Compo's final project (30.05.05 1725)

Contents
1. Abstract.
2. Introduction.
2.1 Ozone.
2.1.1 Ozone Mechanism.
2.1.2 The Criegee Mechanism.
2.1.3 Reductive Nucleophilic Displacement of Oxygen.
2.2 Wittig Reaction.
2.2.1 Structures and Properties of Ylides.
2.2.2 Reactions of Phosphoranes.
2.2.3 Stereochemistry.
2.2.4 Solvent Effects.
2.3 The Project.
3. Results and Discussion.
3.1 In-situ Cinnamonitrile (CCN) Reactions.
3.1.1 1
H NMR of trans-Cinnamonitrile.
3.2 In-situ Benzylidene Succinic Anhydride (BSA) Reactions.
3.2.1 FT-IR of Benzylidene Succinic Acid.
3.2.2 FT-IR of Benzylidene Succinic Anhydride.
3.3 In-situ Methyl Cinnamate (MC) Reactions.
3.3.1 1
H NMR of Methyl trans-Cinnamate
3.4 Calculation of Isomer Ratio for Cinnamonitrile and Methyl Cinnamate.
3.5 Calculation of Isomer Ratio for Benzylidene Succinic Anhydride.
3.6 Discussion of Results.
3.7 Future Work.
4. Conclusions.
5. Experimental.
1

5.1 Analytical Procedures.
5.1.1 GC (Gas Chromatography).
5.1.2 TLC (Thin Layer Chromatography).
5.1.3 FT-IR (Fourier-Transform Infra-Red) Spectroscopy.
5.1.4 1
H NMR (Hydrogen Nuclear Magnetic Resonance) Spectroscopy.
5.2 General Procedure for ‘One Flask’ Synthesis of Cinnamonitrile via an
Ozonolysis then Wittig reaction.
5.3 General Procedure for ‘One Flask’ Synthesis for Benzylidene Succinic
Anhydride via an Ozonolysis then Wittig reaction.
5.4 General Procedure for ‘One Flask’ Synthesis for Methyl Cinnamate via an
Ozonolysis then Wittig reaction.
5.5 Synthesis of Benzylidene Succinic Acid.
5.6 Synthesis of Benzylidene Succinic Anhydride.
6. COSHH Assessment
7. References
8. Acknowledgements
9. Appendix
2

1
Abstract
The aim of this project was to investigate the cis/trans isomerism associated with solvent
effect on the Wittig reaction using stabilised ylides.
Recent work by a work colleague following the same line of work but also investigating the
use of unstabilised ylides and investigated the use of phosphonates using the Wadsworth-
Emmons, or the Horner-Emmons Wittig reaction.1
9 reactions were performed by using 3 different ylides with 3 different solvents. Each reaction
was very individual and produced different yields and cis/trans ratios. It was noted that the
reactions between ozonised styrene and 2-(triphenylphosphoranylidene) succinic anhydride
(2-TSA) to give the product benzylidene succinic anhydride (BSA) were not capable of being
analysed by GC on the method that successfully was used for methyl cinnamate (MC) and
cinnamonitrile (CCN).
It was seen that solvent was in some ways specific to the yilde. Methanol (MeOH) as
expected produced a good mix of cis and trans products, more with
(triphenylphosphoranylidene) acetonitrile (TA)than with methyl
(triphenylphosphoranylidene) acetate (MTA). Yields were also poor.
Dichloromethane (DCM) and ethyl acetate (EtOAc) reactions of TAand MTA produced
predominantly trans products of MC and CCN but these particular experiments were
interesting as the yield of CCN from TA in DCM was 90% trans isomer and was a 46.5%
yield where as the reaction in EtOAc was only 83.5% trans and yield was lower at 40.1%.
Where the TA reaction worked better in DCM, the opposite was true, to a certain aspect, in
3

EtOAc for MTA. In DCM the MTA yielded 35% but the trans product was 97.5%. In EtOAc,
the MTA reaction yielded more product, 55.4%, but only gave 94.8% trans product.
4

2
Introduction.
2.1 Ozone
Ozone was first discovered in Basle in 1840 by Christian Friedrich Schonbein by the slow
oxidation of white phosphorus in air. Ozone has also been detected during the electrolysis of
water by its characteristic odour.1,2
Gaseous ozone is dark blue in colour.3
Ozone is a highly reactive allotrope of oxygen where
the molecule is a triatomic, composed of 3 atoms of oxygen as opposed to diatomic,
composed of 2 atoms of oxygen. The molecule is non-linear with a bond angle of 116°. The
ozone molecule can be describes as a resonance hybrid of four forms.1,2,4
(Figure 1)
Figure 1 - Resonance of Ozone
It is the hybrid forms (3) and (4) where the terminal oxygens possess 3 lone pairs, which
accounts for the electrophilic nature of ozone which many reactions are noted for.3
Ozone is formed naturally by the discharge of electricity during a thunderstorm. Industrially,
silent electrical discharge is now the primary method of ozone generation.2,3
Ozone in large
quantities is produced commercially through the use of the modern day electrical ozone
generator, resembling the original built by Werner Von Siemens in 1857.2
Oxygen is passed
5
O
O
O O
O
OO
O
O O
O
O
(1) (2) (3) (4)

through 2 electrodes which are usually separated by glass. The passage of an alternating high
voltage produces an electrical discharge through the gas stream which results in the
breakdown of molecular oxygen to atomic oxygen.2,3
The formation of ozone is well known, 1
atom of oxygen then combines with 1 molecule of oxygen to form 1 molecule of ozone.
(Figure 2)
Figure 2 – Formation of Ozone
Lab ozonisation requires several steps: ozone generation, introduction of ozone into the
reaction mixture, ozonisation of olefin isolation of the products.
One of the most extensive reactions of ozone which have been researched is the reaction of
ozone with olefinic double bonds. The ozone reaction and susequent work up can lead to
formation of alcohol, aldehyde, ketone, acid and esters depending on the workup method. The
so-called father of ozone chemistry is Professor R Criegee who has provided the mechanism
of ozone attack.2,3,4
6
O2
electrical
discharge
O O+
+O O2 O3

2.1.1 Ozone Mechanism for Addition of Ozone to a Double Bond
Early work by Harries on the ozonisation of a double bond, in the absence of ionic solvents,
gave peroxidic oils. He gave the structure of these oils (5), but he later changed this to (6).2
(Figure 3)
Peroxidic Oil Structures - Figure 3
This 1,2,3-trioxolane structure (6) has been named the mol-ozonide, primary ozonide or the
initial ozonide and is highly unstable. The structure's instability allows decomposition in one
of two ways. Firstly to give an aldehyde and/or ketone and hydrogen peroxide in the presence
of moisture (Scheme 1) or secondly to give an aldehyde and peroxide (Scheme 2).2,3,4,5
Scheme 1 – Decomposition via Moisture to Hydrogen Peroxide and Aldehyde/Ketone
Scheme 2 - Decomposition to a Peroxide and Aldehyde
7
O
CC
O
O
O
CC
O
O
(5) (6)
O
CC
O
O
(6)
H2O
C O COH2O2 ++
CO+
O
O
C
O
CC
O
O
(6)

The work Harries has performed was continued by Staudinger who suggested that the true
structure of the ozonide was a 1,2,4-trioxolane (8). Staudinger proposed that ozone reacts with
olefins to form a 4 membered ring (7) which rearranges to give another ozonide called the
secondary ozonide (Scheme 3).2
Scheme 3 – Staudinger’s Proposed Ozone Reaction
2.1.2 The Criegee Mechanism
In the 1950’s the most extensive research into ozone chemistry and mechanics behind this
was performed by Criegee.2,6,7
He proposed that first step of the mechanism is the dipolar
addition of ozone to the olefin to give the primary ozonide (6), which had earlier been
deduced by Harries and Staudinger. The structure of a primary ozonide has also been proved
by spectral methods.2
The primary ozonide cleaves to form a carbonyl compound such as a
aldehyde or ketone and also a zwitterion (9) (Scheme 4).
Scheme 4 – Dipolar Addition of Ozone, Formation/Cleavage of Primary Ozonide and
Resulting Carbonyl Compound and Zwitterion
8
O
O O
C C
R
R
R
R
C
O
O
O
C
R
R
R
R
C
O
R R
C
O
O
R R
+
(9)(6)
C C
R'
R
R''
R'''
C
O O
C
O
R R'''
R''R'
(7)
O
C
O
C
OR'
R
R''
R'''
(8)
O3

The zwitterions is the mechanism’s key intermediate and can be considered as an oxide of a
carbonyl group possessing 2 resonance forms (Figure 4)
Figure 4 – Zwitterion Resonance
The zwitterion is very reactive and reacts with the carbonyl compound to give the secondary
ozonide (8) (Scheme 5) or with alcohols to give alkoxyhydroperoxides (10) (Scheme 6). It
may even react with itself to give bisperoxide (11) (Scheme 7) or even decompose to give a
carbonyl compound and oxygen (Scheme 8).3,4,5
However it is the reaction of the zwitterion
with the carbonyl group to make the secondary ozonide that is the main reaction.
Scheme 5- Reaction of Zwitterion with a Carbonyl to give a Secondary Ozonide
Scheme 6 – Reaction of Zwitterion with a Alcohol to give a Alkoxyhydroperoxide
9
C O O C O O
(9)
C C
R
R
R
R
O3
C C
O
O
O
R
R
R
R
C O
R
R
C O O
R
R
OO
O
R
R
R
R
+
(9)
(8)
(10)
R
C
OR
O
R'
O
HR'OH+C O O
R
R

Scheme 7 - Reaction of Zwitterion with another Zwitterion to give a Bisperoxide
Scheme 8 – Decomposition of a Zwitterion to give a Carbonyl and Oxygen
However, it is the reaction in scheme 5 which is the favored .
2.1.3 Reductive nucleophilic displacement of oxygen
The final method is the reductive cleavage with a nucleophile on the secondary ozonide to
make aldehydes/ketones. The general mechanism is shown below in scheme 9.
Scheme 9 – Reduction of the Secondary Ozonide with a Nucleophile.
The reduction of ozonides is routinely done using triphenylphosphines as well as triphenyl
and methyl phosphites.8,9
The phosphine is oxidised to the oxide, and phosphite to phosphate
in these reactions. (Scheme 10)
Scheme 10 – The use of Triphenylphosphines in Nucleophilic Reduction
10
(11)
O O
C
OO
C
R
R R'
R'
+ C O O
R'
R'
C O O
R
R
Nu
OO
O
R
R
R
R
+ NuO C O
R
R
2+
OO
C
O
C
R'
R
R''
R'''
OO
C
O
C
PPh3
R'
R
R''
R'''
PPh3
O
R'
R
O
R''
R'''
+ + Ph3PO
O2+
R
C
R
OC O O
R
R
2 2

Is triphenylphosphine is used, the by-product, triphenylphosphine oxide is difficult to remove
from the final product. Phosphates on the other hand readily wash out. Work carried out by
Carles and Flizar using phosphines as a reducing agent found that the reaction proceeds via an
unstable intermediate before breaking down to the corresponding aldehyde or ketone.8
The reduction of ozonides to alcohol using LiAlH4, NaBH4, B2H6 and hydrogenation with
excess H2 has been reported. Ozonides have also undergone oxidation with oxygen,
peroxyacids and peroxides to give ketones and/or carboxylic acids.5
11

2.2 Wittig Reaction
Of all the known chemical reactions, the Wittig reaction is one of the most important in
preparative organic chemistry.10,11
Georg Wittig, who discovered the reaction in 1953 found
that when a aldehyde or ketone was reacted with a phosphorous ylide (also known as a
phosphorane), an alkene (olefin) was given. The three step formation of the phosphorus ylide
formation is shown below.(Scheme 11)12
Scheme 11 – Formation of a Phosphorus Ylide
Phosphorous ylides (or phosphoranes) are normally produced by reaction of
triphenylphosphine with an alkyl halide to form a phosphonium salt which is then reacted
with a strong base e.g. butyllithium, sodium hydride, sodium amide and sodium alkoxide. The
reaction conditions of choice are ylide dependent, air/moisture sensitive phosphoranes must
be produced in anhydrous condition with moisture-free solvents and an inert gas
environment.11,12
In contrast with a earlier method of olefinic formation, this involved the conversion of the
carbonyl compound to an alcohol using a Grignard reagent, followed by dehydration to the
olefin. The Wittig reaction is regiospecific in that the C=C bond can be placed where ever it is
needed. However, during the dehydration of an alcohol produced in the Grignard reaction, the
C=C bond could form in the wrong place in the product.
12
Ph3P H2C X
R
Ph3P CH2R Ph3P CHR
Ph3P CHR
X
Base
(12)
(13)

The Wittig reaction has many advantages over the prior method. One advantage is alkaline
condition in which the Wittig reaction is performed. This is also the only way that sensitive
olefins such as carotenoids, methylene steroid, compounds containing acid-sensitive
functional groups and other natural products can be prepared.11,12
2.2.1 Structure and Properties of Ylides
Ylides may be defined as compounds in which a positively charged atom from group 15 or 16
from the periodic table is connected to a carbon atom carrying a unshared pair or of electrons.
Because of pπ-dπ bonding, two canonical forms can be written for a phosphorus ylide (12)
and (13) as in scheme 11.13
The ylide may possess functional groups and contain double or
triple bonds. Ylides in which the R and R’ groups are hydrogens or alkyl groups have low
stability and hence high reactivity. The reactions of these ylides must be carried out in the
absence of oxygen, water, alcohols, carbonyl compounds and carboxylic esters. When the
reactions are performed with an electron withdrawing group (CN, COOR,CHO) present in the
α position, the ylides are highly stable because the charge on the carbon is stabilised by
resonance. (Figure 5).11,12,14
Figure 5 – Wittig Structure Resonance
The reactions, which use metal alkoxides as proton acceptors are commonly thought of as a
simple method for the preparation of phosphoranes and are one of the most common in use
for phosphorane formation reactions.11
13
C
H
C R
O
Ph3P C
H
C
O
R
Ph3P
(14) (15)

2.2.2 Reactions of Phosphoranes
Hydrolysing a phosphorane would expect to result in formation of phosphonium hydroxides
and a hydrocarbon.11
However, one of the reactions of phosphoranes which is the most
important is their reaction with carbonyl compounds. The addition of the aldehyde or ketone
to the phosphorane happens in a matter of minutes, forming an intermediate structure called a
betaine. This then undergoes rearrangement to form another structure called an
oxaphosphetane ring. Elimination occurs under the reaction conditions where
triphenylphosphine oxide and the olefin is formed. (Scheme 12) 11,12,14
Scheme 12 – Formation of Products via the Betaine and Oxaphosphetane intermediates
2.2.3 Stereochemistry
When carrying out the Wittig reaction, it is an issue to consider the stereochemistry of the
olefinic products. Wittig reactions sometimes give the cis alkene, other times the trans alkene
and occasionally a mix of the two. Total stereoisomeric purity is in fact difficult to obtain.12,13
The reaction stereochemistry has been shown to depend strongly on the reactions conditions
and the structure of the phosphorane.14,15
The electronic nature of the groups in the betaine structure has shown to affect and determine
the stereochemistry of the resulting alkene. In general, when the desired product is an olefin
of the sort R’−CH=CH−R”, where R’ and R” are simple alkyl groups, carbanion stabilisation
14
O
R2C PPh3
- +
R
O PPh3
R
- + O PPh3
R
R
O PPh3
R
R
+
Betaine Oxaphosphetane

results in the predominance of the trans isomer, which is the most thermodynamically stable.
(Scheme 13) Stabilising salts such as lithium or sodium halides, increased temperature,
carbanion stabilisation and excess base result in production of trans isomer. However,
unstabilised phosphoranes at low temperatures give mainly cis isomers or a mixture of cis and
trans isomer.12,14,15,16
15

Scheme 13 - The mechanistic pathway of the Wittig reaction for a phosphorane with a generic
carbonyl compound.17
16
O-
P+
Ph3
R'
R H
R H
O-
R' H'
P+
Ph3
H
C-
P+
Ph3
R' H
O
H R
P+
Ph3
R'H
HR
O- O-
R H
P+
Ph3
HR'
O PPh3
R'R
H H
O PPh3
R H
H R'
H H
R'R
+ Ph3PO Ph3PO+
H R'
HR
Threo-betaine
more stable
Erythro-betaine
less stable
Syn-oxaphosphetane
less stable
Anti-oxaphosphosphetane
more stable
Z-alkene
Kinetic Product
E-alkene
Thermodynamic Product

2.2.4 Solvent Effects
It has been specified that in Wittig chemistry, E selectivity is increased by non-polar solvents
and likewise Z selectivity is increased by protic solvents.18
The change in Z:E ratio on the use
of different solvents can be explained due to the nature of the reaction mechanism.19
Polar
solvents such as methanol and ethanol both have an electronegative atom (oxygen) attached to
the proton. Therefore these solvents are capable of solvating both cations and anions. The
cations are solvated by the use of the oxygen lone pairs whilst anions via the hydrogens. As a
result, these solvents are able to solvate and thus stabilise both of the diastereoisomeric
betaines formed in the 1st
step of the Wittig reaction. This solvent co-ordination to the betaine
is shown below. (Figure 6) 20
Figure 6- Solvation of the Threo Betaine in Methanol
The stabilising ability reduces the tendency for the opposite poles in the betaine to be close
together.18
This is due to both the steric bulk of the surrounding solvent cage and due to the
gain of electronic stability of the opposite changes. Effectively, there is less need for the P+
and O–
to come together and form the new P-O bond. Therefore, this solvent-betaine
interaction slows down the four membered ring (oxophosphetane) formation.20
17
O-
H
H H
O
H3C
O
H3C
O
CH3
R H
P+
Ph3
R'H
O
H CH3

Further to this, extra stability of the betaine reduces the likelihood of the occurrence of the
reverse reaction in the first step of the mechanism and so the interconversion between the
diastereoisomeric betaines is limited. In effect, the equilibrium between the starting materials
and the betaine is shifted heavily to that of the betaine and even so though the phosphorane is
still considered stabilised, the reverse reaction is much less probable. Therefore the more
stable threo-betaine forms in high yield as this is both the kinetic and thermodynamic
intermediate. As a result, this betaine goes onto form the Z-alkene in high yield passing
through the least stable syn-oxaphosphetane four membered ring. This time the increased
stability of the betaine and the shift of the equilibrium to the right makes it difficult for the
interconversion to the erythro betaine to occur. Therefore the formation of the E-alkene is less
likely because the thermodynamic controlled siphoning off of the erythro betaine is less
probable.20
Effectively, the Wittig reaction with stabilised phosphoranes in the presence of polar solvent
causes the reaction mechanism to proceed via more kinetic control as opposed to
thermodynamic control. The rate of elimination to the Z-alkene is now faster than the rate of
interconversion to the erythro betaine. Therefore the yield of the Z-alkene, the kinetic product,
increases at the expense of that of the E-alkene. However, results observed from literature do
not reflect that expected of a pure kinetically controlled reaction. This is because although the
betaine is stabilised, some interconversion will occur to the erythro betaine and allows the
reaction to proceed via thermodynamic control. Consequently, a mixture of both kinetic and
thermodynamic pathways are undertaken and so the reaction is much less stereospecific,
typically yielding a 1:1 product ratio.20
Less polar solvents such as dichloromethane cannot stabilise diastereoisomeric betaines as
effectively. This is because lone pairs on the chlorine atoms still have to co-ordinate to the P+
cations are much weaker bases compared to the lone pair on oxygen atoms in the alcohol
solvents, they are less strongly co-ordinated onto P+
cation. In addition, there are no protons
18

attached to an electronegative atom to solvate the O–
anions in the betaine. Both of these
effects reduce the solvating ability and thus the betaines are only weakly stabilised.
Consequently, a predominant equilibrium is present allowing the interconversion between the
betaines to occur. The reaction can proceed via thermodynamic control and therefore results
in E-selectivity.20
An example study of solvent effect of cis/trans isomer ratio with stabilised ylides is shown
below. (Table 1)
Reaction:
Ph3P+
–CH–
–COOMe + CH3CHO → Ph3P=O + CH3CH=CHCOOMe
Solvent Overall Yield (%) % cis % trans
CH2Cl2 88 6 94
DMF 98 3 97
MeOH 96 38 62
Effect of solvent on cis/trans ratio using a stabilised ylide – Table 1.21
19

2.3 The Project
The primary aim of this investigation is to examine the effects of the reaction medium upon
the stereoselective outcome of the Wittig reaction via an ozonolysis. The reaction will be
implemented in various solvents. However a uniform alkene and different stabilised
phosphoranes will be used in order to make a direct comparison. The project aim is to use the
unstable ozonide as a compound analogous to an aldehyde/ketone.
The techniques infrared radiation (IR), hydrogen nuclear magnetic resonance (1
H NMR)
spectroscopy as well as thin layer (TLC) and gas/liquid (GLC) chromatography will be
employed to characterise and determine the Z:E ratio of the subsequent alkene products.
A recent paper proved that the ‘in-situ’ reaction of ozonides derived from terminal olefins
with Wittig reagents gives the desired carbonyl compound in excellent yields. (Scheme 14) 22
20

Scheme 14 – ‘In-situ’ Reaction of Ozonides with Wittig Reagents
Carrying out the ‘in-situ’ reaction would have economical advantages of value to the
company because the ‘in-situ’ reaction only requires the need of 1 reaction vessel as currently
a related process requires the use of 2 vessels in 2 stages: the 1st
stage, an ozonolysis reaction
in 1 vessel followed by the 2nd
stage, a Wittig reaction on the isolated aldehyde in another
vessel
A 1 vessel ‘in-situ’ reaction would reduce fixed plant costs, reaction vessel usage and
raw material costs such as expensive reducing agents would be dramatically reduced.
21
C C
H
R
H
H
O
O
C C
O
H
R
H
H
O
C
OO
C
H
R
H
H
O
C
OO
C
H
R
H
H
Ph3P CHY
O
C
R H
+
O
C
H O
Deprotonation and
Ring fragmentation
+ Ph3P CH2Y
Fast intramolecular
proton exchange
O
CR
H O
C
H
O
H
+
Ph3P CHY
Acid catalysed
Wittig reactionRCH CHY
+ +Ph3PO HCO2H

3
Results and Discussion.
The ‘in-situ’ reactions of the ozonides produced from the ozonolysis of the starting
material, styrene with Wittig type reagents were carried out as outlined in sections 5.2 – 5.4.
The reaction was performed on 9 occasions: 3 different yildes with 3 different solvents. The
ozonolysis (1) reaction scheme is followed by the Wittig (2) reaction scheme. The results
obtained are outlines in Table 1 to 3.
22

3.1 In-situ Cinnamonitrile (CCN) Reactions
All the ‘in-situ’ reactions that were performed all gave poor yields. The product was not
isolated to an acceptable standard during the subsequent product isolation (Kugelrohr
distillation) so yield quotes are based on the percentage area of the product in solvent prior to
evaporation of the reaction solvent.
The results of the 3 reactions involving the use of the phosphorus ylide,
(triphenylphosphoranylidene) acetonitrile (TA) with a different solvent are shown below .
(Table 1)
Reaction 2 5 8
Solvent Methanol Dichloromethane Ethyl Acetate
Isomer Ratio
(Cis:Trans)
1.385:1 0.111:1 0.198:1
Isomer Ratio %
(Cis:Trans)
58.1%:41.9% 10.0%:90.0% 16.5%:83.5%
Impure purity by GC 13.75% 46.50% 40.05%
Impure isolated wt 6.70g 6.90g 5.90g
Active product wt in
impure sample by
GC
0.92g 3.23g 2.36g
Theoretical yield wt 1.64g 1.64g 1.64g
Yield according to
theoretical calc. by
GC
56.1% 197.0% ??? 143.9% ???
Table 1
23
OO
O
H
H
H
Ph
H
H
H
Ph
O3
Solvent
OO
O
H
H
H
Ph
-30°C
-30°C
Solvent+
HPh
CNH
Ph3PO HCO2H+
Styrene Ozonised Styrene
(Triphenylphosphoranylidene)
acetonitrile
Ph3P C
H
CN
Cinnamonitrile
+
Triphenyl
phosphine
oxide
Formic
Acid
1,
2,

3.1.1 1
H NMR of Cinnamonitrile
For 1
H NMR of trans-Cinnamonitrile, see Appendix A
1
H NMR (270 MHz,CDCl3) δ b. 5.76 (d, J = 17Hz, 1H), c. 7.24 (d, J = 17Hz, 1H), a. 7.37 (s,
5H).
24
HPh
CNH
a b
c

3.2 In-situ Benzylidene Succinic Anhydride (BSA) Reactions
The results of the 3 reactions involving the use of the phosphorus ylide, 2-
(triphenylphosphoranylidene) succinic anhydride (2-TSA) with a different solvent are shown
below (Table 2)
Reaction 3 6 9
Isomer Ratio
(Cis:Trans)
No analysis by GC
possible
No analysis by GC
possible
No analysis by GC
possible
Isomer Ratio %
(Cis:Trans)
Impure purity by GC
impure sample by
GC
Yield according to
GC
Table 2
25
OO
O
H
H
H
Ph
H
H
H
Ph
O3
Solvent
OO
O
H
H
H
Ph
-30°C
-30°C
Solvent+ Ph3PO HCO2H+
2-(Triphenylphosphoranylidene)
succinic anhydride
Benzylidene
Succinic
Anhydride
+
Triphenyl
phosphine
oxide
Formic
Acid
O
O
O
Ph3P C
H
O
O
O
H
Ph H
1,
2,

3.2.1 FT-IR of Benzylidene Succinic Acid
For FT-IR of Benzylidene Succinic Acid, see Appendix B
FT-IR (KBr) 690 and 730cm-1
(−C=C− bend in phenyl), 938cm-1
(−OH bend of acid dimer)
1285 and 1420cm-1
(−CO2H bend/stretch), 1413 and 1460cm-1
(−CH2− stretch), 1450, 1500
and 1601cm-1
(−C=C− stretch in phenyl ring), 1670cm-1
(>C=C< stretch in alkene) 1711cm-1
(−C=O stretch), 2861 and 2932cm-1
(−CH2− bend), 3050cm-1
(−CH stretch on phenyl),
3156cm-1
(−OH stretch of acid dimer).
3.2.2 FT-IR of Benzylidene Succinic Anhydride
For FT-IR of Benzylidene Succinic Anhydride, see Appendix C
FT-IR (KBr) FT-IR (KBr) 690 and 730cm-1
(−C=C− bend in phenyl), 1413 and 1460cm-1
(−CH2− stretch), 1450, 1500 and 1601cm-1
(−C=C− stretch in phenyl ring), 1670cm-1
(>C=C<
stretch in alkene) 1711cm-1
(−C=O stretch), 1750 and 1819cm-1
(−(C=O) −O−(C=O) −
stretch), 2861 and 2932cm-1
(−CH2− bend), 3050cm-1
(−CH stretch on phenyl).
26

3.3 In-situ Methyl Cinnamate (MC) Reactions
All the ‘in-situ’ reactions that were performed all gave poor yields. The product was not
isolated to an acceptable standard during the subsequent product isolation (Kugelrohr
distillation) so yield quotes are based on the percentage area of the product in solvent prior to
evaporation of the reaction solvent.
The results of the 3 reactions involving the use of the phosphorus ylide, methyl
(triphenylphosphoranylidene) acetate (MTA) with a different solvent are shown below .(Table
3)
Reaction 4 7 10
Isomer Ratio
(Cis:Trans)
0.317:1 0.026:1 0.054:1
Isomer Ratio %
(Cis:Trans)
24.1%:75.9% 2.5%:97.5% 5.2%:94.8%
Impure purity by GC 29.02% 35.00% 55.35%
impure sample by
GC
1.86g 2.03g 3.21g
Yield according to
GC
99.4% 109.7g ??? 173.5g ???
Table 3
27
OO
O
H
H
H
Ph
H
H
H
Ph
O3
Solvent
OO
O
H
H
H
Ph
-30°C
-30°C
Solvent+
Ph3PO HCO2H+
Methyl
(triphenylphosphoranylidene)
acetate
Methyl
Cinnamate
+
Triphenyl
phosphine
oxide
Formic
Acid
Ph3P C
H
CO2CH3
H
Ph H
CO2CH3
1,
2,

3.3.1 1
For 1
H NMR of Methyl trans-Cinnamate, see Appendix D
1
H NMR (270 MHz,CDCl3) δ d. 3.72 (s, 3H), 6.38 (d, J = 16Hz, 1H), 7.29 (m, 3H), 7.42 (m,
2H), 7.63 (d, J = 16Hz, 1H).
28
H
Ph H
CO2CH3
a b
c d

3.4 Calculation of Isomer Ratio for Cinnamonitrile and Methyl Cinnamate
Using the gas chromatograph and the retention times gained from the cis and trans isomer of
cinnamonitrile and methyl cinnamate, prior to the evaporation of reaction solvent from the
impure sample of cinnamonitrile and methyl cinnamate, the reaction solution was analysed by
as chromatography given that the sample injection was a representative sample of the reaction
mixture.
The corresponding areas by gas chromatography for the cis and trans isomer were first used to
calculate the cis:trans isomer ratio:
• area of cis isomer ÷ area of trans isomer
= isomer ratio
Then as a % out of a hundred, the ratio was calculated:
• (area of isomer ÷ sum of cis and trans isomer area) × 100
= % isomer ratio
Where the areas have been summed up, this was then used to calculate the amount of product
in the sample: this was done by first considering the presence of solvent in the sample
mixture. Hence the total area of the sample injection was ‘normalised‘, the area of the solvent
in the sample was subtracted from the total sample injection area. This gave a representation
of the sample with no solvent:
• total injection area – solvent area
29

= area of sample with no solvent
With a new total injection area value calculated, considering the exclusion of solvent, this was
then used with the sum of the cis and trans isomer areas to calculate the content of pure
product within the impure sample:
• sum of cis and trans isomer areas ÷ area of sample with no solvent ×100
= % product in impure sample
As it can be seen from the table, the gas chromatography table this analytical technique
cannot be relied on for % yield calculations. It is thought that the gas chromatography was not
complete for the analysis of the sample i.e there is still components in the mixture that have
either decomposed on the column, have not been eluted from the column due to insufficient
analysis time being performed or have remained on the stationary phase as the temperature
needed to ‘free’ them was not high enough. If these uneluted compounds came off the
column, it would contribute to total injection size and obviously effect the % yield calculation
by lowering the value to something hopefully sensible.
30

3.5 Calculation of Isomer Ratio for Benzylidene Succinic Anhydride
As elution of benzylidene succinic anhydride from the gas chromatograph was not possible,
the only evidence given that the reaction might have formed any product was the presence of
triphenylphosphine oxide by gas chromatograph.
Also given that the distillation temperature ‘straddled’ that of triphenylphosphine oxide would
mean that a quantitative/qualitative purification of product would be impossible.
A synthesis of benzylidene succinic anhydride was performed using a patent method to attain
a sample that could be used for identification via other analytical means. It was decided given
that the products in the paper that formed the basis of study were purified by silica gel
chromatography, this method was used via TLC. Using the sample of lab synthesised
benzylidene succinic anhydride and each of other 3 reactions samples, it was proven that
some of the reactions had worked. However, it was a shame that this method could not be
used easily to quantify cis/trans isomer ratio.
31

3.6 Discussion of Results
All experiments were performed using the 1.3 equivalents of ylide as reported in the
literature.
GC was preferred as the way of determining the Z:E ratio as the retention time of the starting
materials (Styrene), solvents (MeOH, DCM and EtOAc) and final products (CCN and MC),
from reference material samples, was determined via this method. The ylides in use for the
project (TA, 2-TSA and MTA) did not analyse via GC and this is thought to have been due to
the compounds breaking down on the column. The product BSA was analysed by GC but as
no reference material was available no peak could be assigned to it from the GC data. It was
also deduced from the literature that the product would not elute from the column as it’s
boiling point is 373±31°C, which is at least 72°C above the maximum temperature of the
column.
The reagents used in the synthesis of the BSA, namely dimethyl succinate and benzaldehyde,
were also analysed by GC. However the intermediate material benzylidene succinic acid and
the final product BSA were not analysed as the melting points were far in excess of the
column’s ceiling temperature. This would explain the absence of a ‘product’ peak with a
substantial GC area during the analysis of the BSA reaction.
The Kugelrohr distillations did not perform well for cinnamonitrile and methyl cinnamate.
Despite the distillations temperatures being adhered to, the fractions that were distilled might
have been obtained in a reasonably high purity, but it could not be performed to the point that
product could be distilled over entirely without taking a little triphenylphosphine oxide into it
or even then, removing light impurities without taking some of the product into it. When
32

analysing each fraction, it was found that the triphenylphosphine oxide and high boiling
impurities still contained product. The light boiling impurities also contained product. It is
assumed that if this was the sacrifice made to obtain a pure product, lose yield to both
impurities to guarantee a good purity, it would be okay. It was however found that the product
still contained a reasonable amount of triphenylphosphine oxide, heavy impurities due to
aggressive and prolonged distillation to maximise yield and again not being aggressive
enough with the product to remove the remaining light impurities, with conservation of yield
being the deciding factor.
Yield has not been determined correctly in this study. This is because, from problems
encountered in the Kugelrohr distillation. As commented upon above, the product was not
completely isolated from the impure sample.
The method of purification in the paper specified that the impure sample, composed of
impurities, triphenylphosphine oxide and the product, was ran on a column in 1:8 ethyl
acetate:hexane to afford pure product. As the method specified was rather brief it was a
decision not to investigate purification by this method. It was also decided that this method
would not be easy to apply to a plant process, and at the time, the short-path distillation using
a Kugelrohr apparatus would be both less time-consuming in use and the distillation would be
a process available for use on plant. The method of column chromatography would had
however provided a quantitative yield and hopefully a qualitative purity.
The 1
H NMR of cinnamonitrile (predominantly trans) and methyl trans-cinnamate was
performed to show that if the reactions that were performed to synthesise these respective
products, the information gained from the NMR spectra would enable identification and
verification of the purified reaction samples. As 2 of the cinnamonitrile samples and 1 of the
methyl cinnamate was successfully distilled but not to acceptable purity, these samples were
not run by NMR as the contamination would make the spectra difficult to integrate. It was an
33

oversight that the lab synthesised benzylidene succinic anhydride was not analysed via 1
H
NMR. It’s assumed that these samples would be a mix of isomers so the 1
H NMR would also
show this. It still doesn’t get away from the problem that all the samples in the impure form
physically appeared to contain a lot of impurities and they would all have to be purified by
other means to make 1
H NMR a viable option for analysis.
It was highlighted in discussion during the analysis of the cinnamonitrile (predominantly
trans) and methyl trans cinnamate, by gas chromatography, that it was almost definite that the
largest peak that eluted from the column was that of the reference material, which in both
cases would be the trans isomer of both reference materials. It would be ignorant to assume
the samples would be completely trans isomer and that they wouldn’t contain any cis isomer.
This was the hope made when the reference material was purchased and that the presence of
cis isomer in the reference material would serve as peak identification for this isomers and
therefore retention times would be identified for both isomers enabling easy identification of
isomer ratio within the samples. In both reference samples, both gas chromatographs were
clean and an additional peak was observed to occur near to that of the peak belonging to the
trans isomer. This was assumed to belong to that of the cis isomer. Calculation of isomer ratio
was made with the known retention time of the trans isomer and the assumed retention time of
the cis isomer.
In the analysis of the cinnamonitrile (predominantly trans) and methyl trans cinnamate, it was
hoped that the 1
H NMR might show some presence of cis isomer in the sample and that would
provide a cis/trans isomer ratio to further strengthen the evidence for assuming some cis
isomer exists in both the ‘trans isomer’ samples of reference materials. The technique was
either not sensitive enough or any cis isomer that was there was virtually non-existent.
The calculated isomer ratios for the 3 reactions of the cinnamonitrile and methyl cinnamate
reactions showed good agreement with table 1 which shows the cis/trans isomer ratio of stable
34

ylides with various solvents. It was encouraging to see that the effect of methanol in table 1
had a very similar effect in this study and also the effect of dichloromethane in table 1 had
similar effect to the use of dichloromethane and ethyl acetate in this study. It is known that
methanol is a polar protic solvent and dichloromethane and ethyl acetate are non-polar. In
table 1, in addition to methanol and dichloromethane being used, N,N-dimethylformamide
was used, a polar aprotic solvent.24
This was a polar solvent with a cis/trans ratio more similar
to that of a non-polar solvent. It is of course as explained in section 2.2.4 that methanol has
acidic hydrogens, typical of a polar protic solvent as opposed to N,N-dimethylformamide
which is polar aprotic, and has no acidic hydrogens. Dichloromethane has no acidic
hydrogens either. In the results, as expected, it can be seen that methanol is responsible for the
formation of more cis isomer. Whereas the use of dichloromethane and ethyl acetate are far in
favor of trans isomer formation. But what governs a non-polar solvents effect of trans isomer
formation. Nearly twice as much cis isomer is formed in the ethyl acetate reactions than
formed in the dichloromethane reactions. Is it because of polarity?
The polarities (in units of ε = dielectric constant) of the solvents in study are 33.0 for
methanol, 9.1 for dichloromethane and 6.0 for ethyl acetate. In table 1, there N,N-
dimethylformamide. This has a polarity of 38.0. At first it would be thought disregarding
table 1 momentarily, on the evidence of methanol and dichloromethane that the higher the
polarity the higher the chance of cis isomer formation. But methanol has acidic hydrogens and
dichloromethane does not, so no argument. But again N,N-dimethylformamide has a different
polarity to dichloromethane but again, one is polar aprotic and the other non-polar
respectively. Ethyl acetate and dichloromethane are both non-polar and the polarity of ethyl
acetate is lower than that of dichloromethane, but ethyl acetate has more cis isomer formed
than that of dichloromethane for both the cinnamonitrile and methyl cinnamate reactions. Is
this a possible line of interest?
35

Another idea which occurs for solvent and choice of ylide is steric bulk. Looking at the
cinnamonitrile and methyl cinnamate reactions again, you can see clearly that more cis was
produced in the cinnamonitrile reactions than that of the methyl cinnamate reactions. This is
probably due to steric bulk. The size of the −C≡N group in steric size to –CO2CH3 is far
smaller. This would give the idea that the existance of a cis isomer of methyl cinnamate is less
favored than that of a trans isomer where the phenyl and –CO2CH3 groups are on opposite
sides of the alkene. Whereas the formation of trans isomer of cinnamonitrile would be
favored, the −C≡N group is not that large and you would expect a larger degree of cis isomer
produced in cinnamonitrile in comparison to that of the methyl cinnamate. In
dichloromethane as it can be seen that more cis is produced of the cinnamonitrile than the
methyl cinnamate. What is surprising is the cis isomer produced in the cinnamonitrile reaction
with methanol, the cis isomer is more that 1:1 in ratio, in fact it is almost 1.4:1 cis to trans
isomer ratio.
The benzylidene succinic anhydride has not been discussed much yet in terms of cis/trans
isomer ratio. This is because, as explained, the product was not able to be analysed via gas
chromatography, which was the preferred method for isomer ratio determination. In fact it
was also the product’s boiling point that caused raised ideas on the attempted purification by
distillation. Again, the immediately available method the isomer ratio could be determined
would be to use the column chromatography purification method followed by 1
H NMR
analysis.
36

3.7 Future Work
It was known that methanol leads to the formation of more cis isomer being produced in the
Wittig reaction. It is also known that ylides are sensitive to water and alcohols, most of which
are polar protic solvents, makes them technically problematic to use. The use of non-polar
solvents and polar aprotic solvents is something to think about, but it must be considered that
the solvent shouldn’t be too expensive to purchase. In this study only polar protic and non-
polar solvent was used. Perhaps the use of a single ylide with other non-polar solvents as well
as a few polar aprotic solvents should be attempted to look at better ways of producing better
ratio favoring higher trans isomer formation.
It was touched on in the discussion that steric bulk may effect the cis/trans stereochemistry.
As the steric bulk on the styrene was always fixed and it was only the functional group on the
ylide that any assumptions were made, it is worth further investigating the use of other ylides,
with consideration however for the product molecule’s physical properties such as boling
point in the case of this study which was a problem with benzylidene succinic anhydride.
A method for pre removal of triphenylphosphine oxide prior to distillation in the case of this
study would have eased the distillation and purification of product, this is if the distillation
was chosen as the final method of isolating the product.
37

4
Conclusions
The reactions were seen to behave as what was expected in the reaction between methyl
(triphenylphosphoranylidene) acetate and acetaldehyde in a polar protic and non-polar solvent
as in table 1. Polar solvent resulted in much more cis isomer formation that the use of non-
polar solvent. But non-polar solvent did not produce only trans isomer but a little of the cis
isomer as well.
The method of Kugelrohr distillation was not applicable for purification for the alkene
product in the lab. It was difficult to isolate the product in a good qualitative purity and
quantitative yield.
The synthesis of benzylidene succinic anhydride from the ozonolysis and subsequent Wittig
reaction went fairly well. Except there was no method of determining the isomer ratio from
the impure product.
38

5
Experimental
The following sections specify the experimental procedures for the synthesis of each of the
products of interest.
All materials used in the syntheses were obtained from the commercial suppliers and used
without further purification.
Ozonolysis was performed on an Ozonia OZAT CFS 1A ozone generator.
Analysis of the reaction mixtures and products was carried out using gas chromatography and
thin layer chromatography using the methods outllined in this section.
39

5.1 Analytical Procedures
5.1.1 GC (Gas Chromatography)
All GC analysis was performed using a Shimadzu GC-14A under the following conditions:
Column: CpSil 5CB 50m × 0.53mm, film thickness = 5.0μm
Injector: 250°C
Detector: 250°C
Oven: 120°C for 10 mins, ramp 10°C/min to 270°C for 40 mins
5.1.2 TLC (Thin Layer Chromatography)
The TLC’s were performed on glass/silica gel plates designed to fluoresce under an ultra-
violet lamp at 254nm. The chromatography was run in 1:8 ethyl acetate:hexane to develop.
5.1.3 FT-IR (Fourier-Transform Infra-Red) Spectroscopy
All IR spectroscopy analysis was performed using a Perkin-Elmer PARAGON 1000 FT-IR
Spectrophotometer using KBr disks.
5.1.4 1
H NMR (Hydrogen Nuclear Magnetic Resonance) Spectroscopy
1
H NMR was performed on the Jeol EX270 (Eclipse) NMR Spectrometer running with Delta
workstation at the University of Northumbria at Newcastle.
40

5.2
General Procedure for ‘One Flask’ Synthesis of Cinnamonitrile
via an Ozonolysis then Wittig reaction.
A 100ml four necked round bottomed flask was set up, with a cold trap (cold finger) filled
with solid CO2/acetone, temperature probe, overhead stirrer and a glass gas dispersing tube
(fitted with a sinter tip) as shown in appendix E.
The substrate, styrene (1.33g, 12.76 mmol, 1.0 equiv.) and solvent (60ml) were added to the
round bottomed flask and stirred. The flask contents were cooled to –30°C under an oxygen
purge.
Ozone was sparged through the solution whilst maintaining the temperature at –30°C ± 2°C.
Ozonolysis was stopped when the flask contents formed a blue colour. Excess ozone was
purged out with oxygen at –30°C.
When the blue colour had gone from solution, (triphenylphosphoranylidene) acetonitrile
(5.0g, 15.59 mmol, 1.3 equiv. based on styrene) in chilled solvent (30ml) was added to the
ozonised styrene at –30°C. The cold finger on the flask was replaced by a water condenser
with a nitrogen bubbler attached to maintain a inert atmosphere within the flask.
After the addition of ylide to the ozonised styrene solution at -30°C, the reaction was agitated
and allowed to warm to ambient. It was then left to stir overnight (~12 hours) to ensure
completion of reaction. The reaction was then analysed the next day by gas chromatography
to check for reaction completion and profile.
41

The resulting solution was transferred to a 1st
one-necked Kugelrohr flask and concentrated
under vac (30”Hg) on a rotary evaporator to a maximum temperature of 45°C to give a dark
brown/red solution that later crystallised on cooling due to the presence of triphenylphosphine
oxide.
The crystalline material was purified by Kugelrohr distillation under vac (10mbar). At
760mm, atmospheric pressure, the distillation temperatures of triphenylphosphine oxide and
cinnamonitrile are 360°C and 254-255°C and at 10mbar, the distillation temperatures are
lowered to 210°C and 124°C respectively. The product and lights were distilled over to the 2nd
Kugelrohr flask at a maximum temperature of 200°C/10mbar, then followed by distillation of
the light volatile impurities over to the 3rd
Kugelrohr flask at 110°C/10mbar to give pure
cinnamonitrile.
The distilled fractions in both stages of the distillation were analysed by gas chromatography
and the purity was monitored to attain how long to perform the distillation.
42

5.3
General Procedure for ‘One Flask’ Synthesis for Benzylidene Succinic Anhydride
purge.
When the blue colour had gone from solution, 2-(triphenylphosphoranylidene) succinic
anhydride (5.0g, 13.875 mmol, 1.3 equiv. based on styrene) in chilled solvent (30ml) was
added to the ozonised styrene at –30°C. The cold finger on the flask was replaced by a water
condenser with a nitrogen bubbler attached to maintain a inert atmosphere within the flask.
completion of reaction.
43

The reaction completion was unable to be established via gas chromatography as the boiling
point of the product was far in excess of the capability of the gas chromatograph.
Triphenylphosphine oxide was however found by gas chromatography.
brown viscous liquid that later crystallised on cooling due to the presence of
triphenylphosphine oxide.
The crystalline material was not purified by Kugelrohr distillation as the temperature at which
the product distills at atmospherically is reported to be 373±31°C. At 10mbar, the distillation
temperatures of triphenylphosphine oxide and benzylidene succinic anhydride are 210°C and
220±25°C respectively. As the benzylidene succinic anhydride has a 50°C range across
220°C, which also crosses the distillation temperature of triphenylphosphine oxide, there is a
good chance at some point during the distillation that both the impurity and product will co-
distill.
The success of the reaction, if product had been made, was proved by thin layer
chromatography. A small sample of benzylidene succinic anhydride from each reaction was
solubilised in a portion of dichloromethane. The solution was then spotted onto the silica gel
plate. A synthesised sample of benzylidene succinic anhydride was also solubilised in
dichloromethane and also spotted onto the plate to act as a standard. The solvent on the plate
was then allowed to evaporate. It was then placed in a thin layer chromatography tank
containing development solvent.
The thin layer chromatography silica plate was allowed to dry and then was placed under a
UV lamp at 254nm and the spot positions were noted. The position of the spot from the
44

synthesised benzylidene succinic anhydride standard and the spots belonging to each of the
other three reactions were seen to all appear at a similar height on the plate.
45

5.4
General Procedure for the ‘One Flask’ Synthesis for Methyl Cinnamate
purge.
When the blue colour had gone from solution, methyl (triphenylphosphoranylidene) acetate
(5.0g, 14.95 mmol, 1.3 equiv. based on styrene) in chilled solvent (30ml) was added to the
ozonised styrene at –30°C. The cold finger on the flask was replaced by a water condenser
completion of reaction. The reaction was then analysed the next day by GC to check for
reaction completion and profile.
46

brown/red solution that later crystallises on cooling due to the presence of triphenylphosphine
oxide.
The crystalline material was purified by Kugelrohr distillation under vac (10mbar). At
760mm, atmospheric pressure, the distillation temperatures of triphenylphosphine oxide and
methyl cinnamate are 360°C and 260-262°C and at 10mbar, the distillation temperatures are
lowered to 210°C and 125°C respectively. The product and lights were distilled over to the 2nd
Kugelrohr flask at a maximum temperature of 200°C/10mbar, then followed by distillation of
the light volatile impurities over to the 3rd
Kugelrohr flask at 110°C/10mbar to give pure
methyl cinnamate.
The distilled fractions in both stages of the distillation were analysed by GC and the purity
was monitored to attain how long to perform the distillation.
47

5.5
Synthesis of Benzylidene Succinic Acid
The method for this synthesis and the information gathered from it was obtained via a
patent.23
A 250ml four necked round bottomed flask was set up for an anhydrous addition by
equipping the flask with a 100ml addition funnel, temperature probe and water condenser
Dimethyl succinate (51.15g, 350 mmol) and methanol (20ml) were added to the flask and
stirred. This was followed by sodium methoxide (7.85g, 145 mmol) and methanol (80ml).
The flask was heated to reflux (80°C). On reaching reflux, benzaldehyde (12.5g, 118 mmol)
and methanol (20ml) were added dropwise to the reaction over a period of 1 hour.
After the benzaldehyde addition, the reaction was refluxed for 1 hour to complete the
reaction. It was noted during the 1 hour reflux that the physical appearance of the reaction did
not change. It was further refluxed for 3 hours to see if any change occurred.
The reaction was analysed by GC after the 3 hour stir at reflux and the starting materials were
still found to be remaining.
As the reaction was incomplete after 4 hours at reflux and 1 hour was all that was initially
needed to take the reaction to completion, it was decided that either the original sodium
methoxide material that was used might have been ‘old’ material that had partly reacted with
48

moisture or the methanol may have contained traces of water. Whatever the problem, it was
decide to use 20% w/w sodium methoxide in methanol (21.35g,of which 4.27g, 79 mmol
active) which was 0.54 equiv of the original charge. The reaction was then refluxed for an
additional 2 hours to attain completion.
When the reaction was again analysed by GC, the corresponding benzaldehyde peak had
gone, an assumption the reaction had gone to completion.
The flask was then setup for distillation. Methanol (100ml) was removed by distillation under
vacuum at 60°C. 25% w/w sodium hydroxide (120ml) was charged to the flask. The flasks
contents thickened substantially on the addition of the sodium hydroxide.
The flasks contents occupied the majority of the 250ml four necked round bottomed flask so
for the ease of distillation, the contents were transferred to a 500ml four necked round
bottomed flask to distill the remaining methanol from the flask under vac at 60°C. The flask
and its contents were returned to ambient temperature under vacuum.
When the vacuum was released from the flask, water (150ml) and dichloromethane (150ml)
were added to the flask. A white biphasic slurry was produced. 36% w/w hydrochloric acid
(150ml) was added dropwise to the flask contents via a 250ml dropping funnel over 1 hour
keeping the temperature below 20°C to precipitate the product. No precipitation was
observed.
Additionally, half the original charge of hydrochloric acid (75ml) was added dropwise.
Around ¾ of the way through the addition of acid to the flask contents, precipitation occurred.
The remaining ¼ of the acid was added to the flask.
49

The flask contents were then filtered and washed with water (2 × 50ml) then dichloromethane
(2 × 50ml) and the resulting solid was dried under vac at 100°C.
As the resulting solid’s purity could not be established by gas chromatography, it was decided
that the purity would be determined via melting point. The literature states that the melting
point of benzylidene succinic anhydride is 168°C. The melting point of the material made in
this synthesis melted over 150-151°C. The material was placed in the oven overnight and
when the material was retested, it melted between 160-162°C.
50

5.6
Synthesis of Benzylidene Succinic Anhydride
The method for this synthesis and the information gathered from it was obtained via a
patent.23
A 100ml four necked round bottomed flask was set up for an anhydrous reaction by equipping
the flask with a temperature probe and water condenser with a nitrogen bubbler attached to
maintain a inert atmosphere within the flask.
Benzylidene succinic acid (15g, 72.8 mmol) and isopropyl ether (45ml) were added to the
flask and stirred. This was followed by acetic anhydride (8.2g, 80 mmol).
The reaction was heated to reflux (70-80°C) and stirred for 4 hours. During this time it was
noted that the reaction turned from a white to a yellow colour.
The reaction was then cooled back to 0°C and stirred for 30 mins.
The flask contents were then filtered and washed with isopropyl ether (2 × 50ml) and the
resulting solid was dried under vac at 100°C.
As the resulting solid’s purity could not be established by gas chromatography, it was decided
that the purity would be determined via melting point. The literature states that the melting
point of benzylidene succinic anhydride is 199°C. The melting point of the material made in
this synthesis melted over 180-185°C. The material was placed in the oven overnight and
when the material was retested, it melted between 193-195°C.
51

6
COSHH Assessment
The major risks to health when carrying out this project are detailed below. For all material
safety sheets, refer to Appendix F
Formation and use of ozone:
Ozone is a toxic and irritant gas that has a characteristic odour. It is a powerful oxidant and
can react or decompose in an explosive manner. Ozone forms unstable interemediates with
many organic compounds that can also decompose in an explosive manner. Care must
therefore be taken when using ozone and strict monitoring of reaction conditions and
subsequent differential scanning calorimetry (DSC) analysis of quenched reaction mixtures
will determine safe decomposition of the potentially explosive intermediates.
Working with flammable liquids:
When using flammable solvents it is important to handle only them in a fume cupboard
wearing appropriate personal protective equipment. All sources of ignition should be removed
from the area when handling flammable solvents. In this occasion flammable solvents are
being used in an oxygen rich environment and extra care should be taken at all times.
52

The following list details the chemicals used in the project and any associated hazards.
Ozone
Ozone is a toxic, irritant gas. It reacts with most organic compounds and explosively in the
presence of activated metals. Ozone reacts violently with vacuum grease and all reaction flask
joints must not be lubricated with grease. The ozone generator must be installed in a fume
cupboard with all pipework that carries ozone also within. The reaction flask must also be
vented to the rear of the fume cupboard via scrubbers to minimise exposure.
Styrene
Flammable. Harmful by inhalation. Irritating to eyes and skin. Vapour may travel a
considerable distance to source of ignition and flash back. May polymerise on exposure to
light. Avoid oxidising particulary copper and copper oxides. Hazardous decomposition
products include carbon monoxide and carbon dioxide. Evidence of carcinogenic, mutagenic,
teratogenic and disruption to reproduction.
Methyl trans-Cinnamate
Non-hazardous. Observe good hygiene when using chemical. Forms toxic gases such as
carbon monoxide and carbon dioxide on combustion. Avoid strong oxidising agents. The
chemical, physical and toxicological properties have not been thoroughly investigated.
53

Cinnamonitrile
Irritating to eyes, respiratory system and skin. Forms toxic gases such as carbon monoxide,
carbon dioxide and nitrogen oxides on combustion. Avoid strong oxidising agents. The
chemical, physical and toxicological properties have not been thoroughly investigated.
Triphenylphosphine Oxide
Harmful if swallowed. Irritating to eyes, respiratory system and skin. Forms toxic gases such
as carbon monoxide, carbon dioxide, phosphorus oxides and phosphines on combustion.
Avoid strong oxidising agents. The chemical, physical and toxicological properties have not
been thoroughly investigated.
Formic Acid
Causes severe burns. Avoid ingestion, inhalation and contact with skin and eyes. Vent
periodically, may develop pressure, open carefully. Hygroscopic. Combustible liquid. Forms
toxic gases such as carbon monoxide and carbon dioxide on combustion. Avoid strong
oxidising agents, strong bases and finely powdered metals. Mutagenic evidence.
Benzylidene Succinic Acid
White solid. Avoid contact with eyes and skin. The chemical, physical and toxicological
properties have not been thoroughly investigated. May form toxic gases such as carbon
monoxide and carbon dioxide on combustion.
54

Benzylidene Succinic Anhydride
Yellow solid. Avoid contact with eyes and skin. The chemical, physical and toxicological
properties have not been thoroughly investigated. May form toxic gases such as carbon
monoxide and carbon dioxide on combustion. May decompose on exposure to moist air or
water.
(Triphenylphosphoranylidene) Acetonitrile
White to cream solid which is in compatible with oxidising agents and the air. Forms toxic
gases such as carbon monoxide, carbon dioxide, phosphine oxides, phosphine, nitrogen
oxides and hydrogen cyanide on combustion. Irritating to eyes, respiratory system and skin.
Avoid strong oxidising agents. The chemical, physical and toxicological properties have not
been thoroughly investigated.
Methyl (Triphenylphosphoranylidene) Acetate
gases such as carbon monoxide, carbon dioxide, phosphine oxide and phosphine on
combustion. Irritating to eyes, respiratory system and skin. Avoid strong oxidising agents.
The chemical, physical and toxicological properties have not been thoroughly investigated.
55

2-(Triphenylphosphoranylidene) Succinic Anhydride
gases such as carbon monoxide, carbon dioxide, phosphine oxide and phosphine on
combustion. Irritating to eyes, respiratory system and skin. Avoid strong oxidising agents.
May decompose on exposure to moist air or water. The chemical, physical and toxicological
properties have not been thoroughly investigated.
Methanol
Highly flammable, toxic solvent. Can be absorbed through the skin causing systemic toxic
effect. Hazardous reactions reported with aluminium and oxidisers. Use only in a fume
cupboard and use nitrogen inerting on reaction flasks. Remove all sources of ignition when
handling solvent.
Dichloromethane
Is a category 3 carcinogen and has a possible risk of irreversible effects. Inhalation can be
fatal. Dichloromethane is irritating to eyes, skin and all contact should be avoided.
Decomposes in a flame to give off toxic gases (phosgene and hydrogen chloride).
Hexane
Highly flammable solvent. Hexane is a narcotic and also has a risk of electrostatic charge
generation. Possible teratogen. Hexane is also thought to impair fertility. Incompatible with
strong oxidisers including chlorine. Can form explosive mixtures at 28°C with NOx. Keep
away from all forms of ignition.
56

Ethyl Acetate
Highly flammable. Vapour/air mixtures are explosive. An electrostatic charge may be
generated during movement. Reacts violently with chlorosulphonic acid. A mild narcotic
which also effects the liver and the kidneys. Irritant to eyes, skin and respiratory tract. Keep
away from all sources of ignition.
Sodium Methoxide
White powder which is corrosive on contact with skin and eyes. Incompatible with acids,
oxidisers and is unstable in moist air which may lead to risk of ignition. Decomposition on
heating leads to the formation of toxic fumes.
36% Hydrochloric Acid
Concentrated hydrochloric acid is a colourless liquid which forms very corrosive acid fumes
in contact with air. It is corrosive and irritating to skin and eyes. Inhalation of fumes should
be avoided. Incompatible with strong bases and strong oxidants.
Dimethyl Succinate
Irritating to eyes. Forms toxic gases such as carbon monoxide and carbon dioxide on
combustion. Avoid strong oxidising agents, acids, bases and reducing agents. The chemical,
physical and toxicological properties have not been thoroughly investigated.
57

Benzaldehyde
Harmful if swallowed. Combustible liquid. Forms toxic gases such as carbon monoxide and
carbon dioxide on combustion. Avoid strong oxidising agents, strong reducing agents and
strong bases. Avoid light, moisture and air. Mutagenic effects. The chemical, physical and
toxicological properties have not been thoroughly investigated.
Sodium Hydroxide
Causes severe burns. Contact with aluminium, tin and zinc liberates hydrogen gas. Contact
with nitromethane and other similar nitro compounds causes formation of shock-sensitive
salts. In the event of a fire, do not use water to extinguish. Absorbs carbon dioxide from air.
Heat of solution is very high, and with limited amounts of water, violent boiling may occur.
Never add water to this material, always add this to water. Do not allow water to enter
container because of violent reaction. Avoid strong oxidising agents, strong acids and organic
materials. Forms sodium/sodium oxides on decomposition. Mutagenic effects. The chemical,
physical and toxicological properties have not been thoroughly investigated.
Diisopropyl Ether
Highly flammable. May form explosive peroxides on storage. Repeated exposure may cause
skin dryness or cracking. Vapours may cause drowsiness and dizziness. Vapour may travel a
considerable distance to source of ignition and flash back. Avoid strong oxidising agents.
Forms toxic gases such as carbon monoxide and carbon dioxide on combustion. Teratogenic
effects. May form a static charge on movement.
58

Acetic Anhydride
Flammable. Harmful by inhalation and if swallowed. Causes burns. Combustbile liquid.
Forms toxic gases such as carbon monoxide and carbon dioxide on combustion. Do not allow
water to enter container because of violent reaction. Avoid contact with alcohols, acids,
oxidising agents, bases, reducing agents and finely powdered metals. Lachrymator.
59

7
References
1. Kirk Othmer , Encyclopedia of Chemical Technology, 3rd
Edition, 16, Pg 683-713, J.
Wiley and Sons, 1981.
2. P.S. Bailey, Ozonisation in Organic Chemistry, 1, Academic Press, London, 1978.
3. J.S. Belew. Ozonisation, Chapter 6, Oxidation: Techniques and Applications in
Organic Synthesis, R.L. Augustine, Pg 259-300, 1, Marcel Dekker Inc., New York,
1969.
4. H.F. Oehlschleager, Reactions of Ozone with Organic Compounds, Ozone/Chlorine
Dioxide Products of Organic Material. G. Rice and J.A. Cortruvo, Pg 20-37, Syracuse
Lithographing Co., New York, 1978.
5. M.B. Smith and J. March, March’s Advanced Organic Chemistry, 5th
Edition, Pg
1522-1528, John Wiley and Sons Ltd., 2001.
6. R. Criegee, Chem. Int. Eng., 1975, 14, Pg 745-752,
7. R.W. Murry, Chem. Res., 1968, 1, Pg 313-323
8. J. Carles and S. Flizar, J. Chem., 1972, 50, Pg 2552.
9. W.S. Knowles and Q.E. Thompson, J. Org. Chem., 1960, 25, Pg 1031.
10. A. Streitwieser, C.H. Heathcock and E.M. Kosower, Introduction to Organic
Chemistry, 4th
Edition, Pg 408-410, Macmillan Publishing Co., 1992.
11. A. Maecker, The Wittig Reaction, Chapter 3, Organic Reactions, A.C. Cope, 14, Pg
270-490, J .Wiley and Sons Ltd., 1965.
Edition, Pg
1231-1237, John Wiley and Sons Ltd., 2001.
Edition, Pg 45-
46, John Wiley and Sons Ltd., 2001.
60

14. B.S. Fumiss, A.J. Hannaford, P.W.G. Smith and A.R. Tatchel, Vogels Textbook of
Practical Organic Chemistry, 5th
Edition, Pg 495-498, Longman Ltd., 1989.
15. F.A. Carey and R.J. Sundberg, Advanced Organic Chemistry, 3rd
Edition, Part B –
Reactions and Synthesis, Pg 95-101, Plenum Press, London, 1990.
16. H.J. Bestmann, Old and New Ylide Chemistry. Pure and Appl Chem., 1980, 52, Pg
771-788.
17. Notes of C. Fieldhouse, Reactive Intermediates Course, Option Module, University of
York, 2004
18. C. Harcken, S.F. Martin, Improved E-selectivity in the Wittig reaction of stabilized
ylides with α-alkoxyaldehydes and sugar lactols, Org.Lett, 2001, 3 (22), Pg 3591-
3593.
19. S. Patai, The chemistry of double-bonded functional groups, Part 1, J. Wiley and
Sons, London, 1977
20. Notes from C. Fieldhouse, An investigation to determine the most important factors
that control the stereochemical outcome of the Wittig reaction, University of York,
2005.
21. B.J. Walker, Organophosphorus Chemistry, 1st
Edition, Pg 144 – 149, Penguin
Education, 1972.
22. Y-S. Hon, L. Lu, R-C. Chang, S-W. Lin, P-P Sun and C-F Lee, Synthesis of α, β-
Unsaturated Carbonyl Compounds from the Reactions of Monosubstituted Ozonides
with Stable Phosphonium Ylides, Tetrahedron, 2000, 56, Pg 9269-9279.
23. J-P. Lecouvre, C. Fugier, J-C. Souvie, Method for preparing a substituted
perhydroisoindole, Adir et Compagnie, US Patent US006133454A, France, 1998.
24. Solvents URL: http://en.wikipedia.org/wiki/Solvent (23 May 2005)
61

8
Acknowledgement
I would first like to express my thanks to my two project supervisors, Dr Steve Stanforth at
University of Northumbria at Newcastle for picking up on things I should have given a little
bit more thought to which was highlighted in the poster presentation.
Also I would like to thank my work-based supervisor Dr James Rooney for guiding me
through the project and being there for assistance.
I would like to also give a great big thanks to Paul Hewett for his additional help from his
experience gained through doing related ozonolysis/wittig work and helping me avoid
problems that he encountered with his work.
I would also like to thank Charlottle Fieldhouse for letting me study her work on Wittig
stereochemistry and supplying me with the names of the books she used in her study to aid
my work.
Lastly, I would like to thank Dr Simon Rowell and Andrew Deacon for helping me with the
small problems you occassionally encounter in chemical synthesis and rectifing them for me.
62

Appendix A
1
H NMR of trans-Cinnamonitrile
64

Appendix B
FT-IR of Benzylidene Succinic Acid
66

Appendix C
FT-IR of Benzylidene Succinic Anhydride
68

Appendix D
1
70

Appendix E
Ozonolysis Apparatus
72

Appendix F
Material Safety Data Sheets
74

Compo's final project (30.05.05 1725)

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