Bifunctional Hydrogen Bond Donor‐Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement

Abstract

The selectivity and rate enhancement of bifunctional hydrogen bond donor‐catalyzed Diels–Alder reactions between cyclopentadiene and acrolein were quantum chemically studied using density functional theory in combination with coupled‐cluster theory. (Thio)ureas render the studied Diels–Alder cycloaddition reactions exo selective and induce a significant acceleration of this process by lowering the reaction barrier by up to 7 kcal mol−1. Our activation strain and Kohn–Sham molecular orbital analyses uncover that these organocatalysts enhance the Diels–Alder reactivity by reducing the Pauli repulsion between the closed‐shell filled π‐orbitals of the diene and dienophile, by polarizing the π‐orbitals away from the reactive center and not by making the orbital interactions between the reactants stronger. In addition, we establish that the unprecedented exo selectivity of the hydrogen bond donor‐catalyzed Diels–Alder reactions is directly related to the larger degree of asynchronicity along this reaction pathway, which is manifested in a relief of destabilizing activation strain and Pauli repulsion.

How Lewis Acids Catalyze Ring-Openings of Cyclohexene Oxide

“…These results clearly illustrate that the concept of Pauli-lowering catalysis is a general phenomenon that is not only limited to Lewis acid-catalyzed Michael addition and cycloaddition reactions. 7 …”

“…, reducing the HOMO–LUMO gap) but instead by diminishing the steric (Pauli) repulsion between the reactants. 7 The complexation between a Lewis acid and the reactant induces a polarization of the occupied orbital densities of the reactant away from the reactive region, resulting in less repulsive occupied–occupied orbital overlap and hence a lower reaction barrier. 7 We envision that this concept of Pauli-repulsion lowering catalysis might also be the driving force in Lewis acid-catalyzed epoxide ring-opening reactions.…”

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

“…In analogy with conventional Lewis acids, hydrogen‐bonded organocatalysts are also able to significantly modify both the reactivity and selectivity of the DA reaction. For example, hydrogen‐bonded solvents can activate ketones to undergo a DA reaction, [7] or bifunctional hydrogen bond donor organocatalysts, such as differently substituted thioureas, are able to increase both the reaction rate as well as the endo / exo ‐selectivity of DA reactions between a diene and α, β‐unsaturated carbonyl compounds [8,9a] . Similar catalytic effects were also reported using catalysts featuring similar weak interactions such as pnictogen, [10] chalcogen, [11] and halogen bonds (Scheme 1).…”

Nature of the Hydrogen Bond Enhanced Halogen Bond

“…To complete this study, we were curious to analyze the effect of replacing the amide group, responsible for the intramolecular hydrogen bond, by a thioamide group on the relative strength of the enhanced halogen bond. This was motivated by the well-known superior activity of related thioureas over their urea counterpart in organocatalysis [32][33][34], in line with their comparatively stronger acidity (for instance, pKa = 21.1 and 26.9, for For completeness, we also included in Table 2 the experimentally prepared trifluorinated and pyridinium systems 1 and 6, where the bulky CPh 3 group was replaced by a CH 3 group [14]. According to the EDA data, the effect of the three fluorine atoms in the aryl group of 1 is comparable to that of the p-NO 2 group, as the computed ∆E int , as well as its main energy contributors, are rather similar (see Table 2).…”

“…To complete this study, we were curious to analyze the effect of replacing the amide group, responsible for the intramolecular hydrogen bond, by a thioamide group on the relative strength of the enhanced halogen bond. This was motivated by the well-known superior activity of related thioureas over their urea counterpart in organocatalysis [32][33][34], in line with their comparatively stronger acidity (for instance, pK a = 21.1 and 26.9, for thiourea and urea, respectively) [35]. Therefore, with the help of the EDA-NOCV method, we analyzed the nature of the halogen bond involving the thioamide analogues of the parent 4•Cl − and 5•Cl − systems (Table 3).…”