Application of the cross-metathesis reaction as alternative methodology for the synthesis of paramethoxycinnamate analogues as sunscreen components
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Date
2016-01
Authors
Swart, Marthinus Rudi
Journal Title
Journal ISSN
Volume Title
Publisher
University of the Free State
Abstract
2-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.
Description
Keywords
Dissertation (M.Sc. (Chemistry))--University of the Free State, 2016, Metathesis, Grubbs 2nd generation catalyst, Cresol, Trans-β-methylstyrene, Acrylate, Cinnamate, Associative mechanism, Ultra-violet spectroscopy, Sunscreens (Cosmetics)