The theoretical calculation of pKa values for Brønsted acids is a challenging task that involves sophisticated and time-consuming methods. Therefore, heuristic approaches are efficient and appealing methodologies to approximate these values. Herein, we used the maximum surface electrostatic potential (VS,max) on the acidic hydrogen atoms of carboxylic acids to describe the H-bond interaction with water (the same descriptor that is used to characterize σ-bonded complexes) and correlate the results with experimental pKa values to obtain a predictive model for other carboxylic acids. We benchmarked six different methods, all including an implicit solvation model (water): Five density functionals and the Møller–Plesset second order perturbation theory in combination with six different basis sets for a total of thirty-six levels of theory. The ωB97X-D/cc-pVDZ level of theory stood out as the best one for consistently reproducing the reported pKa values, with a predictive power of 98% correlation in a test set of ten other carboxylic acids.

N-triflylphosphoramides (NTPA), have become increasingly popular catalysts in the development of enantioselective transformations as they are stronger Brønsted acids than the corresponding phosphoric acids (PA). Their highly acidic, asymmetric active...

σ-Holes are shown to promote the electrophilic behavior of chlorine atoms in a trichloromethyl group when bound to an electron-withdrawing moiety. A halogen bond-type non-covalent interaction between a chlorine atom and a negatively charged sulfur atom takes place, causing the abstraction of such a chlorine atom while leaving a carbanion, subsequently driving the chemical reduction of the trichloromethyl group to a sulfide in a stepwise process. The mechanism for the model reaction of trichloromethyl pyrimidine 1 with thiophenolate and thiophenol to yield phenylsulfide 4 was followed through H-NMR and studied using DFT transition state calculations, and the energy profile for this transformation is fully discussed. MP2 calculations of the electrostatic potential were performed for a series of trichloromethyl compounds in order to assess the presence of σ-holes and quantify them by means of the maximum surface electrostatic potential. Such calculations showed that the chlorine atoms behave as electrophilic leaving groups toward a nucleophilic attack, opening a new possibility in the synthetic chemistry of the trichloromethyl group.

Eribulin (Halaven) is the most structurally complex non-peptidic drug made by total synthesis and has challenged preconceptions of synthetic feasibility in drug discovery and development. However, despite decades of research, the synthesis and manufacture of eribulin remains a daunting task. Here, we report syntheses of the most complex fragment of eribulin (C14–C35) used in two distinct industrial routes to this important anticancer drug. Our convergent strategy relies on a doubly diastereoselective Corey–Chaykovsky reaction to affect the union of two tetrahydrofuran-containing subunits. Notably, this process relies exclusively on enantiomerically enriched α-chloroaldehydes as building blocks for constructing the three densely functionalized oxygen heterocycles found in the C14–C35 fragment and all associated stereocenters. Overall, eribulin can now be produced in a total of 52 steps, which is a significant reduction from that reported in both academic and industrial syntheses.