Kinetics and Mechanism of Oxirane Formation by Darzens Condensation of Ketones: Quantification of the Electrophilicities of Ketones

Abstract

The kinetics of epoxide formation by Darzens condensation of aliphatic ketones 1 with arylsulfonyl-substituted chloromethyl anions 2 (ArSOCHCl) have been determined photometrically in DMSO solution at 20 °C. The reactions proceed via nucleophilic attack of the carbanions at the carbonyl group to give intermediate halohydrin anions 4, which subsequently cyclize with formation of the oxiranes 3. Protonation of the reaction mixture obtained in THF solution at low temperature allowed the intermediates to be trapped and the corresponding halohydrins 4-H to be isolated. Crossover experiments, i.e., deprotonation of the halohydrins 4-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted chloromethyl anions 2, provided the relative rates of backward ( k) and ring closure ( k) reactions of the intermediates. Combination of the kinetic data ( k) with the splitting ratio ( k/ k) gave the second-order rate constants k for the attack of the carbanions 2 at the ketones 1. These k values and the previously reported reactivity parameters N and s for the arylsulfonyl-substituted chloromethyl anions 2 allowed us to use the linear free energy relationship log k(20 °C) = s( N + E) for deriving the electrophilicity parameters E of the ketones 1 and thus predict potential nucleophilic reaction partners. Density functional theory calculations of the intrinsic reaction pathways showed that the reactions of the ketones 1 with the chloromethyl anions 2 yield two rotational isomers of the intermediate halohydrin anions 4, only one of which can cyclize while the other undergoes retroaddition because the barrier for rotation is higher than that for reversal to the reactants 1 and 2. The electrophilicity parameters E correlate moderately with the lowest unoccupied molecular orbital energies of the carbonyl groups, very poorly with Parr's electrophilicity indices, and best with the methyl anion affinities calculated for DMSO solution.

Predicting experimental electrophilicities from quantum and topological descriptors: A machine learning approach

“…[17,18] Up to now, the most predictive models have been those based on the calculation of methyl anion affinities (MAAs). [19,20] This promising approach however differs from that retained in this paper. In fact, MAA corresponds to the reaction energy of the various electrophiles with a unique selected nucleophile (CH 3…”

“…[40] Conversely, we decided in this work to focus on global and atomic descriptors based on quantum chemistry, and in particular on CDFT, which could treat in principle all types of mole- More precisely, the "one star" compounds have an experimental value determined roughly using only one nucleophile. This method (used for instance for ketones [20] ) only provides broadly estimated experimental values. [21] As Mayr stated, they should be used only to "give a good idea about relative reactivities of strong nucleophiles towards weak electrophiles and of weak nucleophiles toward strong electrophiles."…”

“…For example, benzaldehyde has a previously reported electrophilicity value of −19.50 [41] but was recently re-adjusted to −12.90. [20] For such reasons, we excluded all one and two stars com- proposed but rarely considered). [42] They are epitomized by the electronic chemical potential μ and the chemical hardness η (where E e denotes the total electronic energy):…”

Electrophilicities of 4‐Nitrobenzochalcogenadiazoles

“…The slopes close to 1 indicate the applicability of Eq (1). [30][31][32][33][34] On this basis, the values of the electrophilicity parameters E of Table 3. Characteristic 13 C NMR in DMSO-d6 of the 4-nitrobenzochalcogenadiazoles 1 and σ-adducts 4 c and 4 f [a] Values reported by Miranda and al.…”

Synthesis and Organocatalytic Asymmetric Nitro-aldol Initiated Cascade Reactions of 2-Acylbenzonitriles Leading to 3,3-Disubstituted Isoindolinones

“…In recent years, cascade reactions have been one of the main topics in organic chemistry because of the convenient construction of complex scaffolds in one-pot procedures without the isolation of the intermediates [1][2][3][4]. The electrophilic additions to ketones are particularly challenging because of the poor reactivity of this functional group when compared to the aldehydes despite the great potential in the construction of quaternary carbons [5][6][7]. Accordingly, the applications of ketones as electrophiles in nitro-aldol cascade type reactions are very limited [1][2][3][4].…”