Previous W ork on the Three Phase Test

Although the concept is simple, in undertaking the three phase test with aryl aldehyde derived organozinc carbenoids Mothen/vell and Nutley encountered several problems.

Styrene was selected as the parent alkene utilised to trap the carbenoid intermediates, given the precedent for high yielding cyclopropanation {vide supra 2.1.2.4). Using styrene as the trap would present the carbenoid with a reactive target som e way distant from the solid phase "surface", an essential prerequisite according to Rebek's findings. He reported that a minimum of three atom spacers between the solid phase and the reactive centre were necessary for good results.

Merrifield's resin was chosen as the polymer support. The resin is a polymer with a polystyrene backbone, 2% crosslinked with divinyl benzene. A cross linked polymer is essential in order that it be milled to a fine powder. The backbone is chlorom ethylated to the extent of one milli- equivalent of chlorine per gram (scheme 117).

scheme 117

In order to attach a removable styrene onto the polymer, the chlorom ethylated residues were to be functionalised by coupling with a para-vinylbenzoate moiety. It was reasoned that the ester linkage thus formed should be stable to the reaction conditions necessary for zinc carbenoid generation and would be readily saponified when necessary under conditions to which the cyclopropane or parent alkene would be stable (scheme 118).

O' ZnHg,IV%SiCI,ArCHO KOH.BOH OH HO R R = Ar scheme 118

After substantial testing of an analogous two phase system, Motherwell and Nutley succeeded in forming the resin bound alkene by the reaction of the sodium salt of para-vinylbenzoic acid with the polymer. Cl analysis of the resulting polym er suggested that the coupling was 80% complete, and the IR stretch of the carbonyl carbon was clearly visible in the polym er infrared spectrum.200

S u b se q u e n t reaction w ith p -a n is a ld e h y d e in the p re se n ce of zin c a m a lg a m and chlorotrim ethylsilane was perform ed. The polym er was then purified, and the saponification attem pted using ethanolic potassium hydroxide. Unfortunately, only a trace of material was obtained from the saponification process and although analysis of this by GOMS showed that it contained some of the alkene and also the adduct cyclopropane, no firm conclusions could be drawn. Due to the constraints of time, no further investigation of the carbenoid species via the Three Phase Test was performed.

2.2.2 2. Recent W ork on the Three Phase Test

In order to quantify and resolve the problem s encountered in the three phase test performed by Nutley, it was first necessary to prepare the appropriate coupled polymer. To this end, a DMF solution of the sodium salt of vinylbenzoic acid was added to a suspension of Aldrich Merrifield resin in DMF and the whole system heated at 80°C for 24 hours. It should be noted that the use of DMF as the reaction solvent is essential to the success of the coupling. Most polym er reactions are carried out in solvents such as DMF, DMSO, pyridine and benzene which swell the polymer in order to allow accessibility to all the reactive sites (scheme 119).^G3a

NaO

O'

scheme 119

It was clearly important to ensure that when the coupling procedure was complete, any resident acid had been washed from the polym er. A ny residual vinylbenzoic acid trapped w ithin the polym er could of course trap an hom ogenous zinc carbenoid especially if, as the results of Nutley seem to show, the degree of carbenoid infiltration into the polym er phase is likely to be low at best. This introduces one of the m ajor complications inherent in all polym er work, namely the purification and characterisation of polymeric systems.

Having filtered the polym er from the reaction mixture, repeated washing first with DMSO and then with acetone was performed. Thorough washing was continued until no trace of organic material could be recovered from the filtrate. The resin was then dried and the resulting solid exam ined. The polym er resembled the original free flowing fine powder, and in the infra-red spectrum showed a strong carbonyl stretch at 1710 cm""'. Chlorine microanalysis of the original resin had shown the chlorine content to be 3.7%, equivalent to 1.07 m illi-equivalents of chlorinated residues per gram of polymer. The new m icroanalysis showed that the chlorine content was now 1.5% suggesting that the coupling had been reasonably effective. Given that the m olecular weight of styrene is 104gm ol'^ and the degree of crosslinker quite small, the frequency of chlorinated residues in the initial polym er can be estimated as roughly 1 in every 10. Thus, as the increase in w eight due to the coupling is sm all, the am ount of coupled vinylbenzoic acid can be estimated by the change in chlorine content of the polymer. Hence it can be estimated that the total coupling of vinylbenzoic acid accounted for roughly 60% of all the chlorinated residues, or O.Smmolg’ "' of alkene.

Given this microanalytical data, the polym er was titrated to ascertain firstly if the saponification could be achieved efficiently and secondly to test the accuracy of the characterisation of the system. Hence, stirring O.Sg of resin overnight with potassium hydroxide in 9:1 ethanol-w ater gave 50 mg of a cream solid which was 90% vinylbenzoic acid mixed with some unidentified aromatic compounds.

2.2.2 3. The Three Phase Test with Homogenous Zinc Carbenoids

A s p re v io u s ly d o cu m e n te d { v id e s u p r a 2 .2.1.) the w o rk of C loss and M oss w ith aryldiazom eth anes had dem onstrated that hom ogenous zinc carbenoids can be readily generated by the reaction of com pounds such as phenyldiazom ethane with zinc chloride in ether. In order to test whether the system we had devised was suitable for the form ation and isolation of cyclopropane adducts of the polym er bound vinylbenzoic acid, we elected to first investigate the efficiency of the acknowledged homogenous reagent. Bearing in mind that the effectiveness of our strategy was dependent on the carbenoid, acknowledged to have a half life of the order of 10 seconds, being sufficiently miscible with the polymer to encounter the alkene, it was vital that this reaction was successful.

Phenyldiazom ethane was prepared by reaction of the tosylhydrazine 168 according to the m ethod of Closs and Moss. The tosylhydrazine was readily prepared from benzaldehyde (scheme 120).

S NH

I o - ' o

NaOMe

The phenyldiazomethane was generated just prior to reaction with the polymer, by treatm ent of the tosylhydrazone 168 with sodium m ethoxide. The deep red solution isolated from the mixture was added via dropping funnel to a suspension of the polym er resin in an ethereal solution of zinc chloride . The polymer was then filtered and washed (scheme 121).

o o

ZnC^

Ph

scheme 121

Analysis of the washings presented ample evidence of the form ation of the zinc carbenoid species as well as a large amount of unidentified aromatic residues. The major com ponent was the product of ether insertion, 170 isolated in 6% yield relative to phenyldiazomethane. Equally encouraging was that no vinyl benzoic acid (or cyclopropane adduct) were present in the washings.

ZnClg E^O

k

170

The polym er residue was dried before saponification, sim ilarly to the earlier titration, with potassium hydroxide in ethanol-water. NMR of the resulting solid suggested that it was a mixture of unidentified arom atic com pounds, vinylbenzoic acid, and the desired cyclopropane 171 Chromatography afforded 20mg of a mixture of the vinyl acid and the desired cyclopropane 172 in a ratio of approxim ately 1 0 : 1 . This amounts to about 21% vinylbenzoic acid recovery from the polymer, giving roughly 0.13m m ol, and more vitally a 3% yield of cyclopropane relative to the amount of alkene present in the reaction (scheme 122).

KOH

HO HO-

R =

171 21% 172 3%

The low yield of cyclopropane was a disappointm ent, although not a surprise given the measured lifetime of the arylzinc carbenoid in ether. It is also probable that, as was envisaged from the outset, there is a problem with the swelling of the polymer in the unsuited diethyl ether solvent. It is also interesting to speculate on the fate of the majority of the zinc carbenoid, since the level of insertion into ether was relatively low. It is likely that the compound simply inserted into the activated C-H bonds in the polym er or alternately was trapped as highly strained cyclopropane adducts with the polymeric aryl rings."I

Despite these setbacks, the cyclopropane was isolated and clearly the challenge now lay in repeating the reaction with the chlorotrimethylsilane, benzaldehyde and zinc amalgam system. It was also now apparent as to w hy N utley had been unable to sa tisfactorily isolate the cyclopropane during the previous study. The task was to duplicate if possible the results obtained with the phenyldiazomethane system, and in so doing dem onstrate conclusively that the zinc carbenoids produced were homogenous entities.