F. De Proft

Atomic charges are a key concept to give more insight into the electronic structure and chemical reactivity. The Hirshfeld-I partitioning scheme applied to the model protein human 2-cysteine peroxiredoxin thioredoxin peroxidase B is used to investigate how large a protein fragment needs to be in order to achieve convergence of the atomic charge of both, neutral and negatively charged residues. Convergence in atomic charges is rapidly reached for neutral residues, but not for negatively charged ones. This study pinpoints difficulties on the road towards accurate modeling of negatively charged residues of large biomolecular systems in a multiscale approach.

Bond dissociation enthalpies (BDEs) of a large series of molecules of the type A−B, where a series of radicals A ranging from strongly electrophilic to strongly nucleophilic are coupled with a series of 8 radicals (CH2OH, CH3, NF2, H, OCH3, OH, SH, and F) also ranging from electrophilic to nucleophilic, are computed and analyzed using chemical concepts emerging from density functional theory, more specifically the electrophilicities of the individual radical fragments A and B. It is shown that, when introducing the concept of relative radical electrophilicity, an (approximately) intrinsic radical stability scale can be developed, which is in good agreement with previously proposed stability scales. For 47 radicals, the intrinsic stability was estimated from computed BDEs of their combinations with the strongly nucleophilic hydroxymethyl radical, the neutral hydrogen atom, and the strongly electrophilic fluorine atom. Finally, the introduction of an extra term containing enhanced Pauling electronegativities in the model improves the agreement between the computed BDEs and the ones estimated from the model, resulting in a mean absolute deviation of 16.4 kJ mol−1. This final model was also tested against 82 experimental values. In this case, a mean absolute deviation of 15.3 kJ mol−1 was found. The obtained sequences for the radical stabilities are rationalized using computed spin densities for the radical systems.

The regioselectivity of ring-forming radical reactions is investigated within the framework of the so-called spin-polarized conceptual density functional theory. Two different types of cyclizations were studied. First, a series of model reactions of alkyl- and acyl-substituted radicals were investigated. Next, attention was focused on the radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals (a three-step mechanism). In both of these reactions, the approaching radical (carbon or nitrogen centered) adds to a carbon−carbon double bond within the same molecule to form a radical ring compound. In this process, the number of electrons is changing from a local point of view (a charge transfer occurs from one part of the molecule to another one) at constant global spin number Ns (both the reactant and the product ring compound are in the doublet state). It is shown that the experimentally observed regioselectivities for these ring-closure steps can be predicted using the spin-polarized Fukui functions for radical attack, (r).