Under neutral conditions, spontaneous mirror symmetry breaking has been occasionally reported for aldol reactions starting from achiral reagents and conditions. Chiral induction might be interpreted in terms of autocatalysis exerted by chiral mono-aldol or bis-aldol products as source of initial enantiomeric excesses, which may account for such experimental observations. We describe here a thorough Density Functional Theory (DFT) study on this complex and otherwise difficult problem, which provides some insights into this phenomenon. The picture adds further rationale to an in-depth analysis by Moyano et al, who showed the isolation and characterization of bis-aldol adducts and their participation in a complex network of reversible steps. However, the lack of enantiodiscrimination (ees vanish rapidly in solution) suggests, according to the present results, a weak association in complexes formed by the catalysts and substrates. The latter would also be consistent with almost flat transition states having similar heights for competitive catalyst-bound transition structures (actually, we were unable to locate them at the level explored). Overall, neither autocatalysis as once conjectured nor mutual inhibition of enantiomers appears to be operating mechanisms. Asymmetric amplification in early stages harnessing unavoidable enantiomeric imbalances in reaction mixtures of chiral products represents a plausible interpretation.
Monoaza- and diaza-derivatives of malondialdehydes, in short aminoacroleins and vinamidines, are prototypical examples of open-chain structures prone to π-electron delocalization, for which intramolecular hydrogen bonding enhances (or diminishes) their pseudoaromaticity depending on the substitution pattern. This interplay is illustrated herein by DFT-based calculations of aromaticity indices in the gas phase and polar solvents. Elucidation of transition structures involved in tautomeric conversions helps to solve how the intramolecular hydrogen transfer occurs. While TSs exhibit a high degree of aromaticity, the dichotomy between forward and backward pathways points to a complex trajectory. Addition of thermal corrections to the electronic energy decreases both the enthalpy and free energy leading to negative ΔH(‡) and ΔG(‡) values. This variational effect accounts for the otherwise elusive distinction between transition structures and saddle points (usually overlooked for high electronic barriers). Also, this rationale fits well within the framework of Marcus' theory.
Mesoionic rings are
among the most versatile 1,3-dipoles, as witnessed
recently by their incorporation into bio-orthogonal strategies, and
capable of affording unconventional heterocycles beyond the expected
scope of Huisgen cycloadditions. Herein, we revisit in detail the
reactivity of thiazol-3-ium-4-olates with alkynes, leading to thiophene
and/or pyrid-2-one derivatives. A structural variation at the parent
mesoionic dipole alters sufficiently the steric outcome, thereby favoring
the regioselective formation of a single transient cycloadduct, which
undergoes chemoselective fragmentation to either five- or six-membered
heterocycles. The synthetic protocol benefits largely from microwave
(MW) activation, which enhances reaction rates. The mechanism has
been interrogated with the aid of density functional theory (DFT)
calculations, which sheds light into the origin of the regioselectivity
and points to a predictive formulation of reactivity involving competing
pathways of mesoionic cycloadditions.
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