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dc.contributor.advisorMarais, C.
dc.contributor.advisorBezuidenhoudt, B. C. B.
dc.contributor.authorSwart, Marthinus Rudi
dc.date.accessioned2016-10-26T14:17:58Z
dc.date.available2016-10-26T14:17:58Z
dc.date.issued2016-01
dc.identifier.urihttp://hdl.handle.net/11660/4228
dc.description.abstract2-Ethylhexyl p-methoxycinnamate [Octyl methoxycinnamate (OMC)] is an organic compound that is commercially used in the cosmetic industry as a UV blocker in sunscreen creams and lotions. Commercial production of this compound, however, is hampered by multiple synthetic steps, high temperatures, tedious work-up procedures, halogenated by-products, and low atom economy. Due to the abundance of naturally occurring essential-oil phenylpropenoids like estragole, eugenol, and safrole, which can easily be transformed into anethole, isoeugenol, and isosafrole by catalytic double bond isomerisation, the possibility of utilizing one of these b-methylstyrenes, i.e. anethole, together with 2-ethylhexyl acrylate in metathesis based methodology for the preparation of OMC looked promising and was investigated. Model metathesis reactions between trans-b-methylstyrene and methyl acrylate over Grubbs 2nd generation catalyst, however, produced only the homometathesis product, trans-stilbene, in very high yields (>99%). Solvent, temperature and reactant ratio studies failed to change the course of the reaction towards the desired cross-metathesis product. Since Forman et al. reported the addition of phenol to the reaction mixture to enhance crossmetathesis over self-metathesis, the reaction was repeated with p-cresol (2 eq.) as additive. In order to prevent secondary metathesis reactions from occurring, the propene side-product was also stripped away by entrainment with argon, which led to the successful formation of methyl cinnamate in 38% yield. In order to determine the general applicability of the new process, the electronic effect, if any, of substituents in the para-position of the b-methylstyrene and the steric/electronic influence of the alkyl group attached to the α,b-unsaturated carbonyl compound on the outcome of the reaction were investigated. Trans-pmethoxy- b-methylstyrene (trans-anethole) (1 eq.) and trans-4- trifluoromethylsulfonyloxy-b-methylstyrene (1 eq.) were therefore reacted with methyl acrylate (2 eq.) under the optimized reaction conditions [Grubbs 2nd generation catalyst (0.5 mol%), p-cresol (0.25 eq.), refluxing DCM (10 mL), 2 hours] and it was found that an electron-donating group in the para-position caused a slight decrease in cross-metathesis product formation (36% vs 38% for unsubstituted trans-b-methylstyrene) whereas an electron-withdrawing group (triflate) in the same position enhanced cinnamate formation (43% vs 38%). The concomitant homo-metathesis reaction followed the opposite trend with the p-triflate suppressing stilbene formation (4% vs 18% for unsubstituted trans-b- methylstyrene) and a p-methoxy group enhancing the formation of the stilbene (50% vs 18%). When the influence of the O-alkyl group attached to the α,b-unsaturated carbonyl moiety was investigated, it was found that the yield of the cinnamate product increased with increasing steric bulk of the alkyl group. For the reaction of unsubstituted trans-b-methylstyrene with methyl acrylate and n-butyl acrylate, respectively, the yield increased from 38 to 55%, while for reaction between trans-anethole and these acrylates it went from 36 to 41%. Substituting the ester O-alkyl moiety in the α,b-unsaturated system with an alkyl group (3-buten- 2-one) and a hydrogen (acrolein), resulted in moderate yields of 34 and 32% for the reactions between the ketone and unsubstituted trans-b-methylstyrene and trans-anethole, respectively, while with acrolein only trace amounts (< 5%) of the cross–metathesis products were obtained. In all these reactions, the respective stilbenes were formed in 18 (for the reaction between methyl or nbutyl acrylate and trans-b-methylstyrene) to 58% (for the reaction of acrolein with trans-b-methylstyrene) yield. Finally, trans-β-methylstyrene and transanethole were reacted with 2-ethylhexyl acrylate to form 2-ethylhexyl cinnamate and the desired 2-ethylhexyl p-methoxycinnamate (OMC), which could be isolated as major products from the reaction in 64 and 47% yields, respectively. Due to the higher reactivity of trans-anethole, the cross-metathesis product (OMC) in this instance was accompanied by 32% of 4,4’-dimethoxystilbene. In an effort to determine how p-cresol addition affects the catalytic cycle of Grubbs 2nd generation catalyst and thus how it influences product formation, a full NMR study of the addition of cresol to the catalyst, the catalyst and trans-b-methylstyrene, the catalyst and methyl acrylate, as well as all the reactants together, was embarked upon. Despite severely restricted rotation, which necessitated the spectra to be recorded at 60 oC, room temp., and -40 oC, all the 1H and 13C NMR resonances in the spectra of the Grubbs II catalyst could be allocated unambiguously to the appropriate protons and carbon atoms. 31P NMR studies allowed for the confirmation of a hydrogen bonding complex between cresol and the catalyst, while it also indicated some dissociation of the tricyclohexylphosphine from the catalyst to occur. The liberated tricyclohexylphosphine, however, prefers to react with the acrylate in a 1,4- addition process rather than forming a complex with the cresol as was postulated by Forman et al. This was confirmed by the preparation of the zwitterionic phosphonium salt through reaction of tricyclohexylphosphine with methyl acrylate in the presence of LiCl. Addition of cresol to the reaction mixture enhances the formation of the salt in its protonated form, while it also induces accelerated formation of oligomeric forms of the initially formed monomeric zwitterionic phosphonium salt. Although Forman et al. proposed the addition of phenols to stabilize the Grubbs catalyst by slowing down the dissociation of the tricyclohexylphosphine from the metal and once dissociated, prevents the phosphine from binding to the metal again, this explanation does not allow for the fact that the more reactive styrene analogue becomes less reactive than the acrylate moiety when cresol is added to the reaction mixture, as is evident from the fact that cresol addition enhances cross-metathesis. It was determined during the current study that the crossmetathesis products (cinnamates) are indeed the result of the primary metathesis process and are not formed through secondary metathesis of the stilbene products. In order to explain the formation of the cross-metathesis over homo-metathesis products in the presence of cresol, it is proposed that an associative mechanism rather than a dissociative process is prevailing when cresol is added to the reaction mixture. In this instance the co-ordination number of the ruthenium temporarily increases from 5 to 6 to allow for the additional ligand to be attached to the metal centre. The catalyst complex therefore becomes sterically more crowded and the steric size of the incoming ligand (reactant) would play a decisive role in its ability to react with the metal centre in the first step of the reaction. Since acrylate represents a mono substituted alkene and the alkyl group resides in a remote location with regard to the reaction centre, it would be sterically less demanding when compared to trans-b-methylstyrene and lead to enhanced formation of the cross-metathesis product. This assumption was proven by substituting methyl acrylate with methyl crotonate during the reaction and the resulting drop in cross-metathesis product from 38 to 31% yield observed. Support for this proposal comes from results by Fogg and co-workers, who reported cross-metathesis to be the dominant reaction when b-methylstyrenes were reacted with acrylates over the Hoveyda-Grubbs catalyst. Finally, with a number of cinnamates (OMC, methyl p-methoxycinnamate, methyl cinnamate, n-butyl cinnamate, n-butyl p-methoxycinnamate, and 2- ethylhexyl cinnamate) and 3-buten-2-ones [4-phenyl-3-buten-2-one and 4-(4- methoxyphenyl)-3-buten-2-one] available, it was decided to evaluate the UV-B blocking properties of these compounds through utilization of UV spectroscopy in an effort to determine if OMC would, in principle, be the best sunscreen component of the series. By comparing the UV spectra of OMC to that of the other compounds, it was determined that methyl cinnamate, n-butyl cinnamate, methyl p-methoxycinnamate and n-butyl p-methoxycinnamate could be promising candidates in the development of new and maybe better sunscreen lotions and should be subjected to biological evaluation processes.en_ZA
dc.language.isoenen_ZA
dc.publisherUniversity of the Free Stateen_ZA
dc.subjectDissertation (M.Sc. (Chemistry))--University of the Free State, 2016en_ZA
dc.subjectMetathesisen_ZA
dc.subjectGrubbs 2nd generation catalysten_ZA
dc.subjectCresolen_ZA
dc.subjectTrans-β-methylstyreneen_ZA
dc.subjectAcrylateen_ZA
dc.subjectCinnamateen_ZA
dc.subjectAssociative mechanismen_ZA
dc.subjectUltra-violet spectroscopyen_ZA
dc.subjectSunscreens (Cosmetics)en_ZA
dc.titleApplication of the cross-metathesis reaction as alternative methodology for the synthesis of paramethoxycinnamate analogues as sunscreen componentsen_ZA
dc.typeDissertationen_ZA
dc.rights.holderUniversity of the Free Stateen_ZA


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