Kinetics of the Strain-Promoted Oxidation-Controlled Cycloalkyne-1,2-quinone Cycloaddition: Experimental and Theoretical Studies

Abstract

Stimulated by its success in both bioconjugation and surface modification, we studied the strain-promoted oxidation-controlled cycloalkyne–1,2-quinone cycloaddition (SPOCQ) in three ways. First, the second-order rate constants and activation parameters (ΔH⧧) were determined of various cyclooctynes reacting with 4-tert-butyl-1,2-quinone in a SPOCQ reaction, yielding values for ΔH⧧ of 4.5, 7.3, and 12.1 kcal/mol, for bicyclo[6.1.0]non-4-yne (BCN), cyclooctyne (OCT), and dibenzoazacyclooctyne (DIBAC), respectively. Second, their reaction paths were investigated in detail by a range of quantum mechanical calculations. Single-configuration theoretical methods, like various DFT and a range of MP2-based methods, typically overestimate this barrier by 3–8 kcal/mol (after inclusion of zero-point energy, thermal, and solvation corrections), whereas MP2 itself underestimates the barrier significantly. Only dispersion-corrected DFT methods like B97D (yielding 4.9, 6.4, and 12.1 kcal/mol for these three reactions) and high-level CCSD(T) and multireference multiconfiguration AQCC ab initio approaches (both yielding 8.2 kcal/mol for BCN) give good approximations of experimental data. Finally, the multireference methods show that the radical character in the TS is rather small, thus rationalizing the use of single-reference methods like B97D and SCS-MP2 as intrinsically valid approaches.

Multireference Approaches for Excited States of Molecules

“…91 The method has been applied to the biradicaloid character in singlet and triplet states of triangular non-Kekulé structures and zethrenes 91 and to the calculation of the reaction barrier of the strain-promoted oxidation-controlled cycloalkyne-1,2-quinone cycloaddition (SPOCQ) reaction. 92 A linear scaling local MRCI version has been developed by the Carter group [93][94][95] with application to excited states. 96…”

autoDIAS: a python tool for an automated distortion/interaction activation strain analysis

“…This analysis can be applied to single geometries or multiple geometries along a scan or reaction coordinate, to provide information on the nature of interaction between the fragments and the potential energy surface. This method has been widely applied for a broad range of chemical systems such as cycloadditions, ene reactions, metal complexes and catalysis, organocatalysis, and addition and substitution reactions …”

Strain‐Promoted Cycloaddition of Cyclopropenes with o‐Quinones: A Rapid Click Reaction

“…The TS geometries also suggest that the cycloaddition is favored on the face away from the 3‐methyl substituent of the cyclopropene ring. These activation energies are higher than those calculated for bicyclo[6.1.0]non‐4‐yne and cyclooctyne, with barriers of 4.9 and 6.9 kcal mol −1 , respectively, and rate constants of 838 and 51 m −1 s −1 , but lower than that of dibenzoazacyclooctyne (12.1 kcal mol −1 , with k 2 =0.51 m −1 s −1 ), and those reported for the Diels–Alder reaction of cyclopropenes and butadiene (21–27 kcal mol −1 ) . The marginally slower reaction of 7 and 8 , the cycloaddition proceeds similarly via a non‐synchronous endo ‐TS with an activation barrier of 7.9 kcal mol −1 (vs. 7.5 kcal mol −1 for 5 ; vide supra).…”

“…Density functional theory (DFT) calculations were performed using Gaussian 16, in order to study the reaction mechanism of this exothermic reaction (Δ H calc =−31 to −35 kcal mol −1 ) in more detail. For that purpose, we used the dispersion‐corrected B97D density functional, which has been proved to give accurate activation energies for SPOCQ cycloaddition reactions, and the conductor‐like polarizable continuum model (CPCM) to mimic methanol. These computations yield that the cycloaddition reaction proceeds through a non‐synchronous transition state (TS), as shown by the distances for both new C−C bonds (see Figure ).…”