ASYMMETRIC ORGANOCATALYSIS

Dear Reader, Two basic reactions that were taught to us in the organic chemistry courses were the aldol condensation reaction and the Diels-Alder reaction. In aldol condensation, discovered by the French chemist Charles Wurtz in 1872, an enolate ion reacts with a carbonyl compound in the presence of an acid/ base catalyst to form a β-hydroxy aldehyde or a β-hydroxy ketone, usually followed by dehydration to give a conjugated enone. If the enolate ion and the carbonyl group are present in the same molecule, then the aldol reaction is intramolecular. It is an extremely useful carbon-carbon bond-forming reaction. The Diels-Alder reaction, discovered in 1928 by the German chemist Otto Diels and his student Kurt Alder, is the reaction between a conjugated diene and an alkene, a so-called dienophile, to form an unsaturated six-membered ring. It is called a cycloaddition reaction, since the reaction involves the formation of a cyclic product via a cyclic transition state. Uncatalysed Diels– Alder reactions usually require extended reaction times at elevated pressures and temperatures with the formation of by-products, hence various catalysts are employed. The Diels-Alder reaction also has great industrial relevance and the discoverers were crowned with the 1950 Nobel Prize in Chemistry. The aldol condensation reaction and the Diels-Alder reaction typically require catalysts, basically Brønsted acids, Brønsted bases, Lewis acids or Lewis bases. This triggered the minds of Dr. David MacMillan and Dr. Benjamin List for different reasons at different locations in USA around not so different times, more than twenty years ago, culminating in their being jointly awarded the Nobel Prize in Chemistry for this year.

Confronting the Challenging Asymmetric Addition of Vinyl Arene Pronucleophiles into Ketones: Ligand-Controlled Regiodivergent Processes Through a Dearomatized Allyl-Cu Species

The selective reductive coupling of vinyl arenes and ketones represents a versatile approach for the rapid construction of enantiomerically enriched tertiary alcohols. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl arenes and ketones, in which the selectivity is controlled by the ancillary ligand. This approach leverages an in situ generated benzyl- or dearomatized allyl-Cu intermediate, yielding either the dearomatized or exocyclic addition products, respectively. The method exhibits excellent regio-, diastereo- and enantioselectivity, and tolerates a range of common functional groups and heterocycles. Computational studies suggest that the regio- and enantioselectivity are controlled by the ancillary ligand, while the diastereoselectivity is enforced by steric interactions between the alkyl-Cu intermediate and ketone substrates in a six-membered cyclic transition state.

Confronting the Challenging Asymmetric Addition of Vinyl Arene Pronucleophiles into Ketones: Ligand-Controlled Regiodivergent Processes Through a Dearomatized Allyl-Cu Species

The selective reductive coupling of vinyl arenes and ketones represents a versatile approach for the rapid construction of enantiomerically enriched tertiary alcohols. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl arenes and ketones, in which the selectivity is controlled by the ancillary ligand. This approach leverages an in situ generated benzyl- or dearomatized allyl-Cu intermediate, yielding either the dearomatized or exocyclic addition products, respectively. The method exhibits excellent regio-, diastereo- and enantioselectivity, and tolerates a range of common functional groups and heterocycles. Computational studies suggest that the regio- and enantioselectivity are controlled by the ancillary ligand, while the diastereoselectivity is enforced by steric interactions between the alkyl-Cu intermediate and ketone substrates in a six-membered cyclic transition state.

Determination of the activation parameters ∆H≠ and ∆S≠ via a kinetic study of d,l-mandelic acid oxidation by using chromic acid in the presence of 1,10-phenanthroline as a promoter in an aqueous micellar acid medium

Chromic acid oxidation of d,l-mandelic acid in the presence and absence of 1,10-phenanthroline (Phen) is studied in an aqueous micellar medium under kinetic conditions, [d,l-mandelic acid] >> [Phen]T >> [Cr(VI)]T at different temperatures. From studies on the effect of temperature on the rate constant (k), the activation parameters ∆H≠ (enthalpy of activation) and ∆S≠ (entropy of activation) are evaluated by using the Eyring equation [−ln (kh/kBT) = ∆H≠/RT − ∆S≠/R]. The high value of ∆H≠ indicates that the phen-catalysed path is favoured mainly due to very high negative value of ∆S≠. The negative value of ∆S≠ and the composite rate constant kcat support the suggested cyclic transition state. Both the catalysed and uncatalysed paths show a first-order dependence on [H+], and both also show a first-order dependence on [d,l-mandelic acid]T and [Cr(VI)]T. The Phen-catalysed path is first order in [Phen]T. These observations remain unaltered in the presence of externally added surfactants. The cationic surfactant N-cetylpyridinium chloride is found to retard the rate of the reaction.

Rationalization of the effects of hydrogen bond donor solvent and nucleofugicity of fluoride ion on nucleophilic aromatic substitution reactions in non-polar aprotic solvent: reaction of 2,4-dinitrofluorobenzene with cyclohexylamine in toluene and toluene

The kinetics of the reaction of 2,4-dinitrofluorobenzene with cyclohexylamine were studied at different concentrations in toluene and toluene-alkanol mixtures. The reaction was not base-catalysed in toluene. Addition of small amounts of hydrogen-bond donor solvent, alkanol (ranging from methanol to hexanol) to the toluene medium of the reactions produced a different effect in comparison to uncatalysed reactions — slight increase in rate of reaction. The results are rationalized in terms of the effect of amine-solvent interaction on the nucleophilicity of the amine in addition to some other factors operating through cyclic transition states leading to products. It is also attributed to the peculiar nature of fluoride ion as a leaving group.

Quantum-chemical study of mechanisms of benzamide and benzenesulfonamide reactions with 3-nitrobenzenesulfonic acid chloride in the gas phase

Quantum-chemical simulation of mechanisms of 3-nitrobenzenesulfonic acid chloride interactions with benzoic and benzenesulfonic acids amides in the gas phase was carried out by calculating the three-dimensional potential energy surfaces of these reactions (DFT//B3LYP/6-311G(d,p) level). It was found that in both of the processes considered, a single route can be realized containing a single saddle point and starting as an axial attack of the nucleophile. Further approach of the reagent molecules proceeds with a decrease in the angle of nucleophilic attack to ≈ 130o in the reaction transition state and ≈ 100o – in the reaction product – sulfonamide. It was shown that the studied reactions proceed according to the bimolecular concerted mechanism of nucleophilic substitution SN2, which implies the formation of a single transition state along the reaction pathway. It was found that the geometric structure of the reaction centers in the transition states of the processes is intermediate between the trigonal bipyramid and the tetragonal pyramid, which is explained by the change in the angle of nucleophilic attack when the reagent molecules approach each other. It was found that in benzamide sulfonylation reaction, a cyclic transition state is formed, in which the forming and loosening bonds lie in the same plane, and the H-Cl distance corresponds to the length of the hydrogen bond. In benzenesulfonamide reaction with 3-nitrobenzenesulfonyl chloride, the transition state is not cyclic. The activation energies of the reactions are calculated; they were 155 kJ/mol in the benzamide sulfonylation reaction and 150 kJ/mol in the process with the participation of benzenesulfonic acid amide. The closeness of the obtained values is associated with the similar structure of the amide and sulfamide groups containing electrophilic centers near the amino groups. A significant difference in the rate constants of the studied reactions, which was found earlier, when they occur in aqueous dioxane, is explained by the features of –CONH2 and –SO2NH2 groups specific solvation and the contribution of the entropy factor to the reaction rate: the cyclic transition state of the benzamide reaction with 3-nitrobenzenesulfonyl chloride is more ordered in comparison with a non-cyclic transition state of the reaction with benzenesulfonamide participation, which can promote faster occurence of the first process.