DFT-assisted design and evaluation of bifunctional copper(I) catalysts for the direct intermolecular addition of aldehydes and ketones to alkynes

Abstract

Bifunctional catalysts containing discrete metal pi-acid and amine sites were designed and investigated for the direct intermolecular addition of aldehydes and ketones to unactivated alkynes. Copper(I)-based catalystswere prioritized based on intramolecular (Conia-ene type) reactions, and complexes were designed with tridentate ligands and potentially hemilabile heterocyclic spacers. The structures of the designed catalysts were computed using density functional theory (DFT), and the relative energies of putative catalytic intermediates were estimated and used to prioritize catalyst designs. Novel bifunctional precatalysts containing a thiazole spacer were synthesized via a 9-step sequence and combined with transition metals before screening for the direct addition of aldehydes and ketones to several internal and terminal alkynes. Despite the lack of desired intermolecular reactions, DFT calculations of putative catalyst intermediates appears to be a promising strategy for the design and prioritization of bifunctional catalysts for C C bond formation.

Computationally‐Guided Investigation of Dual Amine/pi Lewis Acid Catalysts for Direct Additions of Aldehydes and Ketones to Unactivated Alkenes and Alkynes

“…We previously reported this observation for a Cu(I)-phenylacetylene complex, where the alkyne was displaced upon the addition of an enamine. [14] We hypothesized that a bulkier enamine would coordinate less favorably to the sterically congested π-acidic metal than a smaller alkene. To test this hypothesis, we performed ground state DFT calculations for the addition of enamines 10 or 11 to the (t-Bu-PyBOX)-Pt 2 + ethylene complex (Figure 4).…”

“…[10,11] Efforts in our laboratories have been focused on the preparation and study of bifunctional catalysts that have the potential to activate both aldehyde/ketone "donors" (pronucleophiles) and various "acceptors" (electrophiles), [12,13] most recently alkenes and alkynes (Figure 1, top). [14,15] The strategy is centered on the use of an amine to activated the donor substrate, which is tethered to a π-Lewis acid suitable for electrophilic activation of alkenes/alkynes. This strategy was driven by our hypothesis, substantiated by certain NMR studies, [14] that additions of enamine intermediates to unactivated alkenes/alkynes are complicated by the fact that the enamines may be superior ligands for π-Lewis acids than the alkene/alkyne acceptors.…”

“…[14,15] The strategy is centered on the use of an amine to activated the donor substrate, which is tethered to a π-Lewis acid suitable for electrophilic activation of alkenes/alkynes. This strategy was driven by our hypothesis, substantiated by certain NMR studies, [14] that additions of enamine intermediates to unactivated alkenes/alkynes are complicated by the fact that the enamines may be superior ligands for π-Lewis acids than the alkene/alkyne acceptors.…”

“…[20] We developed a density functional theory (DFT)-based approach to prioritizing our own bifunctional catalyst designs, which estimates the free energy change upon CÀ C bond formation within the putative catalytic cycle. [14,15] It should be emphasized that rational de novo catalyst design has yet to be established as a reliable strategy, though in recent years successful examples of the modification of established organometallic catalysts driven by computation have been reported. [21][22][23] Thus far, our approach has been complicated by apparent catalyst-catalyst interactions, which current work is aiming to minimize.…”