Correction: Not antiaromaticity gain, but increased asynchronicity enhances the Diels-Alder reactivity of tropone.

Correction for 'Not antiaromaticity gain, but increased asynchronicity enhances the Diels-Alder reactivity of tropone' by Eveline H. Tiekink et al., Chem. Commun., 2023, 59, 3703-3706, https://doi.org/10.1039/D3CC00512G.

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.

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.

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.

The Origin of Catalysis and Regioselectivity of Lewis Acid-Catalyzed Diels-Alder Reactions with Tropone.

We have studied the uncatalyzed and Lewis acid (LA)-catalyzed cycloaddition reaction between tropone and 1,1-dimethoxyethene using dispersion-corrected relativistic density functional theory (DFT). The LA catalysts BF3 , B(C6 H5 )3 , and B(C6 F5 )3 efficiently accelerate both the competing [4+2] and [8+2] cycloaddition reactions by lowering the activation barrier up to 12 kcal mol-1 compared to the uncatalyzed reaction. Our study reveals that the LA catalyst promotes both cycloaddition reaction pathways by LUMO-lowering catalysis and demonstrates that Pauli-lowering catalysis is not always the operative catalytic mechanism in cycloaddition reactions. Judicious choice of the LA catalyst can effectively impart regiocontrol of the cycloaddition: B(C6 H5 )3 furnishes the [8+2] adduct while B(C6 F5 )3 yields the [4+2] adduct. We discovered that the regioselectivity shift finds its origin in the ability of the LA to absorb distortion by adopting a trigonal pyramidal geometry around the boron atom.

Not antiaromaticity gain, but increased asynchronicity enhances the Diels-Alder reactivity of tropone.

Tropone is an unreactive diene in normal electron demand Diels-Alder reactions, but it can be activated via carbonyl umpolung by using hydrazone ion analogs. Recently, the higher reactivity of hydrazone ion analogs was ascribed to a raised HOMO energy induced by antiaromaticity (L. J. Karas, A. T. Campbell, I. V. Alabugin and J. I. Wu, Org. Lett., 2020, 22, 7083). We show that this is incorrect, and that the activation barrier is lowered by increased asynchronicity.

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.

Stability of alkyl carbocations.

The traditional and widespread rationale behind the stability trend of alkyl-substituted carbocations is incomplete. Through state-of-the-art quantum chemical analyses, we quantitatively established a generally overlooked driving force behind the stability of carbocations, namely, that the parent substrates are substantially destabilized by the introduction of substituents, often playing a dominant role in solution. This stems from the repulsion between the substituents and the C-X bond.

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

Hierarchical, convergent ab initio benchmark computations were performed followed by a systematic analysis of DFT performance for five pericyclic reactions comprising Diels-Alder, 1,3-dipolar cycloaddition, electrocyclic rearrangement, sigmatropic rearrangement, and double group transfer prototypes. Focal point analyses (FPA) extrapolating to the ab initio limit were executed via explicit quantum chemical computations with electron correlation treatments through CCSDT(Q) and correlation-consistent Gaussian basis sets up to aug'-cc-pV5Z. Optimized geometric structures and vibrational frequencies of all stationary points were obtained at the CCSD(T)/cc-pVTZ level of theory. The FPA reaction barriers and energies exhibit convergence to within a few tenths of a kcal mol-1. The FPA benchmarks were used to evaluate the performance of 60 density functionals (eight dispersion-corrected), covering the local-density approximation (LDA), generalized gradient approximations (GGAs), meta-GGAs, hybrids, meta-hybrids, double-hybrids, and range-separated hybrids. The meta-hybrid M06-2X functional provided the best overall performance [mean absolute error (MAE) of 1.1 kcal mol-1] followed closely by the double-hybrids B2K-PLYP, mPW2K-PLYP, and revDSD-PBEP86 [MAE of 1.4-1.5 kcal mol-1]. The regularly used GGA functional BP86 gave a higher MAE of 5.8 kcal mol-1, but it qualitatively described the trends in reaction barriers and energies. Importantly, we established that accurate yet efficient meta-hybrid or double-hybrid DFT potential energy surfaces can be acquired based on geometries from the computationally efficient and robust BP86/DZP level.

The 1,3-Dipolar Cycloaddition: From Conception to Quantum Chemical Design.

The 1,3-dipolar cycloaddition (1,3-DCA) reaction, conceptualized by Rolf Huisgen in 1960, has proven immensely useful in organic, material, and biological chemistry. The uncatalyzed, thermal transformation is generally sluggish and unselective, but the reactivity can be enhanced by means of metal catalysis or by the introduction of either predistortion or electronic tuning of the dipolarophile. These promoted reactions generally go with a much higher reactivity, selectivity, and yields, often at ambient temperatures. The rapid orthogonal reactivity and compatibility with aqueous and physiological conditions positions the 1,3-DCA as an excellent bioorthogonal reaction. Quantum chemical calculations have been critical for providing an understanding of the physical factors that control the reactivity and selectivity of 1,3-DCAs. In silico derived design principles have proven invaluable for the design of new dipolarophiles with tailored reactivity. This review discusses everything from the conception of the 1,3-DCA all the way to the state-of-the-art methods and models used for the quantum chemical design of novel (bioorthogonal) reagents.

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.

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 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.

σ-Electrons Responsible for Cooperativity and Ring Equalization in Hydrogen-Bonded Supramolecular Polymers.

Invited for this month's cover are collaborators from the TheoCheM group of the Vrije Universiteit Amsterdam and the University of Perugia. The cover picture shows a σ-electron traveling through a hydrogen-bonded squaramide linear chain. The charge transfer within the σ-electronic system is the cause for the cooperativity in the investigated urea, deltamide, and squaramide polymers. More information can be found in the Full Paper by Célia Fonseca Guerra, and co-workers.

σ-Electrons Responsible for Cooperativity and Ring Equalization in Hydrogen-Bonded Supramolecular Polymers.

We have quantum chemically analyzed the cooperative effects and structural deformations of hydrogen-bonded urea, deltamide, and squaramide linear chains using dispersion-corrected density functional theory at BLYP-D3(BJ)/TZ2P level of theory. Our purpose is twofold: (i) reveal the bonding mechanism of the studied systems that lead to their self-assembly in linear chains; and (ii) rationalize the C-C bond equalization in the ring moieties of deltamide and squaramide upon polymerization. Our energy decomposition and Kohn-Sham molecular orbital analyses reveal cooperativity in all studied systems, stemming from the charge separation within the σ-electronic system by charge transfer from the carbonyl oxygen lone pair donor orbital of one monomer towards the σ* N-H antibonding acceptor orbital of the neighboring monomer. This key orbital interaction causes the C=O bonds to elongate, which, in turn, results in the contraction of the adjacent C-C single bonds that, ultimately, makes the ring moieties of deltamide and squaramide to become more regular. Notably, the π-electron delocalization plays a much smaller role in the total interaction between the monomers in the chain.

Origin of asynchronicity in Diels-Alder reactions.

Asynchronicity in Diels-Alder reactions plays a crucial role in determining the height of the reaction barrier. Currently, the origin of asynchronicity is ascribed to the stronger orbital interaction between the diene and the terminal carbon of an asymmetric dienophile, which shortens the corresponding newly formed C-C bond and hence induces asynchronicity in the reaction. Here, we show, using the activation strain model and Kohn-Sham molecular orbital theory at ZORA-BP86/TZ2P, that this rationale behind asynchronicity is incorrect. We, in fact, found that following a more asynchronous reaction mode costs favorable HOMO-LUMO orbital overlap and, therefore, weakens (not strengthens) these orbital interactions. Instead, it is the Pauli repulsion that induces asynchronicity in Diels-Alder reactions. An asynchronous reaction pathway also lowers repulsive occupied-occupied orbital overlap which, therefore, reduces the unfavorable Pauli repulsion. As soon as this mechanism of reducing Pauli repulsion dominates, the reaction begins to deviate from synchronicity and adopts an asynchronous mode. The eventual degree of asynchronicity, as observed in the transition state of a Diels-Alder reaction, is ultimately achieved when the gain in stability, as a response to the reduced Pauli repulsion, balances with the loss of favorable orbital interactions.

Chemical reactivity from an activation strain perspective.

Chemical reactions are ubiquitous in the universe, they are at the core of life, and they are essential for industrial processes. The drive for a deep understanding of how something occurs, in this case, the mechanism of a chemical reaction and the factors controlling its reactivity, is intrinsically valuable and an innate quality of humans. The level of insight and degree of understanding afforded by computational chemistry cannot be understated. The activation strain model is one of the most powerful tools in our arsenal to obtain unparalleled insight into reactivity. The relative energy of interacting reactants is evaluated along a reaction energy profile and related to the rigidity of the reactants' molecular structure and the strength of the stabilizing interactions between the deformed reactants: ΔE(ζ) = ΔEstrain(ζ) + ΔEint(ζ). Owing to the connectedness between the activation strain model and Kohn-Sham molecular orbital theory, one is able to obtain a causal relationship between both the sterics and electronics of the reactants and their mutual reactivity. Only when this is accomplished one can eclipse the phenomenological explanations that are commonplace in the literature and textbooks and begin to rationally tune and optimize chemical transformations. We showcase how the activation strain model is the ideal tool to elucidate fundamental organic reactions, the activation of small molecules by metallylenes, and the cycloaddition reactivity of cyclic diene- and dipolarophiles.

Origin of the α-Effect in SN 2 Reactions.

The α-effect is a term used to explain the dramatically enhanced reactivity of α-nucleophiles (R-Y-X:- ) compared to their parent normal nucleophile (R-X:- ) by deviating from the classical Brønsted-type reactivity-basicity relationship. The exact origin of this effect is, however, still heavily under debate. In this work, we have quantum chemically analyzed the α-effect of a set of anionic nucleophiles, including O-, N- and S-based normal and α-nucleophiles, participating in an SN 2 reaction with ethyl chloride using relativistic density functional theory at ZORA-OLYP/QZ4P. Our activation strain and Kohn-Sham molecular orbital analyses identified two criteria an α-nucleophile needs to fulfill in order to show α-effect: (i) a small HOMO lobe on the nucleophilic center, pointing towards the substrate, to reduce the repulsive occupied-occupied orbital overlap and hence (steric) Pauli repulsion with the substrate; and (ii) a sufficiently high energy HOMO to overcome the loss of favorable HOMO-LUMO orbital overlap with the substrate, as a consequence of the first criterion, by reducing the HOMO-LUMO orbital energy gap. If one of these two criteria is not fulfilled, one can expect no α-effect or inverse α-effect.

How metallylenes activate small molecules.

We have studied the activation of dihydrogen by metallylenes using relativistic density functional theory (DFT). Our detailed activation strain and Kohn-Sham molecular orbital analyses have quantified the physical factors behind the decreased reactivity of the metallylene on going down Group 14, from carbenes to stannylenes. Along this series, the reactivity decreases due to a worsening of the back-donation interaction between the filled lone-pair orbital of the metallylene and the σ*-orbital of H2, which, therefore, reduces the metallylene-substrate interaction and increases the reaction barrier. As the metallylene ligand is varied from nitrogen to phosphorus to arsenic a significant rate enhancement is observed for the activation of H2 due to (i) a reduced steric (Pauli) repulsion between the metallylene and the substrate; and (ii) less activation strain, as the metallylene becomes increasingly more predistorted. Using a rationally designed metallylene with an optimal Group 14 atom and ligand combination, we show that a number of small molecules (i.e. HCN, CO2, H2, NH3) may also be readily activated. For the first time, we show the ability of our H2 activated designer metallylenes to hydrogenate unsaturated hydrocarbons. The results presented herein will serve as a guide for the rational design of metallylenes toward the activation of small molecules and subsequent reactions.