A Mechanistic Investigation into the Zinc Carbenoid-Mediated Homologation Reaction by DFT Methods: Is a Classical Donor−Acceptor Cyclopropane Intermediate Involved?

Abstract

An extensive density functional theory (DFT, M05-2X) investigation has been performed on the zinc carbenoid-mediated homologation reaction of β-keto esters. The mechanistic existence of a classical donor–acceptor cyclopropane intermediate was probed to test the traditional school of thought regarding these systems. Calculations of the carbenoid insertion step, following enolate formation, unmasked two possible pathways. Pathway B was shown to explain the proposed, but spectroscopically unobservable donor–acceptor cyclopropane intermediate, while the second (pathway A) reveals an alternative to the classical intermediate in that a cyclopropane transition state leads to product.

A Combined DFT and NMR Investigation of the Zinc Organometallic Intermediate Proposed in the Syn-Selective Tandem Chain Extension–Aldol Reaction of β-Keto Esters

“…7 Three possible dimeric structures ( 17a , 17b and 17c ) were calculated and are illustrated in Scheme 4. 4 …”

“…4 Therefore, the calculations presented in this body of work concentrate solely on dimeric structures. To simulate the reaction conditions most efficiently, the aldol reaction mechanism has been calculated including C-PCM solvent effects resembling dichloromethane, which is also the solvent used in the experimental investigations.…”

“…For reduction in calculation time, the iodomethyl residue resulting from the Furukawa reagent as implemented in our earlier work has been exchanged to an ethyl residue, as it is not expected to participate in the aldol reaction mechanism. The reaction steps leading up to the inserted carbene moiety in the TCA pathway have been investigated thoroughly; 4 therefore, the theoretical study herein will focus specifically on the reaction sequence starting from the chain-elongated intermediate.…”

“…More recently, an extensive DFT study was performed to gain a better understanding of the mechanistic process and an alternative pathway involving a cyclopropane transition state was also identified. 4 which suggests that the presence of a cyclopropane intermediate (classical) and a cyclopropane transition state (non-classical) are both viable.…”

Calculation of Heats of Formation for Zn Complexes: Comparison of Density Functional Theory, Second Order Perturbation Theory, Coupled-Cluster and Complete Active Space Methods

“…4 Eger et al, used density functional study to study the mechanism of the zinc carbenoid-mediated homologation of β-keto esters. 5 In 2009, van Gastel et al, complemented their EPR/ENDOR study of bis(a-iminopyridinato)zinc with B3LYP/TZV calculations used to support experimental determination of the proton hyperfine coupling constants. 6 In yet another application, Govind and coworkers utilized TDDFT calculations in order to probe the excitation energies of zinc porphyrin in aqueous solution.…”