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 1H 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 1H 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 1H 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

OO

O OO

OOO

O OO

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

electricaldischarge

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

OO

O

CC

OO

(5) (6)

O

CC

OO

(6)

H2OC O COH2O2 ++

CO+O

OC

O

CC

OO

(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

OO O

C C

R

R

R

RC

OO

O

CR

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

CO

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

OO

OR

R

R

R

C O

R

RC 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

CO

C

R'

R

R''

R'''

OO

CO

C

PPh3

R'

R

R''

R'''

PPh3

O

R'

R

O

R''

R'''

+ + Ph3PO

O2+R

C

R

OC O O

R

R2 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

RR

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 HR 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'RH H

O PPh3

R HH R'

H H

R'R

+ Ph3PO Ph3PO+

H R'

HR

Threo-betainemore stable

Erythro-betaineless stable

Syn-oxaphosphetaneless stable

Anti-oxaphosphosphetanemore stable

Z-alkeneKinetic Product

E-alkeneThermodynamic 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-

HH H

O

H3C

O

H3C

O

CH3

R H

P+Ph3

R'H

OH 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 % transCH2Cl2 88 6 94DMF 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 (1H 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

OO

C C

OH

R

H

HO

C

OO

CH

R

H

H

OC

OO

CH

R

H

H

Ph3P CHY

O

CR H

+

O

CH O

Deprotonation and Ring fragmentation

+ Ph3P CH2Y

Fast intramolecularproton exchange

O

CR

H O

C

H

O

H

+

Ph3P CHY

Acid catalysedWittig 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 8Solvent Methanol Dichloromethane Ethyl AcetateIsomer 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 5.90gActive product wt in impure sample by GC

0.92g 3.23g 2.36g

Theoretical yield wt 1.64g 1.64g 1.64gYield 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°CSolvent+

HPh

CNH

Ph3PO HCO2H+

Styrene Ozonised Styrene

(Triphenylphosphoranylidene)acetonitrile

Ph3P C

H

CN

Cinnamonitrile

+

Triphenylphosphine

oxide

FormicAcid

1,

2,

3.1.1 1 H NMR of Cinnamonitrile

For 1H NMR of trans-Cinnamonitrile, see Appendix A

1H 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)


No analysis by GC possible



Isomer Ratio %(Cis:Trans)Impure purity by GCImpure isolated wt 6.30g 6.80g 5.50gActive product wt in impure sample by GCTheoretical yield wt 2.00g 2.00g 2.00gYield according to theoretical calc. by 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°CSolvent+ Ph3PO HCO2H+


2-(Triphenylphosphoranylidene)succinic anhydride

BenzylideneSuccinic

Anhydride

+

Triphenylphosphine

oxide

FormicAcid

O

O

OPh3P 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)


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 isolated wt 6.40g 5.80g 5.80gActive product wt in impure sample by GC

1.86g 2.03g 3.21g

Theoretical yield wt 1.85g 1.85g 1.85gYield according to theoretical calc. by 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°CSolvent+

Ph3PO HCO2H+


Methyl (triphenylphosphoranylidene)

acetate

MethylCinnamate

+

Triphenylphosphine

oxide

FormicAcid

Ph3P C

H

CO2CH3 H

Ph H

CO2CH3

1,

2,

3.3.1 1 H NMR of Methyl trans-Cinnamate

For 1H NMR of Methyl trans-Cinnamate, see Appendix D

1H 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 1H 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 1H

NMR. It’s assumed that these samples would be a mix of isomers so the 1H 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 1H 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 1H 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 1H 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

1H 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.

12. M.B. Smith and J. March, March’s Advanced Organic Chemistry, 5th Edition, Pg

1231-1237, John Wiley and Sons Ltd., 2001.

13. M.B. Smith and J. March, March’s Advanced Organic Chemistry, 5th 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

9

Appendix

63

Appendix A

1H 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

1H NMR of Methyl trans-Cinnamate

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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