Ambident Nucleophilic Substitution: Understanding Non-HSAB Behavior through Activation Strain and Conceptual DFT Analyses

The ability to understand and predict ambident reactivity is key to the rational design of organic syntheses. An approach to understand trends in ambident reactivity is the hard and soft acids and bases (HSAB) principle. The recent controversy over the general validity of this principle prompted us to investigate the competing gas-phase S_N2 reaction channels of archetypal ambident nucleophiles CN⁻, OCN⁻, and SCN⁻ with CH₃Cl (S_N2@C) and SiH₃Cl (S_N2@Si), using DFT calculations. Our combined analyses highlight the inability of the HSAB principle to correctly predict the reactivity trends of these simple, model reactions. Instead, we have successfully traced reactivity trends to the canonical orbital-interaction mechanism and the resulting nucleophile–substrate interaction energy. The HOMO–LUMO orbital interactions set the trend in both S_N2@C and S_N2@Si reactions. We provide simple rules for predicting the ambident reactivity of nucleophiles based on our Kohn–Sham molecular orbital analysis.     

Lewis Acid-Catalyzed Diels-Alder Reactions: Reactivity Trends across the Periodic Table

The catalytic effect of various weakly interacting Lewis acids (LAs) across the periodic table, based on hydrogen (Group 1), pnictogen (Group 15), chalcogen (Group 16), and halogen (Group 17) bonds, on the Diels-Alder cycloaddition reaction between 1,3-butadiene and methyl acrylate was studied quantum chemically by using relativistic density functional theory. Weakly interacting LAs accelerate the Diels-Alder reaction by lowering the reaction barrier up to 3 kcal mol⁻¹ compared to the uncatalyzed reaction. The reaction barriers systematically increase from halogen<hydrogen<chalcogen<pnictogen-bonded LAs, i. e., the latter have the least catalytic effect. Our detailed activation strain and Kohn-Sham molecular orbital analyses reveal that these LAs lower the Diels-Alder reaction barrier by increasing the asynchronicity of the reaction to relieve the otherwise destabilizing Pauli repulsion between the closed-shell filled π-orbitals of diene and dienophile. Notably, the reactivity can be further enhanced on going from a Period 3 to a Period 5 LA, as these species amplify the asynchronicity of the Diels-Alder reaction due to a stronger binding to the dienophile. These findings again demonstrate the generality of the Pauli repulsion-lowering catalysis concept.     

Ion‐Pair SN2 Reaction of OH− and CH3Cl: Activation Strain Analyses of Counterion and Solvent Effects

We have theoretically studied the non‐identity S_N2 reactions of M_nOH^(n?1)+CH₃Cl (M⁺=Li⁺, Na⁺, K⁺, and MgCl⁺; n=0, 1) in the gas phase and in THF solution at the OLYP/6‐31++G(d,p) level using polarizable continuum model (PCM) implicit solvation. We want to explore and understand the effect of the metal counterion M⁺ and solvation on the reaction profile and the stereoselectivity of these processes. To this end, we have explored the potential energy surfaces of the backside (S_N2‐b) and frontside (S_N2‐f) pathways. To explain the computed trends, we have carried out analyses with an extended activation strain model (ASM) of chemical reactivity that includes the treatment of solvation effects.     

Frontside versus Backside SN2 Substitution at Group 14 Atoms: Origin of Reaction Barriers and Reasons for Their Absence

We have theoretically studied the gas‐phase nucleophilic substitution at group‐14 atoms (S_N2@A) in the model reactions of Cl^?+AH₃Cl (A=C, Si, Ge, Sn, and Pb) using relativistic density functional theory (DFT) at ZORA‐OLYP/TZ2P. Firstly, we wish to explore and understand how the reaction coordinate ζ, and potential energy surfaces (PES) along ζ, vary as the center of nucleophilic attack changes from carbon to the heavier group‐14 atoms. Secondly, a comparison between the more common backside reaction (S_N2‐b) and the frontside pathway (S_N2‐f) is performed. The S_N2‐b reaction is found to have a central barrier for A=C, but none for the other group‐14 atoms, A=Si–Pb. Relativistic effects destabilize reactant complexes and transition species by up to 10 kcal mol^?1 (for S_N2‐f@Pb), but they do not change relative heights of barriers. We also address the nature of the transformation in the frontside S_N2‐f reactions in terms of turnstile rotation versus Berry‐pseudorotation mechanism.     

Double Group Transfer Reactions: Role of Activation Strain and Aromaticity in Reaction Barriers

Double group transfer (DGT) reactions, such as the bimolecular automerization of ethane plus ethene, are known to have high reaction barriers despite the fact that their cyclic transition states have a pronounced in‐plane aromatic character, as indicated by NMR spectroscopic parameters. To arrive at a way of understanding this somewhat paradoxical and incompletely understood phenomenon of high‐energy aromatic transition states, we have explored six archetypal DGT reactions using density functional theory (DFT) at the OLYP/TZ2P level. The main trends in reactivity are rationalized using the activation strain model of chemical reactivity. In this model, the shape of the reaction profile ΔE(ζ) and the height of the overall reaction barrier ΔE^≠=ΔE(ζ=ζ^TS) is interpreted in terms of the strain energy ΔE_strain(ζ) associated with deforming the reactants along the reaction coordinate ζ plus the interaction energy ΔE_int(ζ) between these deformed reactants: ΔE(ζ)=ΔE_strain(ζ)+ΔE_int(ζ). We also use an alternative fragmentation and a valence bond model for analyzing the character of the transition states.     

How Oriented External Electric Fields Modulate Reactivity

A judiciously oriented external electric field (OEEF) can catalyze a wide range of reactions and can even induce endo/exo stereoselectivity of cycloaddition reactions. The Diels–Alder reaction between cyclopentadiene and maleic anhydride is studied by using quantitative activation strain and Kohn–Sham molecular orbital theory to pinpoint the origin of these catalytic and stereoselective effects. Our quantitative model reveals that an OEEF along the reaction axis induces an enhanced electrostatic and orbital interaction between the reactants, which in turn lowers the reaction barrier. The stronger electrostatic interaction originates from an increased electron density difference between the reactants at the reactive center, and the enhanced orbital interaction arises from the promoted normal electron demand donor–acceptor interaction driven by the OEEF. An OEEF perpendicular to the plane of the reaction axis solely stabilizes the exo pathway of this reaction, whereas the endo pathway remains unaltered and efficiently steers the endo/exo stereoselectivity. The influence of the OEEF on the inverse electron demand Diels–Alder reaction is also investigated; unexpectedly, it inhibits the reaction, as the electric field now suppresses the critical inverse electron demand donor–acceptor interaction.     

Nucleophilic Substitution at Phosphorus Centers (SN2@P)

We have studied the characteristics of archetypal model systems for bimolecular nucleophilic substitution at phosphorus (S_N2@P) and, for comparison, at carbon (S_N2@C) and silicon (S_N2@Si) centers. In our studies, we applied the generalized gradient approximation (GGA) of density functional theory (DFT) at the OLYP/TZ2P level. Our model systems cover nucleophilic substitution at carbon in X^?+CH₃Y (S_N2@C), at silicon in X^?+SiH₃Y (S_N2@Si), at tricoordinate phosphorus in X^?+PH₂Y (S_N2@P3), and at tetracoordinate phosphorus in X^?+POH₂Y (S_N2@P4). The main feature of going from S_N2@C to S_N2@P is the loss of the characteristic double‐well potential energy surface (PES) involving a transition state [X? CH₃? Y]^? and the occurrence of a single‐well PES with a stable transition complex, namely, [X? PH₂? Y]^? or [X? POH₂? Y]^?. The differences between S_N2@P3 and S_N2@P4 are relatively small. We explored both the symmetric and asymmetric (i.e. X, Y=Cl, OH) S_N2 reactions in our model systems, the competition between backside and frontside pathways, and the dependence of the reactions on the conformation of the reactants. Furthermore, we studied the effect, on the symmetric and asymmetric S_N2@P3 and S_N2@P4 reactions, of replacing hydrogen substituents at the phosphorus centers by chlorine and fluorine in the model systems X^?+PR₂Y and X^?+POR₂Y, with R=Cl, F. An interesting phenomenon is the occurrence of a triple‐well PES not only in the symmetric, but also in the asymmetric S_N2@P4 reactions of X^?+POCl₂? Y.     

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.     

Type‐I Dyotropic Reactions: Understanding Trends in Barriers

To understand the factors that control the activation barrier of type‐I 1,2‐dyotropic reactions (X‐EH₂‐CH₂‐X*→X*‐EH₂‐CH₂‐X, with E=C and Si, X=H, CH₃, SiH₃, F to I) and trends therein as a function of the migrating groups X, we have explored ten archetypal model reactions of this class using relativistic density functional theory (DFT) at ZORA‐OLYP/TZ2P. The main trends in reactivity are rationalized using the activation strain model of chemical reactivity, which had to be extended from bimolecular to unimolecular reactions. Thus, the above type‐I dyotropic reactions can be conceived as a relative rotation of the CH₂CH₂ and [X???X] fragments in X‐CH₂‐CH₂‐X. The picture that emerges from these analyses is that reduced C? X bonding in the transition state is the origin of the reaction barrier. Also the trends in reactivity on variation of X can be understood in terms of how sensitive the C? X interaction is towards adopting the transition‐state geometry. A valence bond analysis complements the analyses and confirms the picture emerging from the activation strain model.     

Switch From Pauli‐Lowering to LUMO‐Lowering Catalysis in Brønsted Acid‐Catalyzed Aza‐Diels‐Alder Reactions

Brønsted acid‐catalyzed inverse‐electron demand (IED) aza‐Diels‐Alder reactions between 2‐aza‐dienes and ethylene were studied using quantum chemical calculations. The computed activation energy systematically decreases as the basic sites of the diene progressively become protonated. Our activation strain and Kohn‐Sham molecular orbital analyses traced the origin of this enhanced reactivity to i) “Pauli‐lowering catalysis” for mono‐protonated 2‐aza‐dienes due to the induction of an asynchronous, but still concerted, reaction pathway that reduces the Pauli repulsion between the reactants; and ii) “LUMO‐lowering catalysis” for multi‐protonated 2‐aza‐dienes due to their highly stabilized LUMO(s) and more concerted synchronous reaction path that facilitates more efficient orbital overlaps in IED interactions. In all, we illustrate how the novel concept of “Pauli‐lowering catalysis” can be overruled by the traditional concept of “LUMO‐lowering catalysis” when the degree of LUMO stabilization is extreme as in the case of multi‐protonated 2‐aza‐dienes.     

A Unified Framework for Understanding Nucleophilicity and Protophilicity in the SN2/E2 Competition

The concepts of nucleophilicity and protophilicity are fundamental and ubiquitous in chemistry. A case in point is bimolecular nucleophilic substitution (S_N2) and base-induced elimination (E2). A Lewis base acting as a strong nucleophile is needed for S_N2 reactions, whereas a Lewis base acting as a strong protophile (i.e., base) is required for E2 reactions. A complicating factor is, however, the fact that a good nucleophile is often a strong protophile. Nevertheless, a sound, physical model that explains, in a transparent manner, when an electron-rich Lewis base acts as a protophile or a nucleophile, which is not just phenomenological, is currently lacking in the literature. To address this fundamental question, the potential energy surfaces of the S_N2 and E2 reactions of X⁻+C₂H₅Y model systems with X, Y = F, Cl, Br, I, and At, are explored by using relativistic density functional theory at ZORA-OLYP/TZ2P. These explorations have yielded a consistent overview of reactivity trends over a wide range in reactivity and pathways. Activation strain analyses of these reactions reveal the factors that determine the shape of the potential energy surfaces and hence govern the propensity of the Lewis base to act as a nucleophile or protophile. The concepts of “characteristic distortivity” and “transition state acidity” of a reaction are introduced, which have the potential to enable chemists to better understand and design reactions for synthesis.     

Activation Strain Analyses of Counterion and Solvent Effects on the Ion-Pair SN2 Reaction of and CH3Cl

We have computationally studied the bimolecular nucleophilic substitution (S_N2) reactions of M_nNH₂⁽ⁿ⁻¹⁾ + CH₃Cl (M⁺ = Li⁺, Na⁺, K⁺, and MgCl⁺; n = 0, 1) in the gas phase and in tetrahydrofuran solution at OLYP/6-31++G(d,p) using polarizable continuum model implicit solvation. We wish to explore and understand the effect of the metal counterion M⁺ and of solvation on the reaction profile and the stereochemical preference, that is, backside (S_N2-b) versus frontside attack (S_N2-f). The results were compared to the corresponding ion-pair S_N2 reactions involving F⁻ and OH⁻ nucleophiles. Our analyses with an extended activation strain model of chemical reactivity uncover and explain various trends in S_N2 reactivity along the nucleophiles F⁻, OH⁻, and , including solvent and counterion effects. © 2019 Wiley Periodicals, Inc.     

Understanding E2 versus SN2 Competition under Acidic and Basic Conditions

Our purpose is to understand the mechanism through which pH affects the competition between base-induced elimination and substitution. To this end, we have quantum chemically investigated the competition between elimination and substitution pathways in H₂O+C₂H₅OH₂⁺ and OH⁻+C₂H₅OH, that is, two related model systems that represent, in a generic manner, the same reaction under acidic and basic conditions, respectively. We find that substitution is favored in the acidic case while elimination prevails under basic conditions. Activation-strain analyses of the reaction profiles reveal that the switch in preferred reactivity from substitution to elimination, if one goes from acidic to basic catalysis, is related to (1) the higher basicity of the deprotonated base, and (2) the change in character of the substrates LUMO from C^β−H bonding in C₂H₅OH₂⁺ to C^β−H antibonding in C₂H₅OH.     

How Dihalogens Catalyze Michael Addition Reactions

We have quantum chemically analyzed the catalytic effect of dihalogen molecules (X₂=F₂, Cl₂, Br₂, and I₂) on the aza‐Michael addition of pyrrolidine and methyl acrylate using relativistic density functional theory and coupled‐cluster theory. Our state‐of‐the‐art computations reveal that activation barriers systematically decrease as one goes to heavier dihalogens, from 9.4 kcal mol^?1 for F₂ to 5.7 kcal mol^?1 for I₂. Activation strain and bonding analyses identify an unexpected physical factor that controls the computed reactivity trends, namely, Pauli repulsion between the nucleophile and Michael acceptor. Thus, dihalogens do not accelerate Michael additions by the commonly accepted mechanism of an enhanced donor–acceptor [HOMO(nucleophile)–LUMO(Michael acceptor)] interaction, but instead through a diminished Pauli repulsion between the lone‐pair of the nucleophile and the Michael acceptor's π‐electron system.     

Factors Controlling β‐Elimination Reactions in Group 10 Metal Complexes

Trends in reactivity of β‐chloride and β‐hydride elimination reactions involving Group 10 transition‐metal complexes have been computationally explored and analyzed in detail by DFT. These reactions do not require the initial formation of a vacant coordination site; they proceed concertedly without a prior ligand‐dissociation step. Whereas β‐chloride elimination is associated with relatively moderate activation barriers, the high barriers calculated for analogous β‐hydride eliminations suggest that the latter process is unfeasible for this type of compounds. This differential behavior is analyzed within the activation strain model, which provides quantitative insight into the physical factors controlling these β‐elimination reactions. The effects of the nature of the Group 10 transition metal (Ni, Pd, Pt), as well as the substituents attached to the β‐eliminating fragment (R₂C?CR₂X; R, X=H, Cl) on the transformation have also been considered and are rationalized herein.     

Switch From Pauli-Lowering to LUMO-Lowering Catalysis in Brønsted Acid-Catalyzed Aza-Diels-Alder Reactions

Brønsted acid-catalyzed inverse-electron demand (IED) aza-Diels-Alder reactions between 2-aza-dienes and ethylene were studied using quantum chemical calculations. The computed activation energy systematically decreases as the basic sites of the diene progressively become protonated. Our activation strain and Kohn-Sham molecular orbital analyses traced the origin of this enhanced reactivity to i) “Pauli-lowering catalysis” for mono-protonated 2-aza-dienes due to the induction of an asynchronous, but still concerted, reaction pathway that reduces the Pauli repulsion between the reactants; and ii) “LUMO-lowering catalysis” for multi-protonated 2-aza-dienes due to their highly stabilized LUMO(s) and more concerted synchronous reaction path that facilitates more efficient orbital overlaps in IED interactions. In all, we illustrate how the novel concept of “Pauli-lowering catalysis” can be overruled by the traditional concept of “LUMO-lowering catalysis” when the degree of LUMO stabilization is extreme as in the case of multi-protonated 2-aza-dienes.     

Experimental and theoretical multiple kinetic isotope effects for an SN2 reaction. An attempt to determine transition-state structure and the ability of theoretical methods to predict experimental kinetic isotope effects

The secondary alpha-deuterium, the secondary beta-deuterium, the chlorine leaving-group, the nucleophile secondary nitrogen, the nucleophile (12)C/(13)C carbon, and the (11)C/(14)C alpha-carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the S(N)2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 degrees C. Then, thirty-nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the structure of the transition state, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the transition states and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated transition structures, which are all early and loose, agree with the late (product-like) transition-state structure suggested by interpreting the experimental KIEs.     

Understanding the Reactivity of Planar Polycyclic Aromatic Hydrocarbons: Towards the Graphene Limit

The Diels–Alder reactivity of maleic anhydride towards the bay regions of planar polycyclic aromatic hydrocarbons was explored computationally in the DFT framework. The process becomes more and more exothermic and the associated activation barriers become lower and lower when the size of the system increases. This enhanced reactivity follows an exponential behavior that reaches its maximum for systems having 18–20 benzenoid rings in their structures. This peculiar behavior was analyzed in detail by using the activation strain model of reactivity in combination with energy decomposition analysis. The influence of the change in the aromaticity of the polycyclic compound during the process on the respective activation barriers was also studied.