Kinetic, Thermodynamic, and Dynamic Control in Normal vs. Cross [2 + 2] Cycloadditions of Ene-Keteniminium Ions: Computational Understanding, Prediction, and Experimental Verification

Abstract

Almost all reported intramolecular [2 + 2] reactions of ene-keteniminium ions gave normal [2 + 2] products with a fused bicycle framework, but not cross [2 + 2] products with a bicyclo[3.1.1]heptane skeleton, a highly pursued bioisostere in pharmaceutical chemistry. How to rationalize this and design new cross [2 + 2] reactions? Theoretical studies using density functional theory, high-level ab initio single-point energy calculations, and molecular dynamics showed that this [2 + 2] reaction has all three patterns of regiochemical control: the reaction is controlled either kinetically, thermodynamically, or dynamically. A carbocation model of forming endo and exo carbocations has been proposed to rationalize the reaction outcomes, revealing that the tethers (between alkenes and keteniminium ions), substituents (on the alkenes), and alkene configurations in ene-keteniminium ions play critical roles. These understandings were further used to predict that introducing a substituent in the terminal position of alkene with a trans configuration in eneketeniminium ions can realize the cross [2 + 2] reaction, which is dynamically controlled for alkyl substituents or kinetically controlled for aryl substituents. These and more other predictions were realized experimentally, and many cross [2 + 2] products with a bicyclo[3.1.1]heptane skeleton can be achieved. Both molecular dynamics and new experiments have also been applied to correct a key but misassigned [2 + 2] product reported in the literature, further supporting the insightful mechanisms reported here.

Dynamically or Kinetically Controlled? Computational Study of the Mechanisms of Electrophilic Aminoalkenylation of Heteroaromatics with Keteniminium Ions

“…The ωB97X-D functional was chosen for its high accuracy in simulating keteniminium ion-related reactions (see the SI for more discussion). 3 Unscaled harmonic frequency calculations at the same level were performed to validate each structure as either a minimum or a transition state and to evaluate its zeropoint energy and thermal corrections at 298.15 K. Intrinsic reaction coordinate (IRC) 9 calculations were carried out to confirm the transition states connecting the right reactant(s) and product(s). High-level single-point energies were calculated at the DLPNO−CCSD(T) 10 /def2-TZVPP 8 (with the def2-TZVPP/C 11 auxiliary basis set; "TightPNO" and "TightSCF" settings were used) level using the ORCA 4.2.1 12 software package.…”

“…Structure optimizations were performed at the SMD­(DCM)/ωB97X-D/def2-SVP level of theory, unless otherwise specified. The ωB97X-D functional was chosen for its high accuracy in simulating keteniminium ion-related reactions (see the SI for more discussion) . Unscaled harmonic frequency calculations at the same level were performed to validate each structure as either a minimum or a transition state and to evaluate its zero-point energy and thermal corrections at 298.15 K. Intrinsic reaction coordinate (IRC) calculations were carried out to confirm the transition states connecting the right reactant(s) and product(s).…”

“…Usually, a reaction's selectivity is controlled by one of these three patterns. In 2023, we discovered that the intramolecular [2 + 2] reaction of keteniminium ions with alkenes has all these three patterns of regiochemistry control, 3 depending on the tethers and substituents in the alkene part of the substrates. This is the first reported reaction with three patterns of selectivity control.…”

Bispericyclic Ambimodal Dimerization of Pentafulvene: The Origin of Asynchronicity and Kinetic Selectivity of the Endo Transition State

“…A mechanistic insight into chemical reactions tracks the transformation of reactants into products and plays a crucial role in the physical perception of the reaction and predicting the most plausible product. − The sophisticated analytical techniques currently available are either expensive, time-consuming or unable to detect very fast, highly exoergic reactions, and highly unstable transition states (TSs). − Theoretical simulation aided by experimental evidence is the inexpensive and best-determining tool for the fundamental understanding of the reaction mechanisms. ,,,,, …”