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.

Atomic charges provide crucial information about the electronic structure of a molecular system. Among the different definitions of these descriptors, the one proposed by the Quantum Theory of Atoms in Molecules (QTAIM) is particularly attractive given its invariance against orbital transformations although the computational cost associated with their calculation limits its applicability. Given that Machine Learning (ML) techniques have been shown to accelerate orders of magnitude the computation of a number of quantum mechanical observables, in this work, we take advantage of ML knowledge to develop an intuitive and fast neural network model (NNAIMQ) for the computation of QTAIM charges for C, H, O, and N atoms with high accuracy. Our model has been trained and tested using data from quantum chemical calculations in more than 45 000 molecular environments of the near-equilibrium CHON chemical space. The reliability and performance of NNAIMQ have been analyzed in a variety of scenarios, from equilibrium geometries to molecular dynamics simulations. Altogether, NNAIMQ yields remarkably small prediction errors, well below the 0.03 electron limit in the general case, while accelerating the calculation of QTAIM charges by several orders of magnitude.

Among the different noncovalent interactions, halogen bonds have captured wide attention in the last years. Their stability has been rationalized in electrostatic terms by appealing to the σ-hole concept, a charge-depleted region that is able to interact favorably with electron rich moieties. This interpretation has been questioned, and in this work a set of anionic halogen model systems are used to shed some light on this issue. We use the interacting quantum atoms method, which provides an orbital invariant energy decomposition in which pure electrostatic terms are well isolated, and we complement our insights with the analysis of electrostatic potentials (ESPs) as well as with traditional descriptors of charge accumulation like the Laplacian of the electron density. The total electrostatic interaction between the interacting species is surprisingly destabilizing in many of the systems examined, demonstrating that although σ-holes might be qualitatively helpful, much care has to be taken in ascribing the stability of these systems to electrostatics. It is clearly shown that electron delocalization is essential to understand the stability of the complexes. The evolution of atomic charges as the aggregates forms reveals a charge transfer picture in which the central, σ-hole bearing halogen acts as a mere spectator. These systems may then be not far from engaging in a classical 3c-4e interaction. Since the presence of a σ-hole as characterized by the ESP mapped on a suitable molecular envelope isosurface does not guarantee attractive electrostatic interactions, we encourage to employ a wider perspective that takes into account the full charge distribution.

Copper(I) [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 L)] n (L = OMe, NEt 2 , NH t Bu) compounds supported by flexible functionalized NHC-based polydentate ligands have been prepared in a one-pot procedure by reacting the corresponding imidazolium salt with an excess of copper powder and Ag 2 O. An X-ray diffraction analysis has revealed that [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 NEt 2 )] n is a linear coordination polymer formed by bimetallic [Cu(μ-Br)] 2 units linked by the lutidine-based NHC-py-NEt 2 ligand, which acts as a heteroditopic ligand with a 1κC-2κ 2 N,N′ coordination mode. We propose that the polymeric compounds break down in the solution into more compact tetranuclear [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 L)] 2 compounds with a coordination mode identical to the functionalized NHC ligands. These compounds have been found to exhibit high catalytic activity in the Cu-catalyzed azide−alkyne cycloaddition (CuAAC) reaction. In particular, [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 NEt 2 )] 2 efficiently catalyzes the click reaction of a range of azides and alkynes, under an inert atmosphere at room temperature in neat conditions at a very low catalyst loading, to quantitatively afford the corresponding 1,4-disubstituted 1,2,3-triazole derivatives in a few minutes. The cycloaddition reaction of benzyl azide to phenylacetylene can be performed at 25−50 ppm catalyst loading by increasing the reaction time and/or temperature. Reactivity studies have shown that the activation of the polynuclear catalyst precursor involves the alkyne deprotonation by the NHC moiety of the polydentate ligand to afford a copper(I)-alkynyl species bearing a functionalized imidazolium ligand. DFT calculations support the participation of the dinuclear species [(CuBr) 2 (μ-t BuImCH 2 pyCH 2 NEt 2 )], resulting from the fragmentation of the tetranuclear compound, as the catalytically active species. The proposed reaction pathway proceeds through zwitterionic dinuclear intermediates and entails the active participation of both copper atoms, as well as the NHC moiety as an internal base, which activates the reacting alkyne via deprotonation.

Bimolecular nucleophilic substitution (S N 2) and elimination (E2) reactions are prototypical examples of competing reaction mechanisms, with fundamental implications in modern chemical synthesis. Steric hindrance (SH) is often considered to be one of the dominant factors determining the most favorable reaction out of the S N 2 and E2 pathways. However, the picture provided by classical chemical intuition is inevitably grounded on poorly defined bases. In this work, we try to shed light on the aforementioned problem through the analysis and comparison of the evolution of the steric energy ( E ST ), settled within the IQA scheme and experienced along both reaction mechanisms. For such a purpose, the substitution and elimination reactions of a collection of alkyl bromides (R-Br) with the hydroxide anion (OH – ) were studied in the gas phase at the M06-2X/aug-cc-pVDZ level of theory. The results show that, generally, E ST recovers the appealing trends already anticipated by chemical intuition and organic chemistry, supporting the role that SH is classically claimed to play in the competition between S N 2 and E2 reactions.

Resonance-assisted hydrogen bonds (RAHB) are intramolecular contacts that are characterised by being particularly energetic. This fact is often attributed to the delocalisation of π electrons in the system. In the present article, we assess this thesis via the examination of the effect of electron-withdrawing and electron-donating groups, namely −F, −Cl, −Br, −CF3, −N(CH3)2, −OCH3, −NHCOCH3 on the strength of the RAHB in malondialdehyde by using the Quantum Theory of Atoms in Molecules (QTAIM) and the Interacting Quantum Atoms (IQA) analyses. We show that the influence of the investigated substituents on the strength of the investigated RAHBs depends largely on its position within the π skeleton. We also examine the relationship between the formation energy of the RAHB and the hydrogen bond interaction energy as defined by the IQA method of wave function analysis. We demonstrate that these substituents can have different effects on the formation and interaction energies, casting doubts regarding the use of different parameters as indicators of the RAHB formation energies. Finally, we also demonstrate how the energy density can offer an estimation of the IQA interaction energy, and therefore of the HB strength, at a reduced computational cost for these important interactions. We expected that the results reported herein will provide a valuable understanding in the assessment of the energetics of RAHB and other intramolecular interactions.

The interacting quantum atoms approach (IQA) as applied to the electron-pair exhaustive partition of real space induced by the electron localization function (ELF) is used to examine candidate energetic descriptors to rationalize substituent effects in simple electrophilic aromatic substitutions. It is first shown that inductive and mesomeric effects can be recognized from the decay mode of the aromatic valence bond basin populations with the distance to the substituent, and that the fluctuation of the population of adjacent bonds holds also regioselectivity information. With this, the kinetic energy of the electrons in these aromatic basins, as well as their mutual exchange-correlation energies are proposed as suitable energetic indices containing relevant information about substituent effects. We suggest that these descriptors could be used to build future reactive force fields.

A novel tripodal carbamate-based steroidal architecture works as an efficient catalyst on the Michael-type addition reaction between dimethyl malonate and nitrostyrene. Its action mode has been disclosed by quantum chemical calculations. It comprises the preorganization and confinement of the reagents within the active chiral cavity of the steroid, which are held together by means of cooperative Hbond contacts. Organocatalysis consists in the acceleration of chemical reactions employing small organic frameworks typically assembled from C, H, O, N, S and P atoms. [1] Some privileged structures have been widely used for building up asymmetric organocatalysts: derivatives of 1,2-diamines, 1, BINOL, 2, proline or other natural amino acids, 3, and cinchona alkaloids, 4 (Figure 1). Alternative chiral scaffolds are extensively sought after. Herein we describe the ability of a steroidal platform, based on cholic acid, 5, to work as an enantioselective organocatalyst that makes use of cooperative weak H-bonding interactions.