Examining The Synthesis Of A Range Of Vinylcyclopropane Biology Essay

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Vinylcyclopropanes at standard room temperature and atmospheric pressure were efficiently synthesised using the Wittig reaction. The reaction involved the use of a strong base (benzyltriphenylphosphonium chloride) dissolved in ethanol and cyclo-propylphenyl ketone reacted with sodium ethoxide solution. A relatively pure product was obtained at a yield of 4.54g (73.2%). A melting point of 145-148oC was obtained and infra-red of the product was taken.



Vinylcyclopropane were first synthesised by Gustavson in 1896.1 Vinylcyclopropane in 1922 was then prepared by exhaustive methylation of amine acquired from the oxime of methyl cyclopropyl ketone. Demjanov and Dojarenko supposed these hydrocarbons couldn't be synthesised by the dehydration of methylcyclopropylcarbinol.1 In recent research vinylcyclopropane was successfully synthesised via the dehydration of methylcyclopropylcarbinol.

Vinylcyclopropanes are made from a 3 carbon propane ring and a vinyl group attached.

Vinyl is an organic compound which has a chemical formula of -CH=CH2 which is a derivative of ethene.

Vinyl Cyclopropane

Primary alkenes contain a vinyl group and on a skeletal structure sp2 hybridised carbons are called vinylic.

The synthesis of vinylcyclopropane in a pure form is quite difficult due to the tendency of the hydrocarbon to form azeotropic mixtures with some solvents.2

The aim of this research project is to synthesise various vinylcyclopropanes using efficient routes of synthesis.

To synthesise compound A the reaction would be carried out in a 3 step process:

First γ-chorobutyryl chloride will be prepared following the preparation of 'Close'13 then reacted with phenyl in AlCl3 reaction conditions to produce the intermediate product.

The second step is to react the intermediate with methyl magnesium iodide and produce the second intermediate in diethyl ether reaction conditions.

In the third step the second intermediate was heated in Ac2O conditions to prepare the final product.

The reaction mechanism below shows the reaction steps which will be carried out:


The mechanism above illustrates the planned reaction scheme which was proposed but the process could not be completed. Step 1 was successfully carried out, but due to the lack of time the required compound was not obtained and the other steps could not be accomplished.

Compound B will be synthesised from methyltriphenylphosphonium bromide which will be reacted with the sodium ethoxide solution and then the cyclopropyl phenyl ketone will be added. The Wittig reaction is used to convert the aldehydes/ketone to an alkene by replacing the oxygen atom with CH2. The scheme below shows briefly an example of a Wittig process.

Ketone Alkene

The synthesis of compound C would involve the same synthesis as compound B but the Wittig reagent used would be benzyltriphosphonium chloride as this is a stronger base and would be more efficient to deprotonate the phosphonium ion.

The Wittig reaction is generally one of the most leading reactions which convert ketones/ aldehydes to alkenes using phosphorus ylides which are the Wittig reagents.

The scheme shown below is a general Wittig reaction to synthesise alkenes.5

The phosphorus ylide attacks the carbonyl compound due to its electrophillic nature and two smaller carbon atoms join together to make the alkene double bond.

The solvents commonly used in Wittig reactions are the following:

Benzyltriphenylphosphonium chloride

Dimethyl sulfoxide (DMSO)

Tetrahydrofuran (THF)

Phosphorus ylides can also be prepared using a two step process. Alkyl halides are used to prepare the reagents, the following steps are carried out to prepare the Wittig reagent:

Triphenylphosphine is reacted with alkyl halide to produce the alkyltriphenylphosphonium halide.

This salt is ionic and crystallises from non-polar solvents, so when extracted the salt is reacted with a strong base, it is deprotonated, to form the desired triphenylphosphonium ylide.

Common strong bases used to deprotonate the phosphonium ions are butyl lithium. This base requires a moisture free environment. Other bases which could be used as an alternative are sodium hydroxide.

An ylide is known to be a neutral molecule which has a negative carbon adjacent to a positive heteroatom.

The two resonance structures shown below are phosphorous ylides which can be characterised as hybrid.

The Wittig reaction is a regioselective reaction where the E-isomer is favoured so it's obtained in a larger quantity than the Z-isomer.

Disadvantages of using the Wittig reagents are that simple ylides can be very reactive in air or moisture therefore a volatile product may be formed. The by-product triphenylphosphine has to be separated from the alkene product as it is an organic soluble compound

Compound C would be synthesised using the Wittig reaction. Cyclopropyl phenyl ketone would be reacted with benzyltriphenyl phosphonium chloride in the presence of sodium ethoxide solution. This process would convert the ketone to an alkene as shown in the diagram below.

Wittig reaction

Articles researched for project ideas

Close and co-workers studied13 compounds containing cyclopropyl groups and the methods of synthesis to produce their derivatives. This report gives a thorough method to synthesise γ-butyrolactone and also the intermediate γ-chlorobutyryl chloride can be used to synthesise many different cyclopropyl aromatic ketones. The common procedures used have developed a γ-halogenated butyronitrile which is the common intermediate. γ-chlorobutyryl chloride is successfully produced by treating butyrolactone with hydrochloric acid and thionyl chloride in an 88% yield. The product can be further condensed with benzene to give the chloro ketone which thereafter is cyclised with methanolic potassium hydroxide to form the cyclopropyl phenyl ketone in approximately 77% yield.

Friedel-Craft reactions were carried out with the γ-halogenated acid chlorides where the acyl halide from the α-halogenated acid chlorides only entered in to the reaction.

They found it difficult to completely eliminate the replacement of γ-chloro groups but when the reaction was carried out at low temperatures of less than 20oC the by-product formed was in a very low yield.

The Friedel-Crafts substitution reactions involving aromatic compounds such as chlorobenzene, toluene, phenetole and naphthalene were treated with γ-chlorobutyryl chloride to produce the required products.

Sarel and co-workers reported in 1963, 12 the methods of synthesis for some para substituted cyclopropylstyrenes. "The study investigated the effects of substitutions in the aromatic nucleus and the capability of vinycyclopropane moiety to enter in to the conjugative addition reactions." Many aryl cyclopropyl ketones were reacted with methyl magnesium iodide which resulted in other possible methods to be found to synthesise cyclopropylstyrenes. The proposed Grignard reaction methods were suitable to prepare tertiary carbinols and 3 catalytic methods were found for the dehydration of methylcyclopropylcarbinol. The most acidic solvents gave a low yield and in some cases none of the required product was formed but using acetic anhydride as the least acidic a 55% yield was obtained.

C. Larock and Kgun Yum reported in 1996,14 high yields of heterocycles and carbocycles can be prepared when aryl iodide is substituted in the ortho position by the polymers OH, CH2OH, NH2, NHT and CH(CO2Et)2 groups. These substituted aryl iodides react with the vinylic cyclopropanes and cyclobutanes with a catalyst present in the reaction such as palladium. Also a suitable base was required to fulfil the requirements of the reaction. The products were formed by the addition of palladium in to the carbon iodide bond. A ring was formed by the insertion of the catalyst and a palladium intermediate is formed, other contributing factors to the ring formation were:

The arypalladium addition across the carbon to carbon double bond of the alkene.

Carbon-palladium beta elimination caused the opening of the ring of cyclopropane or the cyclobutane.

Rearrangement of the unsaturated alkylpalladium to a π-allypalladium compound by a sequence of reversible palladium hydride beta elimination and re-addition steps.

The arene contains a functional group from where the proton was removed to form an anion.

The caboannulation process was carried out resulting in high yields of 80-82% obtained for the NaOAc, KOAc in the absence of PPH3.

The structures of alkenes were varied examining the effect on the yield of the carbocycle. This resulted in low yields and longer reaction times were required.

The heteroannulation of the cyclopropanes and cyclobutanes was examined and the best results achieved were of 70% yield using KOAc as the base with other iodophenols and alkenes but PPH3 was not used.

H. Yamaoka, Y. Yamada, S. Ono and T. Hanafusa reported in 1979 their procedure for the synthesis of vinylcyclopropane. 15 Also the derivatives of vinylcyclopropane are used in further cycloaddition reactions with electron rich olefins via the Zwitterionic intermediates.

The research showed the vinylcyuclopropane can be synthesised from α, β-unsaturated thione derivatives and dimethyloxosulfonium methylide. The addition of tetracyanoethylene with 4-methylene-4H-homochromenes formed dihydrobenzoxazepine derivatives.

The report15 above will not be used for this research project due to the fact that diazo compounds are used in this method and have explosive properties. Therefore for health and safety issues in a university laboratory and in the presence of other students these compounds are not safe to use.

From reading the various journals and research articles it was decided to use the method proposed by W. J. Close, 13 which requires the use of methoxy-benzene which would give the best results due to a solid product being formed.

Results and Discussion

A general Friedal-Crafts reaction was carried out in the synthesis of the cyclopropyl p-tolyl ketone. The γ-chlorobutyryl chloride was purchased from Sigma-Aldrich and the aryl cyclopropyl ketone was produced by condensing γ-chlorobutyryl chloride with toluene in the presence of AlCl3. A proton and carbon NMR was taken to further analyse the ketone intermediate acquired. A peak at 200ppm shows the carbonyl (C=O) is present in the product. At approximately 130ppm the (C=C) bonds from the phenyl ring are also present. The (C-C) bonds from the cyclopropyl ring can be seen at 11.3ppm and 16.8ppm. The methyl peak is present at 21.5ppm. The proton NMR shows the hydrogen peaks from the cyclopropyl ring at 1.02ppm and 1.20ppm. The single hydrogen from the ring is shown at 2.65ppm. The protons on the methyl group can be seen at 2.40ppm. The H atoms from the phenyl ring closest to the carbonyl are present at 7.24ppm and the H atoms closest to the methyl group are shown at approximately 7.92ppm. This indicates the intermediate product was obtained. This ketone would have been further reacted with methyl magnesium iodide in the second step but due to lack of time available the reaction could not be completed. Figure shows the two isomers which could be the product.

The next Wittig reaction to synthesise α-phenylvinylcyclopropane was analysed and during the reaction there was only a slight cloudiness in the solution whereas the colour of the solution should have changed to show the reaction was successful. An infrared of the product was taken which showed the ketone present at a wave number of 1725cm-1. This proved the reaction was not successful as the ketone should have been converted to an alkene and the oxygen would have been removed. The reaction possibily wasn't successful because the base methyltriphenylphosphonium bromide might have not been strong enough to de-protonate the acid. A spot t.l.c was carried out and an Rf value of 0.456 was obtained. This was used to indicate if the reaction did work but showed no change in the spots observed under ultraviolet light. Figure shows the expected product from this reaction.

In the next Wittig reaction to synthesise Ph(cyclo-C3H5)C=CH(CH2Ph) carried out a stronger base was used. This time the stronger base used was benzyltriphenylphosphonium chloride and a colour change was observed. When the sodium ethoxide solution was added the colour of the ylid was a yellow which was present for a short period of time. A solid product was obtained after rotary evaporation and the Infra-red spectrum taken showed the vinyl (C=CH) peak present at a wave number of 3057cm-1. The alkene (C=C) at 1676cm-1 was present and an aromatic (C=C) stretch at 1598cm-1. The monosubstituted benzene was also shown at a peak of 747cm-1 and the C-H bend was visible at 993cm-1. The infra-red spectrum indicated the reaction was successful therefore this method was the most efficient route to synthesise a Vinylcyclopropane.


Compound A

Synthesis of α-Cyclopropyl-4-methyl-styrol

Cyclopropyl p-tolyl ketone was prepared using the following method:

In a 500ml 3-necked round bottomed flask anhydrous aluminium chloride (20g, 3.17mol)

was suspended in toluene (100ml, 1.09 mol) an orange solution was observed. The mixture

was stirred whilst cooling the temperature of the solution to 10-15oC. A solution of toluene

(20ml, 1.09 mol) with γ-chlorobutyryl chloride (16ml) was placed in a dropping funnel to be

added to the mixture. The mixture was added to the aluminium chloride solution whilst the

temperature was maintained at 15-20oC, a dark brown solution was observed. 20 minutes

were required for the addition and heat was produced from the solution whilst the addition

was carried out. Removing the ice bath stirring was continued at room temperature for a

further 20 minutes. The mixture was poured in to ice water (200ml) to separate the toluene

layer. The organic layer was separated and dried over magnesium sulphate. Solution was

decanted and solvent was removed using rotary film evaporator. An oil was obtained with

some precipitate formed. The ketone was treated with Potassium hydroxide pellets (14.14g,

4.5 mol) were dissolved in methanol (57ml, 1.09 mol). A gas evolved and a cloudy cream

coloured precipitate was observed. The mixture was left to stand for 30 minutes whilst

regularly shaking the flask. The mixture was cooled in ice and filtered to remove the

methanol. The residue was washed in ether and water then the ether layer was separated using

a separating funnel. The organic layer was again washed with water and dried over

magnesium sulphate to remove the water from the product. Dissolved in dichloromethane the

residue was then vacuum distilled to yield a blue coloured solid which altered to a yellow

coloured solid whilst cooling in ice. Solid was recrystallised to remove any remaining impurities and yielded 9.07g (50.6%) of product.

Note: Further synthesis would be carried out to complete synthesis of first Vinylcyclopropane if more time would be available.

The reaction of toluene can produce the methyl group to be in the ortho or para position. This molecule can be further reacted and then dehydrated with acetic anhydride to gain the required Vinylcyclopropane.

Compound B

Preparation of α-phenylvinylcyclopropane using the Wittig reaction

In a dry conical flask sodium metal (0.76g) was added to ethanol (100ml) to prepare sodium

ethoxide solution. In another dry flask methyltriphenylphosphonium bromide (9.65g,

0.0270mol) was dissolved in ethanol (150ml) and cyclo-propyl-phenyl ketone (3.87g,

0.0265mol) was added. The solution was stirred at a constant pace and slowly the sodium

ethoxide solution was added at intervals. The mixture turned cloudy after the addition was

complete. The mixture was left to stand for 30 minutes minimum at room temperature to

allow the reaction to complete.

T.l.c of the product was taken to confirm if the reaction had worked.

The solvents used were less polar to more polar solvents.

T.l.c 1

Light petroleum ether (60-80) used as solvent

T.l.c 2

70% petroleum ether (60-80) and 30% dicloromethane

T.l.c 3

50% petroleum ether (60-80) and 50% dichloromethane

T.l.c 4

30% petroleum ether (60-80) and 70% dichloromethane

The t.l.c indicated that the reaction was not successful therefore the next steps to purify and gain a solid product were not carried out.

An infrared of the product was also taken to see if the ketone was still present in the product.

Wavenumber (Cm-1)

Bond vibration

Functional groups


O-H stretch



Weak band C=O stretch


Compound 3

Preparation of Ph(cyclo-C3H5)C=CH(CH2Ph)

In a dry 3-necked round bottom flask sodium metal (0.75g) was added to ethanol (100ml) to

prepare sodium ethoxide solution. In another dry flask Benzyltriphenylphosphonium chloride

(10.50g, 0.0270mol) was dissolved in ethanol (150ml) and cyclo-propyl-phenyl ketone

(3.87g, 0.0265mol) was added. The solution was stirred at a constant pace and slowly the

sodium ethoxide solution was added at intervals. The mixture turned yellow for a short period

and turned to a white solution after the addition was complete. The mixture was left to stand

for 30 minutes minimum at room temperature to allow the reaction to complete.

A t.l.c was taken with 30% petroleum ether (60-80) and 70% dichloromethane as the solvent

for an indication to see if reaction had worked. The solvent was extracted via rotary film

evaporator and an oil was obtained. The oil was filtered over silica gel in a fritted funnel and

washed with portions of dichloromethane. The solvent was extracted again and a solid

product was gained in a yield of 9.54g.

Infrared was taken of the ketone used.

Cyclopropyl phenyl ketone

Wavenumber (Cm-1)

Bond vibration

Functional groups


C-H stretch

Aromatic (mono-substituted)





C=C stretch



C-C stretch



C-H bend


Infrared of product in nujol

Wavenumber (Cm-1)

Bond vibration

Functional groups


C=CH Stretch



C=C Stretch



C=C Stretch



C-H bend



C-C stretch

Aromatic monosubstituted

A carbon, proton NMR and infrared of the product were submitted.*

*NMR not received for further analysis.

The products shown above are the two possible products which can be formed from the reaction to determine the correct product the results have to be further analysed.


The aim of the experiment was to synthesise various vinylcyclopropanes and use alternative routes to synthesise the molecule in a university laboratory. This was partly accomplished as from the three synthesis carried out the third reaction was successful. The synthesis was the reaction involving the sodium ethoxide solution reacting with benzyltriphenylphoshonium chloride and cyclo-propy phenyl ketone. The vinyl peak was present on the infrared spectra also the alkene peak proving the synthesis was successful.

The infra-red was taken and allowed the determination of the Vinylcyclopropane. The aim of the project was fulfilled and if given more time the dehydration of methylcyclopropylcarbinol over alumina would be carried out as it is a safe synthesis to be carried out and gives a reasonable yield.

Further study/research

If further research was carried out or there was more time available then from the many other articles and journals researched, the methods of synthesis for vinylcyclopropanes can be improved or more efficient methods could be used to gain high yields and in some cases a final product.

Vernon A. Slabey in 1952 reported a method of synthesis. This method could be tried to replicate which involves the dehydration of methylcyclopropylcarbinol over alumina. A yield of 54% was obtained which shows a good yield could be obtained but the temperatures used are quite high at 270oC of heating required.

Another method proposed by Toshio Tsumoda and Tomas Hudlicky synthesised a 62.9% yield of the vinylcyclopropane. The product distilled at suitable temperatures and it also involves the Wittig reaction.