•■• 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 I TJ OF LONDON Thorpe-Whiteley Laboratory, August 1974 Department of Chemistry, imperial College, London. S.W.7.
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MICHAELIS-BIJCIM REACTION'...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
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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
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
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
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
(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
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
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
/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
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.
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
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°).
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
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
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)
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
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
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
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.___:
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
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
(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.
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
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:
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
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).
(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).
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
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
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
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
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
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
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
(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
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
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
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
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
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%:
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).
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
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
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,
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
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
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.
)=( 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
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
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/
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)
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
(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
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.