Revisiting the bonding evolution theory: a fresh perspective on the ammonia pyramidal inversion and bond dissociations in ethane and borazane.

This work offers a comprehensive and fresh perspective on the bonding evolution theory (BET) framework, originally proposed by Silvi and collaborators [X. Krokidis, S. Noury and B. Silvi, Characterization of elementary chemical processes by catastrophe theory, J. Phys. Chem. A, 1997, 101, 7277-7282]. By underscoring Thom's foundational work, we identify the parametric function characterizing bonding events along a reaction pathway through a three-step sequence to establish such association rigorously, namely: (a) computing the determinant of the Hessian matrix at all potentially degenerate critical points, (b) computing the relative distance between these points, and (c) assigning the unfolding based on these computations and considering the maximum number of critical points for each unfolding. In-depth examination of the ammonia inversion and the dissociation of ethane and ammonia borane molecules yields a striking discovery: no elliptic umbilic flag is detected along the reactive coordinate for any of the systems, contradicting previous reports. Our findings indicate that the core mechanisms of these chemical reactions can be understood using only two folds, the simplest polynomial of Thom's theory, leading to considerable simplification. In contrast to previous reports, no signatures of the elliptic umbilic unfolding were detected in any of the systems examined. This finding dramatically simplifies the topological rationalization of electron rearrangements within the BET framework, opening new approaches for investigating complex reactions.

A simple topology-based model for predicting the activation barriers of reactive processes at 0 K.

This work reveals an underlying correlation between the topology and energetic features of matter configurations/rearrangements by exploiting two topological concepts, namely, structural stability and persistency, leading thus to a model capable of predicting activation energies at 0 K. This finding provides some answers to the difficulties of applying Thom's functions for extracting energetic information of rate processes, which has been a limitation for exact, biological, and technological sciences. A linear relationship between the experimental barriers of 17 chemical reactions and both concepts was found by studying these systems' topography along the intrinsic reaction coordinate. Such a procedure led to the model , which accurately predicts the activation energy in reacting systems involving organic and organometallic compounds under different conditions, e.g., the gas-phase, solvent media, and temperature. This function was further recalibrated to enhance its predicting capabilities, generating the equation for this procedure, characterized by a squared Pearson correlation coefficient (r2 = 0.9774) 1.1 times higher. Surprisingly, no improvement was observed.

On the Notation of Catastrophes in the Framework of Bonding Evolution Theory: Case of Normal and Inverse Electron Demand Diels-Alder Reactions.

This paper generalizes very recent and unexpected findings [J. Phys. Chem. A, 2021, 125, 5152-5165] regarding the known "direct- and inverse-electron demand" Diels-Alder mechanisms. Application of bonding evolution theory indicates that the key electron rearrangement associated with significant chemical events (e. g., the breaking/forming processes of bonds) can be characterized via the simplest fold polynomial. For the CC bond formation, neither substituent position nor the type of electronic demand induces a measurable cusp-type signature. As opposed to the case of [4+2] cycloaddition between 1,3-butadiene and ethylene, where the two new CC single bonds occur beyond the transition state (TS) in the activated cases, the first CC bond occurs in the domain of structural stability featuring the TS, whereas the second one remains located in the deactivation path connecting the TS with the cycloadduct.

Photochemically Induced 1,3-Butadiene Ring-Closure from the Topological Analysis of the Electron Localization Function Viewpoint.

The electronic rearrangement featuring the photochemically-induced 1,3-cis-butadiene is discussed within a bonding evolution theory (BET) perspective based on the topological analysis of the electron localization function and Thom's catastrophe theory. The process involves the vertical singlet-singlet excitation S0 →S2 , and the subsequent deactivation implying the S2 /S1 and S1 /S0 conical intersection regions. BET results reveal that the new CC bond is finally formed on the S0 surface, as also recently found in the photochemical addition of two ethylenes [Phys. Chem. Chem. Phys. 23, 20598, (2021)].

On Electron Pair Rearrangements in Photochemical Reactions: 1,3-Cyclohexadiene Ring Opening.

1,3-Cyclohexadiene ring opening has been studied within the bonding evolution theory (BET) framework. We have focused on describing for the first time the electron pair rearrangements leading to the cis-1,3,5-hexatriene (HT) product from CHD. The nature of bonding in this process begins with the weakening of the double bonds in the Franck-Condon region. Along the 11B surface, the C-C sigma bond weakens. Meanwhile, its density redistributes toward the whole CHD ring, mainly over double bonds. Breaking of this bond occurs on the 21A surface due to the symmetrical splitting of pair density from this region. This density redistributes toward the reaction center once the pericyclic minimum is reached. The formation of the double bonds that characterize HT occurs gradually in the ground state. However, near the 21A/11A intersection, these bonds are partially established.

Unraveling the Bonding Nature Along the Photochemically Activated Paterno-Büchi Reaction Mechanism.

The photochemically activated Paterno-Büchi reaction mechanism following the singlet excited-state reaction path was analyzed based on a bonding evolution framework. The electronic rearrangements, which describe the mechanism of oxetane formation via carbon-oxygen attack (C-O), comprises of the electronic activation of formaldehyde and accumulation of pairing density on the O once the reaction system is approaching the conical intersection point. Our theoretical evidence based on the ELF topology shows that the C-O bond is formed in the ground-state surface (via C-O attack) returning from the S1 surface accompanied by 1,4-singlet diradical formation. Subsequently, the reaction center is fully activated near the transition state (TS), and the ring-closure (yielding oxetane) involves the C-C bond formation after the TS. For the carbon-carbon attack (C-C), both reactants (formaldehyde and ethylene) are activated, leading to C-C bond formation in the S1 excited state before reaching the conical intersection region. Finally, the C-O formation occurs in the ground-state surface, resulting from the pair density flowing primarily from the C to O atom.

On the nature of bonding in the photochemical addition of two ethylenes: C-C bond formation in the excited state?

In this work, the 2s + 2s (face-to-face) prototypical example of a photochemical reaction has been re-examined to characterize the evolution of chemical bonding. The analysis of the electron localization function (as an indirect measure of the Pauli principle) along the minimum energy path provides strong evidence supporting that CC bond formation occurs not in the excited state but in the ground electronic state after crossing the rhombohedral S1/S0 conical intersection.

Are There Only Fold Catastrophes in the Diels-Alder Reaction Between Ethylene and 1,3-Butadiene?

This work revisits the topological characterization of the Diels-Alder reaction between 1,3-butadiene and ethylene. In contrast to the currently accepted rationalization, we here provide strong evidence in support of a representation in terms of seven structural stability domains separated by a sequence of 10 elementary catastrophes, but all are only of the fold type (F and F†), that is, C4H6 + C2H4:1-7-[FF]F[F†F†][F†F†][FF]F†-0: C6H10. Such an unexpected finding provides fundamental new insights opening simplifying perspectives concerning the rationalization of the CC bond formation in pericyclic reactions in terms of the simplest Thom's elementary catastrophe, namely, the one-(state) variable, one-(control) parameter function.

Rational Design of Novel Glycomimetic Peptides for E-Selectin Targeting.

E-selectin is a cell-adhesion receptor with specific recognition capacity toward sialo-fucosylated Lewis carbohydrates present in leukocytes and tumor cells. E-selectin interactions mediate the progress of inflammatory processes and tumor metastasis, which aroused the interest in using this protein as a biomolecular target to design glycomimetic inhibitors for active targeting or therapeutic purposes. In this work, we report the rational discovery of two novel glycomimetic peptides targeting E-selectin based on mutations of the reference selectin-binding peptide IELLQAR. Sixteen single or double mutants at Ile1, Leu3, Leu4, and Arg7 residues were evaluated as potential candidates for E-selectin targeting using 50 ns molecular dynamics (MD) simulations. Nine peptides showing a stable association with the functional pocket were modified by adding a cysteine residue to the N-terminus to confer versatility for further chemical conjugation. Subsequent 50 ns MD simulations resulted in five cysteine-modified peptides with retained or improved E-selectin binding potential. Then, 300 ns accelerated MD (aMD) simulations were used to examine the binding properties of the best five cysteine-modified peptides. CIEELQAR and CIELFQAR exhibit the most selective association with the functional pocket of E-selectin, as revealed by potential of mean force profiles. Microscale thermophoresis experiments confirmed the E-selectin binding capacity of the selected peptides with KD values in the low micromolar range (CIEELQAR KD = 35.0 ± 1.4 µM; CIELFQAR KD = 16.4 ± 0.7 µM), which are 25-fold lower than the reported value for the native ligand sLex (KD = 878 µM). Our findings support the potential of CIEELQAR and CIELFQAR as novel E-selectin-targeting peptides with high recognition capacity and versatility for chemical conjugation, which are critical for enabling future applications in active targeting.

A Close Look to the Oxaphosphetane Formation along the Wittig Reaction: A [2+2] Cycloaddition?

The Wittig reaction between triphenylphosphine methylide and benzaldehyde has been studied both from conceptual and computational approaches. The supernucleophilic character of ylide accounts for the feasibility of the initial nucleophilic attack. The nature of bonding driving the formation of the first oxaphosphetane (OPA) intermediate in such a domino reaction is examined within a topological-based bonding evolution theory perspective. The sequence of the electronic flow associated to the changes in electron density supports a rationalization via two main electronic stages characterizing the single kinetic step: first, the C-C bond formation, which takes place via donation of electron density of the ylide carbon to the carbonyl carbon of benzaldehyde at a C-C distance of 2.02 Å, is formally associated to the transition state region; then, the P-O bond formation via the donation of electron density of the nonbonding region of the carbonyl oxygen to phosphorus at a P-O distance of 2.06 Å is located at the end of the reaction path. The detailed picture of bonding patterns suggests that the OPA formation in the Wittig mechanism can be better understood in terms of a two-stage one-step mechanism beyond molecular orbital considerations behind the traditionally accepted [2+2] cycloaddition proposal.

On the electron flow sequence driving the hydrometallation of acetylene by lithium hydride.

The sequence of the electronic flow driving the hydrometallation of acetylene by lithium hydride (and that of the opposite ß-hydride elimination reaction from the alkenyl metal intermediate), was examined within the perspective provided by the bonding evolution theory (BET). The analysis was based on the application of catastrophe theory to the changes of the electron localization function topology along the intrinsic reaction coordinate. The description of the electronic processes occurring on the process was represented in terms of topological structural stability domains (SSDs) and the associated elementary bifurcation catastrophes. Within such a framework of representation, the "evolution" of the system through the different SSDs reveals the key chemical events driving the transformation, including the large polarization effect as a consequence of Pauli repulsion between ions of the positive cationic metal on the hydride domain, the activation of the CC triple bond to attack the cationic center, and the agostic stabilizing interactions involving the hardest cationic metal, followed by the attack of the hydride center. These results contribute to emphasizing the intrinsic value and usefulness of using topological-based approaches and associated tools to increase our knowledge and understanding of the subtleties underlying the electronic flow as nuclei evolve along the reaction coordinate, providing detailed and complementary insights in comparison to other interpretative tool such those based on orbital-based representations, concerning the intimate nature of the electronic rearrangement of key mechanistic processes in chemistry. Graphical abstract The sequence of the electron flow (indicated by letters a and b) along the intrinsic reaction path for the hydrometallation of acetylene by lithium hydride to yield ethenyl lithium via a four-membered transition structure (TS), as determined within the bonding evolution theory to provide the key chemical events driven the changes in the key bonding patterns. Blue arrow Main event on the side HC ≡ CH + LiH → TS, red arrow the TS → HLiC=CH2 pathway, green arrows relative motion of nuclei along the imaginary frequency at the position of TS on the intrinsic reaction coordinate.

Understanding the Highly Varying pKa of Arylamines. A Perspective from the Average Local Ionization Condensed-to-Atom Framework.

The highly varying experimental pKa values for 36 arylamines spanning 7 orders of magnitude is carefully examined. Within this framework, a valence condensed-to-atom model for the average ionization energy is introduced and tested. The theoretical approach is connected to orbital Fukui functions directly mapped into semilocal or regional site-specific responses. It is revealed that the average local ionization energies associated with the amino nitrogen atom is linearly correlated to the basicity of the substituted arylamines, properly reproducing the experimental ordering of basicity. The condensed-to-atom descriptor exhibits a high predictive power, providing a new direct reactivity evaluation of significant value.

Understanding the thermal [1s,5s] hydrogen shift isomerization of ocimene.

α-Ocimene, ß-ocimenes and alloocimenes are isomeric monoterpenes occurring naturally as oils within several plants and fruits. These thermally unstable compounds are employed in the pharmaceutical and fine-chemicals industries due to their natural plant defense properties and pleasant odors. In this work, and in the context of a recent revival in attention on the subject, we provide new theoretical insights concerning the nature of the electronic reorganization driving the decomposition of cis-ß-ocimene to alloocimene. Our findings support the experimental proposal of a rearrangement via a six-membered cyclic transition state in a one-step concerted and highly synchronic process.

Theoretical investigation of the selectivity in intramolecular cyclizations of some 2'-aminochalcones to dihydroquinolin-8-ones and indolin-3-ones.

The selectivity of the intramolecular cyclizations of a series of 2'-aminochalcones was investigated with an approach that combines spin-polarized conceptual density functional theory and energy calculations. To that aim, condensed-to-atoms electrophilic Fukui functions, f NN (+) (r), were utilized as descriptors of the proclivity for nucleophilic attack of the NH2 group on the unsaturated α and ß carbons. The results of our model are in excellent agreement with the experimental available evidence permitting us in all cases to predict when the cyclization processes led to the formation of 5-exo and 6-endo products.

Intrinsic relative scales of electrophilicity and nucleophilicity.

The formulation of the second-order perturbation approach to the stabilization energy of the A-B interacting species due to charge transfer is revisited. Intrinsic (i.e., electronic) theoretical indices for both relative electrophilicity and nucleophilicity are proposed for any electrophile (A)-nucleophile (B) pairs of combining species. By using the new descriptors, an electronic analogue to the Mayr-Patz linear free relationship has been successfully tested in the context of available experimental evidence reported for reactions of primary and secondary amines with benzhydrylium ions.