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.     

How Lewis Acids Catalyze Diels–Alder Reactions

The Lewis acid(LA)‐catalyzed Diels–Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled‐cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I₂<SnCl₄<TiCl₄<ZnCl₂<BF₃<AlCl₃. Emerging from our activation strain and Kohn–Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels–Alder reaction by a diminished Pauli repulsion between the π‐electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels–Alder reaction by enhancing the donor–acceptor [HOMO_diene–LUMO_dienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.     

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.     

Origin of the “endo rule” in Diels–Alder reactions

Detailed density functional theory calculations definitively rationalize the preference for the endo cycloadduct (also known as endo rule) in text‐book thermal Diels–Alder reactions involving maleic anhydride and cyclopentadiene or butadiene. This selectivity is mainly caused by an unfavorable steric arrangement in the transition‐state region of the exo pathway which translates into a more destabilizing activation strain. In contrast with the widely accepted, orbital‐interaction‐based explanation for the endo rule, it is found that neither the orbital interactions nor the total interaction between the deformed reactants contributes to the endo selectivity. © 2013 Wiley Periodicals, Inc.     

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.     

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.     

Rational Tuning of the Reactivity of Three-Membered Heterocycle Ring Openings via SN2 Reactions

The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the “electrophilic trap” that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. Here we investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with a nitrogen (aziridine), phosphorus (phosphirane), oxygen (epoxide) or sulfur atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring opening of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C₆H₁₀Y with Y=NH, PH, O, S). It was revealed that the activation energy of the ring opening does not necessarily follow the trend that is expected from C−Y leaving-group bond strength, but steeply decreases from Y=NH, to PH, to O, to S. We illustrate that the HOMO_Nu–LUMO_Substrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.     

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.     

Friedel-Crafts-Type Acylation and Amidation Reactions in Strong Brønsted Acid: Taming Superelectrophiles

In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions, not exhaustively, but mainly based on our research results. The electrophilic species involved are isocyanate cation and acylium cation, respectively, and both have a common ⁺C=O structure, which can be generated from carboxylic acid functionalities in a strong Brønsted acid. Carbamates substituted with methyl salicylate can be easily ionized to the isocyanate cation upon (di)protonation of the salicylate. Carboxylic acids can be used directly as a source of acylium cations. However, aminocarboxylic acids are inert in acidic media because two positively charged sites, ammonium and acylium cation, will be generated, resulting in energetically unfavorable charge-charge repulsion. Nevertheless, the aromatic acylation of aminocarboxylic acids can be achieved by using tailored phosphoric acid esters as Lewis bases to abrogate the charge-charge repulsion. Both examples tame the superelectrophilic character.     

Activation of the Unreactive Bond in C70 Fullerene toward Diels‐Alder Reaction by Encapsulation of a Lithium Atom

Diels‐Alder cycloaddition reaction is useful for generation of covalent derivatives of fullerenes. Diels‐Alder reactions of C₇₀ and dienes usually take place at the carbon‐carbon bond that has a short bond length in C₇₀, while the bonds with long lengths are generally unreactive. In this paper, we investigated the reactivities of Li⁺@C₇₀ and Li@C₇₀ toward Diels‐Alder reactions with cyclohexadiene by means of density functional theory calculations. We found that the thermodynamic and kinetic reactivities of the fullerene cage are changed significantly after the encapsulation of the lithium ion or atom. The encapsulated lithium ion causes a remarkable decrease of the activation barrier for the cycloaddition reaction, which can be ascribed to the enhanced orbital interaction between cyclohexadiene and the fullerene cage. The unreactive bond with a long length in C₇₀ is activated efficiently after the encapsulation of the lithium atom. According to the activation‐strain model analysis, the improved reactivity of the long bond is associated with the small deformation energy and large interaction energy of the reactants. Unlike conventional Diels‐Alder reactions that proceed through concerted mechanism, the reaction of Li@C₇₀ and cyclohexadiene undergoes an unusual stepwise mechanism because of the open‐shell electronic structure of Li@C₇₀.     

Gold‐Catalyzed Tandem Hydroamination/Formal Aza‐Diels–Alder Reaction of Homopropargyl Amino Esters: A Combined Computational and Experimental Mechanistic Study

A tandem gold‐catalyzed hydroamination/formal aza‐Diels–Alder reaction is described. This process, which employs quaternary homopropargyl amino ester substrates, leads to the formation of an intrincate tetracyclic framework and involves the generation of four bonds and five stereocenters in a highly diastereoselective manner. Theoretical calculations have allowed us to propose a suitable mechanistic rationalization for the tandem protocol. Additionally, by studying the influence of the ligands on the rate of the gold‐catalyzed reactions, it was possible to establish optimum conditions in which to perform the process with a variety of substituents on the amino ester substrates. Notably, the asymmetric version of the tandem reaction was also evaluated.     

On the Effect of Tether Composition on cis/trans Selectivity in Intramolecular Diels–Alder Reactions

Intramolecular Diels–Alder (IMDA) transition structures (TSs) and energies have been computed at the B3LYP/6‐31+G(d) and CBS‐QB3 levels of theory for a series of 1,3,8‐nonatrienes, H₂C?CH? CH?CH? CH₂? X? Z? CH?CH₂ [? X? Z? =? CH₂? CH₂? ( 1 ); ? O? C(?O)? ( 2 ); ? CH₂? C(?O)? ( 3 ); ? O? CH₂? ( 4 ); ? NH? C(?O)? ( 5 ); ? S? C(?O)? ( 6 ); ? O? C(?S)? ( 7 ); ? NH? C(?S)? ( 8 ); ? S? C(?S)? ( 9 )]. For each system studied ( 1 – 9 ), cis‐ and trans‐TS isomers, corresponding, respectively, to endo‐ and exo‐positioning of the ? C? X? Z? tether with respect to the diene, have been located and their relative energies (E_rel^TS) employed to predict the cis/trans IMDA product ratio. Although the E_rel^TS values are modest (typically <3 kJ mol^?1), they follow a clear and systematic trend. Specifically, as the electronegativity of the tether group X is reduced (X?O→NH or S), the IMDA cis stereoselectivity diminishes. The predicted stereochemical reaction preferences are explained in terms of two opposing effects operating in the cis‐TS, namely (1) unfavorable torsional (eclipsing) strain about the C4? C5 bond, that is caused by the ? C? X? C(?Y)? group’s strong tendency to maintain local planarity; and (2) attractive electrostatic and secondary orbital interactions between the endo‐(thio)carbonyl group, C?Y, and the diene. The former interaction predominates when X is weakly electronegative (X?N, S), while the latter is dominant when X is more strongly electronegative (X?O), or a methylene group (X?CH₂) which increases tether flexibility. These predictions hold up to experimental scrutiny, with synthetic IMDA reactions of 1 , 2 , 3 , and 4 (published work) and 5 , 6 , and 8 (this work) delivering ratios close to those calculated. The reactions of thiolacrylate 5 and thioamide 8 represent the first examples of IMDA reactions with tethers of these types. Our results point to strategies for designing tethers, which lead to improved cis/trans‐selectivities in IMDAs that are normally only weakly selective. Experimental verification of the validity of this claim comes in the form of fumaramide 14 , which undergoes a more trans‐selective IMDA reaction than the corresponding ester tethered precursor 13 .     

Trio Catalysis Merging Enamine,Brønsted Acid,and Metal Lewis Acid Catalysis: Asymmetric Three‐Component Aza‐Diels–Alder Reaction of Substituted Cinnamaldehydes,Cyclic Ketones,and Arylamines

A trio catalyst system, composed of arylamine, BINOL‐derived phosphoric acid, and Y(OTf)₃, enables the combination of enamine catalysis with both hard metal Lewis acid catalysis and Brønsted acid catalysis for the first time. Using this catalyst system, a three‐component aza‐Diels–Alder reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine is carried out with high chemo‐ and enantioselectivity, affording a series of optically active 1,4‐dihydropyridine (DHP) derivatives are obtained in 91–99 % ee and 59–84 % yield. DHPs bearing a chiral quaternary carbon center are also obtained with good enantioselectivity and moderate yield (three examples). Preliminary mechanistic investigations have also been conducted.     

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.     

Theoretical and Structural Analysis of Long CC Bonds in the Adducts of Polycyanoethylene and Anthracene Derivatives and Their Connection to the Reversibility of Diels–Alder Reactions

X‐ray structure determinations on four Diels–Alder adducts derived from the reactions of cyano‐ and ester‐substituted alkenes with anthracene and 9,10‐dimethylanthracene have shown the bonds formed in the adduction to be particularly long. Their lengths range from 1.58 to 1.62 Å, some of the longest known for Diels–Alder adducts. Formation of the four adducts is detectably reversible at ambient temperature and is associated with free energies of reaction ranging from ?2.5 to ?40.6 kJ mol^?1. The solution equilibria have been experimentally characterised by NMR spectroscopy. Density‐functional‐theory calculations at the MPW1K/6‐31+G(d,p) level with PCM solvation agree with experiment with average errors of 6 kJ mol^?1 in free energies of reaction and structural agreement in adduct bond lengths of 0.013 Å. To understand more fully the cause of the reversibility and its relationship to the long adduct bond lengths, natural‐bond‐orbital (NBO) analysis was applied to quantify donor–acceptor interactions within the molecules. Both electron donation into the σ*‐anti‐bonding orbital of the adduct bond and electron withdrawal from the σ‐bonding orbital are found to be responsible for this bond elongation.     

A Complete Guide on the Influence of Metal Clusters in the Diels–Alder Regioselectivity of Ih‐C80 Endohedral Metallofullerenes

The chemical functionalization of endohedral metallofullerenes (EMFs) has aroused considerable interest due to the possibility of synthesizing new species with potential applications in materials science and medicine. Experimental and theoretical studies on the reactivity of endohedral metallofullerenes are scarce. To improve our understanding of the endohedral metallofullerene reactivity, we have systematically studied with DFT methods the Diels–Alder cycloaddition between s‐cis‐1,3‐butadiene and practically all X@I_h‐C₈₀ EMFs synthesized to date: X=Sc₃N, Lu₃N, Y₃N, La₂, Y₃, Sc₃C₂, Sc₄C₂, Sc₃CH, Sc₃NC, Sc₄O₂ and Sc₄O₃. We have studied both the thermodynamic and kinetic regioselectivity, taking into account the free rotation of the metallic cluster inside the fullerene. This systematic study has been made possible through the use of the frozen cage model (FCM), a computationally cheap approach to accurately predicting the exohedral regioselectivity of cycloaddition reactions in EMFs. Our results show that the EMFs are less reactive than the hollow I_h‐C₈₀ cage. Except for the Y₃ cluster, the additions occur predominantly at the [5,6] bond. In many cases, however, a mixture of the two possible regioisomers is predicted. In general, [6,6] addition is favored in EMFs that have a larger charge transfer from the metal cluster to the cage or a voluminous metal cluster inside. The present guide represents the first complete and exhaustive investigation of the reactivity of I_h‐C₈₀‐based EMFs.     

Mechanistic Insights into the Ni‐Catalyzed Reductive Carboxylation of C−O Bonds in Aromatic Esters with CO2: Understanding Remarkable Ligand and Traceless‐Directing‐Group Effects

The mechanism of the Ni⁰‐catalyzed reductive carboxylation reaction of C(sp²)?O and C(sp³)?O bonds in aromatic esters with CO₂ to access valuable carboxylic acids was comprehensively studied by using DFT calculations. Computational results revealed that this transformation was composed of several key steps: C?O bond cleavage, reductive elimination, and/or CO₂ insertion. Of these steps, C?O bond cleavage was found to be rate‐determining, and it occurred through either oxidative addition to form a Ni^II intermediate, or a radical pathway that involved a bimetallic species to generate two Ni^I species through homolytic dissociation of the C?O bond. DFT calculations revealed that the oxidative addition step was preferred in the reductive carboxylation reactions of C(sp²)?O and C(sp³)?O bonds in substrates with extended π systems. In contrast, oxidative addition was highly disfavored when traceless directing groups were involved in the reductive coupling of substrates without extended π systems. In such cases, the presence of traceless directing groups allowed for docking of a second Ni⁰ catalyst, and the reactions proceed through a bimetallic radical pathway, rather than through concerted oxidative addition, to afford two Ni^I species both kinetically and thermodynamically. These theoretical mechanistic insights into the reductive carboxylation reactions of C?O bonds were also employed to investigate several experimentally observed phenomena, including ligand‐dependent reactivity and site‐selectivity.