M. J. Aurell

Understanding the origin of the asynchronicity in bond-formation in polar cycloaddition reactions. A DFT study of the 1,3-dipolar cycloaddition reaction of carbonyl ylides with 1,2-benzoquinones

The origin of the asynchronicity in bond-formation in polar cycloadditions has been studied by an ELF analysis of the electron reorganisation along the 1,3-dipolar cycloaddition of Padwas carbonyl ylide 4 with the 1,2-benzoquinone 8. This reaction presents an unexpected asynchronous bond-formation, which is initialised through the nucleophilic attack of Padwas carbonyl ylide on the carbonyl oxygen atom of the strongly electrophilically activated 1,2-benzoquinone. The present study allows for the establishment that along an asynchronous bond-formation, the more favourable two-center interaction begins at the most electrophilic center, which is the center with the highest spin density achieved through the charge transfer process, and not, as expected, at the center that presents the larger positive charge.

ALKYLATION OF LITHIUM DIENEDIOLATES OF BUTENOIC ACIDS. REGIOSELECTIVITY EFFECTS OF STRUCTURE AND LEAVING GROUP OF THE ALKYLATING AGENT

Abstract Regioselectivity of alkylation of but-2-enoic acids 1 and 2 by alkyl halides strongly depends on the reactivity of the electrophile. High α selectivity results for saturated alkyl halides, whereas poor α-selectivity is obtained for highly reactive allyl and benzyl halides. For reactive alkylating halides selectivity is partly governed by the ion pairing aggregates of the dienediolates. Lithium bromide and the carboxylate generated in the ongoing reaction cause opposite effects on regioselectivity.

Understanding the polar mechanism of the ene reaction. A DFT study

The molecular mechanism of ene reactions has been characterised by DFT methods at the MPWB1K/6-311G(d,p) level of theory. Most reactions take place along a two-stage one-step mechanism in which the C-C bond formation takes place before the hydrogen transfer process. A very good correlation between the polar character of the reaction measured by the global electron density transfer at the transition state and the activation energy has been found. This behaviour allows establishing a useful classification of ene reactions in N-ene having a very high activation energy, P-ene reactions having activation energies between 35 and 20 kcal mol(-1), and H-ene reactions having activation energies below 20 kcal mol(-1). ELF topological analysis allows the characterisation of the two-stage one-step mechanism associated with a two-centre nucleophilic/electrophilic interaction. Formation of the C-C single bond is achieved by the C-to-C coupling of two pseudoradical centres formed at the two interacting carbon atoms in the first stage of the reaction. This topological analysis establishes that bonding changes are non-concerted. Finally, a DFT reactivity analysis makes it possible to characterise the electrophilic/nucleophilic behaviour of the reagents involved in ene reactions, and consequently, to predict the feasibility of ene reactions.

Understanding the mechanism of the Povarov reaction. A DFT study

The molecular mechanism of the Povarov reaction in acetonitrile has been studied at the MPWB1K/6-311G** level of theory. This reaction follows a domino process that comprises two sequential reactions: (i) a Lewis acid catalysed aza-Diels–Alder (A-DA) reaction between a N-aryl imine and a nucleophilic ethylene yielding a formal [4 + 2] cycloadduct; (ii) a stepwise 1,3-hydrogen shift at this intermediate affording the final tetrahydroquinoline. At this computational level, the Lewis acid catalysed A-DA reaction presents a two-step mechanism as a consequence of the large stabilisation of the corresponding zwitterionic intermediate. Our study allows establishing that the N-aryl substituent has no remarkable incidence in the activation energy, but the presence of a second C-aryl substituent has a relevant role in the reaction rate. Analysis of the DFT-based reactivity indices of the reagents provides further explanation of the behaviours of the mechanism of the A-DA reaction involved in the Povarov reaction.

On the mechanism of the addition of organolithium reagents to cinnamic acids

The regioselectivity of the addition of tert-butyllithium to cinnamic acid is subject to reaction conditions and to substituent electronic effects. Significant effects are observed in the presence of several additives including a radical trap such as α-methylstyrene. Competition experiments by addition of the organolithium reagent to mixtures of substituted cinnamic acids show that the relative rates of both conversion of the starting acids and formation of the 1,3-adducts are subject to electronic effects, whereas rates for 1,4-addition are independent of the substituents. These features are in agreement with a polar addition mechanism, but a fast SET equilibrium followed by slow radical combination would be possible as well.

Addition of organolithium reagents to cinnamic acids

Abstract Reaction of tert -butyllithium with p - and m -substituted cinnamic acids at low temperature affords mixtures of 1,4- and 1,3-addition products, whose composition depend on the nature of the substituents. Electron-donating and electron-withdrawing groups favour 1,4- and 1,3-additions, respectively. Linear correlations are obtained with electronic effect and with radical substituent constants.

Conjugate addition of organolithium reagents to α,β-unsaturated carboxylic acids

Abstract Conjugate addition of primary, secondary, tertiary alkyl and phenyl lithium reagents to 2-alkenoic acids affords good yields of branched saturated carboxylic acids. Methyl groups at the α- and β-carbon of the 2-alkenoic acid decrease reactivity as acceptors, and foster deprotonation, respectively. The lithium enediolate resulting from the conjugate addition can react with electrophiles. PM3 calculations are in agreement with the substituent effects.

Dienediolates of unsaturated carboxylic acids in synthesis. Synthesis of cyclohexenones and polycyclic ketones by tandem Michael-Dieckmann decarboxylative annulation of unsaturated carboxylic acids.

Abstract Substituted 2-cyclohexenones 4 to 7 and hexaxydronaphthalenones and hexahydroindenones 13 to 18 are prepared by tandem Michael-Dieckmann addition of lithium dienediolates of acyclic and alicyclic unsaturated carboxylic acids to the lithium salts of the same or other unsaturated carboxylic acids.

Trienediolates of hexadienoic acids in synthesis. synthesis of retinoic and nor-retinoic acids.

Abstract Double deprotonation of either (E,E)-3-methyl-2,4-hexadienoic acid 2, or 4,6-dimethyldihydro-2-pyrone 3 generates apparently the same lithium trienediolate, which affords ω-hydroxy acids 9 on reaction with ketones 7. Hydroxy acids 9 are easily dehydrated to octatrienoic acids 5, which are structurally related to retinoic acid. Similarly, sorbic acid 1 leads to nor-retinoic acid analogs 6.

Silver ion oxidative coupling of diene and triene-diolates of unsaturated carboxylic acids: a facile synthesis of octa- and dodeca-dienedioic acids

Abstract Polyunsaterated dicarboxylic acids 3 and 5 are very easily prepared by oxidative coupling of lithium diene- and triene-diolates 1 and 2 with silver nitrate.