isomeric mixture of dimethyl 1-methyl 2-chloro vinyl phosphate (XVIII) was obtained (E/'Z - determined by IH nmr integration of the
vinylic signals). Small amounts of the ketophosphonate (XXXVII) and traces
of dimethyl methyl phosphonate (XXXI) could also be detected by tic, 1H nmr
but proved impossible to isolate and so be fully characterised.
- 126 -
(CH30)3P + CH3A-CHC12
(0H30)2.._01 4 (OH 0) L0-0.<1 3 2 6113 H3
E-92% Z 8%
XVIII
(CH30)2 CHC1-g-CH + (CH 0) ItCH. 3 2 3
XXXI
The 1H nmr of (XVIII) showed resonances at 6 6.15 and 5.63 ppm which are consistent with the calculated chemical shifts for the vinylic
protons in dimethyl 1-methyl 2-chloro vinyl phosphate (E/Z) of -6.06 and -5.65 ppm - see Chapter 2.
With more than one halogen atom on C-2 in the ketone, the Perkow
reaction proceeds almost exclusively to give vinyl phosphate formation. 2-Chloroacetophenone reacts with trimethyl phosphite to give dimethyl 1-phenyl vinyl phosphate (XI) as the only observable product. No
ketophosphonate could be detected by either tic or 1H nmr.
CH3CN
(CH3 ' 0\ P.+ C6 H5 COCH_Cl 20° > (CH 0)2KOTCH2
65
XI
When 2,2-dichloroacetophenone was reacted with trimethyl phosphite
an isomeric mixture of dimethyl 1-phenyl 2-chloro vinyl phosphate (XVII).
The E/Z isomer ratio_ 40:60% was determined as before by integration of
the vinylic signals in the 1H nmr spectrum. This result is in agreement with that of Horowitz35 (prepared (XVII) with 0 ratio 35:65%), allowing for the reversal in the stereochemistry of his assignments - see Chapter 2
and ref. 37. The slight variation in the isomer distribution could be due
to a solvent effect since our result was obtained in acetonitrile solution
at room temperature, while his reactions were conducted in the absence of a solvent.
XXXVII
CH3CN
(cH30)3P C6H5C00HC12 (CH3 0)2 ?-0.
200
(36115
H (CH30
Cl
- 127 -
E - 40% z - 6o%
XVII
When trimethyl phosphite was treated with 202-dibromoacetophenone at elevated temperatures exclusive formation of dimethyl 1-phenyl 2-bromo vinyl phosphate (XXXVIII) was observed. The isomer ratio E - 1%, Z - 99%
determined by integration of the vinyl signals in the 1H nmr again differs
slightly from the one observed by Borowitz (E Z 97% obtained from
triethyl phosphite and 2,2-dibromoacetophenone),
(CH30)3P C6H5COCEBr2 (CH30)2P-0,
C65 5
E 1%
(CH30)2P->.e/Br
C 65 z - 99%
XXXVIII
This result is surprising since phenacyl bromide has been shown to 0 react with triethyl phosphite6 to give ketophosphonate (XXXIX) - 85% as
the major isomer, with vinyl phosphate (XL) - 15j0 150° 9
(m3c11203p + c6H5000nBr2 (cH3cH2o)2p-cH24-005
85%
XXXIX
(cH3CH20)2P- C-.CH2
-6H5
15%
XL
Table 29. Reaction of ac-halocarbonyl compounds with trialkyl phosphite - Perkow reaction
(R0)3P + R1-g-CHXY (R0)2F =CHY
+ (RO)2P-CHY-g-R1
R R1 X .;10 (110)2L0- =CHY 1
% (RO) , -
------, Conditions
Temperature/Solvent
CH3
CH3
c1 91 9 110 - 120°
CH3 CH3
Br 30 70 110 - 120o
CH3 CH3
H Br 44 56 20°
CH3
CH3 Cl Cl 100 (92% E,8% z) Trace 110-115°
CH3
C6H5 H Cl 100a - 110-120o
CH3
C6H5
Cl Cl 100 (40% E,60%t) - 20°/CH3CN
C2H5 C6II5
H Br 15b
8513
150°
CH3
C6H5 Br Br 100 (1% E,99% z) - 90 - 100o
a See Ref. 31 b See Ref. 69
•
- 129 -
2. Reaction of dialk 1 chosphonate with cc-halocarbonyl compounds -
'abnormal? Michaelis--Becker reaction
It has already been established that dimethyl phosphonate
reacts with 2-chloro acetophenone in a variety of bases to give dimethyl
1-phenyl vinyl phosphate (XI) as the only product - see Chapter 1.
When 2-chloro propiophenone was treated with dimethyl phosphonate in ammonium/methanol two new compounds could be detected by tic. These
were separated by column chromatography and characterised by 1H nmr
as dimethyl 1-phenyl 2-methyl vinyl phosphate (XLI) and dimethyl 1-phenyl
2-methyl epoxyethyl phosphonate (XLII).
NH5/750H
>. (CH3G)2F-H C6H51-0H(01)CH3 2o0
The isomer distribution was established by 1H nmr integration
of the crude reaction mixture since the methyl resonances in (XLI)
(E - 6 1.72 (3H, dd; J.H.4) 2.7 Hz; JR_H 7.3 Hz) ppm, Z - 6 1.85 (3H, dd; JHe 3.0 Hz; JH_H 7.0 Hz) ppm) are well separated from those in (XLII)
(6 0.99 (3H, dd; J//...1> 1.1 Hz; J11..H 5.4) PPm), Dimethyl 1-phenyl 2-methyl
vinyl phosphate (XLI) was identified by the presence of vinylic
resonances in the 111 nmr 5.60 (Hi, m), 6 5.75 (HE, m) ppm, and the absorption1670 cm-1 in the infre-red spectrum (>4- , stretching
vibration). The 1H nnr of dimethyl 1-phenyl 2-methyl epoxy ethyl
phosphonate (XLII) - 6 0.99 (3H, dd; J11_1, 1.1 Hz; JH6H 5.4 Hz) suggested that only one geometric isomer of the epoxide was present. Dimethyl
1-phenyl 2-methyl epoxy ethyl phosphonate (XLII) on treatment with
hydrogen chloride gas gave a clean cystalline compound which was
(cH30)2P-0-t.CHCH3
6H5
48% (E/Z = 1:2)
XLI
(CH30)2V- ItCH3
6H5
52%
XLII
- 130 -
characterised as dimethyl 2-methyl-2-chloro-l-hydroxy-l-phenyl ethyl
phosphonate (XLIII). 1H nmr of this compound suggested that it was
in fact one diastereoisomer and that the hydroxy function was attached
to carbon-1 showing a considerable coupling to phosphorus 6 3.37 (1H, d; 41.J) 20 Hz) ppm - disappears on D20 exchange*
HCI (CH30)2P H.CH
3
---4 (CH30)2P- -CH(C1)CH3
6H5 6H5
XLII XLIII
The dimethyl 2-methyl-2-chloro-l-hydroxy-l-phenyl ethyl phosphonate
(XLIII) is the product of an epoxide ring opening in (XLII) where the chloride nucleophile has attacked the least hindered carbon atom to give
the most stable carbonium-ion intermediate. Treatment of (XLIII) with ammonium in methanol gave the same isomeric mixture of (XLI) - E/Z = 1:2
and (XLII) as was obtained when dimethyl phosphonate reacts with
2-chloropropiophenone in the presence of base. This strongly suggests
that dimethyl phosphonate and 2-chloropropiophenone may be in equilibrium
with hydroxyphosphonate (XLIII) before (XLI) and (XLII) are produced.
9 Base 9 OH (cH30)2P-H + CH5c00H(C1)cH3 (cH30)2P- -CH(C1)CH3
6E5
XLIII
Indeed when (XLIII) was treated with 2,2121,41-tetrachloroacetophenone
- a highly reactive acctophenone, in the presence of base, it was possible to isolate dimethyl 1-?1,41-dichlorophenyl 2-chloro vinyl phosphate (XLIV).
The product of intercepting dimethyl phosphonate with the activated aceto-
H
(cH3o
Cr
phenone(., OH
(CH30)2 -CH(C1)CH3
6E5
XL1II
9 Cl_((”c-cHc12
Cl
(CH30)2LH + C H5c0CH(CI)CH3
XLIV
- 131
In a similar reaction dimethyl phosphonate reacts with desyl
chloride (2-chlorobenzyl phenyl ketone) in ammonia/methanol to give
an isomeric mixture of dimethyl 1,2-,diphenyl vinyl phosphate (XLV)
and dimethyl 1,2-diphenyl epoxy ethyl phosphonate (XLVI).
(CH30)2P-H + C6H5COCH(C1)C6H5 C ------4-4. (030) ?-0-C=CHC6 H H
3OH 2 1 5
06115
30% - all E-isomer
70%
XLVI
The dimethyl 1,2-diphenyl vinyl phosphate (XLV) was assigned to be only the E-isomer by 1H nmr 6 6.65 (1H (vinylic), d; J..a_p 2.7 Hz) ppm and I.H.)max 1650 m (>4( - stretching vibration). A mixture of
dimethyl 1,2-diphenyl vinyl phosphate (E/Z) prepared fromt7imethyl
phosphite and desyl chloride (see Chaper 2) shows two vinylic resonances
in the 1H nmr 6 6.33 (1H, d; H-P 1.4 Hz), 6.65 (1H, d; J11.4, 2.7 Hz) PPm• It was possible to separate the isomers (XLV) and (XLVI) by
column chromatography enabling them to be individually charactersied.
The dimethyl 1,2-Biphenyl epoxy ethyl phosphonate (XLVI) is a crystalline
solid and shows a resonance at 6 4.75 (1H, d; jp_H 4.2)ppm in the 1H nmr
which was assigned to the proton attached tc carbon-2 for one geometric
isomer of (XLVI).
Treating 2-chloroisobutyrophenone'with dimethyl phosphonate in
the presence of ammonia/methanol as a base gave dimethyl 1-phenyl
2,2-dimethyl vinyl phosphate (XLVII) as the only detectable product.
No epoxide formations could be detected by either t]c cr 1H nmr.
H3 0 NH
3/cH
3OH c 3
c6H5-00 -01 (CH30)2P-H (CH30)2P-0-74„,_-".CH C H. 3 6 5
XLVII
CH3
- 132 -
111 nmr 8 1.69 (3H, d; Jp_H 3.2 Hz), 1.88 (3H, d; Jp_H 2.4 Hz), 3.46 (6H, d;J"p_H 11.2 Hz), 7.21 (5H, m)ppm is consistent for dimethyl
1-phenyl 2;2-dimethyl vinyl phosphate (XLVII) and I.R. shows .N) max 1640 w ()=(- stretching vibration).
In these reactions the formation of an epoxy phosphonate can be explained by the attack of dimethyl phosphonate at the carbonyl carbon
atom of the substituted acetophenone. This gives a. hydroxy phosphonate-
type intermediate which can ring-close to the epoxide - Scheme 11.
0 Base 9 A cw (CH30)2ILI' + (C6H5ICH(X)R ------4(CH3 0)2 P-1-CH-X
C6H5
(CH30)2P
R -u- A
OBR
- 6H5
X . Cl, R = CH3 or C6H5
Scheme 11'
When the substituent on C-2, R = halogen, no epoxide formation
could be detected, whereas when R = CH3
or C6H5 a considerable amount of
epoxide was produced. This observation supports the mechanism proposed
in Scheme 11 since any substituent on carbon-2 which stabilises the
carbonium ion formed when the chlorine leaves (or facilitates the loss
of the chlorine atom) should lead to epoxide formation. From the results
it appears that phenyl is better than methyl at stabilising a carbonium
ion and hence gives a higher proportion of epoxide formation. The fact
that no epoxide formation was observed with 2-chloro isobutyrophenone
would appear to be anomalous since two methyl groups on C-2 should lend
a greater stabilising- ability to the carbonium ion formed. Presumably
carbon-2 is too sterically crowded to allow epoxide formation and the
reaction proceeds by an alternative pathway to give vinyl phosphate as
the only product. 2-Phenyl desyl chloride (XLVIII) did not react with
dimethyl phosphonate in the presence of base. Probably, the carbonyl group is sterically crowded by the neighbouring phenyl groups and so
does not allow the phosphorus nucleophile to attack;
C6 SOC1 /pyr.
-> C5H5- -C6H5
vH2Ci
cl 9 C H 6 5( 65 IL
CH3
- 133 -
base T6H5
C6 H-CO-C-C1 + (CH30)2CP1-H D I
6H5
XL VI I I 2-Methyl desyl chloride (IL) which would hare been an interesting
compound to study proved difficult to make since chlorination of the
2-methyl benzoin with thionyl chloride/pyridine gave 1-phenyl 2-chioro
propiophenone (L) 152 and not ((IL)) as expected155.
These reactions were repeated using triethylamine as the tertiary
base and the results are reported along with the ones obtained using the
ammonia procedure in Table...Z.). In general very similar products were
obtained but with some slight variations in isomer distributions due to
effects of changing the base-and solvent.
It was thought that the reactions of substituted bromo-ketones
with dialkyl phosphonates should parallel the chloro-ketones to some extent.
The greater leaving ability of bromide ion relative to chloride ion might
lead to a larger proportion of epoxide formation - if the reaction proceeds
by a mechanism already suggested in Scheme 11. However there was some
evidenceo9 which indieated that dialkyl phosphonates react with bromo
ketones in the presence of tertiary bases (e.g. ammonia and triethylamine)
to give dehalogenaied materials (reduced JDroducts), e.g. phenacyl bromide
can be reduced to acetophenone in good yields using diethyl phosphonate
and ammonia69 - Scheme 12.
(C2H50)2
NH C6H5COCH2Br 3) C6 H5 COCH3 ` + (C2 H 0
F3r
Scheme 12
8 9 P‘OCH32 Et#-H
6 U5 -c-- CH,CN
)
(g 'Br ir:P Ph3 ------->
O + 0 PPH
3Br
- 134 -
When bromoacetone was treated with dimethyl phosphonate in
triethylamine/acetonitrile it was impossible to isolate any phosphorylated
products. It could be 'that a reduction was taking place when the product,
being acetone, would be difficult to isolate. A similar reaction with
chloroacetone using the same conditions would also explain why no
product could be detected - see Chapter 1. For all bromo-ketones studied,
a reaction with dimethyl phosphonate/triethylamine/acetonitrile gave
preferentially dehalogenated products (reduced products) with only trace
amounts of vinyl phosphate and epoxide - see Table 30. The products were
identified and characteristed by tic and 1H nmr, and were similar in all
respects with authentic samples. Only with 2-bromo propiophenone was a
significant amount of the expected phosphorus-containing product formed.
The mechanism for the dehalogenation of bromo-ketones to ketones probably
involves the attack of the dialkyl phosphonate anion on positive bromine
- Scheme 13.
Scheme 13
011at3
C05-LCRIII2
Br-P 9 (OCH3)2
CH51-CER-li 2 .-1)
g( _0CH3)2 Br° 1_
Trivalent phosphorus compounds are known to react readily with
halogens and Hudson has shown that triphenyl phosphine reacts rapidly
with 2-bromocyclohexanone to give the enol phosphonium salt '( -I) whereas
the corresponding chloAne compound does not react at all154.
LI
,Br
fl
Scheme 14
(F? Tr
c6H5- Br-P(OC2H5)3]
°\\C=CHBr 4. 02- H5 Br C 65
- 135
Borowitz37 has suggested that dibromo ketones react with P(III)
species (egg. triethyl phosphite) via attack on bromine followed by
o-phosphorylation of the resultant enolate halophosphonium ion pair
- Scheme 14, to give the expected vinyl phosphate.
ln:P(002H5)3
If this is the case then significant vinyl phosphate formation
should be observed when 2,2-dibromo acetophenone is treated with dimethyl
phosphate and trimethylamine. Naybe the intermediate dimethyl phosphoro
bromidate is quenched by the triethylamine instead of phosphorylating the
oxygen of the enolate anion.
To overcome this problem of dehalogenation when studying bromo-ketones
it was found more convenient to use sodium dimethyl phosphonate as the
phosphorylating species rather than dimethyl phosphonate and triethylamine.
The sodium salt of dimethyl phosphonate was prepared by treating the acid
with an equivalent amount of sodium hydride in T.H.F. solution. Treatment
of this solution with bromoacetone gave an isomeric mixture of dimethyl
1-methyl vinyl phosphate (XIII) - 8% and dimethyl 1-methyl epoxy ethyl
phosphonate (XIV) - 92%.
T.H.F. (CH3 (cH30)2?19 Na
E) CH3-g-CH2
Br -NaBr C
0=CH2 H3
(CH30)2Y_ --CH2 H5 9 27.2
XIV
- 136 -
This isomer ratio is different than the one obtained using
chloroacetone,see Chapter 1 ((XIII) - 39%, (XIV) - 61%) as might be predicted,
since more epoxide formation is expected for bromo-ketones as already
discussed.
Phenacyl bromide reacts with sodium dimethyl phosphonate at
room temperatures to give a mixture of dimethyl 1-phenyl vinyl phosphate
(XI) - 32%, dimethyl 1-phenyl epoxyethyl phosphonate (XIII)-56%, and
acetophenone - 12%. Arbuzov59 reports the formation of (XI, C2H50 -
instead of CH30-) and (XII, C2H50- instead of CH50-) as well as a
small amount of diethyl benzonyl phosphonate (LII, C2Hc0- instead of
CH30-) when phenacyl bromide reacts with sodium diethyl phosphonate in
ether. But no (LII) was detected under our conditions.
(CH50)2 -ilk 32% .CH c _,/ 2 XI
6bi5
56% T.H.F (CH 0, XII Na C6H5COCH2Br
5
C6H5COCH3 12%
, (0113o)2P
P -CH2-c-c II5 LII
Meisters and Swann60 state that the acetophenone is formed
by hydrolysis of the vinyl phosphate (XI) but this seems very unlikely
since the reaction is conducted under non-hydrolytic conditions. Direct
formation of acetophenone involving attack by the dimethyl phosphonate
anion at positive halogen atom does seem more probable. Indeed for all
the reactions of bromo-ketones with dimethyl phosphonate studied, it
was possible to identify products of dehalogenation by both tic and IH nmr. Dimethyl 1-phenyl vinyl phosphate (XI) was identified by means
of I.R. and IH nmr which were identical with an authentic sample.
Dimethyl 1-phenyl epoxyethyl phosphonate (XII) was characterised by 1H nmr 8 2.89 (1H, dd; JH_p 4.5 Hz; JH_H 6.1 Hz), & 3.45 (1H, dd;
JHeP 4.5 Hz, JH-H 6.1 Hz), 3.75 (3H, d; J 11.4 Hz), 3.80 (3H, d; H-P H-P 11.5 Hz), 7.53 (3H, m), 8.03 (2H, m) ppm. Where the resonances at
137
& 2.89 and 6 3.45 ppm were assigned to the methylene protons in the oxiran ring.
This reaction was repeated with the corresponding chloro-
ketone, phenacyl chloride, and the product ratios determined by 37H nmr
integration of the most convenient resonances - Table 30. Initially
when phenacyl chloride was added to sodium dimethyl phosphonate in T.H.P.
at room temperature only a 68% yield of the dimethyl 1-phenyl vinyl
phosphate (XI) was obtained along with 32% acetophenone. The acetophenone
was formed by reduction of phenacyl chloride with an excess of sodium
hydride which had not been neutralised by the dimethyl phosphonate.
Repeating the experiment with an excess of dimethyl phosphonate (so that
all the sodium hydride had been consumed) gave quantitative yields of the vinyl phosphate (XI). A similar procedure with phenacyl bromide (using
and excess of dimethyl phosphonate) did not eliminate the acetophenone
formation. All the subsequent reactions were studied using an excess of the dimethyl phosphonate and all the bromo-ketones under these conditions
gave dehalogenated materials along with the expected phosphorylated products. It was possible to compare the effect of changing the nature of the leaving group from chlorine to bromine on the course of the reaction
between oc-halocarbonyl compounds and sodium dimethyl phosphonate.
2,2-Dichloroacetophenone gave dimethyl 1-phenyl 2-chloro vinyl
phosphate (XVII) - all E-isomer, as the only product of the reaction
between 2,2-dichloroacetophenone and sodium dimethyl phosphonate - see Chapter 1.
T.H.F. (CH0)3-0., (CH30)2?9Na! C6H5COMIC?2 o ---->
3 "0„, 20 1
XVII E-isomer
While 2,2-dihromoacetcphenone gave dimethyl 1-phenyl 2-bromo vinyl phosphate
(XXXVIII) - 70% all Z-isomer with additional small amounts of phenacyl
bromide (15%) acetophenone (3%) and dimethyl 1-phenyl vinyl phosphate (XI) - 12%. These smaller amounts were the products of reduction. The dimethyl
1-phenyl vinyl phosphate (XI) is formed by phosphorylation of phenacyl
- 138
9e El) T.H.F. (CH30) ?-(1,, (CH30)2KO, 06H5COCHBr2 + (CH30)2P Na )=CHBr + t.=CH
20o C 11.' C 2
6 5 6
70% 12%
(all Z-isomer)
XXXVIII XI
+ C6 H5 - COC72 Br + C6H500CH3
15% 3%
2-Bromopropiophenone on reaction with sodium dimethyl phosphonate gave mainly dimethyl 1-phenyl 2-methyl epoxy ethyl phosphonate (XLII) 80%
as already reported by Arbuzov58 C2F50- instead of CH30-). In
addition small amounts of dimethyl 1-phenyl 2-methyl vinyl phosphate
(XLI) - 5% and propiophenone 15% were isolated and characterised by tic and 1H nmr ((XLI) and (XLII).have been fully characterised earlier in
this section).
06H5COCH(Br)CH3 + OH 0) ti e Ned --o--). (CH30)2 -..0-rCH.CH7 + (CH O) ACH.CH
3 3 2 20 . 3 6, T.H.F.
6H5 6H5
55 80%
XLI XLII
C6H5COCH2CH3
15%
A similar reaction with 2-chloro propiophenone gave (XLI) - 73% E/Z = 3:1 and (XLII) - 27% which was an almost identical mixture to the
one obtained when triethylamine was used as base. The variation in the
E/Z ratio of the dimethyl 1-phenyl 2-methyl vinyl phosphate (XLI) might
be a consequence of changing the solvent and how this may affect any
possible intermediate formed.
bromide in the usual way. It is interesting to observe the precedence
for Z-isomer formation of dimethyl I-phenyl 2-bromo vinyl phosphate
(XXXVIli) which has already been established for the reaction of
trimethyl phosphite with 2,2-dibromoacetophenone - see earlier discussion
of the Perkow reaction.
- 139 -
2-Chloro isobutyrophenone reacts with sodium dimethyl phosphonate to give dimethyl 1-phenyl 2,2-dimethyl vinyl phosphate (XLVII) in good
yield as the only observable product. The specific formation of (XLVII)
from 2-chloro isobutyrophenone has already been shown when using dimethyl
phosphonate, in ammonia or triethylamine as base. However, 2-bromo
isobutyrophenone gave in addition to dimethyl 1-phenyl 2,2-dimethyl vinyl
phosphate (XLVII) - 55%, smaller amounts of dimethyl 1-phenyl 2,2-dimethyl epoxy ethyl phosphonate (LIII) - 27% and isobutyrophenone - 18% which
were identified by tic and IH nmr.
55% XLVII H3
C H 6 5 0113
18%
3 NC H
6H5 3
27% LIII
06115
CH,
0 -Br t (CH30)2
113
e cEz ----*(cH
30)2?-0-Q. (CH
3o)2P
671. NCH, -5
Dimethyl 1-phenyl 2,2-dimethyl vinyl phosphate (XLVII) has already
been fully characterised by 1H nmr and I.R. Dimethyl 1-phenyl 2,2-dimethyl
epoxy ethyl phosphonate (LIII) was purified by column chromatography and
characterised by 1H nmr 6 0.95 (3H, d3 Jli_p 1.0 Hz), 1.92 (3H, d; JR_p 0.5 Hz),
3.50 (3H, d; 311-1, 11.0 Hz), 3.70 (3H, d;JH-P 11,4 Hz), 7.35 (5H, m) ppm. The resonances at 6 0.95 and 1.92 ppm were assigned to the methyl groups
attached to the oxiran ring.
In general for the reaction between dialkyl phosphonate and an
0C-halo carbonyl compound in the presence of a convenient base, changing the halogen from chlorine to bromine results in a greater percentage of
epoxide formation - Table 30. This is associated with the greater leaving
ability of bromine relative to chlorine from what must be an intermediate hydroxy phosphonate, since epoxide formation is explained via an initial
attack of the dialkyl phosphonate anion on the carbonyl carbon atom -
Scheme 11 X = Cl or Br. Increased epoxide formation is observed:
i. By changing the nature of the leaving group X from Cl to Br -
since the nucleophilic oxygen in the intermediate hydroxy phosphonate
will displace a bromine atom more readily by an SN2 type process. This
observation is similar to the vinyl phosphate/ketophosphonate ratios
- 140 -
obtained for the Perkow reaction when X = Cl or Br - see Table 29.
ii. By placing electron-releasing substituents on carbon-2 of the
halo-ketone, such as CH3 or CE5' will increase the leaving ability of
the halogen X by stabilising the carbonium ion formed in a limiting SN1
type process. It is possible to limit epoxide formation by sterically
crowding carbon-2 e.g. 2-chloroisobutyrophenone with dimethyl phosphonate
in base gives only the vinyl phosphate, whereas 2-bromoisobutyrophenone
under the same conditions gives, in addition to vinyl phosphate, a small
amount of epoxide. This again illustrates the greater leaving ability
of the bromine atom.
Table 30. Reaction of x-halocarbgalEguanga with dimethyl phos-Oonate in presence of base -'abnormal' Michaelis-Becker reaction
(cH30)2tl-H + Base
(CH30)2 -0..C=CR1 Y + (CH3 0)2 +
0 NH../CH
----------------
AD
3 OH/ 20°q)
°A © e P
Et3N/cH
3cN/ 10° (i) -
NaH/T.H.F. 100 (47.)
00 %© % c/L 1 %© V0
CH3
CH,
CH,,
3 C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
c6H5
H
H
H
H
H
H
H
H
CH3
CH3
H
H
Cl
H
H
Cl
Br
CH3
CH3
CH3
CH3
5
Cl
Br
Cl
01
Br
Cl
Br
Cl
Br
Cl
Br
c1
-
-
-
100
Trace
100 (95A45%z)
0
48 (160E,32%7,
-
100
30 (all E)
-
-
-
0
Trace
0
0
52
-
0
-
70
-
-
-
0
100
0
100'
0
-
0
0
-
no (a11 E) 100
Trace
100 (95V,t,5%z)
0
75 (15c/E)600)
0
100
Trace
-
-
-
Trace 0
Trace
0
0
23
20
0
0
-
-
-
0
0
100
0
100
0
80
' 0
100
-
39
6 100 (all E) 100
32
100 (all. E)
70a (all 0
73 c5eEil8P,)
• 5
100
55
-
61
92
Trace
0
56
0
Oa
27
80
0
27
-
0
0
0
0
12
0
15a
0
15
0
16
-
a Also (CH30)2 -0-y=CH2 (120
e6H5
06H5COCH3 (3/0)
.142 -
Experimental
Dimeth 1 1-metlylai3atftastLate (prepared by Perkow reaction of trimethyl phosphite and monochloroacetone)
Monochloroacetone (1.85 g, 0.02 mol.) was added dropwise to
trimethyl phosphite (3.10 g, C.025 mol.) and the mixture heated at 110-120° in a nitrogen atmosphere for sixteen hours. Tic (silica eluted with ethyl
acetate/benzene 1:1) showed absence of the monochloroacetone starting
material. 1H nmr integration of the methyl region indicated a mixture
of dimethyl I-methyl vinyl phosphate - 915 and dimethyl acetonyl phosPhonate
- 95 ( see later). The dimethyl 1-methyl vinyl phosphate was isolated by
column chromatography and was identical in all respects with an authentic sample.
Monobromoacetone
Bromine (220.9 g (71.0 ml), 1.38 mol.) was added dropwise to a
stirred solution of acetone (79.0 g (110 ml), 1.36 mol.), acetic acid
(75.0 ml), aid water (320 ml) at 65° over a period.of two hours. After
addition the solution was stirred until decolourised, diluted with water
(150 ml), cooled to 10°, neutralised with sodium carbonate (200 g) and
the oil which separates dried over anhydrous calcium chloride (16.0 g).
After filtration, the product was distilled at reduced pressure and the
fraction boiling at 56-58°/15 mm Hg collected. Repeated distillation at
reduced pressure gave monobromo acetone (41.1 g, 305) as a colourless
liquid b.p. 34-35°/10 mm Hg (Lit.156 39.5°/18 mm Hg). 1H nmr 6 2.37 (3H, s), 3.93 (2H, s) ppm.
32j_m te (prepared by Perkow reaction of
trimethyl phosphite and monobromoacetone
Monobromoacetone (2.74 g, 0.02 mol.) was added dropwise to
trimethyl phosphite (3.10 g, 0.025 mol.) with stirring in a nitrogen
atmosphere. The mixture was heated at 110-120° for sixteen hours. The
crude orane liquid (3.2 g, 91q was purified by column chromatography
silica eluted with ethyl acetate/benzene 1:1 giving dimethyl I-methyl
vinyl phosphate (Found: 0,35.97; H, 6.87; P,
0, 36.15; H, 6.67; P, 18.655.) e)max 3000 m,
'1- 1295 vs, 1240 m, 1190 m, 1040 vs, 990 s, 915 nmr 6 1.95 (3H, s); 3074 (6H, d;11 H-P
18.82%: 051111PO4 requires:
2850 s, 1450 m, 1375 w, m, 860 s, 810 cm-1.
.4 Hz), 4.48 (1H, m),
- 143
4.69 (III, m) ppm. Dimethyl acetonyl phosphonate (Found: C, 36.22; Hy 6.52;
P, 18.48%: C5E11PO4 requires: 0, 36.15; H, 6.67; P, 18.655:)-Imax 2950 w,
2900 w, 1720 s, 1360 m, 1260 vs, 1190 m, 1040 vs, 980 w, 870 m, 830 s2 cm-1. 1.H nmr 6 2.28 (311, s), 3.07 (2H, d; Ju_p22 Hz), 3.76 (6H, d; .71u-p, 11.2 Hz)
Room temperature reaction
Trimethyl phosphite (11.66 g, 0.094 mol.) was added dropwise
to freshly distilled monobromoacetone (10.28 g, 0.075 mol.) with stirring
in a nitrogen atmosphere (in the dark) at 00. After complete addition
the solution was allowed to warm up to room temperature and then stirred
at 20° for twenty-four hours. Tic (silica eluted with ethyl acetate/benzene
1:1) showed an absence of the monobromoacetone starting material and IH nmr indicated a mixture of dimethl 1-methyl vinyl phosphate (44 and dimethylE22.12ELlIlosphonate (56%).(By integrating the methyl region of the spectrum)
DimILLLL1:Efthyllchloav122yLphosphate (prepared by Perkow
reaction of trimethyl phosphite and 1,1-dichloro acetone
1,1-Dichioro acetone (2.54 g, 0.02 mol.) was added dropwise with
stirring to trimethyl phosphite (3.10 g, 0.025 mol.) at room temperature
in a nitrogen atmosphere. After the addition the solution was stirred
at 110° for fifteen hours. Tic silica eluted with ethyl acetate/benzene
1:1 showed the absence of assym dichloroacetone and 111 nmr showed dimethvl 1-meth 1 2-chloro vinyl phosphate as the major product
2.10 (3H, d;JH_p 0.9 Hz), 3.86 (6119 d; .L13.,..p 11.5 Hz), 5.63(m, Z-isomer),
6.15 (m, E-isomer) ppm. (E/Z ratio 92%/85 from integration of the vinylic region of the spectrum).
Di....2Lic h.enr.lyin_jLha-Le (prepared by Perkow reaction
of trimethyl phosphite with phenacyl chloride)
Trimethyl phosphite (1.24 g, 0.01 mol.) was added dropwise to
a stirred solution of phenacyl chloride (1,54 g, 0.01 mol.) in dry
acetonitrile (5.0 ml) at room temperature and the solution stirred at room temperature for twenty-four hours. Tic showed almost complete disappearance of phenacyl chloride and 111 nnr the complete formation of dimethyl - identical in all respects with an
authentic sample.
- 144 -
2.1122IhZ11.7.222nY1 2-chloro vinyl phosphate (prepared by Perkow reaction of trimethyl phosphite and 2,2-dichloroacetophenone)
.Trimethyl phosphite (1.24 g, 0.01 mol.) in acetonitrile (4.0 ml)
was added dropwise to a stirred solution of 2,2-dichloroacetophenone
(1.89 g, 0.01 mol.) in acetonitrile (6.0 ml) at room temperature. After
stirring at 20° for fifteen hours tle showed vinyl phosphate formation
with almost complete absence of phenacyl chloride starting material. The
acetonitrile and excess trimethyl phosphite were removed at the pump.
-H nmr was identical with an authentic sample - integration of the vinylic
resonances 6 6.45 (d; Jil_p 2.8 Hz) and 6.15 (d; J1/..p 2.1 Hz) gave an isomer ratio E/Z of 40/60.
2.12-Dibromo acetophenone
Bromine (8.0 g, 0.05 mol.) in ahydrous chloroform (15.0 ml) was
added slowly to a boiling solution of phenacyl bromide (10.0 g, 0.05 mol.)
in chloroform (50.0 ml) under bright sunlight over a period of five hours. Further portions of bromine/chloroform were added until tic (silica eluted
with benzene) showed absence of phenacyl bromide with complete 2,2-dibromo
acetophenone formation. The solution was cooled to room temperature and the
chloroform removed at the pump to give an orange liquid which was distilled
at reduced pressure. Pure 2)2edibromo acetophenone (9.5 g, W) was
obtained as a colourless liquid b.p. 82-83°/0.5 mm Hg.
. Dimethvl 1-phenyl 2-bromo vksirilhluLe (prepared by Perkow
reaction of trimethyl phosphite and 212-dibromoacetophenone
Trimethyl phosphite (1.56 g, 0.0125 mol.) was added dropwise to 2,2-dibromo acetophenone (2.79 g, 0.01 mol.) with stirring under nitrogen at room temperature. A vigorous reaction takes place and.some
cooling is required. After complete addition the reaction was stirred at 20° for two hours and then at 90-100° for a further fifteen hours.
Tlc and 1H nmr showed complete formation of 9:iretkphfnyro12.Eov1.___:
phosphate (2.21 g, 805) b.p. 120°/0.1 mm Hg. 6 3.73 (6H, d; JH.4„ 11.5 Hz). 6 6.23 (1H, d-' JH-P d; 1.5 Hz) - Z-isomer, ii) 6.55 (1H d- JH-P 2.8 Hz) -
E-isomeri 6 7.45 (3H, a), S 8.05 (2H, m). Integration of the vinylic resonances showed an isomer ratio Eft of 1W99;%.
- 145
amatlyI -ILme- v1212:.....sehate and Dimethyl 1-methyl epoxy ethyl
phosphonate
Dimethyl phosphonate (2.75 g, 0.025 mol.) was added dropwise to a
stirred suspension of sodium hydride (1.20 g, 0.025 mol., since NaH is
50% suspension in oil) in dry T.H.F. (25.0 ml) at 0°. The solution was
stirred at room temperature and a further portion of dimethyl phosphonate
added to neutralise any excess sodium hydride.
Monobromo acetone (3.43 g, 0.025 mo4.) was added dropwise to the solution at 5-10° and a white solid precipitated out. The solution was
stirred at room temperature for twenty-four hours and finally refiuxed
for a further two hours. After cooling to room temperature the solution
was filtered to remove sodium chloride, dried over anhydrous Na2 SO4
and
the ether removed to give a pale yellow liquid (3.5 g, 840). H nmr showed this to be a mixture of dimethyl phosphate (8%)
and dlyaAilyljLem,tethycerethvlhosphonate.,_p (92%) - integration of the methyl region. These isomers were separated by column chromatography
(silica eluted with ethyl acetate/benzene 1:1) and were identical in all
respects with authentic samples which had already been fully characterised.
Reaction of phenacyl bromide and dimethyl phosphonate with base
A. Ammonia procedure
Ammonia (1.4 g, 0.08 mol.)-was passed as a slow stream into a
solution of phenacyl bromide (5.10 g, 0.026 mc:.), dimethyl phosphonate
93.3 g, 0.03 mol.) and methanol (50 ml) at 30°. After one hour the methanol was removed at the pump and the residue taken up in ether (50.0 ml),
washed with water (3 x 30 ml), dried over anhydrous Na2SO4, and the ether
removed in vacuo to give a colourless liquid. Distillation at reduced pressure
gave acetcphenone (2.65 g, 85%) as a colourless-liquid b:p. 85-86°/12 mmHg
(Lit.158 88-89°/16 mmHg). 1H nmr 6 1.60 (3H, s), 7.53 (3H, in), 8.03 (2H, m). B. Tri11L2Jeineetl- prure
Dimethyl phosphonate (2.75 g, 0.025 mol.) and phenacyl bromide
(5.0 g, 0.025 mol.) in acetonitrile (10.0 ml) were stirred together at 0°.
Triethylamine (2.53 g, 0.025 mol.) in acetonitrile (15.0 ml) was added
dropwise over a period of thirty minutes so that the temperature did not
rise above 10o. After complete addition the solution was stirred at 20o
for fifteen hours. The acetonitrile was removed at the pump and the
residue taken up in ether (100 ml) washed with water (3 x 70 ml) then
dried over Na2SO4. Removal of the ether gave a pale yellow liquid (2.10 g,
70%) - acetophenone b.p. 85-86°/12 mmHg.
146 -
C. Sodium hvdride procedure Dimethyl phosphonate (1.1 . g, 0.01 mol.) was added dropwise to a
stirred suspension of sodium hydride (0.5 g, 0.01 mol. - since NaH is 50% suspension in oil) in dry T.H.F. (20.0 ml) at 0°. A further portion
of dimethyl phosphonate was added to neutralise any excess sodium hydride in the solution.
Phenacyl bromide (1.99 g, 0.01 mol,) in dry T.H.F. (10.0 ml) was added dropwise to the stirred solution of sodium dimethyl phosphonate over a period of thirty minutes and the solution stirred at room temperature for fifteen hours. A white precipitate of sodium bromide was produced and tic (silica eluted with ethyl acetate/bezene 1:1) showed the
formation of acetophenone, dimethyl 1-phenyl vinyl phosphate, and dimethyl 1-phenyl epoxy ethyl phosphonate. 1H nmr integration of the crude reaction
mixture gave a product distribution of afe2talelsre (12%), dimethyl
miLyiEimullala (320) and j: erlylepo...e'riphosj-,honate (56%). Column chromatography (silica eluted with ethyl acetate/benzene
1:1) gave:,
29-LDitzlphepa2leaLE12m-ahA2 (0.53 g, 23%) b.p. 105-110°/0.5 mmHg
as a colourless liquid imax 3050 w$ 2950 w, 2850 w, 1640 a, 1580 wr 1490 m,
1450 m, 1290vs, 1190 ml 1110 w, 1060 vs, 1020 s, 860 vs., 780 s, 760 wt 720 mt
700 w, cm-1.
1H riser f), 3.75 (6H, d; 3114, 11.3 Hz), 520 (2H, m), 7.25 (3H, m) 7.53 (2H, m)
Om. Dimethyl 1-phenyl ej2PMe..--LY---11 118 (1.07 g, 47%) as
colourless needles (ethyl acetate) m.p. 77-78° (Found: 0, 52.81; HI 5.74;
CloHl P, 1).59%; 3P0 requires: C, 52.63; Et 5.74; P, 15.570.) max 3050 w,
2950 m, 2850 w, 1600 w, 1500 m, 1450 st 1410 mt 1270 s, 1230 vs, 1185 st
1040 vst 1000 mt 950 w, 910 w, 855 s, 780 s, 765 s, 700 s, 670 m, cm 1.
-H nmr & 2.89 (12, dd; J1/..p 4.5 Hz, Jr_H 6.1 Hz), 6 -2.45 (1H, dd; JH-1, 4.5 Hz,
3H..41 6.1 Hz), 3.75 (3H, d; JH..p 11.4 Hz), 3.80 (3H, d; .111.4, 11.5 Hz), 7.53
(3H, m), 8.03 (2E, m) -ppm.
Dimethyl 1-phenyl 2-chloro vinyl phosphate was prepared in good yield
by Method A (90% - E, z), B (84%-95% E, 5% Z) and C (75% - all E isomer).
Reaction of 2 2-dibromo acetophenone with dimethyl phosphonate
A. Ammonia procedure
Ammonia was passed as a slow stream through a solution of
2,2-dibromo acetophenone (2.78 g, 0.01 mol.) and dimethyl phosphonate
147
(1.10 g. 0.01 mol.) in methanol (10.0 ml) for one hour. The solution was stirred at room temperature for ten hours and then worked up in the normal way to give phenacyl bromide (1.53 g, 7Z) as a cystallirie solid m.p. 50° (colourless plates from 40-60 petroleum ether) - Lit.1" m.p. 50-51o
Bo Trieth lemine nrocedure
Dimethyl phosphonate (1.10 g, 0.01 mol.), 2,2-dibromo acetophenone
(2,78 g, 0.01 mol.) in acetonitrile (4.0 m3) were stirred together at -5°
Triethyl amine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml) was added dropwise over thirty minutes so that the temperature did not rise above 000 After complete addition the solution was stirred at room temperature for ten. hours and worked up in the usual way to give phenacyl bromide
(1.69 g, 8Z) as a crystalline solid m.p. 500. C. Sodium h -dride procedure
Dimethyl phosphonate (1.1 g, 0.01 mol.) was added dropwise to a
stirred suspension of sodium hydride (0.5 g, 0.01 moi. - since Naa is 50%
suspension in oil) in dry T.H.F.(10.0 ml) at 0°. A further portion of
dimethyl phosphonate was added to neutralise any excess sodium hydride.
2,2-Dibromo acetophenone (2.78 g, 0.01 mol.) was added dropwise to the stirred solution at 0°. The solution went orange and then became
whiter as the dibromo acetophenone was added due to the precipitation of
sodium bromide. After stirring at room temperature for four hours the
solution was finally refluxed for five hours, cooled to room temperature,
filtered to remove sodium bromide and dried over anhydrous Na2SO4. Removal
of the solvent gave a colourless liquid. III nmr showed 50/, reaction
(on the basis of 2,2-dibromo acetophenone consumed) - the product was a mixture of 21E2Llallnyi 2-bromo vinaphosnhate (70% - all Z isomer), dimethyl 1-phenyl vin yl ,phos I ate (12%), khenaclide (15%), and
7-71t7elly(73:s
ate( ::
1.(
Let a -:tnyE:bor:m° 14:11tIos::
elated with ethyl acetate/benzene 1:1). They were identical in all respects with authentic samples whiolo have already been fully characterised.
2-ChloIapmE1012none159
2-Chlcro propionyl chloride (88.9 g, 0.7 mol.) - prepared in 70% yield
by chlorination of 2-chloropropionic acid with thionyl chloride, was added dropwise to a stirred solution of anhydrous aluminium chloride (93.45 g, 0.7 mol.) in sodium dried benzene (640 m1). A violent reaction occurred
and some cooling was required. After addition of the acid chloride, the
- 148 -
solution was heated at reflux for five hours, cooled to room temperature and
c.FiCl (100 ml) added to regenerate the aluminium chloride. The organic
layer was separated off, washed with water, dried over calcium chloride,
and the benzene removed at the pump to give an orange liquid. Distillation
at reduced pressure gave 2-chloro propiopbenone (90.96 g, 7n as a
colourless liquid b.p. 135-138°/20 mmHg (Lit159b.p. 131-6°/26 mmHg).
1H nmr o 1.67 (3H, d; JH-H 6.5 Hz), 5.15 (1H, q; JH-H 6.5 Hz), 7.33 (3H, m), •
7.83 (2H, m) ppm. A Reaction of dimethvl .hos honate with 2-chloro -ro-ic-henone in the
presence of ammonia
2-Chloro propiophenone (8.43 g, mol.) and dimethyl rhosphonate
(5.5 g, 0.05 mol.) in methanol (60 ml) were saturated with ammonia over a
period of one hour at 200. The solution was stirred at room temperature for
fifteen hours to complete the reaction. After removing the methanol at the
DU= the residue was extracted into ether (100 ml), washed with water
(3 x 70 ml) and dried over MgSO4. Removal of the ether gave a pale yellow
liquid (10.1 g, 82%). IH nmr showed an isomeric mixture of dimethyl
2-methyl vinyl Phosphate (48% - 16% El 32% z) and dimethyl 1-phenyl
(52!7A). Column chromatography (silica eluted with hexane/acetone 1:1) gave two
pure isomers;
Dimetlal vinyl (4.48 g, 37%) as a pale yellow liquid (Found: C, 54.30; H, 6.25; P, 12.80%: C 11H1 51,04 requires:
0, 54.54; Hy 6.25; P, 12.79'70.) 0 242. fliax 3050 w,- 3000 m, 2850 w, 1670 w, 1500 w, 1450 m, 1360 w, 1285 s, 1195 mt
1050 vs, 980 m, 910 s. 865 s, 780 s, 710 m, cm•-1 0
6 1.72 (3H, dd; JE_p 2.7 Ezi j'H_H 7.3 Hz), 3.74 (6H, d; •
JH-P 11.2 Hz), 5.75 (1H, m), 7.34 (5H, m) ppm. zam:s(zri.s 6 1.85 (3H, dd; J11.4, 3.0 Hz, Ja_H 7.0 Hz), 3.72 (6H, d;
JH-P 11.2 Hz), 5.60 (iii, m), 7.34 (511, m)ppm. 2ipalthD. 1-phehyl 2-methyl epoxy ethyl phosphonate (4.54 g, 37.5(A)
a pale yellow liquid (Found: C, 54.34; H, 6.25; P, 12.50: C111115PO4
requires: C, 54.54; H, 6.25; P, 12.80.)m+//e 242. Nmax 3050 w, 3000 m, 2850 w, 1500 w, 1450 m, 1400 w, 1270 s, 1230 m, 1190 m,
1080 s, 1050 vs, 940 w, 520 w, 900 w, 850 3, 800 w, 780 w, 760 m, 715 m, cm-1.
1H nmr 6 0.99 (3H, dd; Jim, 1.1 Hz, j11-H 5.4),
3.60 (1H, dq; J .p 4.9 Hz,
JH-H 5.4 Hz), 3.60 (3H, d; JH_p 10.4 Hz), 3.72 (3H, d; JH_p 10.2 Hz),
7.34 (5H, m)
- 149 -
B Triethvlamine procedure
A similar reaction using triethylamine as base gave an isomeric
mixture of liEelhy11:212ELI 2-methyl vihyl phosphate (75;E/Z 1:4) and
dimethyl 1-phenyl 2-methyl epoxy ethyl phosphonate (25,0) which was
characterised by tic (silica eluted with ethyl acetate/benzene 1:1) and IH nmr.
C. Sodium hvdrldt_procedure DLrtth.1....p-hen- 12-nivilrhosphate (7351 E/Z3:1)
and dimetla117phenyl 2-methyl epoxy ethyl phosphonate (27%) was similarly prepared-from scdium dimethyl phosphonate and 2-chloro propiophenone.
Dimethyl L._.-;,-1:2Ldrazc- 27...r_zeohen1 2-chicro ethyl phosphonate
Dimethyl 1-phenyl 2-methyl epoxy ethyl phosphonate (0.5 g, 0.002 mol.)
was dissolved in 60/80 petroleum ether (10.0 ml) and sodium-dried ether
(5.0 m1). Hydrogen chloride gas was bubbled through the stirred solution as a slow stream for four hours (some cooling being required). The stirring
was continued overnight and an oil deposited in increasing amounts.
Evaporation of the solvents gave a viscous oil which was taken up in ether
(50 ml), washed with water (3 x 30 nil) and dried over anhydrous Na2SO4. Removal of the ether at the pump gave a viscous oil which was crystallised from hot Petroleum as colourless needles of dimethyl 171Lialtraz 2-phenyl 2-chloro ethyl phosphonate (047 g, 84 m.p. 1080. (Found:
C, 47.40; Hf 5.75; Cl, 12.75; P, 11.153
0, 47.26; H, 5.93; Cl, 12.83; P, 11.1 C11H16C1P°4 requires:
IH nmr 1.83 (3H, d; JH_Ii 6.5 Hz), 3.37 (1H, d; Jll_p 2.0 Hz - exchangeable
with D20), 3.38 (3H d; J d; H-P 11.8 Hz), 3.82 (3H, d. JH-P 11.5 Hz), 4.95 " (1H, dq; J11-H 6.5 Hz, JH.4, 2.5 Hz), 7.47 (3H, m), 7.72 (2H, m).
Treatment of dimethyl 1-phenyl-1-hydroxy 2-chloro 2-methyletlyi Phosphonate in base
Dimethyl 1-phenyl-1-hydroxy 2-chloro 2-methyl ethyl phosphonate (0.5 g, 0.0018 mol.) Was dissolved in absolute methanol (5.0 ml). Ammonia was passed as a slow stream through the solution for one hour and the
solution stirred for a further twenty-four hours at room temperature.
Normal work-up gave a pale yellow liquid, tic and 1H nmr showed a mixture
of dimethyl 1-phenyl 2-methyl vilspto...te (505 E/Z = 1:2) and
cliiLEtjtli'1 1-th...,.....fleth th1711_,......_22anate (50%).
272EallaamIalLusalp1.53
N-bromo sucoinimide (17.8 g, 0.1 mol.) was added to propiophenone
13.4 g, 0.1 mol.) in carbon tetrachloride (150 ml) at room temperature
- 150 -
and the solution heated at 100° for twenty-four hours. Succinimide
separated out and was filtered off. The filtrate was evaporated and
distilled at reduced pressure to give 2-bromo propiophenone (18.1 g,
85%) as a colourless liquid b.p. 95-96°/C.5 mmHg. (Lit.153 b.p. 96°/l.0 mmHg). 1H nmr 6 1.89 (3H, d-'
H-H 7.0 hz), 5.32 (1H, q; JH-H 7.0 Hz), 7.57 (3H, m), 8.08 (2H, m) ppm.
Reaction of 2-bromoprociophenone with dimethyl phosphonate in
the!resence of base B. Triethylamine Procedure
Dimethyl phosphonate (0.55 g, 0.005 mol.) and 2-bromo propiophenone
(1.07 g, 0.005 mol.) in acetonitrile (3.0 ml) were stirred in an ice-bath
at 0°. Triethylamine (0.51 g, 0.005 mol.) in acetonitrile (2.0 ml) were
added dropwise over a period of thirty minutes and the solution stirred
at 20o for two hours. The acetonitrile was removed at the pump and the
residue taken up in ether (70.0 ml) washed with water (3 x 40 ml) and
dried over sodium sulphate. Removal of the ether gave a colourless
liquid (0.85 g) which was a mixture of di12- ,,thyllzpl- h- 121osy
ethyl phosphonate (W), 222LoprLeiom (655), and 2-bromo propiophenone
(19%) - by comparative IH nmr and tic (silica eluted with benzene).
Prulaphalsm (0.35 g, 57%) b.p. 100-2°/10 mmHg (Lit.I58 b.p. 123°/25 mmug)
was isolated by column. chromatography (silica eluted with benzene).
C. Sodium hydride procedure
A mixture of dimethyl 1-phenyl 2-methyl epoxy_flIglphsEphorlats
(80ro), dimethyl 1-phenyl 7-meth,T1 vinyl phosphate (5%) and Tzopiapp_
(15%) was prepared by treating sodium dimethyl phosphonate (prepared by
addition of sodium hydride to dimethyl phosphonate) with 2-bromo
propiophenone in dry T.H.F. at room temperature and refluxing the solution
for several hours to complete the reaction.
Ia2k11 EaL2110ne Freshly distilled isobutyryl chloride (53.25 g, 0.5 mol.) -
prepared by chlorination of isobutyric acid with thionyl chloride
(b.p. 90-92o Lit. C4 b.p. 92°) was added dropwisato a stirred suspension
of anhydrous aluminium chloride (66.75 g, 0.5 mol.) in sodium-dried
benzene at 10° over a period of two hours. The reaction mixture darkened
considerably as the aluminium chloride dissolved. When all the acid
- 151 -
chloride had been added the mixture was refluxed for thirty minutes,
cooled to room temperature, and poured into ice water (100 ml). The
benzene solution was separated washed with 10% NaCH (4 x 70 ml). water
(3 x 70 ml) and dried over anhydrous Na2SO4. RemoVal of the benzene
at the pump gave a pale yellow liquid which was distilled at reduced
pressure to give lEolatpLnone (43.24 g, 58%) as a colourless liquid b.p. 86-88°/5 mmHg. Lit.1 0b.p. 86°/4 mmHg,
2-Chloroia2buiyrophenone161
Chlorine was bubbled through a solution of isobutyrophenone
(5.1 g, 0.035 mol.) in Analar chloroform (15.0 ml) at room temperature.
The yellow colour persisted for about thirty minutes until the reaction was
initiated and the passage of chlorine continued until the yellow colour
was again detected in the solution - which was after about four hours.
The CHC13Aci was removed at the pump and the product distilled under
reduced pressure to give2=211121-oilELymplgmat (6.13 g, 96%) as a colourless liquid b.p. 54-56°,/0.1 mmHg (Lit.1 1 b.p. 72-73°/0.7 mmHg).
1450 m, 1290 s, 1230 w,
s, 860 a, 780 m, 720 s, em-1
d; Jr_H 2.4 Hz), 3.46
1_ nmr 6 1.72 (3H, d; Jil_u 6.5 Hz), 5.30 (1R, q; 6.5 Hz), 7.53
(3H, m), 8.03 (2H, m).
Reaction of 2-chloroisobutyrophenone with dimethvl hosnhonate
in presence of base
A. A;rvryon a procedure
A solution of 2-chloroisobutyrophenone (4.56 g, 0.025 m01.)
and dimethyl phosphonate (2,75 g, 0.025 mol.) in methanol (50.0 ml) were
saturated with ammonia at room temperature. The solution was stirred at room
temperature for twenty-four hours to complete the reaction. The methanol
was removed at the pump and the residue taken up in ether (100.0 ml),
washed with water (4 x 70 ml) and-dried over anhydrous sodium sulphate.
Removal of the ether gave a pale yellow liquid (5.6 g, 875). Purification
by column chromatography (silica eluted with ethyl acetate/benzene 1:1) gave
dim2Lhy11-nhenyl 2_12-din i-Laja.... (4.5 g, 70%) as a pale yellow liquid. (Found: C, 56.03; H, 6.57; P, 12.06%: Cl2H17PO4 requires:
C, 56.24 H, 6.68; P, 12.09%).
imax 3050 w, 3000 m, 2900 w, 1640 w$ 1500 w,
1190 w, 1130 s, 1050 vs, 1030 vs, 920 s, 890
nmr 6 1.69 (3H, d; JII_p 3.2 Hz), 1.88 (3H, (6H, d; Jp_H 11.2 Hz), 7.21 (5H, m) ppm.
- 152 -
B. TriethylLateltprocedure
amftthyl 1-phenyl 2,17diatthylIfinyLT102112.te (83%) was the only product formed by treating 2-chioro isobutyrophenone and dimethyl phosphonate with triethylamine in acetonitrile at 10°. C. Sodium hydride procedure
Dimethyl 1_-phenyl 2,2-dimethyl vinyl phosphate (90%) was the only
observable product formed by treating 2-chioro isobutyrophenone with sodium
dimethyl phosphonate at 20° in the usual way. The product was isolated by column chromatography and identified by tic and 1H nmr.
2-Bromo isobutyrclanft153
A solution of bromine (32.0 g, 0.2 mol.) in CC14 (30 ml) was
added dropwise to a stirred solution of isobutyropheonone (29.2 g, 0.02 mol.) in CC14 (50 ml) at 0-5 - some cooling was required. After complete addition the flask was kept at 25° for one hour. When all the bromine
colour had disappeared the CC14
was removed at the pump and the residue
distilled at reduced pressure to give 2-bromo isobutyrophenone (36.3 g,
80%) as a colourless liquid b.p. 127-e/10 mmHg (Lit.153 b.p. 15e/13 mmHg). IH nmr 6 2.02 (6H, 8), 7.47 (3H, m), 8.15 (2H, m).
Reaction of 2-:bromoisob ddimet-hi ehoeoeate_
with base
B. Trieth lamine procedure
Dimethyl phosphonate (1.1 g, 0.01 mol.), 2-bromo isobutyrophenone
(2.27 g, 0.01 mol.) in CH3CN (4.0 ml) were stirred together at 0°. Triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml) were added dropwise over thirty minutes and some cooling was required to maintain
the temperature at 0° ±2°. After stirring at 20° for a further fifteen hours the 0E
3 ON was removed at the pump and the residue taken up in ether
(50 ml), washed with water (2 x 25 ml), and dried over Na2SO4. .Removal
of the ether at the pump gave a colourless liquid (1.47 g) which was
mainly isobutyrophenone with a trace of dimethyl 1-phenyl 2,2-dimethyl
vinyl phosphate, Column chromatography (silica eluted with benzene)
gave isobutyrophenone (1.41 g, 95%) as a colourless liquid b.p. 86-88°/5 moiHg (Lit.160 86°/4 mmHg).
C. Sodium hydride procedure
In a similar reaction dimethyl 1-phenyl 2,2-din t
(555), ( 27), and isobutyrophenone (18%) were formed by treating 2-bromo isobutyrophenone
with sodium dimethyl phosphonate in T.H.F. at 10°, and isolated by column
- 153 -
chromatography (silica eluted with ethyl acetate/benzene 1:1).
Died 1-phenyl 2,2-dimethyl epoxy ethyl phosphonate 111 nmr 6 0.95 (3H, d;JH-P 1.0 Hz), 1.92 (3H, d; JH-1, 0.5 Hz), 3.50 (3H, d; .TH..p 11.0 Hz), 3.70 (311, d: JH..p 11.4 Hz), 7.35 (5111 m) ppm. .
Desyl chloride 2-chloro 2- henvl acetophenone162
Benzoin (25.0 g, 0.118 mol.) and pyridine (12.5 g, 0.137 mol.) were warmed. until dissolved and then cooled in a salt-ice bath until solid.
The solid was crushed to a powder and thionyl chloride (19.0 g, 0.16 mol.)
was added dropwise - some cooling was necessary to control the violent
reaction with SO2 and HC1 being evolved. After about one hour the mass
sets solid and is ground with water (10.0 ml) and filtered to remove
the pyridine hydrochloride. The solid was triturated (2 x 10 ml) with
water, dried over c.H,S04 in a desiccator and recrystallised ( x 3) from
60/80° petroleum ether to give colourless crystals of desyl chloride
(15.4 6", 5V;) m.p. 68-70° (Lit.162
Reaction of desyl chloride and dimeth 1 phosphonate in the resence
of ammonia
Desyl chloride (2.31 g, 0.01 mol.) was dissolved in methanol (50 ml)
and dimethyl phosphonate (1.1 g, 0001 mol.) added in one portion. Ammonia
was slowly bubbled through the solution which was maintained at 20° until saturated and the solution stirred at room temperature for fifteen hours.
The methanol was removed at the pump and the residue taken up in ether (200 ml), washed with water (3 x 150 nil) and dried over anhydrous Na2SO4. Evaporation of the ether gave a !semi-solid/ - tic and 111 nmr indicated
a mixture of dimeth pleplate (30% - all E-isomer)
and dimeth 11 2-diphen 1 e o ethiLlphlullanaLeL72a. Recrystallisation from ether gave dimethvl 1 2-dithelnyl_tpszy
elyitasIE-2119 (1.o g, 325) as colourless nuggets m.p. 115-116°C. (Found: CI 63.32; H, 5.59; P, 10.32%: C16-17PO4 requires: C, 63.15; H, 5.63; P, 10.18%).
IH nmr 8 3.75 (3H, d;H-P 11.0 Hz), 3.89 (3H, d: JH-P 11.0 Hz), 4.75 (1H, d; JH..p 4.2 Hz), 7.15 (511, m), 7.30 (5H, m) ppm.
Evaporation of the mother liquors gave a pale yellow liquid
which was purified by column chromatography (silica eluted with ethyl
acetate/benzene 1:1) as dimethyl 1,2-Biphenyl vinyl phosphate (0.7 g, 235 - all E-isomer) b.p. 152-155°/0.05 mmHg. (Found: C, 62.99; HI 5.74; P, 10.40: C16H17PO4
requires: C, 63.15; H, 5.63; P, lo.lag).
68.5°).
154 -
qmax 3050 m, 3000 m, 2850 w, 1650 m, 1600 w, 1500 m, 1450 s, 1290 vs,
1220 m, 1190 s, 1050 vs, 950 s, 920,mi 860 s, 800 8, 780 s, 735 w, 725 s, cm-1. 1H neir 6 3.70 (6H, d; 3
H-P 11.2 Hz), 6.65 (1H, d; j
H-P 2.7 Hz), 7.22
(3H, m), 7.47 (2H, m), ppm.
2.:2112.22.2.1.1.1163
To benzil (32.0 g, 0.15 mol.) dissolved in sodium-dried ether
(200 ml) was added an ethereal solution of phenyl magnesium bromide (prepared from 30.0 g of bromo benzene). The reaction was quite vigorous
and a precipitate of the bromo magnesium salt of phenyl benzoin was formed. After Complete addition the mixture was refluxed for one hour, cooled to
room temperature, and the salt filtered off under reduced pressure -
washed with a little dry ether. The salt was broken down with dilute
H2SO4 (50 ml), washed with water (4 x 100 ml), and dried over anhydrous Na2S0
4. Removal of the solvent gave a pale yellow oil which was
crystallised from benzene-petroleum ether as colourless needles m.p. 85-86°
(Lit.163 87-88°) of 2-phenyl benzoin (20.3 g,
1:LkimyLLe... 164 2-Phenyl benzoin (5.76 g, 0.02 mol.) was warmed with pyridine
(1,83 g, 0.023 mol..) until dissolved. The solution cooled to room
temperature and thionyl chloride (3.33 g, 0.028 mol.) added dropwise
over a period of thirty minutes - some cooling being required to maintain a temperature of 20o. After complete addition the solution was stirred for ten hours at room temperature, the residue taken up in ether (250 ml),
washed with water (4 x 150 ml) and dried over anhydrous sodium sulphate.
Removal of the ether gave a yellow oil which crystallised on standing.
Recrystaliisation from benzene/petroleum ether gave nuggets of 2-phenyl
desyl chloride (4.52 g, 74) m.p. 82-85° (Lit.164 m.p. 82-84°).
Reaction of 2-phenyl desyl chloride dimethyl phosphonate with triethy1 amine
Treating a solution of dimethyl phosphonate (0.55 g, 0.005 mol.) and 2-phenyl desyl chloride (1.53 g, 0.005 mol.) in CH30N (2.0 ml) with
triethylamine (0.5 g, 0.005 mol.) in CH3CN (3.0 ml) at 5-10° gave no
observable product even after several days. 2.7112ILy1 benzoin15 • 6
To benzil (32.0 g, 0.15 mol.) dissolved in sodium-dried ether
(200 ml) was added dropwise an ethereal solution of methyl magnesium iodide
(prepared from methyl iodide (0.16 mol.)) with vigorous stirring. A pink
- 155 -
precipitate of the iodo-magnesium salt of methyl benzoin was produced*
After complete addition the solution was refluxed for a further one hour,
the precipitate filtered off at the pump and the complex was destroyed with dilute H
2SO4 (50 ml). The methyl benzoin was taken up in ether
(100 ml), washed with water (4 x 70 ml) and dried over anhydrous sodium
sulphate. Removal of ether gave a dark yellow oil which was recrystallised
from 40/60 petroleum ether as colourless crystals of 2-methyl benzoin
(18.9 g, 56%) m.p. 88-89° (Lit.165 m.p. 65-66°). (Found: C, 79.54;
H, 6.15;: 0151:11402 requires: 0, 79.62; H, 6.24%.) 1H nmr 6 1.83 (3H, s), 4.75 (1H, s - exchangeable with D20), 7.37 (611, m),
7.73 (4H, m) Fpm. 2-Phenyl 3-chloro erepiophenona166
2-Methyl benzoin (9.04 g, 0.04 mol.) was dissolved in warm
pyridine (3.66 g, 0.043 mol.) and the solution cooled until solid - then
crushed to a powder. Thionyl chloride (6.66 g, 0.056 mol.) was added dropwise and the solution stirred for ten hours at 20°. The residue was
taken up in ether (250 ml), washed with water (4 x 150 ml) and dried Over
anhydrous Na,)SO4. Removal of the ether gave a pale yellow oil which recrystallised from 40/60 petroleum-ether as colourless needles of
2-phenyl 3-chloro eoropio henone (4.52 g, 46%), m.13, 57-58° (Lit.153
m.p. of 2-methyl desyl chloride 57-58°) m+/e 244. (Found: C, 72.39,
H, 6.03; Cl, 14.915: Cl5H15C10 requires: C, 73.02; H, 6.13; C1, 14.37%).
nmr E 3.70 (la, dd; J11.41 10.5 Hz, 311-H 6.0 Hz), 4.30 (1H, dd; JE-H 10.5 Hz, jHell 8.5 Hz), (6H, m), 8.00 (4H, m), ppm.
2-Ethylbenzoin
An ethereal solution of ethyl magnesium iodide (prepared from
ethyl iodide (0.1 mol.)) was added dropwise to a stirred solution of
benzil (21.0 g, 0.1 mei.) in sodium-dried ether (200 ml) and T.H.F.
(50.0 ml) over a period of one hour at 0-5°. After complete addition
the reaction was stirred for a further one hour and the pink precipitate
filtered off, washed several times with ether to remove unreacted benzil.
The precipitate was broken down with 105 N14C1 solution (100 ml),
extracted into ether (400 ml), washed with water (4 x 70 ml) and dried
over anhydrous Na2SO4. Removal of the solvent gave a red oil (15.4 g),
which was purified by column chromatography (silica eluted with benzene)
4.93 (1H, dd; 8.5 Hz, J11-11 6.0 Hz), 7.37
- 156 -
to give 2=ethyl benzoin (8.21 g, 34 as a colotrless solid mop. 55-58°0 (Found: 0, 79.92; H, 6.76%: 016111602 0
2 requires: C, 79.97; H, 6.71%).
1H nmr 6 0.33(3H, t; JH_H 7.0 Hz), 2.40 (2H, q; ,TH,41 7.0 Hz), 4.70 (1H, s - exchangeable with D20), 7.38 (6H, m), 7.67. (4H, m) ppm.
2-Pheny15-chloro blpouhenone
Crude 2-ethyl benzoin (0.6 g, 0,0025 mol:) was dissolved in warm
pyridine (0.2 g, 0.0025 mol.) and thionyl chloride (0.3 g, 090025 mol.) added dropwise to the stirred solution at room temperature. After one
hour the residue was extracted into ether (100 ml), washed with water
(4 x 70 ml) and dried over Na2SO4. Removal of the ether gave a pale
yellow oil (0.63 g) which was purified by column chromatography (silica
eluted with benzene) to give the major product as a solid.
1H nmr b 1.29, 1.60 (3H, perturbed doublets:j1I-H 6.0 Hz), 4.70, 4.85
(2H, multiplets), 7.33 (8H, m), 7.98 (2H, m) ppm, is consistent with
a diastereomeric mixture of
Recrystallisation from 40/60 petroleum ether/ether gave colourless needles of 2-phenyl 3-chloro butyrophenone m.p. 75-76° (Found: C, 74.07; H, 5.76; C11 13.90%: 0161115010 requires: C, 74.27; H, 5.84; Cl, 13.70%).
S
- 3.57 -
* CHIPM_A
s
- 158 -
CHAPTER 4
The Effect of Aromatic Substituents uron the E'Z' Isomer RatioutfiLml
Phosphates 'Formed in the Reaction of 2 2-Dichloro Substituted Aceto henone with Dimethyl Phosphonate in the Presence of Base
1. Aromatic rind substituted 2,2-dichloro acetophenone
2 ,1 1 0 -oubstituted 2,2-dichioro acetophenone (LIV) have previously been prepared by Friedel-Crafts reaction of 1,3-disubstituted benzene with dichloro acetyl chloride
CHC12COC1/A1C1,
CS2
ON0//CHC12 X
(LIV) 2,2,21,41-Tetrachloro acetophenone (LIV, X, Y = C1) reacts
with diethyl phosphonate in the presence of base to give diethyl, 1-23-4 -dichloro phenyl 2-chloro vinyl phosphate (LV, X, Y = Cl, 0 = 30/70)
whereas the simpler 2,2-dichloro acetophenone (LIV, X, Y = H) under the same conditions gives mostly the E-isomer of diethyl 1-phenyl 2-chloro vinyl
phosphate (LV, X, Y = H)69.
OHC12 , 9 (C2H50) P
NH /C H OH 2 2 (C 11,0) KH 0 -5—>
E-isomer
2 2
•
Y H or Cl
Z -isomer
LV
In order to investigate the nature of this aromatic substituent effect_ it was necessary to prepare a number of mono-substituted 2,2-dichioro
acetophenones.
„„/CHC12 X = H
C1
Br
LVI CH
3 NO2
- 159 -
21-Substituted 2,2-dichloro acetophenones (LVI) were prepared
in general by treating 21-substituted acetophenones, which are readily available
with chlorine gas in formic acid solution see Table 31.
Chlorination of 21-methyl acetophenone under these conditions
gave predominantly the required 21-methyl 2,2-diohloro acetophenone (LVI,
X = CH3) along with a small amount of material containing chlorine substituted in the methyl group directly attached to the aromatic ring. This was
conveniently purified by distillation using a spinning-band column. The 1
chlorination of e-methoxy acetophenone in formic acid solution at room
temperature gave 2,2,51-trichloro-21-methoxy acetophenone (LVII) in good
yield but it was impossible to isolate a compound in which the ring had
not been chlorinated„
H3 CHC12
(,,OC H3 Cl2 /HCO H
OC H3
2)
LVII
The required 21-methoxy 2,2-dichloro acetophenone (LVI, X = OCH ) was conveniently prepared by chlorination of 21-methoxy acetophenone with chlorine in CS, solution at -5°•
CH3
CHC12
H Cl /CS H3 - 2' 2 -
-50 LVI
When o-acetyl methyl benzoate was treated with chlorine gas in
formic acid solution at 400, a mixture of 21-carbcxy 2-chloro acetophenone
(LVII) and 21-carboxy 2,2-dichloro acetophenone (LIX) was obtained, which
was converted to the methyl ester using diazo methane. The 21-carbomethoxy
Oke/CH2C1
0,H CH,N,
Ether
Nt/CH2C1
02CH3
LX LVIII
- 160 -
2-chloro acetophenone (LX) and 21-carbomethoxy 2,2-dichloro acetophenone
(m ) were separated by column chromatography - Scheme 1.
0 CHC12
02H CH2N2 Ether
LIX
LXI
Scheme 15
21-Hydroxy 2,2-dichloro acetophenone (LVI, X --. OH) was prepared
by chlorination of 4-hydroxy coumarin followed by the subsequent hydrolysis of the 3,3-dichloro-2,4-dioxo chroman - Scheme 16.
S02012
.LVI Scheme 16
All attempts to make the 21-amino 2,2-dichloro acetophenone(INI,I=NH3) were unsuccessful. Reduction of 2-nitro 2,2-dichloro acetophenone with a
variety of reducing agents was tried.
1. SnC12.2H20 - Et0H
2. SnC12.2H20 - HCI
3. H2N.NH2 - Pd/C
- 161
In all cases the nitro group was reduced but with additional
hydrogenolysis of the carbon-chlorine bonds. Direct chlorination of
21-amino acetophenone with chlorine in hydrochloric acid solution was
also attemcted but with no success.
41-Substituted 2,2-dichloro acetophenones(LXII) - Table 33
were prepared in a similar way by the chlorination of the 41-substituted
acetophenones in formic acid solution - Scheme 170
012/I 02H
X . H
F
Cl
Br
NO2 LXII
Scheme 17
However, 41-methoxy 2,2-dichloro acetophenone could not be prepared
by direct chlorination of 41-methoxy acetophenone under these conditions,
but was made by careful chlorination of 41-methoxy acetophenone in carbon
disulphide solution at -5o
21,41,61-Trisubstituted 2,2-dichloro acetophenones(LXIII) - Table 35
were prepared by Friedel-Crafts reaction of dichloro acetyl chloride with
the appropriate 1,3,5-trisubstituted benzene - Scheme 18.
X X ,,,CH C12 X F
CHC1 COC1/A1C12/CS2, X Cl CH3
LXIII
Scheme 18
21t41,61-Trimethyl 2,2-dichloro acetophenone was simple to prepare
since the inductive effects of the methyl substituents in 1,3,5-trimethyl
benzene activate the ring to electrophilic substitution. The small steno
effects for the fluorine substituents in 1,3,5-trifluoro benzene render it
more reactivity than might otherwise be expected for electrophilic substitution 1
and 21 ,41 16--trifluoro 2,2-dichloro acetophenone was relatively easy to
prepare. For 1,36-trichlorobenzene to undergo the Friedel-Crafts reaction,
reaction with dichloro acetyl chloride required refluxing in carbon
disulphide for several days.
,
10°
OH30)2P-Cl e (CH30)2L 1
V.--\
[X NE t /CH3 ON Cl
CHC12
LXIX
- 162 -
2. Reaction_of dialkyl 'rhosphonate qthring substituted 2,2-dichloro
acetophenones
The reaction of dialkyl phosphonate with a variety of 21-substituted dichloro acetophenones was carried out under standard
conditions, using triethylamine as base and acetonitrile as solvent
- Scheme 19.
(C1130)2ILH
X= .H
.Cl
.Br
.CH3
.003
.NO2
Scheme 19
In all cases (X = H, F, Cl, Br, CH3, OCH
3 or NO2) good yields of
the corresponding vinyl phosphates (LXIX) were obtained. The vinyl phosphates
(LXIX) consisted of E- and Z- isomeric mixtures. E/Z isomer ratios were
determined by 1H nmr integration of the vinylic protons (the vinylic proton
in the B-isomer resonates to low field of the vinylic proton in the Z-isomer
- see Chapter 2, also the magnitude of 4J E is greater than 4Jim )• These isomer ratios were confirmed by gas liquid chromatography (gic) analysis
using both flame ionisation detection (F.I.D.) and phosphorus detectioe.
The isomer ratios determined by the glc technique we in very good
agreement with those obtained by 1H nmr integration. All subsequent isomer
ratios were determined for convenience by 111 nmr integration.
2,2-Dichloro acetoihenohe gave predominantly the vinyl phosphate
with E- stereochemistry whereas with large ortho substituents (e.g. X = Cl,
Br and 00H3' ) mostly the vinyl phosphate with Z- stereochemistry was
produced,- see Table 32. However, for the substituent X = CH3
the
These isomer ratios were also confirmed by 31P nmr (noise-decoupled from
1H) - see Chapter 2,
— 163 —
predominant isomer had E-stereochemistry which is surprising since CH3—
is similar in size to Cl-. The variation in the 0 isomer ratio with the nature of the ortho substituent is therefore very difficult to explain in terms of a simple steric effect. This problem is dealt with in detail in Chapter 6 when the mechanism of the reaction is discussed at length.
It was possible to recrystallise the vinyl phosphates (LXIX,
X = Br, NO2) for analysis as pure Z-isomers. All the other vinyl phosphates were purified by column chromatography to give analytically pure compounds
- Table 31.
For one of the 21-substituted 2,2-dichloro acetophenones (LVI,
X = CH) it was impossible to prepare the corresponding vinyl phosphate.
On treatment with dimethyl phosphonate in triethylamine/acetonitrile a good
yield of a compound in which the phenol had been phosphorylated and the
2,2-dichloro acetophenone dechlorinated was produced - Scheme 20. This
can be rationalised by an infra-molecular reaction involving loss of
halogenTollowed by a subsequent phosphorylation of oxygen.
LIC1
(N J-FINEt3
Scheme 2C
A mechanism involving phsophorylation of the phenol followed by
removal of positive halogen seems unlikely because the attack at positive
halogen requires the presence of the phosphorus reagent.
Dehalogenation of bromo-ketones (see earlier section in Chapter 3) with
dimethyl phosphonate/triethylamine does not occur in the absence of dimethyl
phosphonate.
Et3N
CH),CN
10-„,
(CH30)2P-H
- 164 -
Table 31.
•
Substituted acet2phenoneg.
Substituent Analysis:requires f 1 Found %
Cl Br F C H N Cl Br F
-H 50.7 3.2 - 37.4 - 50.6 3.2 - 37.8 - :- -F 46.4 2.4 34.3 9.2 46.1 2.4 - 35.6 - 9.1
-Cl 42.9 2.2 - 47.6 - - 42.8 2.5 - 47.6 - - -Br 35.9 1.9 - 26.5 29.8 36.1 1.9 - 27.3 30.8 -
-CH3 53.2 4.0 - 34.9 - 53.2 3.9 - 35.5 ' - -
-0CH3 49.3 3.7 - 32.4 - - 49.6 3.5 - 33.3 - -
-NO2 41.1 2.2 6.0 30.3 - - 41.4 2.1 5.9 30.7 - -
Substituted vin=yl phosphates
Substituent Analysis : requires% Found %
C H N P Cl Br F C H N P Cl Br F
-H 45.7 4.61 11.8 13.5 - - 45.5 4.7 11.7 14.7 - -
-F 42.8 4.0 - 11.0 12.6 - 6.8 42.5 4.2 11.1 13.3 - 6.9
-Cl 40.5 3.7 - 10.4 23.9 - - 40.8 3.9 - 9.8 25.1 -
-Br 35.2 3.3' - 9.1 10.4 23.4 - 35.3 3.4 - 9.2 10.7 24.2 -
-CH3
47.7 5.1 - 11.2 12.8 - - 47.9 5.2 11.2 14.2 - -
-OCH3 45.1 4.8 - 10.6 12.1 - 44.8 4.9 10.9 13.3 - -
-NO2 39.1 3.8 4.6 10.1 11.5 39.3 3.7 4.4 10.2 11.8 - -
Table 32
(CH0)2
z
(0130)2 -CHOI2 Et N
(0/130)2'"H CH3CN
Substituent
X a HE PPm
a 6 HZ PPm
r ,0 E isomer
, ;2)2 isomer -1
Infra-red° - imax cm nmr glob nmr glo
-H 6.50 6.20 95 95.5 5 45 307011,2950m,2850w,1630w,1490m,1445s.133om,1290vs,
12.85593.0955,1045v5,9255,9103,8558,800w,770m,755m,
6.
-F 6.55 6.50 60 60.4 40 39.6 307ow,295om,2850w,1645w,2615s,1580w,1495s,f455s
1290vs,1250s t31856,1155w,11109,103ovs,920s,850s,
. 82 w 800w 1_760s..,320w
-Cl 6.55 6.00 17 16.1 83 83.9 30701,7,2950m,2850w,1640m,1595m,1490s,14503,1435s,
1290vs,1250m,1185s,1090s,1040vs,9208,8555,855m,7903
pwa s.ww■I**•••** 60515i_____
-Br 6.55 6.00 9 7.3 91 92.7 30800,2950m,2850w,1645m,1590n44505,1440s,1290v8,
1230m,1185m408080.040vs,920s,855s,830s,7903,750s,
omlium
-CH 6.5o 5.80 77 72.4 23 27.6 5080w,2950m,2850w,1645w,1605w,1490w,1455m,1290vs, 3
1230w,1180s01203,1040vs,920s,8503,800m,770m,760th,
• 2 m continued
Table 32 continued
%;E isomer % Z isomer PPma
Hz plea.
nmr g10 nmr gle
6.45 6.30 5 4.6 95 95.4 308514,2950m,2850w,1640w,1600s,1580w914905,1465s,
1.440m0.290vs„1250s0.225m0.185s,33.20m0.040vs,925s,
8 0, 8sss Ow
-NO2 6.55 6.10
37.5
•
62.5
-
3085w,2950m,2850w,1640w,1605m,1575w,15253,1455s,
1365s,1290vs,1245m.1185,1095s,1050v$1915s,885m9860s,
82 s -8 s 5s sZ75s
Substituent
X
-OCH
a Recorded in C0013/T.M.S. using Varian T60 nmr spectrometer. Positive shifts to low field.
3.3m 3mm ID column packed with 50 0V 225 on Chromosorb WHP Pye 104 using T.I.D. and 31P detection.
Perkin-Elmer 257 - liquids as films and solids as nujol mulls.
•
- 167
When the comparable reaction of dimethyl phosphonate with
41-substituted 2,2-dichloro acetophenones (LXII) was carried out, the only products observed were again the dimethyl 1-41-substituted phenyl 2-chloro
vinyl phosphate (LXX) - Scheme 21.
X = -H
-C1
-Br
-NO2 -OCH3
NEt3/CH
3CN
(CH30)2P-H 10°
LXX
Scheme 21
The E/Z isomer ratio was determined by 1H nmr integration of
the vinylic resonances (the vinylic proton in the E-isomer resonates to
low field to the vinylic proton in the corresponding Z-isomer - see Chapter 2).
For the range of substituents studied the E/Z isomer ratio remained constant
E/Z isomer ratio ca 95/5 - Table 34. Since the E/Z isomer ratio obtained for these reactions is independent of the nature of Para-substituent, it is
possible to assume that the variations observed for the 21141-disubstitnted
2,2-dichloro acetophenones (LIV) arises because of the influence of the
ortho-substituent on the transition state. In Chapter 6 we make the assumption, with reasonable supporting evidence, that the transition state
of the reaction resembles a hydroxy phosphonate. Since para-substituents
might be expected to interact electronically favourably in such a transition
state, there should be a variation in the E/Z isomer ratio with change in the
electronic nature of the para-substituent. The results obtained (i.e. E/Z isomer
ratio independent of para-substituent) indicate that any variation in the
E/Z isomer ratio- cannot be explained in terms of a simple inductive or
resonance effect. As shown in Chapter 6, the variation is explained by an elimination from preferred conformations of the transition state determined
by the nature of the ortho-substituent.
All vinyl phosphate's (LXX) were purified by column chromatography
and characterised by micro-analysis - Table 33.
+ (CH30)2LH EtN
CH3CN
10°
- 168 -
Table _a
Substituted acetophenones
Analti sis: Requires
Substituent C H N Cl Br F C Cl Br F
-F 46.4 2,4 - 34.3 - 9.2 46.7 2.6 - 34.7 - 9.2 -Cl 42.9 2.2 - 47.6 - - 42.7 2.2 - 47.1 - - -Br 35.8 1.9 - 26.5 29.9 - 35.8 1.8 - 26.4 29.6 - -0CH3 A9.3 ' 3.7 - 32.4 - - 49.7 3.7 - 32.1 - - -NO
2 41.1 242 6.0 30.3 - - 41.1 2.2 5.8 30.7 -
Substituted vi vl phosphates
Analysis: Pecuires
ubstituent C H N P Cl Br F C H N P Cl Br
-F 42.8 4.0 - 11.0 12.6 - 6.8 42.6 3.9 - 10.6 13.8 - 6.9
-Cl 40.5 3.7 - 10.4 23.9 - - 40.2 3.8 - 10.2 25.4 - -
-Br 35.2 3.3 - 9.1 10.4 23. - 34.9 3.3 - 9.1 11.0 24.7 - -OCH
3 45.1 4.8 - 10.6 12.1 - - 44.7 4.7 - 10.7 13.0 - -
-NO2 39.1 3.8 4.6 10.1 11.5 - - 38.9 3.7 4.5 9.6 12.8 - -
Found %
EtxN (CH30)2 -H
CH3CN 10
(CH30)2?-,■„„ ,1.1
E
(CH30)2P9 -ON r/01
H
Table 34
Substituent X
c 0 HE ppma 6 Hz ppma
E isomer Z isomer ) -1 Infra-redb - \max cm
-H 6.50 6.20 95 5 see Table 32
-P 6.50 6.20 95 5 3070w,2950m,2850w0,630wt1605e451.08446orn441ow,1325m0
1290vs11235s,1185s11160s,1090s,10407s11015s99308,850s,760m . —....- -C1 6.50 6.20 95 5 3070w,2950m,2850w,1630w,1600s,1495sr1460m,1405m,1330m,
1290vs,11905,10953,1040vs,1015s,950w,920s,860s,855s,800w,
i 765m,750m,720w
-Br 6.50 6.20 95 5 3o70w,2950m,2850w,165ow115953,1490e,1460m,1395m033om9
129ovp,119os,1095e,1045ve,1015e995owl92ce,86oe te3oel800w,
765m,740m,720w
-13 ocl 6.40 6.10 95 5 3070w,2950m,2840w,1630w,1610s,1510s,1460m11550m,1290vs
1175s0222al04.0mlI012R2a12s,850s 8 -m 800w 60w
-NO2 6.70 6.60 95 5 3070w,2950m,2850w,1625w01600s,1525s11495w,1460m,1405w,
1550s,1420m,1290vs,1190s,10955,1045vs,1015s1920s,8505,755m
m 700m
aRecorded in CDC13 /T. M. S• using Varian T60 nmr Spectrometer. bPerkin-Elmer 257 - liquids as films and solids as nujol
malls.
sterically hindered in this case - Scheme 22. aEtA
=CHC1
CH ,--"" H3
+ C1-?(Ocii3 )2
HC1
01 r 3
(OCH3)2 CF CH3
HNEt3
- 170 -
It has now been established that any variation in E/Z isomer ratios
of vinyl phosphates obtained for this reaction depends upon the nabaneof the
ortho-substituent. The effect of having two ol-tho-sUbstituents in the ring on the course of the reaction was studied.
When 21 ,41 ,61-trimethyl 2,2-dichloro acetophenone was treated with dimethyl phosphonate and triethylamine in acetonitrile as solvent it
was impossible to detect, either by 1H nnr or tic, any formation of the expected vinyl phosphate. Instead small amounts of 21,41,61-trimethyl 2-monochloro acetohenone was isolated and charactersied by 1H nmr and
mixed melting point. This result was unexpected since 21,41-dimethyl 2,2-dichloro acetophenone has been shown to react with dimethyl phosphonate
in the presence of ammonia to give dimethyl 1-21,41-dimethyl phenyl 2-chloro vinyl phosphate (1,XXI, E/Z = 83/17) as the only product
H /CH OH (CH 0) LI N 3 '2
20°
CHI
LXXI
E/Z = 83/17
The formation of 21 ,41 ,61 -trimethyl 2-monochloro acetophenone can be rationalised by attack of dimethyl phosphonate anion on positive
halogen in preference to the carbonyl carbon atom which is,presumably,
CH El) , Et
3N-kocH3 )2
Scheme 22
01
(CH3 0)2 LI Et N
./CH ON
100
01
C
LXXII - 2 parts
2-isomer
(CH3 0)2 "N■ P-0, ,C1
0/ 1
Cl
LXXIII - 1 part
Scheme 23
- 171
A similar reaction of 21,41,6112,2-pentachloro acetophenone with
dimethyl phosphonate and triethylaminc in acetonitrile gave predominantly 21,41,61,2-tetrachioro acetophenone (90%) which was isolated by column
chromatography and characterised by 1H nmr and micro-analysis. It was
possible to isolate smaller amounts (10%) of a second product containinc phosphorus. 31P and 1 nmr indicated that the product was possibly a
mixture of dimethyl 1-21141 61-trichloro phenyl 2-chloro vinyl phosphate
(LXXII) Z-isomer (2 parts) and dimethyl 1-21 ,41 ,61 -trichloro phenyl
2,2-dichloro vinyl phosphate (LXXIII) - (1 part)-- Scheme 23. OW CHC12 H2C1
90%
When 21,41,61-trifluoro 2,2-dichloro acetophenone was treated
with dimethyl phosphonate and triethylamine almost quantitative yields of
the expected dimethyl 1-21141t61-trifluoro phenyl 2-chloro vinyl phosphate
(cH30)2r.-11 Et,N
OE3ON 10°
- 172 -
(LXXIX - E/Z = 83/17) was obtained. The compound was isolated by column chromatography and identified by 1H nmr and mass spectral analysis. In
this case, presumably, the smaller steric effect; of the two ortho-fluoro
substituents do not prevent the dimethyl phosphonate anion from attacking
the carbonyl carbon atom and thereby giving the normal products.
J(cH30-0,,
(CH 0) P Et VOTI ON 3 2
100
=CHC1
LXXIX
E/Z . 83/17
The E/Z isomer ratio observed in this case is verysimilar to
the one obtained for only one ortho-fluoro substituent (LXIX, X = F;
EIZ = 60/40).
Table 35
Substituted acetonhenones
Analysis: Requires Found %
Substituent C H Cl F C H Cl P
F 39.54 1.24 29.18 23.46 39075 1.51 29.46 1 23.69
Cl 32.86 1.03 60.64 - 33.01 1.04 60.49 -
CH3 57.16 5.24 30.68 - 57.21 5.31 30.66
- 173 -
j . __ Experimental
The 21-substituted acetophenones: Acetophenone
21-Chloro acetophenone
21-Methyl acetophenone
21-Nethoxy acetophenone
21-Nitro acetophenone
21-Amino acetophenone
were all available commercially.
All the other required 21-substituted acetophenones:
21-bromo acetophenone 1 2--fluoro acetophenone
2'-carbomethoxy acetophenone
were prepared by convenient methods.
21-Bromo acplophenone168
A mixture of o-bromo benzoic acid (75.0 g, 0.37 mol.) and thionyl
chloride (225 ml) was maintained at room temperature for-twelve hours and
then refluxed for one hour. Excess thionyl chloride was removed under
vacuum at,the water pump to give a yellow liquid. Distillation at
reduced pressure gave o-bromo benzoyl chloride as a pale yellow liquid
b.p. 116-118°/15 mmHg (Lit.168 b.p. 133-135°/20 mmHg).
Anhydrous ethanol (7.5 ml) and carbon tetrachloride (1.5 ml)
were added to magnesium turnings (11.8 g) contained in a two-litre
three-necked flask. As soon as the reaction was initiated, chloro benzene
(75.0 ml) was added in one portion and then a mixture of diethyl malonate
(78 g, 0.49 mol.) and anhydrous ethanol (30 ml) was added dropwise. The
temperature was not allowed to rise above 70° during the addition - some
cooling being required. At the end of the addition the mass was heated to 75° for three hours - then cooled to room temperature.
At a temperature not exceeding 35° o-bromo benzoyl chloride
(63.5 g, 0.29 mol.) in chloro benzene (125 ml) was added dropwise to the
diethyl ethoxy magnesium malonate solution. After twelve hours at room
temperature, 255 H2SO4 (loo ml) was added and the organic layer separated
off and concentrated at 100° at the water pump. The organic material
which remained was refluxed for seven hours with a mixture of 25% H2SO4
(100 ml) and acetic acid (100 ml) and then concentrated at the water pump
- 174 -
at 100o. The residue was taken up in ether (200 ml), neutralised with
saturated sodium bicarbonate, washed with water (3 x 100 mi) and dried over anhydrous magnesium sulphate. The ether was removed at the pump and the product distilled under reduced pressure to give 21-bromo acetophenone (45.9 g, 75%) as a colourless liquid b.p. 122-123°/17 mmHg (Lit.168
b.p. 133-135°/20 mMHg). 1H nmr 6 2.57 (3H, s), 7.0-7.57 (4H, m)ppm.
21-Fluoro acetophenone168
Method is the same as for 21-bromo acetophenone. o-Fluoro benzoic acid (100 g, 0.715 mol.) in the presence of thionyl chloride was
converted to o-fluoro benzoyl chloride (110.8 g, b.p. 86-89°/15 mmHg. 21-Fluoro acetophenone (53.6 g, 70 obtained as a colourless
liquid b.p. 80-82(715 mmHg (Lit.169 b.p. 80-85(715 mmHg). 1H nmr 6 2.58 (3H, d; -H-F 5.0 Hz), 6.80-7.90 (4H, m)ppm.
21-Carbomethox- acetoehenonel(°2171
A finely ground mixture of phthalic anhydride (105.4 g, 0.72 mol.) and malonic acid (88.0 g, 0.84 mol.$ dried in an oven at 100° for two hours) was heated on a steam bath for three hours with dry pyridine (70 ml - dried over kOH pellets), carbon dioxide was evolved during the entire heating
procedure. The clear yellow solution was diluted with distilled water
(600 ml) causing a colourless solid to separate (phthalic anhydride). This was filtered off and the filtrate neutralised with cHC1 (34.0 ml) to pH 3. The solution was left to crystallise for several days at room
temperature. Colourless crystals were formed which were recrystallised from
benzene as o-acetyl benzoi acid (31.4 g, 27%), m.p. 115-116o (Lit.
170
m.p. 114-115°).
A mixture of o-acetyl benzoic acid (49.2 g, 0.33 mol.) methyl
iodide (51.0 g, 0.27 mol.), potassium carbonate (19.9 g) and acetone
(1 litre) were refluxed with stirring for twenty-four hours. After removal
of all insoltble material by filtration the solvent was removed under reduced pressure. The residue was taken up in ether (500 ml), washed
with dil. H2SO4 (2 x 200 ml), saturated sodium chloride (1 x 200 ml), water (2 x 200 ml), and dried over anhydrous magnesium sulphate. Removal of ether at the pump and distillation of the residue at reduced pressure gave
271carbome none (42.15 g, based,on methyl iodide
consumption) as a colourless liquid b.p. 145-146(710 mmHg (Lit.171
b.p. 127-129V8 mmHg),
1H nmr i) 2.48 (311, 01 3.82 (3H, s), 7.13-7.83 (4H, m) ppm.
- 175 -
242:1Dichloro
Prepared as experimental - see Chapter 2. . 2,2,21 -Trichloro acetophenone
Chlorine (76.0 g,1.07 mol. (75 excess)) was passed in a slow stream through a solution of 21 -chloro acetophenone (77.25 g, 0.50 mol.) in formic
aicd (250 ml) at 400. Some cooling was required to ensure a temperature of
40 - 2°. After complete addition of chlorine the formic acid was removed
at the pump and the resulting oil taken up in ether (400 ml), washed with
saturated sodium bicarbonate ( 2 x 300 ml), water (2 x 300 ml)and dried
over anhydrous magnesium sulphate. The ether was removed at the pump and the residue distilled at reduced pressure to give 2L2121ttrichloro acetophenone
(103.9 g, 935) as a colourless liquid, b.p. 98-99°/0.6 mmHg.
1H nmr 6.65 (1H, s), 7.10-7.57 (4H, m) ppm.
21-fluoro acetophenone
21-Pluoro acetophenone (34.5 g, 0.25 mol.) was converted to 2,2-dichloro 21-fluoro acetophenone (38.7 g, 75%) by a method similar to
preparation of 2,2,21-trichloro acetophenone. 2 2-Dlchioro 21-fluoro
acetophenone b.p. 79-80°/0.75 mmHg.
1H nmr 6 6.72 (1H, d; 2.0 Hz), 6.80-8.00
9 2 Dichloro 2 -bromo acetophenone 1 2 -Bromo acetophenone (34.0 g, 0.17
2 2-dichloro 21 -bromo aceto henone (31.9 g, 7 preparation of 2,2,21-trichloro acetophenone.
aceto henone b.p. 97-98°/0.35 mmHg. IH nmr 6 6.63 (1H, s), 7.10-7.60 (4H, m) ppm.
gLazildchloro 21-methyl acetophenone
21-Nethyl acetophenone (80.4 g, 0.6 mol.) was converted to
22=clieLlorp 21meth 1 acetophenone by a method similar to preparation of
2,2,21-trichloro acetophenone but employing a temperature of 25o for the
chlorination.
2L721_..-co....?1LLeth'isL,cetohenone (48.5 g, 39%) was purified by
distillation through a spinning-band column b.p. 99-104°/2.5-3.5 mmHg.
1H nmr 6 2.48 (3H, s), 6.56 (1H,$), 7.00-7.37(3H, m), 7.50-7.72 (111, m) ppm.
2 2-Dichloro 21-nitro acetophenone
21-Nitro acetophenone (60.0 g, 0.36 mol.) was converted to
2 2-dichloro 21-nitro aceto henone by a method similar to preparation of
tothenone
(4H, m) Pim*
mol.) was converted to 0%) by a method similar to
2 2-Dichloro 21 -bromo
- 176 -
2,2,21-trichloro acetophenone but employing a temperature of 60° for
the chlorination.
2 2-Dichloro 21-nitro acetophenone was recrystallised from
methanol as pale yellow crystals (48.5 g, 57%), m.p. 84-85°. 1H nmr S 6.28 (1H, s), 7.32-7.82 (3H, m), 8.02-8.23 (1H, m).
2,2,51 -Trichloro 21-methoxy acetophenone
Chlorine (25.3 g, 0.36 mol. (7% excess)) was passed as a slow stream through a stirred solution of 21-methoxy acetophenone (25.0 g,
0.17 mol.) in formic acid (80 ml) at 25°. The reaction was followed by
tic (silica eluted with benzene) until the unchlorinated and mono-
chlorinated acetophenones had disappeared - the Rf of the product did not
correspond to the one expected for the dichlorinated acetophenone. The
formic acid was removed at the pump to give a deep red oil which was taken
up in ether (200 ml), washed with saturated sodium bicarbonate (2 x 100 ml),
water (2 x 100 ml) and dried over magnesium sulphate. Removal of the ether
gave a dark brown oil which crystallised on standing. The solid was
recrystallised from methanol to give :620 -trichloro 21-methoxy acetophenone ,1
(15.4 g, 37%) as colourless crystals m.p. 79-80° (Found: C, 42.3; H, 2.7; Cl, 41.4%: C
9H7cl302
requires: C, 42.6; H, 2.7; Cl, 42.00.
nmr 8 3.90 (311, s), 6.82 (IH, d; JII_H 9.0 Hz), 6.90.(1H, s), 7.37 (1H, dd;
Jii-H 9.0 Hz, J11.41 207 Hz), 7.62 (IH, d; Ju_H 2.7 Hz) ppm. :2 12-Dichloro 21-methoxy acetophenone
Chlorine (9.0 g, 0.13 mol.) was passed as a slow stream through
a solution of 21-methoxy acetophenone (10.0 g, 0.067 mol.) in carbon disulphide (100 ml) at -5° over a period of three hours. The reaction
was terminated when only the dichlorinated acetophenone was present.
Removal of carbon disulphide at the pump gave a pale yellow liquid which
was distilled at reduced pressure to give 2,2-dichloro 21-methoxy acetophenone
(14.2 g, 98%) as a colourless liquid b.p. 94-95°/0.5 mmHg. nmr. 6 3.83 (311, s), 6.97(1H, s), 6.70-7.72(4H, m) ppm.
2 2-Dichlorc 21-carbomethoxy acetophenone and 2-chloro 2 -carbo-
methoxy acetophenone
21-Carbomethoxy acetophenone (20.0 g, 0011 mol.) in formic acid
(250 ml) was treated with chlorine gas at 40° over a period of about
five hours until all the starting material had reacted. The formic acid
was removed at the pump and the product recrystallised from chloroform
to give a white solid (10.9 g) m.p. 101-3°.
- 177 -
IH nmr 6 4.38 (s), 6.90 (s), 7.67-8.17 (m), 8.30 (s), 8.95 (broad s) suggests a mixture of 2,2-dichloro 21-carboxy acetophenone (2 parts) and
2-chloro 21-carboxv acetophenone (1 part).
A 40% solution of potassium hydroxide (15.0 ml) was added dropwise to anhydrous ether (50m1) and the solution cooled to 5?. Finely powdered
nitroso methyl urea (5.0 g) was added in email portions over a period of
one to two minutes, and a mixture of the acids (2.16 g) added to the
stirred solution of diazo methane (1.4 g, 0.03 mol.) - brisk effervescence was observed and the stirring was continued for twenty-four hours. The ethereal solution was filtered and the ether removed at the pump to give
a mixture of methyl esters which were purified by column chromatography
(silica gel eluted with methylene chloride). 212-Dichloro 21-carbomethoxv acetophenone (1.13 g) colourless crystals
from benzene mop. 105-106°.
nmr 6 3.92 (3H, s); 6.45 (1H, s), 7.40-7.83 (3Ht 2-Chloro 21 ,carbomethoxy acetophenone (0.
from benzene m.p. 101-102o
IH nmr 6 3.92 (3H, 0, 4.48 (2H, s), 7.25-7.73 (3H, 2,2-Dichlore 21-hydmIyp.att2phenone172
4-Hydroxy coumarin (50.0 g, 0.3 mol.) was treated with sulphuryl chloride (200 ml) for six hours.? When no further reaction was obServed the solution was filtered and freed of excess sulphuryl Chloride. The pale
yellow solid waz washed with carbon tetrachloride and benzene. Recrystallis-
ation from carbon tetrachloride gave lel-dichlo172:114-dioxochroman (34.5 g, 49%) as pale yellow needles m.p. 106-7°.
3,3-Dichloro-2,4-dioxochroman (35.0 g, 0.15 mol.) was treated with water (140 ml) at room temperature for two hours. A yellow oil
separated and was extracted into ether (100 ml), washed with water (2 x 70 ml)
and dried over anhydrous sodium sulphate. Removal of the her at the pump and distillation at reduced pressure gave 2,2-dichloro 21-hydroxY acetophaone (28.8 g, 94) as a yellow liquid b.p. 90-2°/0.5 mmHg
(Lit.172 b.p. 110°/6 mmHg).
1H. nmx & 6.78 (in, s), 6.87-7.13 (2H, m), 7.37-8.00 (2H, m), 1162 (Int s)ppm. .12DimethvlJherjEl.2-phenyl vinyl erhoe2_1Al2
Dimethyl phoaphonate (2.75 g, 25 mmol.) and 2,2-dichioro aceto-phenone (4.7 g, 25 mmol.) were stirred together at 5-10° in acetonitrile (10.0 ml). Triethylaaine (2.53 g, 25 mmol.) in acetonitrile (15.0 ml) was added dropwise to the stirred solution over a period of thirty minutes
m)„ 7.97-8.20 (111, m)ppm. 50 g) colourless crystals
m), 7.93-8.13 (IHt m)ppm.
•
- 178 -
so that the temperature did not rise above 10°. After stirring at room
temperature for two hours the solvent was removed at the pump and the
residue taken up in ether (70.0 ml) washed with 10210E2SO4 (1 x 50 ml),
water (3 x 50 ml) and dried over anhydrous sodium sulphate. The ether
was removed at the pump to give dirnet invlhoshate
(5.4 g, 82%; E/Z = 95/5) as a colourless liquid which was purified by column chromatography (silica gel eluted with ethyl acetate/benzene 1:1).
Dimethyl 1-21-chloroyhenyl 2-chloro vinyl phosphate
Dimethyl phosphonate (2.75 g, 25 mmol.) and 2.2,21 -trichloro
acetophenone (5.6 g, 25 mmol.) were stirred together in acetonitrile (10.0 ml)
at 5-10°. Triethylamine (2.53 g, 25 mmcl.) in acetonitrile (15.0 ml) was
added dropwise over a period of thirty minutes to the stirred solution
so that the temperature did not rise above 10° - some cooling was required.
After two hours the reaction was worked up in the usual way to give
dimethyl (64 g, 86; E/Z = 17/83) as a colourless liquid.
Dimetha_r11-21-bro oaLiyipLesphate
Dimethyl phosphonate (2.75 g, 25 mmcl.) and 212-dichloro 21-bromo acetophenone (6.7 g, 25 mmol.) were stirred together at 5-10° in acetonitrile
(10.0 ml). Triethylamine (2.53 g, 25 mmol.) in acetonitrile (15.0 ml)
was added dropwise to the stirred solution over a period of thirty minutes
so that the temperature did not rise above 10° - some cooling was required.
After two hours the reaction was worked up in the usual way to give
dimethyl 1-21-bronnp12=12=e4loro vinyl phosphate (6.7 g, 80%; E/Z = 9/91) as a pale yellow oil. Recrystallisation from ether/petroleum ether (40/60)
gave dimethyl 1-2--bromo phenyl 2-chloro vinyl phosphate (pure Z isomer) as colourless nuggets map. 59-60°. The mother liquors contained mainly the E-isomer,
Diethyl 1-21-Methyl nhe!yl
2-chloro viEy1 phosphate
Dimethyl phosphonate (2.75 g, 23 mmol.) and 2,2-dichloro 21-methyl
acetophenone (5.1 g, 25.0 mmol.) -were stirred together in acetonitrile (10.0 ml)
at 5-10°. Triethylamine (2.53 g, 25 mmol.) in acetonitrile (15.0 ml) were
added dropwise to the stirred solution over a period of thirty minutes so
that the temperature did not rise aboe 100. After stirring at room
temperature for fifteen hours the reaction was worked up in the usual way
to give dimeth 1 1-21-met4E1_1121al_2-chloro vinyl thosehate (5.5 gl 800;
- 179 -
E/Z = 77/23) as a colourless liquid which was separated by column
chromatography (silica eluted with ethyl acetate/benzene 1:1) into
pure E- and pure Z- isomers.
Dimethyl 1
Dimethyl phosphonate (2.75 g, 25 mmol.) and 2,2-dichloro 21-methoxy
acetophenone (5.4 g, 25 mmol.) in acetonitrile (10.0 ml) were stirred
together at 5-10°. Triethylamine.(2.53 g, 25 mmol.) in acetonitrile (15.0 ml)
was added dropwise over a period of thirty minutes so that the temperatnre
did not rise above 10° - some cooling was required. After stirring at room
temperature for fifteen hours the reaction was worked up in the usual way
to give dimethyl 1-21-methoxy nhenyl 2-chloro vinylILLIELLIIft (5.5 g, 800;
E/Z = 5/95) as a pale yellow liquid which was purified by column chromatography (silica gel eluted with ethyl acetate/benzene 1:1).
Dimethyl 1
Dimethyl phosphonate (2.75 g, 25 mmol.) and 212-dichloro 21-nitro
acetophenone (5.85 g, 25 mmol.) were stirred together at 5-10° in acetonitrile
(10.0 ml). Triethylamine (2.53 g, 25 mmol.).in acetnitrile (15.0 ml) was
added dropwise to the stirred solution over a period of thirty minutes
so that the temperature did not rise above 100 - some cooling being required.
After two hours the solution was worked up in the usual way to give
z-21.-ni.dimethll•tronhenv12-chlo te (6.1 g, 80%; E/Z 38/62) as a brown oil. Recrystallisation from ether ( x 3) gave dimethyl 1-21-nitro phenyl 2-chloro vkalItmEhall (pure Z-isomer) m.p. 68-69°. The mother liquors contained mainly the E-isomer.
Treatment of 2,2-dichloro 21-hydroxy acetophenone with dimethyl
fasphanate and triethylamine
Dimethyl phosphonate (1.10 g, 0.01 mol.) and 2,2-dichloro 21-hydroxy
acetophenone (2.05 g, 0.01 mol.) weie stirred together in acetonotrile
(40 ml) at 0°. Triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml) were added dropwise to the stirred solution at 00 over a period of thirty minutes. The solution was stirred at room temnerature for ten hours and
worked up in the usual way to give a pale yellow liquid which was purified
by column chromatogranhy (silica eluted with ethyl acetate/benzene 1:1) to
give 2-chloro 21-dimethyl phosphoryl acetophenone (2.1 g, 75%) as a pale yellow liquid. (Found: 0, 42.78; H, 4.37; CI, 12.66; P, 10.86%:
10H12P05CI requires: 0, 43.10; H, 4.34; Cl, 12.73; P, 11.12%.)N17e 278.
- 180 -
max 3050 w, 300 m, 2900 w, 1710 s, 1610 s, 1585 w, 1490 s, 1455 s, 1400 w,
1300 vs, 1230 m, 1210 s, 1110 w, 1060 vs, 1010 w, 955 vs, 870 s, 820 s,
780 s, 730 1 w, cm .
1E nmr E. 3.82 (6H, d; JH-P 11.8 Hz), 4.65 (2H, s), 6.77-7.87 (4H, m) ppm.
The 41 substituted acetophenones:
!1-Fluoro acetophenone 1 L-Chloro acetophenone 1 4 -Bromo acetophenone
1-Illetho)aa2312.thtnalft 41-Nitro
were all commercially available.
2,2-Dichloro 41-fluoro acetophenone
A slow stream of chlorine was passed through a solution of
41-fluor° acetophenone (69.0 g, 0.5 mol.) in formic acid (175 ml) at 250
until tic (silica eluted with toluene) showed only the presence of dichlorinated material. The formic acid was removed at the pump and the
residue taken up in ether (150 ml), washed with 10% sodium bicarbonate
solution (1 x 70 ml), water (5 x 70 ml) and dried over anhydrous sodium
sulphate. The solvent was removed to give a yellow liquid (98.3 g, 99s) which was distilled at reduced pressure to give 2,2:clichlo-fl
acetophenone (82.1 g, 79.50) as a colourless liquid b.p. 69-71°/0.3 mmHg.
1H nmr S 6.68 (1H,,$), 7.17 (2H, t; JH-H 8.3 Hz, jH-F 8.3 Hz), 8.13 (2H, dd;
JH-H 8.4 Hz, JH-F 5.0 Hz) ppni.
2,2,41-Trichloro
41-Chloro acetophenone (77.3 g, 0.5 mol.) was converted to
2A24117trichloro actlt2plienone (108.8 g, 98) by a method similar to
preparation of 2,2-dichloro 41-fluoro acetophenone. 2,2,41-trichloro
2.22t2pllenone, was recrystallised from methanol as colourless prisms ni.p. 61-620. IH mu- 6 6.65 (1H, s); 7.47 (2H, d; J_1.1 ) 11 -H 8.7 Hz), 8.03 (2H, d; JH- 8.3 Hz)ppm.
2 2-dj - prepar
acetophenone was recrystallised from methanol as colourless crystals
m.p. 62-63°.
1E nmr b 6.67 (1H, s), 7.62 (2H, d; 8.9 Hz), 7.95 (2H, d; 8.9 Hz)ppm.
2,2-Dichloro 4_1-bromo acetophenone
41-Bromo acetophenone (49.8 g, 0.25 mol.)
chloro 1-bromo acetonhenone (64.7 g, 97%) by
ation of 2,2-dichloro 21-fluor° acetophenone.
was eonverted to
a method similar to
EJ2 g.E1121911:1n222
*- 181 -
2,2-Dichloro 41-nitro acetonhenone
4 -Nitro acetophenone (16.5 g, 0.1 mol) was converted to
2,2-dichloro 41-nitro acetophenone (22.5 g, 96%) by a method similar to
preparation of 2,2-dichloro 41-fluoro acetophenone but employing a temperature of 80o for the chlorination. 2,2-Dichloro 41-nitro acetophenone b.p. 119-120°/0.3 mmHg. 1H nmr 6 6.89 (1H, s), 6 8.33 (4H, s) ppm.
2.22. 1e1173
Chlorine (20.0 g) was passed as a slow stream through a solution of 41-methoxy acetophenone (20.0 g, 0.13 mol) in carbon disulphide (200 ml) at -5° over a period of three hours. A solid precipitated (mono-chlorinated
material) but on vigorous stirring and allowing the solution to come up to
room temperature slowly, this was converted to the dichlorinated product.
On cooling a solid crystallised out (23.0 g) which consisted mainly of 2,2-dichloro 41-metholce acetophenone and a trace of ring-chlorinated material.
Repeated recrystallisation from methanol gave pure 2,2 -nlethem phenone (15.1 g, 53%) m.p. 77-78°. IH nmr 5 3.89 (3H, s), 6.67 (1H, s), 6.97 (2H, d. ,7H-H 8.4 Hz), 8.03 (2H, d; SR-H 8.4 Hz).
1 Dime. _4 0rovinyl phosphate Dimethyl phosphonate (2.75 g, 25 mmol.) and 2,2-dichloro 41-fluor°
acetophenone (52 g, 25 mmol.) were stirred together at 5-10° in acetonitrile (10.0 ml). Triethylamine (2.53 g, 25 mmol.) in acetonitrile (15.0 ml)
were added dropwise over a period of thirty minutes so that the temperature did not rise above 10° - some cooling was required. After stirring at
room temperature for two hours the reaction was worked up in the usual way to give CLi 1 l env12-chloro vin 1 phosphate (60 g,
86%; 0 = 95/5) which was purified by column chromatography, (silica eluted with ethyl acetate/benzene 1:1).
221a2Lallzal:Lloro phenyl 2-chlpro vinyl phosphate
Dimethyl phosphonate (2.75 g, 25 mmol.) and 2,2,41-trichloro acetophenone (5.6 g, 25 mmol.) in acetonitrile (10.0.m1) were stirred at
5-10°. Triethylamine (2.53 g, 25 mmol.) in acetontrile (15.0 ml) were.
added dropwise over a period of thirty minutes so that the temperature did not rise above 10° - some cooling was required. After complete addition the
reaction was stirred at room temperature for two hours and then worked 1 up in the usual way to give _____L_4___d_imeth11--chloroleri_y_1_2-chloro vinyl phosphate
- 182 -
(6.3 g, 855; = 95/5). Column chromatography (silica eluted with ethyl
acetate/benzene 1:1) gave pure E- and pure 7,- isomers. 1 vinylph2tphatt
Dimethyl phosphonate (2.75 g, 25 mmol.) and 2,2-dichloro 41-bromo acetophenone (6.7 g, 25 mmol.) were stirred together at 5-10° in acetonitrile
(10.0 ml). Triethylamine (2.53 g, 25 mmol.) in acetonitrile (15.0 ml) were
added dropwise over thirty minutes so that the temperature didn't rise
above 10° - some cooling being required. After stirring at room temperature
for two hours the reaction was worked up in the usual way to give dimethyl
1-41-bromo phenyl 2-chloro vinyl phosphate (7.1 g, E/Z = 95/5) which
was separated by column chromatography into pure E- and pure 7-isomers.
Dimethyl 1-41-metho!x phenyl 2-chloro vinyl phosphate
Dimethyl phosphonate (0.55 g, 5 mmol.) and 2,2-dichloro 41-methoxY acetophenone (1.1 g, 5 mmol.) were stirred together at 5-10° in acetonitrile (2.0 ml). Triethylamine (0.5 g, 5 mmol.) in acetonitrile (3.0 ml) were added dropwise over thirty minutes so that the temperature did not rise
above 10o cooling was required. After stirring at room temperature for
two hours the reaction was worked up in the usual way to give dimethyl 1-41 nethoy111e12:12-hioro vinyl phosphate (1.2 g, 83%; = 95/5) as a colourless liquid which was further purified by column chromatography
(silica eluted with ethyl acetate/benzen 1:1).
Dimethyl 1-41-nitro phenyl 2-chloro viral phosphate
Dimethyl phosphonate (2.75 g, 25 mmol and 2,2-dichloro 41-nitro acetophenone (5085 g, 25 mmol.) in acetonitrile (10.0 ml) were stirred
together at 5-10°. Triethylamine (2.53 g, 25 mmol.) in acetonitrile (15.0 ml)
were added dropwise over thirty minutes so that the temperature did not rise
above 10° - some cooling was required. After stirring at room temperature
for two hours the reaction was worked up in the usual way to give dimethyl
1-41-nitro phenyl 2-chloro vigil phosphate (6.9 g, 89%; E/Z = 95/5) as a
pale yellow liquid which was purified by column chromatography (silica
eluted with ethyl acetate/benzene 1:1)0
22Lgishlor 41 o 21 o 1.dmethyl acetophenone
Dichloro acetyl chloride (16.23 g, 0.11 mol.) was added dropwise
to a stirred suspension of powdered anhydrous aluminium chloride (14.69 g,
0.11 mol.) in anhydrous carbon disulphide (70.0 ml) at 0° over a period
of thirty minutes. 1,3,5-Trimethyl benzene (12.0 g, 0.1 mol.) in carbon
disulphide (20.0 ml) was added dropwise at 10-15° over a period of one hour
to the stirred solution. The solution goes dark red in colour as the
- 183 -
aluminium chloride dissolves. After complete addition the solution was
stirred at room temperature for fifteen hours and finally refluxed for
two hours. On cooling to room temperature the solution was poured into
crushed ice (200 g) and 12 N Rd (30.0 ml), extracted with chloroform
(3 x 25.0 ml) washed with water (2 x 50 ml) and dried over anhydrous
sodium sulphate. The solvent was removed in vacuo to give a dark red
liquid (19.68 g, 85%) which was purified by column chromatography (30% _,r benzene in petroleum ether - 60-80) to give 2,2-dichloro 21,41,61 c imethyl
acetophenone (10.5 g, 4%). Recrystallisation from petroleum ether (40/60)
gave colourless nuggets m.p. 67-680 .
nmr. 5 2.27 (9H, s), 6.37 (1H, s), 6.97 (2H, m) ppm. 2,2,2124161-Pentachloro acetophenone
Dichloro acetyl chloride (8.12 g, 0.055 mol.) was added dropwise
to a stirred suspension of powdered anhydrous aluminium chloride (7.35 g,
0.055 mol.) in anhydrous carbon disulphide (35.0 ml) at 0° over a period
of thirty minutes. 1,3,5-Trichioro benzene (9.75 g, 0.05 mol.) in carbon
disulphide (10.0 ml) was added dropwise to the stirred solution at room
temperature over a period of one hour. No reaction was observed. The
solution was refluxed for six days, cooled to room temperature, and poured
into crushed ice (100 g) and 12 N HO1 (15.0 ml). This solution was
extracted into chloroform (3 x 25 ml), washed with saturated sodium
bicarbonate (50 ml), water (2 x 50 ml), and dried over anhydrous sodium
sulphate. Removal of the solvent in vacuo gave an orange liquid (10.9 g)
which was purified by column chromatography (silica gel eluted with 20%
benzene/petroleum ether 60/80)to give 2,2,21 t41 ,61 -pentachloro acetophenone
(3.9 g, 24%) as a colourless liquid b.p. 100-102°/0.1 mmHg.
27E nmr 6 6.63 (1H, s), 7.48 (2H, s) pm. 221eZLlaee21a41t61etrifluoro acetophenone
Dichloro acetyl chloride (8.12 g, 0.055 mol.) was added dropwise
to a stirred suspension of powdered anhydrous aluminium chloride (7.35 g, 0.055 mol.) in anhydrous carbon disulphide (35.0 ml) at 0° over thirty
minutes. 1,3,5-Trifluoro benzene (6.6 g, 0.05 mol.) in carbon disulphide
(10.0 ml) was added dropwise at 0° over a period of one hour. No reaction
was observed. The solution was refluxed for fifteen hours, cooled to room
temperature, and poured into a mixture of crushed ice (100 g) and 12 N 1101
(15.0 ml). Extraction into chloroform (3 x 25.0 ml) followed by washing
with saturated sodium bicarbonate (50 ml), water (2 x 50 ml), drying over
anhydrous sodium sulphate and removal of the solvent in vacuo gave a red
- 184 -
liquid. Distillation at reduced Pressure gave 2,2-dichloro 21 ,41,61-trifluoro acetophenone (6.3 g, 520) as a colourless liquid b.p. 70-710/1.0 mmHg. 1H nmr 6.56 (1H, s), 6.85 (2H, m) ppm.
Ilmatmentof22-c 1 1 hyl
dimethyl phosphonate and triethylamine Dimethyl phosphonate (1.10 g, 0.01 mol.) and 2,2-dichloro
21,41,61-trimethyl acetophenone (2.31 g, 0.01 mol.) were stirred together in acetonitrile (4.0 ml) at 5-10°. Triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml) was added dropwise to the stirred solution at 100 over a period of thirty minutes. After stirring at room temperature for seven days the solution was worked up in the usual way. No vinyl phosphate formation could be detected by either tic or 1H nmr. Column chromatography (silica eluted with benzene) of the product gave starting material
1 212:dichloro 21 5,61-trimethyl acetophenone (0.90 g, 39%) and a new compound 1 1 1 which was identified as 2L) L211,6-.x:methlaceto-chenone-chlor (0.63 g,
32%) - coloueless needles from petroleum ether (40/60) m.p. 67-68° (Lit.174 m.p. 69-70°) 1H nmr 5 2.23 (6H, s), 2.32 (3H, s), 4.40 (2H, s), 6.90 (2H, broad s) ppm.
Treatment of 2,2,21 ,41 ,61 -Pentachloro acetophenone with dimethyl
Dimethyl phosphonate (0.55 g, 5 mmol.) and 2,2,21,41,61-pentachloro acetophenone (1.47 g, 5 mmol.) were stirred in acetonitrile (2.0 ml) at 0°. Triethylamine (0.51 g, 5 mmol.) in acetonitrile (3.0 ml) was added dropwise over a period of thirty minutes so that the temperature did not rise above 100 After stirring at room temperature for fifteen hours the reaction was worked up in the usual way. Tic and IH nmr indicated almost complete
1 disappearance of starting material and the formation of 221 21:i61 ftetrachlo:Ea 1 acetophenone (90%) as the major product. 23.2_,JjItL1-l acetccale_.
(o,83 g) was isolated by column chromatography (silica eluted with 30% ethyl acetate/benzene) as colourless needles (from 40/60 petrolenm ether) m.p. 83-84° (Found: C. 57*13; H, 1.77; Cl, 54.69 10:
C H Cl 0 requires : 0, 37.25; 1.56; 54.99c/)._ 18 4 H nmr o 4.53 (2H, s), 7,42 (211, s) ppm.
It was possible to isolate smaller amounts (100) of a product containing phosphorus. 31P nmr 6 +6.15, +6.24 (up field shifts from H
3PO4) and IH nmr 6 3.67 (6H, d;
H-P 11.5 Hz), 3.69 (6H, d; JH..p 11.4 Hz), 5.73 (111, s), 7.31 (broad s), 7.33 (broad s) ppm, indicated this was a mixture of dimethiq 1-21,41,61- trichloro phenyl 2-chloro vinyl phosphate (2 parts - all Z isomer) and
- 185 -
dimethyl 1-211-trichloro phenyl 2 2-dichloro vinyl phosphate (1 part).
max 5020 wt 2950 m, 2850 wt 1640 w, 1580 s, 1550s, 1450 111, 1375 ra,
1300 vs,.1195 m, 1160 m, 1130 m, 1110 m, 1055 vs, 1000 s, 940 wt 885 st
870 s, 830 m, 615 m, cm 1.
Treatment of 2 2-dichloro 21 ̂ 1 61-trifluoro acetophenone with
dimethyl phosphonate and triethylmine
Dimethyl phosphonate (0.55 g, 5 mmol.) and 2,2-dichloro 21,41,61-
trifluoro acetophenone (1.2 g, 5 mmol.) were stirred together in aceto-
nitrile (2.0 ml) at 0°0 Triethylamine (0051 g, 5 mmol.) in acetonitrile
(3.0 ml) was added dropwise to the stirred solution over a period of
thirty minutes so that the temperature did not rise above10° - some cooling was required. After stirring at room temperature for fifteen hours
the reaction was worked up in the normal. way to give dimethyl 1 1 1
trifluoro 'henyl 2-chioro vinyl phosphate (1.35 g, 85%; E/Z = 83/17)
m4le = 316 C1oH9P0401F4 EW = 316 as the only product - this was purified
by column chromatography (silica eluted with 40% ethyl acetate/benzene)
to give a colourless liquid.
Dimethyl 1-21,41,61-trifluoro phenyl 2-chloro vinyl phos-t:thate
.(Z-isomer, IH nmr o 3.75 (6H, d; JH.4, 11.3 Hz), 6.64 (1H, d; 2.4 Hz), 6.72
(2H, M) ppm. , Dirnethi 1 1-21 11_,1 1 s22:triEluQr9 -Ltiely1 2-chlofo vinyl_ -phosphate
(,]-isomer) 1H nmr o 3.76 (6H, d; JH_I, 11.3 Hz), 5.89 (1H, q; J114 0.7 Hz),
6.72 (2H, m) ppm.
`1)max 3020 m, 3000 m, 2900 w, 1640 m, 1600 s, 1595 m, 1500 mt 1450 s,
1360 w, 1300 vs, 1195 s, 1340 c, 1300m, 1050 vs, 1010 m, 930 s, 870s,. -1 780 w, cm .
- 186 -
- 187 -
CHAPTER 5
The Effect of Varying the Nature of the Phosphorus Reagent on the Course
of the 'Abnormal' lachaelis-Becker Reaction
1. Results and Discussion
Thiono analogues of the dimethyl 1-substituted 2-chloro vinyl
phosphates already discussed are difficult to make by Perkow or
Michaelis-Becker type reactions, and reaction of simple chlorinated
aldehydes tends to lead to formation of thiolo rather than thiono derivatives31 '61. These thiono analogues may posses novel insecticidal
activity.
PelchowiCz61 has shown that dialkyl thiophosphonates react with chloral to give good yields of dialkyl S-2,2-dichloro vinyl phosphoro-
thiolates and none of the expected dialkyl 2,2-dichloro vinyl phosphoro-
thionates.
H
(R0)2LO-C1C12
It is possible that the phosphorothionate is formed initially
and this thermally rearranges to the phosphorothiolate at the high
temperatures employed in the reaction96. Some recent work in our laboratories175 has suggested that the initial attack of the phosphorus
on the carbonyl carbon of the aldehyde is of only minor importance, 0 -R /
(RO)2P: C-C-C1 (RO) -C-(141
Cl H N Cl
(R1 H, C1)
and that the major reaction pathway involves attack by sulphur to give
a thiohemiacetal in a reversible reaction:
(RO)2 80o
CC13CHO (RO)2P-S-7.0012
(R0)2P-S:
H
ORO) P-$ R . 2_ / 1 0- -csi
ci The thiohemiacetal undergoes two competing reactions to give dialkyl
phosphonate and thioaidehyde by one .rocess, and dialkyl chloro vinyl phosphorothiolate by the other:
(R0)2P--6
HO- H Cl
2 (10)2 P-S-C=CR101
-HC1 -C1
- 188 -
(R0)2 V AZILI- -C1
Cl
1 R1 > (RO)2 H-C- -C1
Cl
It has also been suggested that dialkyl thio phosphonate can
react with the thioaldehyde,produced in the reaction by way of attack
by sulphur on thiocarbonyl carbon in a similar fashion175. A
Benglesdorf type mechanism71 involving attack by phosphorus at thiocarbonyl
carbon is expecte 1
(RO)2P-S:'kLC‹1 (R0)2P-y R1
H CI s-o
•
(R0)2P-
HS-C- -Cl
HC1 (110)2P-S-CH.CR1C1
The simplest dialkyl thiophosphonate, dimethyl thiophosphonate,
was taken and reacted with 2,2-dichloro acetophenone using a variety of
inorganic and organic bases..
1. sodium methoxide/methanol
2. sodium hydride/T.H.F.
3. ammonia/methanol
4. triethylamine/acetonitrile.
For all these reactions the only product isolated in good yield
was dimethyl 1-phenyl 2-chloro vinyl thiophosphate, (LXXX).
189 -
(CH3 0)2 P-H
(CH30)2
Dimethyl 1-phenyl 2-chloro vinyl thiophosphate was identified
by I.R. (showed no very strong absorption at 'Lax 1250 cm 1 corresponding
to the P.0 compound) and by its reaction with palladium dichloride spray
reagent on tic to give a strong dark-brown coloration which indicated
the presence of a P=S type compound. -H nmr of the purified compound
showed only one resonance in the vinylic region of the spectrum (6 6.31 (1H, d.' JH-P = 3.7 Hz) ppm) and suggested that only one geometric isomer was being formed preferentially in the reaction. This was assigned as being
the E-isomer by a consideration of the chemical shift and coupling constant
- see Chapter 2. Theg®1 coupling
magnitude than the J coupling in H-P about 3.5 - 0.2 Hz. In the case of
for the E-isomer is greater in
the Z-isomer and of the order of
dimethyl 1-21-fluorophenyl 2-chloro
vinyl thiophosphate (see later) a mixture of E/Z isomers was produced. 1H nmr of the mixture showed two resonances in the vinylic region of the
spectrum LT& 6.28 (1H, d: JH-P 2.7 Hz) - Hz, S 6.39 (1H, d; JH-P 3.5 Hz) The assignment of the resonances to E- and Z-isomers was made by assuming
'that the proton cis to phosphorus resonates to low field of the proton
trans to phosphorus. This has been well established for the simple
dialkyl 1,2-disubstituted vinyl phosphates (see Chapter 2). There is
no reason to suggest that changing the nature of the phosphorus from
P=0 to P=S should in any way invalidate this general rule since
the vinylic proton is still being affected by a C-0-P type system on the
adjacent carbon atom.
When 212-diohloro 21 -fluoro acetophenone was treated with
dimethyl thiophosphonate in the presence of triethylamine it was possible
to isolate in good yield dimethyl 1-21-fluorophenyl vinyl thiophosphate
(LXXXI). This compound was again identified by I.R. (showed no P=0
absorption at max 1250 cm-1) and IH nmr (two resonances at o 6.39 and
& 6.28 ppm indicated the presence of two vinylic protons). Integration
of the vinylic signals in the 1H nmr showed that an isomeric mixture of
= 90/10 of dimethyl 1-21-fluorophenyl 2-chlore vinyl thiophosphate
had been formed.
(CH30)2 -H
CHC12 Et N/CH CN (CH30)2 =CHOI
10°
- 190 -
LXXXI
E/Z = 90/10
Under similar conditions 2,2,21-trichloro acetophenone reacted
with dimethyl thiophosphonate in the presence of sodium methoxide as
base to give a good yield of dimethyl 1-21-chloro phenyl 2-chloro vinyl
thiophosphate (LXXXII, 80%). In this case the E/Z isomer ratio
determined by integration of the vinylic signals in the 1H nmr
was E/Z = 40/60. When this reaction was repeated using triethylamine
as base, dimethyl 1-21-chloro phenyl 2-chloro vinyl thiophosphate
(LXXXII, 83%) was again produced in good yield. 1H nmr showed two
vinylic resonances o 6.30 and o 5.92 ppm and suggested that an isomeric
mixture of vinyl thiophosphates had been produced. The 0 isomer '
ratio 28/72 determined by IH nmr integration of the vinylic resonances
differs slightly from the one obtained using methoxide as base and is
probably the result of a slight solvent effect.
(CH 0) P-H 3 (CH30)2 .CHC1 § „CHO'2 Et NCH CN
3 2 Cl • 10° Cl
LXXXII
VLT2131.12.
These results indicate that the reaction of dialkyl thiophosphonate
with 2,2-dichloro 21-substituted acetophenones in the presence of base is
versatile and gives products which are somewhat expected by analogy with
the reactions of di:methyl phosehonate. The most likely reaction pathway
involves initial attack by the phosphorus on carbonyl carbon followed by
a rearrangement, which is in contrast to the reactions of dialkyl thio-
phosphonates with halogenated. aldehydes175. This mode of attack is well
established for aldehyde and ketones bearing substituents other than
halogens176-8. However, the only example in the literature of addition
of dialkyl thiophosphonate to carbonyl carbon involving attack by
sulphur is the reaction of diethyl thiophosphonate with benzophenone83.
- 191 -
(Eto)2P-H -H + Ph2C0 Na
C 6"F 6
(Et0)2P9 -S-CHPh2
In this particular example initial attack by phosphorus on
carbonyl oxygen followed by a 4- centre type eleetrocyclic rearrangement
cannot be ruled out.
(Et0)2T=S Ph
(Et0)2?...S.41iPh2
Ph
Diethyl thiophosphonate was also reacted with 2,2,21-trichloro
acetophenone in a variety of bases to give good yields of diethyl 1-21-chloro
phenyl 2-chloro vinyl thiophosphate' (=XIII). The isomer ratios were determined by 1H mar and glc. They were found to be similar, (E/Z = 50/50 - •
using ammonia/ethanol as the base) and (E/Z = 40/60 - using sodium hydride/
T.E.F. as the base), and in very good agreement with the isomer distribution
obtained with dimethyl thiophosphonate. Clearly the nature of the alkoxy substituents attached to the phosphorus is having very little effect on the course of the reaction.
(EtC)2P-0.\\ C=CH.C1
1 E/Z = 40/60
EtON § +
Et0//
O
LXXXIII
As already illustrated in Chapter 4, the nature of the ortho-substituent influences the course of the reaction between dimethyl
phosphonate and 2,2-dichloro 21-substituted acetophenone and affects
the ratio of E/Z isomers produced. Dimethyl thiophosphonate shows a
E/Z . 50/50 -
CH30) -H + Base
CH3
- 192 -
similar trend in its reactions with 2,2-dichloro 21-substituted acetophenones.
The fluorine substituent appears to behave like hydrogen in giving mostly
E-isomer but chlorine, as before, is giving rise to preferential formation
of the Z-isomer. These dialkyl 1-phenyl 2-chloro vinyl thiophosphates
cannot be made by a Perkow type reaction.
Dimethyl thiophosphinate reacti-HA2,241ddaropacetophenone in the
presence of various bases to give an isomeric mixture of dimethyl 1-phenyl
2-chloro vinyl thiophosphonate (LXXXIX) in almost quantitative yield. The
dimethyl 1-phenyl 2-chloro vinyl thiophosphonate was identified by I.H.
(showed no absorption atqmax 1250 cm-1 corresponding to the P=0 compound
but strong absorption a6?max 1195 and 1050 cm 1 corresponding to P-0-CH3
and
P.-0-a31 stretchingrespectively) and by its reaction with palladium
dichloride to give a dark-brown coloration which is indicative of P=S
type compounds. 1H nmr showed two resonances in the vinylic region
indicating the presence of an isomeric mixture of vinyl thiophosphonates
L76 6.24 (1H, d; J11-1, 4.0 Hz) - E-isomer and 6 6.12 (1H, d; 1111.4) 3.3 Hz) z-isomel7. The assignment of the geometry of the vinyl thiophosphonates
was again made by assuming that the proton cis to phosphorus in the
E-isomer will resonate to low field of the proton which is trans to
phosphorus in the-Z-isomer. This supported by the observation that the
for the E-isomer is once again greater in magnitude than the J H-P H-P for the Z-isomer.. Similarly the 1H nmr for the methyl and methoxy
groups directly bonded to phosphorus also show quite distinct chemical
shift.differences 3.44 (3H (CH30), d;jH-P 14.2 Hz), 1.77 (3H (CH3 ), d;
..TH-F 15.5 Hz) ppm - E-isomer and & 3.50 (3H (CH 0), d; Jil.dp 14.4 Hz), 1.91 (5H (CH3), d; Jil-p 15.6 Hz) ppm - Z-isomerj.
LXXXIX
E/Z = 95/5
The isomer ratio was determined both by glc and 1H nmr
(integration of the vinylic resonances) and was found to be independent
of the base or solvent used. Using ammonia in methanol or triethylamine
- 193 -
in acetonitrile as the base gave the same isomeric mixture of vinyl
thiophosphonates.
When dimethyl thiophosphinate was treated with 2,2-diehloro
21-fluoro acetophenone with either ammonia in methanol solution or
triethylamine in acetonitrile it was possible to ieolate dimethyl 1-21-
fluor° phenyl 2-chloro vinyl thiophosphonate (XC) in good yield as the
only observable product. I.R. analysis showed the absence of any
strong absorption in the 1250 cm-1 region and indicated that the
compound did not contain a P=0 function, 1H nmr of the vinylic region
showed two resonances & 6,28 (1H, d; J114,-3.7 Hz) - E-isomer and 6 6.24 (1H, d; J7.4, 3.2 Hz) - Z-isomer suggesting that the product was an isomeric
mixture of vinyl thiophosphonates0 The geometry was assigned as before,
assuming that the proton in the E-isomer resonates to low field of the
vinylic proton in the Z-isomer. These chemical shifts for the two
isomers 6 6.28 and 6 6.24 are very similar but the corresponding coupling. constants 3.7 Hz and 3.2 Hz are sufficiently different to support the assignment. For all dialkyl 1-phenyl 2-chloro vinyl (thio) phosphates
and (thio) phosphonates studied the proton cis to phosphorus is always
more strongly coupled to the phosphorus than the proton which is trans
to phosphorus. This is in complete contrast to the observations made
for the simpler dialkyl 2-substituted vinyl phosphates where the .°
magnitude of the /J greater than J H-P trans/ is /- H-F cis/. The ratio of isomers obtained in the reactions were determined.
by both glc analysis and IH nmr study (integration of the vinylic
resonances) of the crude reaction mixtures, since the isomer ratios became
modified on purification. By glo analysis the 2-isomer has the sziorter
retention time on the column and can be well separated from the Z-isomer.
It was found that the E/Z isomer ratios obtained by using ammonia/methanol
(45% E, 55% Z) and triethylamine/acetonitrile (44% E, 56% Z) were the same within experimental error. The 2- and Z-isomers are being formed
by an elimination reaction from different conformations of the same
transition state - see Chapter 6,; These conformations do not seem to depend on the nature of the solvent.
NH3 /CH3 OF "
,,aaa2
0
cH30.4
CH3
.CHCI F
XC
CHG,, 2 § ' -O-C=CHC1
P-H CH 3
CH 7 Et N/CH
3 1003
ILL:- 45/55
CH, =CHC1
CH"' Cl NH
:3/CH
3OH
3 0
XCI E/Z
1
XCI
E/z = 5/95
- 194 -
XC E/Z = 44/56
In a similar reaction, 2,2,21-trichloro acetophenone when treated
with dimethyl thiophosphinate in the presence of ammonia/methanol or
triethylamine/acetonitrile gave dimethyl 1-21-chloro phenyl 2-chloro
vinyl thiophosphonate (XCI) as the only product. The isomer ratio in
the crude reaction mixture was determined by both. 1H, nmr Lintegration
of the vinylic resonances 6 5.98 (1H, d; 3.0 Hz) - Z-isomer and
6 6.26 (1H, d; Jil_p 4.0 Hz) - E-isome2 and gic analysis. The ratio was found to be 5% E r 95% Z in both cases. Recrystallisation of the crude oil from methanol gave dimethyl 1-21-chloro phenyl 2-chloro vinyl thio-
phosphonate (XCI) - pure Z-isomer.
C H3 -H +
c 3
,,CHC12 su3Iv/CH
3 CN CH30
' 100 CH
3 =CHC1
- 195 -
These observations can be explained by a mechanism involving
attack by phosphorus at the carbonyl carbon atom, followed by a
rearrangement to give the required vinyl thiophosphonate. The ortho
substituent has a considerable effect on controlling the E/Z isomer
ratios obtained.aotho substituents hycrogen and chlorine give mainly E- and Z-isomers respectively, whereas fluorine gives an almost
equivalent amount of each.
Dimethyl phosphinate, the corresponding oxygen analogue of
dimethyl thiophosphinate has been reacted with some selected 2,2-dichloro
21-substituted acetophenones under controlled conditions. When dimethyl
phosphinate was treated with 2,2-dichloro acetophenone in the presence of
triethylamine and acetonitrile a good yield of dimethyl 1-phenyl 2-chloro
vinyl phosphonate (XCII) was produced. Triethylamine hydrochloride which
forms as a precipitate in all these reactions was removed by filtration.
The dimethyl 1-phenyl 2-chloro vinyl phosphonate was identified by I.R.
(+max 1270 vs; free P=0 stretching, 1195 s; P-0-methyl 1050 vs;
)=( P-0-slkyl, and 1630 w cm-1 );=( stretching vibration) and IH nmr
rvinylic region shows two resonances 6 6.48 (1H, d; Jii_p 2.9 Hz) E-isomer and 6 6.16 (1H, d; JH-P 2.5 Hz) - Z-isome7
XCII
E/Z = 77/23
Assignment of geometry of the vinyl phosphonates was made using
the rule that the proton cis to phosphorus is to low field of the proton
trans to phosphorus. The magnitude of /Jp_a cis/ was once again greater
than /JP-H trans/ which is in agreement with earlier observations and
reinforces Gaydou's agruments that when large substituents are placed
on carbon-1 the gauche-type conformation might be more favoured102
thus changing the magnitude of the coupling constants. 1H nnr integration
of the vinylio resonances enabled the isomer ratio (E/Z 77/23) to be
determined satisfactorily0
A 2,2-dichloro acetophenone containing an ortho-substituent
was taken, 2,2-dichloro 21-fluoro acetophenone, and reacted_ with dimethyl
CH Et3IT/CHCN 3 0-9=CHC1
C, o
C1„11 CH3 +
3
- 196 -
phosphinate using triethylamine as the base. Dimethyl 1-2'-fluoro phenyl
2-chloro vinyl phosphonate (XCIII) was formed in good yield as the only
observable product. It was identified by I.R. ( max 1255 vs, free P=0
stretching, 1185s; P-0-methyl, 1040 vs, P-0-vinyl, and 1640 m, cm-1
.;b4C stretching vibration) and 1H nmr [inylic region shows two resonances
& 6.52 (1H, d; 3114, 2.6 Hz) - E-isomer and p 6.20 (1H, d; 2.3 Hz)
Z-isomer7. These two resonances in the vinylic region were again assigned
to the H- and Z-isomers of the vinyl phosphonates by the usual method.
It was possible to observe differences in the "H nmr for the methyl
groups and methoxy groups directly bonded to the phosphorus.
[6 1.40 (3H (CH3), d; J11.4, 17.6 Hz), 3.59 (3H (030), d; J11.4, 11.2 Hz) ppm for the E-isomer and 6 1.49 (3H (0113), d; JH_p 17.8 Hz), 3.55 (3H (CH30), d; JH-P (11.3 Hz) ppm for the Z-isomer7. Also the 40-pH couplings showed
a significant difference (/44,14E/ = 2.6 Hz and /44Hz/_= 2.3 Hz).
XCIII =L55.L61
The isomer ratio (E/Z = 35/65) was again determined by integration
of the vinylic resonances in the 1H nmr spectrum.
In a similar reaction 212,21-triehlore acetephenone was reacted
with dimethyl phosphinate in the presence of triethylamine/acetonitrile _
to give a good yield of dimethyl 1-2 -chioro phenyl 2-chloro vinyl
phosphonate (XCIV) as the only product. This was identified by I.R.
(+max 1260 vs; free P=0 stretching, 1085 s; P-0-methyl, 1050 s, P-0- vinyl, and 1630 m, cm-1, )=C( stretching vibration) and 1H nmr
region shows two resonances at 6 6.60 (1H, d; JH..p 2.5 Hz) - E-isomer and
6.05 (1H, d; JH-P 2.3 Hz) Z-isomer7. The vinylic resonances being
assigned to the E- and Z-isomers in the usual way and the E/Z isomer
ratio determined by 1H nmr integration.
=CHOI Et_N/CH CH ,CN Cl
3 10°
CH 0- 3 CH3
- 197 -
XCIV
E/Z = 5/95
2,2-Dich1oro acetophenone was treated with methyl ethyl
phosphinate in the presence of ammonia/methanol and the reaction followed
by gic. It was possible to detect increasing amounts of methyl ethyl
1-phenyl 2-chloro vinyl phosphonate (XCV) and the isomer ratio remained
constant (E/Z = 85/15) throughout the course of the reaction. This
isomer ratio was very similar to the one obtained for dimethyl 1-phenyl
2-chlero vinyl phosphonate (XCII) E/Z = 77/23 using dimethyl
phoshinate as the phosphorylating agent.
0,„\.,,,CHC12 CH A 0 - 3N
-H NH,/CH OH C2115
XQV
E/Z = 85/15
In a similar procedure 2,2,21 -trichloro acetophenone and
diethyl ethyl phosphinate in the presence of ammoni methanol gave only
the Z--isomer of methyl ethyl 1-21-chloro phenyl 2-chloro vinyl phosphonate
(XCVI). This isomer was detected byboth glc and IH nmr 5inylic resonance at 6 5.89 (1H, d; 2.0 Hz) - consistent with the vinylic proton
being trans to phosphorus i.e. Z-isomerj•
2 _,C1 NH /CH OH
200
XCVI
All Z-isomer
This result is similar to the one obtained for dimethyl 1-21-
chloro phenyl 2-chloro vinyl phosphate (XCIV) using dimethyl phosphinate
as the phosphorylating agent, where the isomer ratio (E/Z) was 5/95.
1130N'. C2H50
C 2-5
3hj- CH
C 2 5
=CHC1
CH3ON
20° (CH
30)3P +
- 198
These results would serve to indicate that varying the nature of the
alkyl substituent attached to phosphorus is not having a great effect
cn the course of the reaction. However, a greater variation in the
nature of the alkyl substituents would have to be investigated before
this can be certain.
The Perkow reaction
in an earlier observation (see Chapter 3) the Perkow reaction
of trimethyl phosphite with 2,2-dichloro acetonhenone in acetonitrile
as solvent gave an isomeric mixture of dimethyl 1-phenyl 2-chloro vinyl
phosphate (E/Z = 40/60) (XVII) as the only product.
XVII
E/Z 40/60
The dimethyl 1-phenyl 2-chloro vinyl phosphate was identified
by I.R. ("'' max 1295 vs; free P=0 stretching, 1190 s; P-0-methyl, 1060 vs;
P-0-alkyl, and 1630 w cm-1 )0.1 ) and 1H nmr 5inylic region shows two
distinct resonances & 6.45 (1H, d;JH-p 2.8 Hz) ppm - E-isomer and 8 6.15 (1E, d; ,TH-", 2.1 Hz) ppm - Z-isomer. It was possible to determine the -isomer ratio by integration of the vinylic resonances in the 1H nmr as
usual. For this particular reaction with 2,2-dichloro acetophenone more
of the Z-isomer (605) was observed than with any of the other phosphorus reagents already described. 'Of the phosphorus acids studied with
dichloro acetophenone in the presence of base, dimethyl phosphinate
was found to give the greatest proportion of the Z-isomer (237:)). By analogy it might be expected that a Perkow type reaction of trimethyl
phosphite 1-ith 2,2-dichloro 21-substituted acetophenone should lead to
the corresponding vinyl phosphate mixture containing mostly the Z-isomer. When trimethyl phosphite was treated with 2,2-dichloro 21-fluoro
acetophenone in acetonitrile as solvent at room temperature it was possible
to isolate a quantitative yield of dimothyl 1-21fluoro phenyl 2-chloro
vinyl phosphate (LXIX, X . F) as the only product. The reaction was
CH3CN
20°
(CH30)3P , •
(CH50)2QP- .CHC1
- 199 -
carried out in acetcnitrile in order to control the reaction and so that
the conditions were standardised against the ones where the phosphorus acids
were treated with base in acetonitrile. Any variation in the E/Z ratio of
isomers observed cannot be explained by a simple solvent type interaction 1
on the transition state. Dimethyl 1-2--fluoro phenyl 2-chloro vinylohosphate
was identified by I.E. (qmax 1290 vs; free P.0 stretching, 1215 s; C-F
stretching, 1170 s; P-0-methyl, 1110 s; C-F stretching, 1040 vs; P-0-alkyl,
1630 m cm-1; k";-=6c ) and IH MIT 5inylic region shows two distinct
resonances at 8 6.53 (1H, d; J-11_,, 2.6 Hz) ppm - N-isomer and S 6.26 (iN,
d;H-P 2.0 Hz) ppm - Z-isome7g.
LXIX - X = F
E/Z, = 12/88
The isomer ratio (E/Z - 12/78) determined by 1H nmr (integration
of the vinylic resonances) was in good agreement with the one that might
be expected. Since the corresponding reaction with dimethyl phosphinate
in base gave 655 of Z-isomer and the Perkow reaction has already been
shown to give a greater perCentage of the Z.-isomer for 2,2-dichloro
acetophenone.
Similarly a Perkow type reaction of trimethyl phosphite with
2,2,21-trichloro acetophenone under controlled conditions in acetonitrile
at room temlerature gave dimethyl 1-21-chloro phenyl 2-chloro vinyl
phosphate (LXIX, X = C1) as the only observable product. This produot
was identified by I.R. (-R max 1640 m; )7;4 1290s; free P=0 stretching,
1185s; P-0-methyl, 1045scm-1; P-0-alkyl) and 1H nmr which showed two
distinct vinylic resonances ft) 6.50 (1H, d; J H-P and 6 5.93 (IH, d;JH-P 1.5 Hz) ppm - Z-isomeIg. almost exclusive formation of the Z-isomer (E/Z =
2.6 Hz) ppm - E-iscmer
The reaction showed
3/97 by 111 nmr integration
of the vinylic resonances), which is in complete contrast to the isomer
distribution (E/Z = 40/60) obtained for the 2,2-dichloro unsubstituted
acetophenone. It is in good agreement with the observations made for
the reaction of 2,2,21 -trichloro acetophenone with the various phosphorus
acids in the presence of base, where formation of the Z-isomer is preferred.
H Br-ROCH 3'3 Br
CH3Br
:p(ocH3,3
- 200
(CH30)3P CH,CN
200 1
LXIX
The isomer ratio (E/Z = 3/97) is almost identical with that
observed for the reaction of trimethyl phosphite with 2,2-dibromo 77
acetophenone (E/Z = 1/99) - see Chapter 3. Borowitz' has suggested
that the exclusive formation of Z-products can be accounted for by mechanism
invdtring an initial attack by P(III) on positive bromine followed by 0-
phosphorylation of the resultant enolate halo-phosphonium ion pair-e- - ee.e .
- Scheme 24 rather than by attack of P(III) at carbonyl carbon as
generally accepted for the mechanism of the Perkow reaction
Scheme 24
The effect of ortho-substituent upon tit's geometry of dimethyl
1-21-substituted phenyl vinyl phosphates can be explained by involving
a rearrangement/elimination type mechanism from different transition
states (see Chapter 6). The fact that the reacetionoftdmethyl phosphite
with ether 2,2-dibromo acetophenone or 2,2,21 -tricnloro acetophenone
gives almost exclusively the Z-isomer suggests that one is getting
elimination from similar transition states. There is no need to explain
the variation of isomer ratio on going from 2,2-dichloro acetophenone to
2,2-dibromo acetophenone by introducing a different mode of attack for
the P(III) species37. Indeed when attack at positive bromine was
- 201 -
favoured, as in the case of treating 2,2-dibromo acetophenone with
dimethyl phosrhonate/triethylamine/acetonitrile, see Chapter 3, no vinyl phosphate was detected and only phenacyl bromide was formed.
The variation of E/Z isomer ratios obtained on changing the
nature of the phosphorus species with 2.2-dichloro acetophenone,
2,2-dichloro 2--fluoro acetophenone, and 2,2,21-tidchloro acetophenone
are shown in Tables 36, 37 and 38 respectively. For each substituted
2,2-dichloro acetophenone the phosphorus species are tabulated in an
order of priority with respect to formation of the Z-isomer. It is
interesting to note that this order is the same and is independent
of the nature of the 2,2-dichloro 21-substituted acetophenone. This
will be discussed in Chapter 6.
•
- 202 -
Table 36. Reaction of 212-dichloro aceto henone with various phosphorus reagents
CH30,Ai -H +
R
Et3N
CH 3 CN/10v
Su'ostituent Analysis: Requires % Found. %o
R X C H P Cl C H P Cl
(CH3 0 P
- 45.7 4.6 11.8 13.5 45.5 4.7 11.7 14.7
-0H3 C 48.7 4.9 12.6 14.4 49.0 4.9 12.7 14.5
-CH3 S 45.7 4.6 11.8 13.5 46.2 4.7 11.8 13.9
-0CH3 0 45.7 4.6 11.8 13.5 45.5 4.7 11.7 14.7
-00H3 S 43.1 4.3 11.1 12.7 43.8 4.4 11.4 12.4
R HE ppm HZ
ppm ,.; b
E-isomer 5 b
Z-isomer Infra-redc qmax cm-1
(C7 0' 13. 6.45 6.15 40 60 5070v,2950m,2850w11630w11490m11445s,
1330m, 1290vs,1185s,1095s1 1045vs,
62 s 10s,655s800w,770m.695s
-CH3
6.48 6.16 77 23
5
3070w,2950w,1630w,1495m,1450m,1320s,
1270vs,11955,1090s,1080s110508,1040s,
Ovs 8 Os 80:n070m
3070w1 2950w,1615w,1495m,1450p,1410m,
1310m,11953,1090s,1000s,1050s,1035s,
Q2Ovs 820a,780S1710s .1
-CH3
S 6.24 6.12 95
continued
- 203 -
Table 36 continued
R X HE ppm
i 8 liz ppm
%b E-isomer
Ob 2-isomer Infra-redo ' max cm-1
-00H3 0 6.45 6.15 95 5 3070w,2950m,2850w,1630w,1490m,1445s,
1330m,1290vs,1185s,1095s,1045vs,925s,
'10s 8 s 800w 770m m 6
-OCH3 S 6.31 - 100 0 307014,2950m,2850w,1615w,1500m,1450s,
1330m,1195s,1090s,1050vs,940s2930s1860v1
I 785m,7351/11710s
a (CH 0
-CHC1 -2 CH CN 3. ), Perkow reaction
R.T.
b Recorded on Varian, T-60 nmr spectrometer.
Perkin-Elmer 257 - liquids as films and solids as mulls.
HC12 CH7CN
R T . a (CH30)3P
- 204 -
•
Table 37. Reaction of 2,2-dichloro 21-fluor° acetouhenone with
various phosphorus reagents C.,...,CHC
12 !Y____>. CHx0,,ji CH3:0), -H + CH
3 CN/10o R
J „ry-0-q.CHC1 F
Substituent Analysis: Requires % Found (to
R X C H P 01 C H P Cl
(CH3qp 42.8 4.0 11.0 12.6 42.5 4.2 11.1 13.3
-0113
0 45.4 4.2 11.7 13.4 47.1 4.2 11.6 13.8
-CH3
S 42.7 3.9 11.1 12.8 42.9 3.8 11.0 13.0
-0CH3
0 42.8 4.o 11.o 12.6 42.5 4.2 11.1 13.3
_OCH S 40.5 3.7 10.4 12.0 40.9 3.8 10.4 11.8
R ppm 6 H ppm Z
d b p E isomer
d b /0
Z-isomer Infra-reds 3 \max cm-1 -I
g, (CHz0) 1-- 6.53 6.26 12 88 3070w,2950m,2850w91645w,1615s,1580w,
,, 3 1495s,1455s01290vs,1230s,1185s,1155w, 1110s,1030vs,920s,850s,825w,800w,
1 ri-- 21-16°32° -CH 0 6.52 6.20 35 65 3070m,2950m,2850w,1640w,1615s,1580w,
- 14906,1455s,1315s11260s11220311185s, 1110s,1050vs,940vs,04019,8151,795m • 60s
- H3 S 6.28 6.24 44 56 307cw,295om,284ow,164ow,16156,1490s, 1455s,13o5s,122om91185s,lilos,104ovs, 20v'ajq40m,800s,760s,715s
-OCH3 0 6.53 6.26 60 40 3070w,2950m,2850w11645w,1615s,1580w, 14953,14556.1290vs,1230s,1185s,1155w, 10s,1030vs,920s,850s,825w,800w,7605, 20w _____
-OC H3 6.39 6.28 90 10 3070w,2950m,2850w,1645w,1615m11495s, 1455s,1325m,1230s11185s11115s,1040vs 915s,840vs, 60s,74Cw,700w
L 0
Perkow reaction
b Recorded on Varian T-60 spectrometer.
Perkin-Elmer 257 liquids as films and solids as mulls.
- 205
Taneag. Reaction of 2 2 21-trichloro aceto henone with various
phosphorus reagents
CH A_ X 3 %•H
R
CH30,4
-0- .CH01
,A1 Et3N
CH3CN/577
,,CHC12
Substituents Analysis: Reviros /0 Found cio
R X n v H P Cl 0 H P Cl
(CH30)3 40.5 3.7 10.4 23.9 1 40.8 3.9 9.8 25.1
-CH3
0 42.7 3.9 11.0 25.2 42.8 3.9 11.4 25.7
-CH3
S 40.5 3.7 10.4 23.9 40.6 3.7 10.4 23.6
-CH30 0 40.5 3.7 10.4 23.9 40.8 3.9 9.8 25.1
-CH 0 S 38.4 3.5 9.9 22.6 38.5 3.5 9.7 23.0
R X
6
late
N, ,
p'
6 H L
ppm
r. /0
E-isomer
, b i m Z-isoer
c ,.) -1 Infra-red 1 max cm
(CH ̂ :)P 31/415
6.50 5.93 3 97 3070w,2950m,2850w,1640m,1595m,1490s,
1450s,1435s,1290vs,1230m,1185s,1090s, 1040vs99206,855s,855m,790s,760s,720w,
695w
-CH 0 6.60 6.05 5 95 3070w,2950w,2850w21630m,1460m,1430m,
1310s,1260vs,1190w,1085s,1050s,1030vs,
930s,84.0m,820w,760s
-CH S 6.26 5.98 5 95 3070w,2950w,1630w,1495m11450m,1310m,
1190s,1080s,1060s,1030s030vs,840s,
76021720w
-CH-0 0 6.50 5.93 17 83 5070w12950m12850w11640m,15951fl,14905, 9 1450s11435s,1290vs,1250m11185s,1090s,
1040vs,920s,85552835m2790s,760s,720w,
695w
-CH0 S 6.30 5.92 28 72 5070w,290Cw12850w,1650w,1460w$1430m, 3 1500m 1 1230w1 1180m,1050vs,920s,840s,
750s,700W
a (CH30)3P CH3CN>
R.T.
Perkow reaction
Recorded on Varian T-60 mix spectrometer.
Perkin-Elmer 257 liquids as films and solids as mulls.
- 206 -
Experimental
Dimethyl phosphenate and trimethyl phosphite were commercially
available.
Dimethyl phosnhinate179
A mixture of triethylamine (50.5 g, 0.5 mol.) and dry A.R. methanol
(35.0 1.15 mol.) in dry ether (100 ml) was added slowly (over a period of
one hour) to a stirred solution of methyl dichloro phosphine (58.5 g, 0.5 mol.)
in dry ether (300 ml) under nitrogen at 5°. The mixture was then refluxed
gently for half-an-hour, and after cooling the triethylamine hydrochloride
filtered off. Removal of he solvent from the filtrate gave a crude
croduct which was distilled under reduced pressure to give pure dimethyl
nhosphinate (27,1 g, 70) as a colourless liquid b.p. 60-620/1Q mmHg.
r: nmr 8 1.55 (3H, dd; Jp..H = 15 Hz, JE....H 2.0 Hz), 3.78 (3H, d; JE.4, 12.0 Hz), 6 7.18 (17, dq; J11-11 = 2.0 Hz, JH-1, = 54.2 Hz) ppm. 31P nmr 6 - 36.0 ppm (from 80% HzP0 solution).
I 19 Methyl ethyl phoschinate
Ethyl dichloro phosphine (66 g, 0.5 mol.) was treated with methanol
(35 g, 1.15 mol.) and triethylamine (50.5 g, 0.5 mol.) in a method similar
to that for dimethyl chosphinate to give methyl ethyl phosphinate (31.4 g,
5C) as a colourless liquid b.p. 67-68°/15 mmHg. IH nmr 6 1.17 (31Il dt; J11.;"/.7.0 Hz,JH-p 21.6 1/17,), 1083 (2H, m), 3.78 (3H,
d; ,TFdp 11.8 Hz), 7.02 (1H, dt; JH-H 1.8 Hz; sH-1, 5,36 Hz) ppm.
Dimethyl thionhosphinate
Methyl dichloro phosphine (58.5 g, 0.5 mol.)was added to sodium-
dried ether (700 ml) and the solution cooled to 10° under an atmosphere
of dry nitrogen. Methanol (16 g, 0.5 mol.) and pyridine (39.5 g, 0.5 mol,)
were mixed and added slowly over two hours to the cold solution with
stirring. Pyridine (39.5 g, 0.5 mcl.) was then added dropwise to the
continually stirred slurry, whilst H2S gas was bubbled in at an equivalent
rate. Some cooling was necessary to keep the temperature at 20° 2°.
The pyridine hydrochloride was filtered off, washed several
times with ether (3 x 200 ml) and the combined ether extracts stripped and
degassed at the pump to give a pale yellow residue (43.45 g, 79%), Distillation at reduced pressure gave a pale yellow liquid (20.7 g, 38%),
b.p. 22-24°/0.5 mmHg which was further rurified by column chromatography
(silica eluted with methylene chloride) to give dimethyl thiophosphinate
(154 g, 78%) as a colourless liquid.
- 207 -
1H nmr b 1.82 (3H, dd; JpH 3.2 Hz, Jri_p 14.1 Hz), 3.62 (3H, d;
14.0 Hz), 7.68 (1H, dq; J121-11 3.2 Hz, JH_p 504 Hz) ppm. 71 P nmr & - 71.4 ppm (from 80%H PO ).
414 Dimethvl thiophos honate
3 --
Phosphorus trichloride (69.0 g, 0.5 mol.) was slowly added
to trimethyl phosphite (124.0 g, 1.0 mol.) with stirring under a nitrogen
atmosphere at 20-400. After complete addition (forty-five minutes) the
reaction mixture was kept at 400 for a further fifteen hours. The reaction mixture contained mainly dimethyl phosphorochloridate. To the.
crude product pyridine (118.5 g, 1.5 mol.) in ether (400 ml) was added
dropwise and H28 gas bubbled into the solution until saturated. After
three hours the pyridine hydrochloride was removed by washing with water
(3 x 300 ml) and the ethereal solution dried over anhydrous sodium
sulphate. Removal of the ether gave a colourless liquid (106.5 g)
which distilled at reduced pressure to give di1)2. .thion .
(89.6 g, 47% - based on uptake of PC13) as a colourless liquid b.p. 48-49°/ 12 mmHg. 1H nmr S 3.72 (6H,d; Ju 1401 HZ), 7.58 (1H, d; 3n...1, 638 Hz), ppm. 31P nmr 6 - 74.0 ppm (from 80% H3PO4 solution).
Diethyl thiotLanats61'180
Triethyl phosphite (132.8 g, 0.8 mol.) and phosphorus trichloride
(54.8 g, 0.4 mol.) were heated under gentle reflux for one hour (125-13e).
The product was distilled at reduced pressure to give diethyl phosphoro chloridate (77 g, 37% on uptake of PC13) b.p. 62-63°/40 mmHg. Diethyl phosphoro chloridate was converted into diethyl thiophosphonate by a
method similar to the preparation of dimethyl thiophosphonate.
DiethyltiLapLosphonate (64.3 g, 315'; - based on uptake of PC13)
was obtained as a colourless liquid b.p. 73-74°/14mMHg. 1H nmr S 1.33 (6H, 0 Hz), 4.13 (4H, q; 7.0 Hz, Jii_p 11.1 Hz), t; jH-H 7° d -- jii-H 7° 7.62 (1H, d;JH-P 633
Dimeth 1 1-Dhenvl 2-chloro vinyl phosphonate Dimethyl phospbinate (0.94 g, 10 mmol.) and 2,2-dichloro
acetophenone (1.89 g, 10 hmol.) were stirred together at 5° in dry
acetonitrile (4.0 ml). Triethylamine (1.01 g, 10 mmol.) in acetonitrile
(6.0 ml) was added dropwise to the stirred solution over a period of thirty minutes at 100 - no reaction could be detected. The solution
Hz) ppm.
208 -
was stirred at 10° for two hours and then allowed to come up to room
temperature over a period of fifteen hours. The acetonitrile was'removed
at the pump and the residue taken up in ether (70 ml) washed with 10%
H2SO4 (50 ml), water (3 x 50 ml) and dried over anhydrous sodium
sulphate. After filtration the ether was removed at the pump to give
dimethyl 1-phenyl vinyl phosphonate (2.05 g, 8354 - 77/23) as a
dark red liqUid ::hick was further purified by column chromatography
(silica eluted with ethyl acetate) to give a pale yellow liquid.
Dimethyl 1-phenyl 2-chloro vinyl thiophosphonate
Dimethyl thiophosphinate (1.10 g, 0.01 mol.) and 2,2-dichloro
acetophenone (1.89 g, 0.01 mol.) in acetonitrile (4.0 ml) were stirred
together at 0°. A solution of triethylamine (1.01 g, 0.01 mol.) in
acetonitrile (6.0 ml) was added dropwise over thirty minutes so the
temperature did not rise above 10o - some cooling was required. After
addition the solution was allowed to come up to room temperature over
a period of fifteen hours. A white precipitate of triethylamine hydrochloride was produced and the solution became dark red. The
acetonitrile was removed at the pump and the residue worked up in the
usual way to give dimethyl 1-phenyl 2-chloro vinyl thiophosphonate
(2.35 g, 90% E/Z = 95/5) as a dark red liquid which was further
purified by column chromatography (silica eluted with toluene).
Dimethyl 2-chloro'vinyl thic2plIte
Dimethyl thiophosphonate (1.26 g, 0.01 mol.) and 2,2-dichloro acetophenone (1.89 g, 0.01 mol.) were stirred together at 0° in
acetonitrile (4.0 ml). A solution of triethylamine (1.01 g, 0.01 mol.)
in acetonitrile (6.0 ml) was added dropwise to the stirred solution over
half-an-hour so that the temperature' did not rise above 10° - some cooling was required. An innediate precipitate of triethylamine
hydrochloride was produced and the solution allowed to come up to room
temperature over fifteen hours. Work-up in the usual way gave dimethyl
1-Phen1-1 2-chloro vinyl thicychosphate (2.36 g, 85,4 - pure Z-isomer) as a colourless liquid which was purified for analysis by column
chromatography (silica eluted with toluene).
Dimethyl 1-21-fluoro phenyl 2-chloro vinyl phosphate (prepared
by Perkow reaction)
Trimethyl phosphite (1.24 g, 0.01 mol.) in acetonitrile (4.0 ml)
was added dropwise to a stirred solution of 2,2-dichloro 21-fluoro
- 209 -
acetophenone (2.07 g, 0.01 mol.) in acetonitrile (6.0 ml) at 20°. The
solution got quite warm and some cooling was required. After stirring
at room temperature for fifteen hours the acetonitrile was removed at
the pump to give pure dimethyl 1-21-fluoro Phenyl 2-chloro vinyl phosphate
(2.6 g, 93% - E/Z = 12/88) as a colourless liquid. Purified for analysis by column chromatography (silica eluted with ethyl acetate/benzene 1:1).
1 Dirneti2z11:-2-ropi_izler,12-chloro vinyl phosphonate
Dimethyl phosphinate (0.94 g, 0.01 mol.) and 2,2-dichloro 21- fluoro acetophenone(0.01 mol.,2.07 g) were stirred at 5° in dry acetonitrile (4.0 mi). Triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6'.0 ml) was added dropwise to the stirred solution over thirty minutes so that
the temperature did not rise above 10°. After complete addition the solution
was stirred at room temeerature for fifteen hours. A white precipitate
of triethylamine-hydrochloride was Produced and the solution was worked
up in the normal way to give dimeth 1 1-21-fluor° phenyl 2-chloro vinyl
phosphonate (2.3 g, 88% E/Z=35/65) as a dark red liquid which was purified by column chromatography (silica eluted with ethyl acetate/
benzene 1:1) to give a pale yellow liquid.
Limethil-21-fluoroheYY 2212 arL onata Dimethyl thiophosphinate (1.10 g, 0.01 mol.) and 2,2-dichloro
21-fluor° acetophenone (2.07 g, 0.01 mol.) in acetonitrile (4.0 ml)
were -stirred together at 5°. A solution of triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml) was added dropwise over half-an-hour
so that the temperature did not rise above 10° - some cooling was required.
After stirring at room temperature for fifteen hours the reaction was
worked up in the usual way to give dimethyl 1-21-fluor° phenyl 2-chloro
vinyl ILLELpilplIaalte (2.4 g, E/Z = 44/56) as a dark yellow liquid which was further purified for analysis by column chromatography (silica
eluted with toluene/ethyl acetate 9:1).
A mixture of dimethyl thiophosphinate (5.5 g, 0.05 mol.) and 2,2-dichloro 21-fluoro aeetophenone (10.3 g, 0.05 mol.) in methanol (60 ml)
when treated with ammonia gave dimethyl 1-2--flucro phenyl 2-chloro vinyl
thiophosphonate (12.7 g, - E/Z = 45/55). Dimethyl 1-21-fluor° phenyl 2-chlore vinyl thiophosphate
Dimethyl thiophosphonate (1.26 g, 0.01 mol.) and 2,2-dichloro
21-fluoro acetophenone (2.07 g, 0.01 mol.) in acetonitrile (4.0 ml) were stirred at 5°. Trietnylamine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml)
- 210 -
was added dropwise to the stirred solution over half-an-hour so that the temperature did not rise above 100 - some cooling was required. A white
precipitate of triethylamine-hydrochloride was produced almost immediately
and the solution was stirred for a further fifteen hours at room
temperature. The acetonitrile was removed at the pump and the product
worked up in the usual way to give dimethyl 1-21 -fluor() phenyl 2-chloro
yinzLalsLszlate (2.4 g, 805 - E/Z . 90/10) as a colourless liquid which was further purified by column chromatography (silica eluted with benzene).
Dimethyl 1-21-chloro phen,r1 2-chloro vinyl phosphate (prepared
by Perkow reaction)
Trimethyl phosphite (1.24 g, 0.01 mol.) in acetonitrile (4.0 ml)
was added dropwise to a stirred solution 2,2,21-trichloro acetophenone
(2.23 g, 0.01 mol.) in acetonitrile (6.0 ml) at room temperature. The
solution became quite warm and some cooling was required to control the
reaction. After stirring at room temperature for fifteen hours the
acetonitrile was removed to give pure dimethyl 1-21chloro phenyl 2-chloro -
vinyl phosphate (2.70 g, 91% - EjZ = 3/97) as a pale yellow liquid Which was purified for analysis by column chromatography (silica elated with
eithyl acetate/benzene 1:1).
Dimethyl 1-21-chloro phenyl 2-chloro vinylilasphonate
Dimethyl phosphinate (0.94 g, 0.01 mol.) and 2,2,21-trichloro acetophenone (2.23 g, 0.01 mol.) were stirred in acetonWile (4.0 ml)
at 50 Triethylamine (1.01 g, 0.01 mob.) in acetonitrile (6.0 ml)
was added dropwise to the stirred solution over half-an-hour so that the
temperature did not rise above 100 - some cooling was required. After.
stirring at room temperature for fifteen hours the reaction was worked
up in the usual way to give dimethyl 1-21-chloro phenyl 2-chloro vinyl
2hcapLnate (2.28 g, 810 - = 5/95) as a pale yellow liquid which was further purified by column chromatogTap4 (silica eluted with ethyl
Acetate/benzene 1:1). e Dimethyl 1-el -chloro phenyl vinyl thiothosUhonate
Dimethyl thioehosphinate (1.10 g, 0.01 mol.) and 2,2,21-trichloro
acetophenone (2.23 g, 0.01 mol.) were stirred together-in acetonitrile
(4.0 ml) at 3°. Triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6,0 ml)
was added dropwise to the stirred solution over a period of half-an-hour
so that the temperature did not rise above 1000 After stirring at room
temperature for fifteen hours the reaction was worked up in the usual way
- 211 -
to give dimethyl 1-21-chloro phenyl 2-chloro vinyl thiorhosphonate (2.47g190% - = 10/90) as a dark brown oil. Recrystallisation from
methanol gave pale yellow crystals of dimethyl 1-21-chloro phenyl 2-chloro
vinyl thiophosphonate (1.62 g, 55cM - all Z-isomer m.P. 57-58°. Dimethyl 1-21-chloro phenyl 2-chloro vinyl thiophosphate
Dimethyl tLiophosphonate (1.24 g, 0.01 mol.) and 2,2,21-trichloro
acetophenone (2.23 g, 0.01 mol.) were stirred together at 5° in acetonitrile (4.0 ml). Triethylamine (1.01 g, 0.01 mol.) in acetonitrile (6.0 ml) was added dropwise to the stirred solution over a period of
halfan-hour so that the temperature did not rise above 1000 An immediate
precipitation of triethylamine-hydrochloride was produced and the solution
stirred at room temperature for a further fifteen hours. The reaction
was worked up in the usual way to give dimethyl 1-21-chloro phenyl 2-chloro vinyl thiophosphate (2.60 g, . = 28/72) as a pale yellow liquid
which was purified by column chromatography (silica eluted with benzene)
for analysis.
Dimethyl 1-21-chloro phenyl 2-chloro vinyl thiophosphate •
Dimethyl thiophosphonate (3.15 g, 0.025 mol.) and 2,2,21-trichloro acetophenone (5.59 g, 0.025 mol.) were stirred together at -40°. A
solution of sodium methoxide in methanol (25.0 ml of 1.0 N solution) was
added dropwise so that the temperature did not rise above -30° and the solution stirred for one hour at room temperature. The methanol was
taken off at the pump and the residue taken up in ether (100 ml) washed
with.water (3 x 70 ml) and dried over anhydrous sodium sulphate. Removal
of the ether gave dimethyl 1-21-chloro phenyl 2-chloro vinyl thiophosphate
as a pale yellow oil (6.2 g, 80% - 40/60) which was purified for
analysis by column chromatography (silica eluted with benzene).
Diethyl 1-21 chloro phenyl 2-chloro vinyl thiophosphate
Diethyl thiophosohonate (2.32 g, 0.015 mol.) and 2,2,21 -trichloro
acetophenone (2.79 g, 0.015 mol.) in ethanol (12.5 ml) were treated with
ammonia until saturated at 5-10° - some cooling wes reouired. After
stirring at room temperature for fifteen hours the ethanol was removed at the pump and the residue taken up in ether (50 ml), washed with water (4 x 40 ml) and dried over sodium sulphate. The ether was removed at the
pump to give dieth,rl 1-21-chloro phenyl 2-chloro vinyl thiophosphate
(3.15 g, 72% - E/Z = 50/50) as a pale yellow oil.
212
Diethyl 1-21-chloro phenyl 2-chloro vinyl thiophosphate (6.82 g,
30% - E/Z = 40/60) was also prepared by treating sodium diethyl thio-
phosphonate (0.05 mol.) Drop diethyl thiophosphonate (4.62 g, 0.03 mol.)
and sodium hydride (1.44 g, 0.03 mol. - 100% excess since NaH is 50% suspension in oilf with 212,21-trichloro acetophenone (5.6 g, 0.025 nol.)
in dry T.E.F. (25 ml) at 5-10°.
Meth 1 et yl 1-phen,r1 2-chloro vin 1 thosphate
Methyl ethyl phosnhinate (0.54 g, 5 mmol.) and 2,2-dichloro
acetophenone (0.94 g, 5 mmol.) were stirred in A.R. methanol (25.0 ml)
at 20°. Ammonia was passed through the solution as a slow stream until
saturated and the solution left stirring at room temperature for
fifteen hours. The methanol was removed at the pump and the reaction
worked up in the usual way to give methyl ethyl 1-phenyl 2-chloro vinyl
phosphate (1.11 g, 85c/, E/Z = 85/15).
213 -
CHAPTER 6
- 214 -
CHAPTER 6
The Mechanism of the ,Abnormall Michaelis-Becker Reaction
1. Discussion and conclusions
Dialkyl (thio) phosphonates and dialkyl (thio) phosphinates
have been shown to react with a variety of m-halogenated carbonyl compounds
to give either dialkyl vinyl (thio) phosphates and (thio) phosphonates
(XCVII) or dialkyl epoxy ethyl (thio) phosphonates (XCVIII) depending
upon the nature of them-halogenated carbonyl compound. This method of
phosphoxylation has been shown to be successful for halogenated acetones
- it and halogenated phenones ii (i.e. acetophenones, propiophenones,
and butyrophenones) but other halogenated compounds such as halogenated
esters - iii and halogenated dimethyl amides - iv did not give any of
the expected phosphorylated materials. Such an observation is surprising
since -T-halogenated esters and amides have previously been shown to react
readily with trialkylphosPdAiestoevevinyl phosphates or keto phosphonates
depending upon the nature of the T-halogenated compound46'47
R base R1 111,4
113
H3
xcviii
ii
R base R Rr. 4 A
+ C,H 9=CRY 0 1- R2 R20r-
v6115 61-15
XCVII XCVIII
R1 • alkyl or alkoxy
R2 alkyl
H, CH3, CAI b 5
X = Cl or Br
Y = H, CH3, Cl or Dr
+ CH -C- ?=CRY +3R20'/ R2(7
XCVII
+ YXHC -g -0C2H5
iv YXHC-C-N(CH3)2
R1 • alkyl or alkoxy
R2 • alkyl
X = Cl or Br
Y H, Cl or Br
iii
For the reaction of halogenated ketones with various phosphorus
reagents there is a preference for epoxide formation (XCVIII) when the
215
halogen is bromine. The most probable explanation for epoxide formation involves an attack by phosphorus of the dialkyl (thio) phosphonatem
or dialkyl phosohinate at carbonyl carbon to give an intermediate hydroxy phosphonate which probably exists as its salt. This can then
undergo a ring-closure reaction to give an epoxide by means of oxygen
displacing a halogen from the carbon-2, R2 OTIR 12
(CH30)2WTht H it -Y (CH3 0)2 P-O—c-Y A
(cli3o)2 Ri = CH7, C6H5
R2 = H, CH3 Y = H, CH3, C.bH 5 . halogen
It is well known that for an SN2 type displacement reaction bromine is a much better leaving group than chlorine. This explains
very well why when dialkyl phosphonate reacts with mono bromo acetone,
2-bromo acetophenone and 2-bromo propiophenone the major products are
dialkyl 112-disubstituted ethyl epoxy phosphonate and not the dialkyl
1,2-disubstituted vinyl phosphates which are formed predominantly from
the analogous chlorine compounds.
Any 0e-halogenated ketones with substituents attached to carbon-2
which stabilise the carbonium ion character of this carbon (i.e. facilitate
the loss of halogen) such as -CH3 and -C6H5 lead to a large percentage of
epoxide formation. Conversely, 2,2-dichloro acetone, 2,2-dichloro
9 NH,/CHx0H § (CH30)2LH C6H5-c-cH(ci)cH3 '2 ), (km'30)2P-O-C=CH.CH
35% all Z/ isomer
(CH30)2P- JH.0H3 6H5
65r0 - see ref.181
H5 3
216 -
acetophenone and 2,2-dibromo acetophenone give rise to the corresponding
vinyl phosphate with no detectable amount of epoxides. Replacing a
hydrogen onscarbon-2 by a halogen apparently has the effect of disfavouring
the displacement of a halogen atom by oxygen in the hydroxy phosphonate and
increasing the proportion of vinyl phosphate formed by another mechanism.
Presumably the presence of two halogen atoms on carbon-2 does not tend
to facilitate the loss of halide ion from this carbon, whereas the
hyperconjugative-type interaction of the methyl substituent and the resonance
effect of the phenyl substituent on C-2 can promo-1 this adequately.
However, for further substitution at this carbon involving the
replacement of another atom of hydrogen by a methyl group does not lead
to an increase in epoxide formation, which should be expected on the
basis of this rationale, 2-Chloro isobutyrophenone on treatment with sodium
dimethyl phosphonate in a suitable solvent gave only dimethyl 1-phenyl
2,2-dimethyl vinyl phosphate (XLVII) and 2-bromo isob4rophenone gave
mostly dimethyl 1-phenyl 2,2-dimethyl vinyl phosphate (XLVII) - 55%
as well as much smaller amounts of the expected dimethyl 1-phenyl 2,2-dimethyl
epoxy ethyl phosphonate (LIII) 27%. Carbon-2, although being stabilised
by the hypercondugative-type interaction by the additional methyl substituent,
to nucleophilic displacement, is now becoming too sterically crowded for it to
undergo a substitution reaction by an SN2 type process. There appears to be
a very delicate balance -between epoxide and vinyl phosphate formation but a
high degree of substitution at carbon-2 seems to favour vinyl phosphate
formation.
Highly hindered ketones such as 2-phenyl desyl chloride (IC) did not
give any of the expected products of phosphorylation i.e. dimethyl 1-phenyl
2,2-diphenyl vinyl phosphate or dimethyl 1-phenyl 2,2-diphenyl epoxy ethyl
phosphonate could not be detected.
IC
The carbonyl carbon atom is presumably so sterically crowded
that attack by the phosphorus of dimethyl phosphonate is not possible.
This observation suggests that attack by phosphorus at carbonyl carbon
- 217 -
is a necessary first step in the formation of 'both epoxide and vinyl
phosphate. Further support for a mechanism of this nature comes from
the reactions of 21 ,41,61-trisubstituted 2,2-dichloro acetophenones
with dimethyl phosphonate using triethylamine as the base. 21,41 $61 -
Trimethyl 2,2-dichloro acetophenone (LXIII, X = CH) 21941,61,2,2- 3
pentachloro acetophenone ((LXIII), X = Cl)gave 21t41161-trimethyl 2-chloro 1 acetophenone ((c), X . CH
3) and 2- ,41 t61 12-tetra chloro acetophenone
((C), X .C1) respectively - the products of halogen replacement by a
hydrogen atom.
,e/CHC12 CHC12
NEt /CH,CN 3 + (030)2L 2H 10
X
LXIII
X = CH3'
01 X = CH3'
Cl
21,41,61,Trifluoro 2,2-dichloro acetophenone ((LXIII), X . P)
reacts with dimethyl phosphonate/triethylamine in the normal way to give
dimethyl 1,21,41,6-trifluoro phenyl 2-chloro vinyl phosphate (LXXIX)
as expected.
(cH3o)2p-oN .CHC1 X X
(cH30)2 NEyCHACN ,
LXXIX
E/Z = 83/17
Now 21,41-dimethyl 2,2-dichloro acetophenone ((CI), X = CH3
)
and 21,41f21 2-tetrachloro acetophenone ((CI), X = C1) reactswith dimethyl
phosphonate in the presence of ammonia/methanol to give very good yields
of the expected dimethyl 1,21141-dimethyl phenyl 2-chloro vinyl phosphate
((CII), X = CH3 - E/Z = 83/17) and dimethyl 1,2
1,41-dichloro phenyl ,167
2-chloro vinyl phosphate ((CII), X-Cl E/Z 30/70)
- 218
(CH30)2-11 NH3/CH3OH > 10o
(CH,O) a 2
CI
CII
X = CH 01
X = CHz, - E/Z = 83/1/
X = el - Ea_a_MLIP
Further substitution in the 61-position of the aromatic ring should not significantly affect the reactivity of the carbonyl function.
in fact substitution of another chlorine i.e. in the case of 21 v 41 v 61 v 212-
pentachloro acetophenone should make the carbonyl carbon atom more
nucleophilic since the electron-withdrawing ability of the chlorine
atoms gives the carbonyl carbon more potential positive character. The
presence of two large ortho-substituents in the aromatic ring of 2,2-dichloro
acetophenones apparently makes the carbonyl carbon atom too sterically
crowded for the phosphorus to attack there, with the result that reaction
takes place at an alternative site. Attack by the phosphorus at positive
chlorine leads to the formation of dechlorinated material. For 21,4:161-
trifluoro 2,2-dichloro acetophenone the two ortho-fluorine substituents
in the aromatic ring are much smaller and so do not sterically crowd the
carbonyl carbon from attack by the phosphorus of dialkyl phosphonate.
An attack of the dialkyl phosphonate at this centre leads to the formation
of the expected dimethyl 1 -21141,61 -trifluoro phenyl 2-chloro vinyl phosphate
(LXXIX).
These results indicate that the initial step in the formation ,
of dialkyl 1,2-disubstituted vinyl phosphates 'and dialky12,2-disubstituted.
epoxy ethyl phosphonates from dialkyl phosphonate and am-halogenated_
carbonyl compound involves attack by phosphorus on the carbonyl carbon
atom to give the dialkyl 1,2-disubstituted ethyl hydroxy phosphonate
anion (CIII) - Scheme 25.
Whether the hydroxy phosphonate anion (CIII) leads to vinyl
phosphate (CIV) formation by pathway - I or epoxy phosphonate (CV) by
pathway e. 2 depends very much upon the nature of the substituents
Y2 (i)
(B0)2P-OtCR2Y
1
CIV
R1
(R0)2
- 219
CV
Scheme 25
R29 X and Y as already discussed. The dialkyl 1,2-disubstituted ethyl hydroxy phosphonate (CIII) has been Shown to be in equilibrium with the
dialkyl phosphonate and halogenated ketone starting materials. Dimethyl
2-methyl-2-chloro 1-hydroxy-l-phenyl ethyl phosphonate (XLIII) was
prepared as a pure diastereomer by treating one isomer of dimethyl 1-phenyl
2-methyl epoxy ethyl phosphonate (XLII) with hydrogen chloride gas. When
(XLIII) was treated with base it was possible to isolate the same mixture
of dimethyl 1-phenyl 2-methyl vinyl phosphate (XLI 48% E/Z = 1:2) and
- dimethyl 1-phenyl 2-methyl epoxy ethyl phosphonate (XLII 52%) as
obtained from dimethyl phosphonate and 2-chloro propiophenone in the
presence of base. Addition of a highly reactive acetophenone 2,2,21,41-
tetrachloro acetophenone to the mixture of (XLIII) in base gave dimethyl 1,2
41-dichloro -pherLy2-chloro vinyl phosphate (XLIV) which was the product of intercepting the dimethyl phosphonate formed in the equilibration.
Borowitz37 has assumed that the stereochemistry of the Perkow reaction
arises from reversible phosphite addition to carbonyl carbon with subsequent
thermodynamic control in the elimination step leading to E-or Z-isomers
of cinyl phosphate. These experiments, by analogy, would indicate that
this is probably the case.
Once the nature of the intermediate has been established it is
necessary to discuss the effect on the course of-the reaction of eliminating
a halide ion. The epoxide forming reaction is easy to visualise and the
substituent effects in this intermediate on the ratio of epoxide formation:
vinyl phosphate formation now fully understood. Vinyl phosphate formation
involves an addition reaction of the hydroxy phosphonate anion at phosphorus
followed by a subsequent rearrangement with loss of halide ion - Scheme 26,
• 220 -
(R0)2 (Ro), -t2 ® - P cA 4,..(Ro) 2p--cR Y 2
-x°
(R°)2 (R0)2
(-Ro)2P-ON, =CR2Y
R1
Scheme 26
Whether this addition/elimination reaction involves a penta
covalent species as an intermediate - pathway 1 or is a concerted
process - p....thway 2 is difficult to establish. In either case it is
convenient to assume a trans-coplanar (anti) elimination from the
transition state where the phosphorus - carbon-1 and carbon-2 halide
'bonds being broken are trans-coplanar to each other. In the simplest
situation, for the reaction of 2-chloro acetophenone with dimethyl
phosphonate in the presence of base, the dimethyl 1-phenyl, 1-hydroxy,
2-chloro ethyl phosphonate anion (CVI) can only lead to one possible
vinyl phosphate i.e. dimethyl 1-phenyl vinyl phosphate (XI) byany
elimination process.
However, for the reaction of 2,2-dichloro acetophenone with
dimethyl phosphonate in the presence of base the preferred conformations
of the dimethyl 1-pheny1,1-hydroNy, 2,2-dichloro ethyl phosphonate
(CVII) may correspond, in energy, to the transition states (T.S.) of
(CH30)2P C-CH,C1 2
CH3 0)2 P-Q CHO
- 221 -
(JVI
anti-elimination
XI
the reaction. The E- and Z-isomers of dimethyl 1-phenyl 2-chloro vinyl phosphate (XVII) are formed by means of a trans-type elimination from
different transition states.
Z -isomer E-isomer
XVII
222 -
4
Bimolecular olefin-forming reactions are known to occur
Preferentially via an anti steric pathway (1)182,183, although some
recent work has shown that syn (ii) and anti (i) eliminations can proceed
side by side. An important description of the mechanism of a concerted
1,2-elimination is the torsion angle that exists about the dx-C13 bond
in the activated complex. The pinciple of maximum orbital overlap
suggests that arrangements in which the dz.-a and C14-H are anti-periplanar (anti-elimination with torsion angle 1800) and s,m-periplaner (syn-
elimination with torsion angle 00) will be greatly preferred. in.the
transition state of an HX elimination reaction - Scheme 27 (since the
p-orbitals will overlap most effectively to form V-orbitals if they are
parallel to each other).
anti (i)
(ii)
Trans-elimination cis-elimination
Scheme 27
When a single reactant can yield two or more different olefins
in an elimination reaction there is a problem of orientation which can .
be one of two types:
1. Positional orientation
This occurs when the position of'the double bond formed in the
reaction is in dispute 185'1860 An example of this is the reaction of.
2-benzyl bromide with base to give either 2-butene or 1-butene18 I.
CH3 -CH.CH2 CH Etd9 CH3CH=CH.CH3 cH3CH20E=0:2 3 Br
81;40 19%
Certain generalisations concerning
by Hoffmann188189 and Saytzev190, have been known for a long time 192 but more recent studies by Brown 191, have indicated that positional
orientation is a function of the size of the leaving group and that
Hoffmann-type elimination represents steric control.
positional orient at i ons
- 223 -
2. Geometrical orientation
This occurs when the olefin formed by an elimination reaction can
exist in either the cis or the trans forms. For example the 2-butane
formed from elimination of HBr from 2-butyl bromide will in general be
a mixture of trans-2-butene and cis-2-butene. Geometrical orientation
can be explained by considering the elimination to take place from a
preferred conformation. The stability of a particular conformation
can be determined by considering the steric and electronic interactions
of the individual substituents. For 2-butyl bromide the possible conform-
ations are represented in Newman projection by (i), (ii), and (iii). The
most stable conformation being (i).
Bx
CH3
CH3
CH 3
CH3
(i)
However the conformation in the transition state must resemble
(ii) or (iii) for anti-elimination to give 2-butene as the observed
product. Of these two conformations, (ii) has less non-bonded interactions.
and is the more stable. This explains why trans-2-butene is the favoured
oroduct. For elimination from preferred conformations the ratio of the
products formed is independent of the relative free energies of the various
starting forms and depends only on the relative free energies of the
transition states by which the products are formed - Curtin-Hammett
principle194,195. This principle assumes that the activation energy
of the transition state is large compared to the activation energy for
interconversion of the isomeric starting materials.
There are many examples of elimination reactions from specific
conformations to give isomeric mixtures of olef ins196 '197 and the effect
of P-alkyl substituents upon orientation in elimination reactions has been
discussed.198 Little is known about the effects of other substituents
- 224 -
on the course of elimination reactions and in particular the effect of a
?-phosphoryl substituent on the 1,2-elimination reaction of HX. The
fragmentation of 13-halo phosphonic acid leading to trans elimination of
the halide ion and the phosphorus moiety has been known for some time
Recently Maynard and Swan200 have reinvestigated the reaction and sug8ast
that a doubly ionised phosphonate group is required before fragmentation
can occur - Scheme 289
R-CH-CH 2
01 N, 0
RCH=CH2 4.
R1/ H
R-O-P `*OH
Scheme 28
The 1,2-dibromo-l-phenyl propyl phosphonic acids have been shown
to decompose stereospecifically to yield a single isomer of 1-bromo-l-
propenyl benzene2019 Since the erythro dibromide yields the cis-bromo
propenyl benzene and the threodibromide the trans-broMopropenyl benzene
- this suggests a trans elimination mechanism - Scheme 299
06H5 PH3
+ Br- H2PO4
cis
NaOH
H2O Br- H2PO4'
threo trans
Scheme 2
- 225
Some elimination reactions of substituted alkyl Phosphonates
have been studied where the ?-phosphonyl group is retained in the olefin.
For a wide variety of substituents elimination of Hal from 2-chloro alkyl
llhosphonates (CVIII) has been shown to occur stereosPecifically and
always in the same sense to give the olefin (CIX)202
1-1C1 9 (110)7KCHX.CHClY (RO)2P ,.
C.
CIX
(X = Cl, Y = F) (X F, Y = cl, r) (x = H, Y = Net CO2Me,
C1)
The geometry of the products has been shown to resemble the
preferred conformation of the substrate irrespective of whether a formal
svn- or anti- elimination is involved and that elimination appears to
take place from the lowest energy conformation. When-there is a choice
of,leaving group on carbon-2 e.g. diethyl 2,2-dichloro 1-fluoro ethyl
phosphonate (CVII; X . F, Y = C1) eliminetion of HCl gave only the
E-isomer of diethyl 2-chloro 1-fluoro vinyl phosphonate (CIX; X = F, Y = C1).
This is consistent With a mechanism involving the elimination of HCl from
the most stable conformation in solution.
Et3N
Cl =Eta
CVIII X = F, Cl
CIX X = Ft Y= Cl
The reaction of 2,2-dichloro acetoehenone with dimethyl
rhosehonate in base gives rise to almost exclusive formation of the
E-isomer of dimethyl 1-phenyl 2-chloro vinyl phosphate CXVII) E/Z = 95/f. The mechanism of the reaction involves the reversible addition of
dimethyl phosphonate anion at carbonyl carbon of the -acetophenone to
give the dimethyl 1-pheny1,1-hydroxy, 2,2-diohloro ethyl phosphonate anion
(CVII). Followed by a trans co-planar elimination of chloride ion from
R= '0
"
NR
C1)
R P=0
R
- 226 -
a preferred conformation of the phosphonate anion which resembles the
transition state. Assuming fullco-planarity, of the three possible
staggered conformations (i), (iii) only (i) and (ii) will lead
to the loss of chloride ion by a trans co-planar process.
E-isomer 2-isomer
Of these conformations (i) gives rise to E-isomer and (ii)
gives rise to 2-isomer by a trans-type elimination. The preferred
conformation is (i) where the oxygen is flanked by the hydrogen since
95% of E-isomer formation is observed. This situation is similar to that
envisaged for Cram's rule which deals with carbonyl addition reactions
and states that the conformation is preferred in which the carbonyl group
is flanked by the smallest group attached to the adjacent carbon atom203.
Cornforth204 has indicated that when a nucleophilic reagent R4X reacts " 1_ irreversibly_ with antx-chloro ketone (or a-chloro aldehyde) R7H-C1C.COR31
the resulting chlorohydrin should have a preponderance of molecules with conformatjon (CX) wherein R4 is anti to the larger (here R2) of
the two groups R1y R2 when the chlorine and hydroxy groups are anti to each other.
- 227 -
cx
The reactions of 2,2-dichloro 41-substituted acetophenones
with dimethyl phosphonate in the presence of base gave almost exclusive
formation of the E-j.somer of dimethyl 1-41-substituted phenyl 2-chloro
vinyl phosphate (LXX, X = H, F, Cl, Br, NO2 or 0CH3). This indicates
that the p-substituents are having no effect upon the preferred conformation
of the transition state which resembles (i) - where the oxygen is
again flanked by the hydrogen atom.
C1 PXC6 C6
(CH 0 1
X = H
Ci
Br
NO2.
OCH3
Cl
(CH30)2 (cH3o)
(i)
0
p-XC r,..-0-(ocH3)2
C1 `H
LXX LXX
E -isomer
Observations upon the reaction of 2,2-dichloro 21-substituted
acetophenones with dimethyl phosphonate in the presence of base indicate
that the ortho-substituent has a very drastic effect on the course of
the reaction: In all cases dimethyl 1-21-substituted 2-chloro vinyl
phos hates (LXIX) were isolated as the only products but the E/Z isomer
ratio -(determined accurately by both glc and 1H nmr analysis) was
susceptible to the nature of the ortho substituent. The ortho substituents
/19 Fy CH3) behave similarly to give predominantly E-isomer while
the other ortho substituents (X = Cl, Br, OCH3, NO2) give mostly the
Z-isomer
X =-C1
-Br
-OCH3
-NO2
(0:30
0 o-XC H OCH3),) o-XC
(CH30)2F=0
Cl
B-isomer
X =-H
-F
-CH3
- 228 -
Z-isomer. For the halogens (Fp Cl, Br) there is a tendency to increase
the percentage of Z-isomer isolated as the series is descended. This
might indicate that increase in the steric interaction between the
ortho-substituent and a chlorine atom on carbon atom-2 leads to the
stability of conformation (ii) in preference to (i) and hence more
of the Z-isomer.
LXIX
However, the ortho-substituent (X = CHI) which might be expected-
to behave similarly sterically to chlorine gives the B-isomer (77;) as
the major product, whereas chlorine gives mostly Z-isomer (83%).
The results are much more reesonable if it is assumed that the
ortho-substituent can interact with the oxygen function df the dimethyl
1-21-substituted -phenyl, 1-hydroxy, 2,2-dichloro ethyl phosphonate anion
(CXI) which resembles the reaction transition state. It has been shown
229 -
for ortho-substituted para-fluoro-aAC-dimethyl benzyl alcohols that one of two possible orientations is adopted depending upon the nature of the ortho substituent205. Conformation (i) is adopted for molecules in which the ortho-substituent is H, CH3 or F and conformation (ii)
is adopted for Cl, Br or I.
3 3
(i) (ii) X H, CH3, F X = Cl, Br, I
Projection of side chain onto the aromatic ring showing;•
the two possible orientations
For the substituents X . H, F, CH3 a favourable interaction between
the oxygen function in the dimethyl 1-21-substituted phenyl, 1-hydroxy,
2,2-dichloro ethyl phosphonate anion (CXI) fixes the orientation at
carbon-I and the stereochemistry of elimination is decided by
conformational properties about the carbon-1 - carbon-2 bond.
Presumably, conformation (i) with the oxygen function flanked
by the hydrogen atom is most favoured and elimination of chloride ion from
this conformation. leads to formation of the E-isomer.
For the ortho-substituents X = Cl, Br ( and probably X - = OCH3,
NO2) interaction with the oxygen function is unfvourable and the
dimethyl 1-21-substituted phenyl 1-hydroxy 2,2-dichloro phosphonate
anion (CXI) adoits a conformation where the ortho-substituent interferes
with the side chain - CHC12.
Of these two staggered conformations (iii) and (iv), conformation
(iii) in which the ortho-substituent is interacting with the hydrogen
of the side-chain -CIIC12 will be preferred over (iv) where the ortho-
substituent is interacting with a chlorine in the -CHOI2 side-chain.
LXIX Z -isomer (cr,zo
Preferred staggered conformations when X-substituent interacts with the oxygen function
(CH30) 2 J1
1
(CH30)2LC
CXI LXIX
X = Cl, Br, 00H3 , NO2 (iv) E-isomer
- 230
(CH30)2P9 -
LXIX
E-isomer
LXIX
Z-isomer
Preferred stagg:ered conformations when X-substituent interacts with the
side chain
- 231 -
4
An interaction between the X-substituent (X = Cl,, Br) and a chlorine
atom will be unfavourable both on steric and electronic (repulsive-
type interactions) grounds. The formation of the Z-isomer from
conformation (iii) is the most likely mechanism and this agrees with
the experimental observations.
There is a remarkable similarity between the preferred side
chain conformations for the ortho-substituted para-fluoro-m,x-dimethyl
benzyl alcohols205 and the variation of E/Z isomor ratios with change
in the ortho-substituent - Figure 15.
Figure 15,
Side chain conformations for the ortho-substituted para-fluoro-0.',t=diml
benzyl alcohols
HC12
(CH30)2 (CH30)2P-Q,,,, =C„,\
Substituent X E-isomer Z-isomer
H 95 5 CH3 77 23
60 40
Cl 17 83
Br 9 91
Variation of E Z isomer ratio observed in 'abnormal' Michaelis-Becker
reaction with change in substituent-X
(CH30)2Ve
H Base -CH012
catalystc.‘ (e.g.CH
30)
,,P-H R2
- 232 -
4
Although the comparison of the side-chain. conformations of
ortho-substituted para-fluoro-lx,ix-dimethyl benzyl alcohols with those of dimethyl 1,21-substituted phenyl 1-hydroxy 2,2-dichloro ethyl
phosphonates is not fully justified, since the effect of having a
phosphorus substituent present is not known, the interaction of the
X-substituent with the oxygen function is reasonable. It might be
possible to gain information about the preferred conformations of
dimethyl 1-21-substituted 1-hydroxy 2,2-dichloro ethyl phosphonates by
looking at the 33 of the intermediate206. These intermediate hydroxy PH phosphonates are reported to be isolatable frcm a variety of aldehydes
and ketones73,74, 207and in the case of dihalogenated acetophenones stable
at low temperatures. They are reported to be produced at low temperature
by treating the 2,2-dichloro acetophenone with a phosphorus reagent in
the presence of a catalytic amount of base208.
Unfortunately, the 2,2-dichloro acetophenones proved to be so
reactive with dimethyl phosphonate that the dimethyl 1-21-substituted
pheny11 1.,hydrrxy, 2,2-dichloro ethyl phosphonate (just detectable by
tic) was converted almost immediately to the corresponding dimethyl
1-21-substituted phenyl 2-chloro vinyl phosphate (LXIX) even at -400
and an nmr study of the intermediate was therefore not attempted. It
might still be possible to isolate these hydroxy phosphonate intermediates
by using a less reactive phosphorus reagent e.g. dimethyl thiophosphinate
instead of dimethyl phosphonate. 1_ 1 1 2 ,4 ,6 -Trifluoro 2,2-dichloro acetophenone was the the only'
diortho-substituted acetophenone to react with dimethyl phosphonate in the
presence of base to Give good yields of the expected dimethyl 21141,61-
trifluoro phenyl 2-chloro vinyl phosphate (LXXIX). The isomer ratio
= 83/17) suggests the elimination reaction is occurring preferentially
from a conformation (i) where an ortho-fluoro-substituent is interacting
with the oxygen function and the hydrogen in the side chain is flanked
by the oxygen.
CH30-1=
Ja)2 -d-C1 CH3dr
(i) Cl
- 233 -
(CH30)2ti-qg
E -isomer
F- ----t Cl ( CH3 ) 2F9-\
k
Z -isomer
LXXIX
By repeating the reaction of 212-dichloro acetophenones with
various phosphorus reagents, it has been possible to show that the E/Z
isomeric ratios of vinyl phosphates are again determined by the nature of the ortho substituent. For all the phosphorus reagents studied
(dimethyl phosphonate, dimethyl thiophosphonate, dimethyl phosphinate,
dimethyl thiophosphinate and trimethyl phosphite) changing the ortho-
substituent in the 2,2-dichloro acetophenone successively from -H to -2
to -C1 results in an increase in the formation of the Z-isomer. All
the arguments to explain these observations have been dealt with in the
case of dimethyl phosphonate and apply for all these other phosphorus
reagents. Trimethyl phosphite is different from the other phosphorus"
reagents in that it reacts with at:, halogenated carbonyl compounds in
the absence of base - Perkow Reaction, but it shows the same effect
(change in E/Z isomer ratio) with variation in ortho-substituent. There
has been no mention in the literature of the effect of ring-substituents
on the geometry of vinyl phosphates obtained in the Perkow reaction.
Borowitz36 has indicated that meta- and Para-substituents can affect
the rates of reaction of al-chloro isobutyrophenone and Oro-bromo isobutyro
phenone with triethyl phosphite but in these cases there is no
complication by geometric isomerism. The E/Z isomer ratios of various
dimethyl 1,21-substituted phenyl 2-chloro vinyl (thio) phosphates and
4
234 -
(thio) phosphonates (determined by 'F nmr integration of the vinylic
resonances) obtained by reacting 21-substituted 2,2-dichloro acetophenones
with dimethyl (thio) phosphonates, dimethyl (thio) phosphinates, and
trimethyl phosphite are shown in T&219...22.
Table 39
Substituent X --* H F Cl
Phosphorus Reagent "./E Z
(Cy)?
CH.40 LQ I -H cilr 3
cx3-x
CH3
CH, lk Q ) .
,.H CH30
CH3 -
CH3
40
77
95
95
100
6o
23
5
5
0
12
35
44
60
90
88
65
56
40
10
3
5
17
40
97
.) or ..
95
83
60
From Table 39 it can be seen that for all the phosphorus reagents
more of the Z-isomer is produced as the ortho-substituent is varied from
hydrogen through fluorine to chlorine. The Perkow reaction is
greatly affected by the nature of the ortho-svIstituent but it should be
expected that meta and para-substituents have very little effect (the
isomer ratio should be in the region of E/Z = 40/60 for the reaction of
m- and p-2,2-dichloro acetophenones with trimethyl phosphite). Also
the Table 39 shows that for any 21-substituted 2,2-dichloro acetophenone
as the nature of the phosphorus reagent is varied the ratio of E/Z
isomers formed in the reaction also varies. This variation is in the same
sense, no matter what the nature of the ortho-substituent is i.e. as
the series dimethyl thiophosphonate — trimethyl phosphite is ascended
a greater percentage of the Z-isomer is formed.
1
CH3 0--- -OCH
3 di. H3cr
- 235 -
This difference in the E/Z isomer ratios observed for different
phosphorylating species is explained by a difference in the reactivities
of the phosphorus species. For a reactive (nucleophilic) phosphorus
reagent the transition state of the intermediate will resemble the
preferred conformation of the starting acetophencne since Crams s rule
will apPly203,204. This situation represents kinetic control and the
intermediate will collapse very rapidly to the desired product. As
already discussed the preferred conformation for this mode of addition
where the hydrogen of the side chain is flanked by an oxygen function
will lead predominantly to the formation of the E-isomer. For a less
reactive (nucleophilic) phosphorus reagent an equilibrium between the
intermediate and the starting materials will be set up. The unfavourable
interaction that exists in the transition state between the o-substituent
and the chlorine on carbon-2 will be fully developed so that elimination
will take place from the transition state where thecsubstituent is syn
to hydrogen and not chlorine. This represents thermodynamic control and gives rise to a predominance of Z-isomer. Trimethyl phosphite
is much less reactive than the dimethyl phosphonate anion and the
conformation (i) will therefore be fully developed giving rise to
almost exclusive formation of the Z-isomer (97).
(1)
A conformation of this type (i) would also explain why the reaction of dimethyl rhosphonate anion or trimethyl phosphite with
2,2-dibromo acetophenone gives predominantly the Z-isomer (while
2,2-dichloro acetophenone and trimethyl phosphite ----)r E/Z = 40/60).
Clearly a syn-type interaction of bromine with an ortho hydrogen
would be very unfavourable in the other possible conformation.
- 236 -
Such large variations in going from dimethyl thiophosphonate (mostly
E-isomer) to trimethyl phosLhite (mostly Z-isomer) for X = F
might also be explained by a change in the reactivity of the phosphorus
species in the intermediate hydroxy phosT:honate.- These substituents
have been shown to interact with en oxygen function so that changes in
the conformations about the C-1 - C-2 bond will affect the E/Z isomer
ratio obtained on elimination. The populations of these staggered
conformations will clearly be very much affected by the nature of the
phosphorus species.
----* E -isomer
-isomer
It may be that the phosphorus group is giving the chlorine
atoms on 0-2 different rates of reactivity so that one is leaving in
preference to the other - this might be what elimination from a
preferred conformation is implying. Nothing is really known about
elmination reactions where there is a choice of leaving groups attached,
to the same carbon atom. The only analogy in the literature are the , reactions of substituted 2,2-dichlero ethanols to give epoxides2°9 210.
1-Phenyl 1-methyl 2,2-dichloro ethanol and 1-phenyl 2,2-dichloro ethanol
on treatment with potassium hydroxide solution gave only one epoxide.
The geometry of these epoxides have not been very well established but
it appears that a trans ring closure to give epoxide is taking place
from a preferred conformation of the alcohol - Scheme 12.
- 237
sx
Ph- -CHC12 + OHC)
R = Hf CH3
Scheme 30
If our arguments about elimination from preferred conformations
are correct then it should be possible to change the geometry of the
epoxides obtained in these reactions by varying the nature of the
ortho-substituents in the aromatic ring. Conformational preferences
of the side chains in these alcohols can also be studied by looking at
the 191' nnr of 1-methyl 1-ortho-substituted para-fluoro phenyl 2,2-
dichloro ethanols205.
- 238 -
APPENDIX I - TO CHAPTER 2
The 13C nmr spectra were recorded using a Varian XL 100 - 12 WG
spectrometer at 25.16-MHz operating in Fourier transform mode. All spectra
were recorded to infinite dilution in CC14 solution using external D20
for locking purposes, and operating with a pulse width of ca 15-20)usec
(30-40° tip angle). Proton-noise decoupled 13C spectra and off resonance
and gated-decoupled experiments were recorded.
Proton-noise decoupled 31P spectra of CDC13
solutions were
recorded to infinite dilution at 40-505 MHz using Varian XL 100 - 12 WG
spectrometer operating in Fourier transform mode. The 31P resonance
were measured for 250 Hz sweep widths using a pulse width of 30)usec
(60° tip angle).
Additional 31P chemical shifts omitted from Chapter 2 are
shown in Table 400
Table400 31P Chemical shifts of vinyl phosphates
31p Hz
from lock
Shift in ppm
Pa from (CH3 0)3
Shift in ppm
from 80°A PO4 b
0
(CH30),L01.0H2
R
89808.8 + 144.0 + 3.0
(C2H50)2K0TCH2 89757.8 + 145.2 + 4.2
f? (CH3 /\2 0 ...o-q=c1.1
2 , ,11 0 0 5
-T--- 89721.8 + 146.1 + 5.1
a 31P of (CH30)3P recorded in CDC13 to infinite dilution is 95640.2 - positive shift to high field.
b 31p shift of 80'; H3PO4 relative to (CH30)3P is + 141.0 ppm
- positive shifts to high field.
239 -
It is possible to calculate the S.C.S. in the 31P spectra
for a series of diethyl 2-substituted vinyl phosphates (see Table 24) and dimethyl 1-phenyl 2-substituted vinyl phosphates (see Table 25)
knowing these values for diethyl vinyl phosphate and dimethyl 1-phenyl
vinyl phosphate. These are given in Table 41 and Table 42.
Table 41. Substituent chemical shifts (S.C.S.) of diethyl 2-substituted
CH3CH2
CH3CH2
-0-C=CHX
Substituent , 31P - .L-isomera t 31P - Z-isomerb S.C.S. E-isomerb S.O.S. Z-isome
H + 5.1 + 5.1 0 0
Cl + 5.4 + 5.1 + 0.3 0
Br + 5.8 + 5.2 + 0.7 + 0.1
CH3 + 4.9 + 4.4 - 0.2 -0.7
005 + 4.7 c .., 094 a
a Shift in ppm from 80% H34 PO, - positive shift to high field.
b
Only E-isomer available.
Shift in ppm from diethyl vinyl phosphate - positive shift
to high field.
a Shift in ppm from 80% E3PO4 - positive shift to high field.
b Shift in ppm from dimethyl 1-phenyl vinyl phosphite - positive
shift to high field.
240
2211241. Substituent chemical lIf1§222§11211L2ILL1711*Ital 2-substituted vinyl phoshates
clizo.„p P-0-Q.CHX
CH30--6115
Substituent 31P - E-isomera 31P Z-isomera S.C.S. E-isomerb S.C.S. Z-isomerb
H + 4.2 "1" 4.2 0 0
Cl + 3.8 + 4.6 - 0.4 + 0.4 Br + 4.4 + 5.0 + 0.2 + 0.8 CH3
+ 3.5 + 3.5 - 0.7 - 0.7 06H5 + 3.9 + 4.2 - 0.3 - 0.0
c02 C2 5 H_ + 5.4 + 5.5 + 1.2 + 1.3
There would seem to be a reasonable correlation between the
S.C.S. in diethyl 2-substituted vinyl phosphates (Z-isomer) and those
in dimethyl 1-phenyl 2-substituted vinyl Phosphates (2-isomer) -
see Pig. 16, whereas the Corresponding ones for the E-isomers do not
correlate too well at all. This probably indicates the conformational
dependence of the molecules on 31P chemical shifts, and that the
conformations for the 2-isomers are similar and do not depend on the
nature of the substituent at carbon-2.
Relative sins of P-C cou2ling constants
As we have shown in Capter 2 the values of the two and three
bond 31P - 13C coupling constant in substituted vinyl bnosphates can
provide information about the stereochemistry of the olefinic double
bond. However, since knowledge of the magnitude may be ambiguous,
the determination of the relative signs is important.
A straightforward, but often tedious method consists of
perturbing one particular transition with a weak second rf field -
spin-tickling211. To apply this technique to relate the signs of two
coupling constants and and J.0/1 requires the observation of the 13C
- 241 -
31 C)- -P S.C.S. of diethyl 2-substituted vinyl phosphate (Z-isomer)
Plotted against S.C.S. of dimethyl 1-phenyl 2-substituted vinyl_
phosphate (Z-isemer)
al - '1P S.C.S. of diethyl 2-substituted vinyl phosphate (E-isomer)
plotted aainst S.C.S. of diLletial_17phenyl 2-substituted vinyl
phosphate (E-isomer)
242 -
satellites in the proton spectrum while irradiating one of the 13C
transitions.
The same information can be obtained in a more convenient
experiment by observing 13C while partially decoupling the protons.
This is performed by deliberately off-setting the proton decoupler
frequency. Whereas in the noise-decoupled spectrum only one doublet
is observed for each carbon that is coupled-to phosphorus, these two
lines show a residual splitting whenever coherent decoupling off-resonance
is applied. The magnitude of the reduced coupling constant JCrH is
proportional to the direct coupling constant JCR, the frequency offsetAf from resonance, and inversely proportional to the power level Hz/211/124
JCrH jCH
Hz/2 it
However, both splittings in the two submultiplets are not
reduced. to the same extent, since not both of the proton subspectra -
where each corresponds to a definite spin state of the phosphorus nucleus
is equally affected. If e.g. JPC and J have like signs, high field
off-resonance decoupling will result in two reduced multiplets of which
the one at high field shows a smaller splitting
This experiment was performed with dimethyl 1-phenyl 2-chloro
vinyl phosphate (E/Z = 40/60) - neat liquid. Fig.7 ^ shows the noise decoupled where the C-2 carbon atoms for the two isomers have been assigned
from an off-resonance experiment. The spectrum of Fig.l7 A was obtained with simultaneous coherent proton irradiation at - 5.90 ppm relative to T.M.S. using a decoupling power of ca 2.0 W, and recorded with a fourfold plot
expansion of 1200 Hz. spectrum (applying the pulse at the low field end).
Since the decoupling power is high field of the vinylic resonances in
the 1H nmr (HE - 6.450 ppm, Hz = 6.146 ppm) and the high field doublet of C-2 shows a larger spacing for each isomer; this indicates that the two
coupling constants 3Jpo and 1Jppi have opposite signs. This experimental
observation was confirmed by applying a coherent proton irradiation to
low field by the vinylic resonances in the 1H nmr 7.70 ppm. Fig.17 B shows the result obtained with low field doublet of C-2 showing the larger
spacing and inferring that 3JPC and 1JPH are opposite in sign.
C2E I.
Decoupler offset 45824 Hz (Power (Ii) 2.0 W). Sweep width 1200 Hz expanded fourfold
.11AwoN'vrksv,4\%1\APAN-4,17T\Wo.../-11.14,1 ^Art
Decoupler offset 45644.0 Hz (Power (i) 2.0 W). Sweep width 1200 Hz expanded fourfold
i\o\t" 4%,,,,Aromt44 ikuvokfikiNNO
0 - Hic.h-field, low power, off-resonance spectrum of 0-2 in dimethyl 1-phenyl 2-chloro vinyl phosphate (E/Z isomers 40/60)
(!) Low-field, low power, off-resonance spectrum of 0-2 in diemthyl 1-phenyl 2-chloro vinyl phosphate (0 isomer 40/6
244 -
It should be possible to relate these coupling constants to
JCH by performing a similar experiment where phosphorus is irradiated
with a coherent freciuency and effects in the carbon spectra of C-2 are
observed. This experiment. provides information about the signs of IJPH relative to 1JCH and enables the absolute signs of the coupling
constants to be determined - since 1JCH
is positive 215-5
245
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