Energetic Descriptors of Steric Hindrance in Real Space: An Improved IQA Picture**

Abstract

Steric hindrance (SH) plays a central role in the modern chemical narrative, lying at the core of chemical intuition. As it however happens with many successful chemical concepts, SH lacks an underlying physically sound root, and multiple mutually inconsistent approximations have been devised to relate this fuzzy concept to computationally derivable descriptors. We here argue that being SH related to spatial as well as energetic features of interacting systems, SH can be properly handled if we chose a real space energetic stance like the Interacting Quantum Atoms (IQA) approach. Drawing on previous work by Popelier and coworkers (ChemistryOpen 8, 560, 2019) we build an energetic estimator of SH, referred to as E ST . We show that the rise in the self-energy of a fragment that accompanies steric congestion is a faithful proxy for the chemist's SH concept if we remove the effect of charge transfer. This can be done rigorously, and the E ST here defined provides correct sterics even for hydrogen atoms, where the plain use of deformation energies leads to non-chemical results. The applicability of E ST is validated in several chemical scenarios, going from atomic compressions to archetypal S N2 reactions. E ST is shown to be a robust steric hindrance descriptor.

A real space picture of the role of steric effects inSN2reactions

“…Indeed, a wide variety of computational tools and models have been employed in recent years to elucidate the origin of SH. [43][44][45][46][47] Following this trend, and drawing on the previous work developed by Popelier and co-workers, 43 we have recently shown 12 that a real space descriptor of steric effects, the so-called steric energy E ST , can be easily obtained with the aid of the IQA energy partitioning scheme. 48 Such a descriptor is obtained by freeing the deformation energy (E def ) of an atom or fragment from its charge transfer component (E CT ).…”

“…It is precisely within the latter approach, where the steric energy, E ST , descriptor was derived. 12 The IQA approach is a real-space based technique, formulated within the Quantum Theory of Atoms in F I G U R E 1 Schematic representation of the general S N 2 reaction mechanism Molecules (QTAIM) theory, 56 which decomposes the total energy of any chemical system as a sum of one-and two-body energy terms, named self and interaction energies, respectively, as:…”

“…Due to its moderate size, simplicity and relevance, this and other similar reactions have been widely employed as model systems to unravel the nature of chemical bonding and reactivity. [10][11][12] The archetypal example involves a substitution reaction of halogen-like groups taking place over a carbon based electrophile, 6 though substitution reactions of electrophiles of different chemical nature have also been explored. [13][14][15][16] Indeed, the S N 2 reaction constitutes one of the basic kernels of classical organic chemistry and it has been widely studied both computationally [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and experimentally.…”

“…48 Such a descriptor is obtained by freeing the deformation energy (E def ) of an atom or fragment from its charge transfer component (E CT ). It is worth mentioning that our approach prevents any of the well described 49 Considering the success of real space techniques in the analysis of some simple substitution reactions, 11,12 in this work we try to shine light on the actual role that SH plays in the latter, studying in detail the effect of the steric demands of the nucleophile, electrophile and leaving groups. Furthermore, in the latter case, special attention is paid to the distinctive effect of the geminal and vicinal groups belonging to the substrate.…”

“…Due to its moderate size, simplicity and relevance, this and other similar reactions have been widely employed as model systems to unravel the nature of chemical bonding and reactivity 10–12 . The archetypal example involves a substitution reaction of halogen‐like groups taking place over a carbon based electrophile, 6 though substitution reactions of electrophiles of different chemical nature have also been explored 13–16 .…”