More Electropositive is More Electronegative: Atom Size Determines C=X Group Electronegativity.

Opposite to what one might expect, we find that the C=X group can become effectively more, not less, electronegative when the Pauling electronegativity of atom X decreases down Groups 16, 15, and 14 of the Periodic Table. Our quantum-chemical analyses, show that, and why, this phenomenon is a direct consequence of the increasing size of atom X down a group. These findings can be applied to tuning and improving the hydrogen-bond donor strength of amides H2 NC(=X)R by increasingly withdrawing density from the NH2 group. A striking example is that H2 NC(=SiR2 )R is a stronger hydrogen-bond donor than H2 NC(=CR2 )R.

Stabilization of Diborynes versus Destabilization of Diborenes by Coordination of Lewis Bases: Unravelling the Dichotomy.

We have quantum chemically investigated the boron-boron bonds in B2 , diborynes B2 L2 , and diborenes B2 H2 L2 (L=none, OH2 , NH3 ) using dispersion-corrected relativistic density functional theory at ZORA-BLYP-D3(BJ)/TZ2P. B2 has effectively a single B-B bond provided by two half π bonds, whereas B2 H2 has effectively a double B=B bond provided by two half π bonds and one σ 2p-2p bond. This different electronic structure causes B2 and B2 H2 to react differently to the addition of ligands. Thus, in B2 L2 , electron-donating ligands shorten and strengthen the boron-boron bond whereas, in B2 H2 L2 , they lengthen and weaken the boron-boron bond. The aforementioned variations in boron-boron bond length and strength become more pronounced as the Lewis basicity of the ligands L increases.

Blueshift in Trifurcated Hydrogen Bonds: A Tradeoff between Tetrel Bonding and Steric Repulsion.

We have quantum chemically investigated the origin of the atypical blueshift of the H-C bond stretching frequency in the hydrogen-bonded complex X- •••H3 C-Y (X, Y=F, Cl, Br, I), as compared to the corresponding redshift occurring in Cl- •••H3 N and Cl- •••H3 C-H, using relativistic density functional theory (DFT) at ZORA-BLYP-D3(BJ)/QZ4P. Previously, this blueshift was attributed, among others, to the contraction of the H-C bonds as the H3 C moiety becomes less pyramidal. Herein, we provide quantitative evidence that, instead, the blueshift arises from a direct and strong X- •••C interaction of the HOMO of A- with the backside lobe on carbon of the low-lying C-Y antibonding σ* LUMO of the H3 C-Y fragment. This X- •••C bond, in essence a tetrel bond, pushes the H atoms towards a shorter H-C distance and makes the H3 C moiety more planar. The blueshift may, therefore, serve as a diagnostic for tetrel bonding.

Blueshift in Trifurcated Hydrogen Bonds: A Tradeoff between Tetrel Bonding and Steric Repulsion.

The front cover artwork is provided by the TheoCheM group at the Vrije Universiteit Amsterdam. The image shows how, in X- •••H3 C-Y complexes, the Lewis base X- tetrel-binds to the central C while sterically pushing the H atoms towards C; hence, the compression and blueshift of the H-C bonds. Read the full text of the Research Article at 10.1002/cphc.202300480.

Solvent-induced dual nucleophiles and the α-effect in the SN2 versus E2 competition.

We have quantum chemically investigated how microsolvation affects the various E2 and SN2 pathways, their mutual competition, and the α-effect of the model reaction system HOO-(H2O)n + CH3CH2Cl, at the CCSD(T) level. Interestingly, we identify the dual nature of the α-nucleophile HOO- which, upon solvation, is in equilibrium with HO-. This solvent-induced dual appearance gives rise to a rich network of competing reaction channels. Among both nucleophiles, SN2 is always favored over E2, and this preference increases upon increasing microsolvation. Furthermore, we found a pronounced α-effect, not only for SN2 substitution but also for E2 elimination, i.e., HOO- is more reactive than HO- in both cases. Our activation strain and quantitative molecular orbital analyses reveal the physical mechanisms behind the various computed trends. In particular, we demonstrate that two recently proposed criteria, required for solvent-free nucleophiles to display the α-effect, must also be satisfied by microsolvated HOO-(H2O)n nucleophiles.

Correction: Pericyclic reaction benchmarks: hierarchical computations targeting CCSDT(Q)/CBS and analysis of DFT performance.

Correction for 'Pericyclic reaction benchmarks: hierarchical computations targeting CCSDT(Q)/CBS and analysis of DFT performance' by Pascal Vermeeren et al., Phys. Chem. Chem. Phys., 2022, 24, 18028-18042, https://doi.org/10.1039/D2CP02234F.

Cobalt-Catalyzed Enantio- and Regioselective C(sp3 )-H Alkenylation of Thioamides.

An enantioselective cobalt-catalyzed C(sp3 )-H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

Understanding chemistry with the symmetry-decomposed Voronoi deformation density charge analysis.

The symmetry-decomposed Voronoi deformation density (VDD) charge analysis is an insightful and robust computational tool to aid the understanding of chemical bonding throughout all fields of chemistry. This method quantifies the atomic charge flow associated with chemical-bond formation and enables decomposition of this charge flow into contributions of (1) orbital interaction types, that is, Pauli repulsive or bonding orbital interactions; (2) per irreducible representation (irrep) of any point-group symmetry of interacting closed-shell molecular fragments; and now also (3) interacting open-shell (i.e., radical) molecular fragments. The symmetry-decomposed VDD charge analysis augments the symmetry-decomposed energy decomposition analysis (EDA) so that the charge flow associated with Pauli repulsion and orbital interactions can be quantified both per atom and per irrep, for example, for σ, π, and δ electrons. This provides detailed insights into fundamental aspects of chemical bonding that are not accessible from EDA.

How Bases Catalyze Diels-Alder Reactions.

We have quantum chemically studied the base-catalyzed Diels-Alder (DA) reaction between 3-hydroxy-2-pyrone and N-methylmaleimide using dispersion-corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro-DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol-1 , causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO2 , yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO-raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3-hydroxy-2-pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N-methylmaleimide.

Intermolecular Covalent Interactions: Nature and Directionality.

Quantum chemical methods were employed to analyze the nature and the origin of the directionality of pnictogen (PnB), chalcogen (ChB), and halogen bonds (XB) in archetypal Fm Z⋅⋅⋅F- complexes (Z=Pn, Ch, X), using relativistic density functional theory (DFT) at ZORA-M06/QZ4P. Quantitative Kohn-Sham MO and energy decomposition analyses (EDA) show that all these intermolecular interactions have in common that covalence, that is, HOMO-LUMO interactions, provide a crucial contribution to the bond energy, besides electrostatic attraction. Strikingly, all these bonds are directional (i.e., F-Z⋅⋅⋅F- is approximately linear) despite, and not because of, the electrostatic interactions which, in fact, favor bending. This constitutes a breakdown of the σ-hole model. It was shown how the σ-hole model fails by neglecting both, the essential physics behind the electrostatic interaction and that behind the directionality of electron-rich intermolecular interactions. Our findings are general and extend to the neutral, weaker ClI⋅⋅⋅NH3 , HClTe⋅⋅⋅NH3 , and H2 ClSb⋅⋅⋅NH3 complexes.

SN 2 versus E2 Competition of Cyclic Ethers.

We have quantum chemically studied the influence of ring strain on the competition between the two mechanistically different SN 2 and E2 pathways using a series of archetypal ethers as substrate in combination with a diverse set of Lewis bases (F- , Cl- , Br- , HO- , H3 CO- , HS- , H3 CS- ), using relativistic density functional theory at ZORA-OLYP/QZ4P. The ring strain in the substrate is systematically increased on going from a model acyclic ether to a 6- to 5- to 4- to 3-membered ether ring. We have found that the activation energy of the SN 2 pathway sharply decreases when the ring strain of the system is increased, thus on going from large to small cyclic ethers, the SN 2 reactivity increases. In contrast, the activation energy of the E2 pathway generally rises along this same series, that is, from large to small cyclic ethers. The opposing reactivity trends induce a mechanistic switch in the preferred reaction pathway for strong Lewis bases from E2, for large cyclic substrates, to SN 2, for small cyclic substrates. Weak Lewis bases are unable to overcome the higher intrinsic distortivity of the E2 pathway and, therefore, always favor the less distortive SN 2 reaction.

Origin of the Bürgi-Dunitz Angle.

The Bürgi-Dunitz (BD) angle plays a pivotal role in organic chemistry to rationalize the nucleophilic addition to carbonyl groups. Yet, the origin of the obtuse trajectory of the nucleophile remains incompletely understood. Herein, we quantify the importance of the underlying physical factors quantum chemically. The obtuse BD angle appears to originate from the concerted action of a reduced Pauli repulsion between the nucleophile HOMO and carbonyl π bond, a more stabilizing HOMO-π*-LUMO(C=O) interaction, as well as a more favorable electrostatic attraction.

The Pauli Repulsion-Lowering Concept in Catalysis.

Organic chemistry has undoubtedly had a profound impact on humanity. Day in and day out, we find ourselves constantly surrounded by organic compounds. Pharmaceuticals, plastics, fuels, cosmetics, detergents, and agrochemicals, to name a few, are all synthesized by organic reactions. Very often, these reactions require a catalyst in order to proceed in a timely and selective manner. Lewis acids and organocatalysts are commonly employed to catalyze organic reactions and are considered to enhance the frontier molecular orbital (FMO) interactions. A vast number of textbooks and primary literature sources suggest that the binding of a Lewis acid or an iminium catalyst to a reactant (R1) stabilizes its LUMO and leads to a smaller HOMO(R2)-LUMO(R1) energy gap with the other reactant (R2), thus resulting in a faster reaction. This forms the basis for the so-called LUMO-lowering catalysis concept. Despite the simplicity and popularity of FMO theory, a number of deficiencies have emerged over the years, as a consequence of these FMOs not being the operative factor in the catalysis. LUMO-lowering catalysis is ultimately incomplete and is not always operative in catalyzed organic reactions. Our groups have recently undertaken a concerted effort to generate a unified framework to rationalize and predict chemical reactivity using a causal model that is rooted in quantum mechanics. In this Account, we propose the concept of Pauli repulsion-lowering catalysis to understand the catalysis in fundamental processes in organic chemistry. Our findings emerge from state-of-the-art computational methods, namely, the activation strain model (ASM) of reactivity in conjunction with quantitative Kohn-Sham molecular orbital theory (KS-MO) and a matching energy decomposition analysis (EDA). The binding of the catalyst to the substrate not only leads to a stabilization of its LUMO but also induces a significant reduction of the two-orbital, four-electron Pauli repulsion involving the key molecular orbitals of both reactants. This repulsion-lowering originates, for the textbook Lewis acid-catalyzed Diels-Alder reaction, from the catalyst polarizing the occupied π orbital of the dienophile away from the carbon atoms that form new bonds with the diene. This polarization of the occupied dienophile π orbital reduces the occupied orbital overlap with the diene and constitutes the ultimate physical factor responsible for the acceleration of the catalyzed process as compared to the analogous uncatalyzed reaction. We show that this physical mechanism is generally applicable regardless of the type of reaction (Diels-Alder and Michael addition reactions) and the way the catalyst is bonded to the reactants (i.e., from pure covalent or dative bonds to weaker hydrogen or halogen bonds). We envisage that the insights emerging from our analysis will guide future experimental developments toward the design of more efficient catalytic transformations.

How Ionization Catalyzes Diels-Alder Reactions.

The catalytic effect of ionization on the Diels-Alder reaction between 1,3-butadiene and acrylaldehyde has been studied using relativistic density functional theory (DFT). Removal of an electron from the dienophile, acrylaldehyde, significantly accelerates the Diels-Alder reaction and shifts the reaction mechanism from concerted asynchronous for the neutral Diels-Alder reaction to stepwise for the radical-cation Diels-Alder reaction. Our detailed activation strain and Kohn-Sham molecular orbital analyses reveal how ionization of the dienophile enhances the Diels-Alder reactivity via two mechanisms: (i) by amplifying the asymmetry in the dienophile's occupied π-orbitals to such an extent that the reaction goes from concerted asynchronous to stepwise and thus with substantially less steric (Pauli) repulsion per reaction step; (ii) by enhancing the stabilizing orbital interactions that result from the ability of the singly occupied molecular orbital of the radical-cation dienophile to engage in an additional three-electron bonding interaction with the highest occupied molecular orbital of the diene.

How Ionization Catalyzes Diels-Alder Reactions.

Invited for the cover of this issue are Pascal Vermeeren, Trevor A. Hamlin, and F. Matthias Bickelhaupt of the TheoCheM group at the Vrije Universiteit Amsterdam. The cover art depicts how ionizing the dienophile lowers the Diels-Alder reaction barrier between 1,3-butadiene and acrylaldehyde by reducing the destabilizing steric Pauli repulsion and enhancing the stabilizing orbital interactions. Read the full text of the article at 10.1002/chem.202200987.

Probing the Lewis Acidity of Boronic Acids through Interactions with Arene Substituents.

Boronic acids are Lewis acids that exist in equilibrium with boronate forms in aqueous solution. Here we experimentally and computationally investigated the Lewis acidity of 2,6-diarylphenylboronic acids; specially designed phenylboronic acids that possess two flanking aromatic rings with tunable aromatic character. Hammett analysis of 2,6-diarylphenylboronic acids reveals that their Lewis acidity remains unchanged upon the introduction of EWG/EDG at the distant para position of the flanking aromatic rings. Structural and computational studies demonstrate that polar-π interactions and solvation effects contribute to the stabilization of boronic acids and boronate forms by aromatic rings. Our physical-organic chemistry work highlights that boronic acids and boronates can be stabilized by aromatic systems, leading to an important molecular knowledge for rational design and development of boronic acid-based catalysts and inhibitors of biomedically important proteins.

C-X Bond Activation by Palladium: Steric Shielding versus Steric Attraction.

The C-X bond activation (X = H, C) of a series of substituted C(n°)-H and C(n°)-C(m°) bonds with C(n°) and C(m°) = H3 C- (methyl, 0°), CH3 H2 C- (primary, 1°), (CH3 )2 HC- (secondary, 2°), (CH3 )3 C- (tertiary, 3°) by palladium were investigated using relativistic dispersion-corrected density functional theory at ZORA-BLYP-D3(BJ)/TZ2P. The effect of the stepwise introduction of substituents was pinpointed at the C-X bond on the bond activation process. The C(n°)-X bonds become substantially weaker going from C(0°)-X, to C(1°)-X, to C(2°)-X, to C(3°)-X because of the increasing steric repulsion between the C(n°)- and X-group. Interestingly, this often does not lead to a lower barrier for the C(n°)-X bond activation. The C-H activation barrier, for example, decreases from C(0°)-X, to C(1°)-X, to C(2°)-X and then increases again for the very crowded C(3°)-X bond. For the more congested C-C bond, in contrast, the activation barrier always increases as the degree of substitution is increased. Our activation strain and matching energy decomposition analyses reveal that these differences in C-H and C-C bond activation can be traced back to the opposing interplay between steric repulsion across the C-X bond versus that between the catalyst and substrate.

SN2 versus SN2' Competition.

We have quantum chemically explored the competition between the SN2 and SN2' pathways for X- + H2C═CHCH2Y (X, Y = F, Cl, Br, I) using a combined relativistic density functional theory and coupled-cluster theory approach. Bimolecular nucleophilic substitution reactions at allylic systems, i.e., Cγ═Cß-Cα-Y, bearing a leaving-group at the α-position, proceed either via a direct attack at the α-carbon (SN2) or via an attack at the γ-carbon, involving a concerted allylic rearrangement (SN2'), in both cases leading to the expulsion of the leaving-group. Herein, we provide a physically sound model to rationalize under which circumstances a nucleophile will follow either the aliphatic SN2 or allylic SN2' pathway. Our activation strain analyses expose the underlying physical factors that steer the SN2/SN2' competition and, again, demonstrate that the concepts of a reaction's "characteristic distortivity" and "transition state acidity" provide explanations and design tools for understanding and predicting reactivity trends in organic synthesis.

How Solvation Influences the SN2 versus E2 Competition.

We have quantum chemically investigated how solvation influences the competition between the SN2 and E2 pathways of the model F- + C2H5Cl reaction. The system is solvated in a stepwise manner by going from the gas phase, then via microsolvation of one to three explicit solvent molecules, then last to bulk solvation using relativistic density functional theory at (COSMO)-ZORA-OLYP/QZ4P. We explain how and why the mechanistic pathway of the system shifts from E2 in the gas phase to SN2 upon strong solvation of the Lewis base (i.e., nucleophile/protophile). The E2 pathway is preferred under weak solvation of the system by dichloromethane, whereas a switch in reactivity from E2 to SN2 is observed under strong solvation by water. Our activation strain and Kohn-Sham molecular orbital analyses reveal that solvation of the Lewis base has a significant impact on the strength of the Lewis base. We show how strong solvation furnishes a weaker Lewis base that is unable to overcome the high characteristic distortivity associated with the E2 pathway, and thus the SN2 pathway becomes viable.

Through-Space Stabilization of an Imidazolium Cation by Aromatic Rings.

Imidazole-based compounds are widely found in natural products, synthetic molecules, and biomolecules. Noncovalent interactions between the imidazole ring and other functional groups play an important role in determining the function of diverse molecules. However, there is a limited understanding of the underlying noncovalent interactions between imidazoles and aromatic systems. In this work, we report physical-organic chemistry studies on 2-(2,6-diarylphenyl)-1H-imidazoles and their protonated forms to investigate the noncovalent interactions between the central imidazole ring and two flanking aromatic rings possessing substituents at the para/meta position. Hammett analysis revealed that pKa values and proton affinities correlate well with Hammett σ values of para-substituents at the flanking rings. Additional quantitative Kohn-Sham molecular orbital and energy decomposition analyses reveal that through-space π-π interactions and NH-π interactions contribute to the intramolecular stabilization of the imidazolium cation. The results are important because they clearly demonstrate that the imidazolium cation forms energetically favorable noncovalent interactions with aromatic rings via the through-space effect, a knowledge that can be used in rational drug and catalyst design.