Transition state modeling and catalyst design for hydrogen bond-stabilized enolate formation

Yimin Zhu, Dale G. Drueckhammer

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Abstract

A catalyst for enolate formation was designed that incorporates an amine base along with a thiourea to bind to the oxygen atom of the substrate and enolate through hydrogen bonding. A computational model of the transition state was developed in which the thiourea (modeled initially as a urea) and amine were separate molecules. This model and models incorporating one or two methanol molecules in place of the urea showed an out-of-plane hydrogen bond, apparently to the carbonyl π-bond, in addition to an in-plane hydrogen bond to an unshared electron pair. In contrast, optimized complexes of the ketone and the fully formed enolate showed only in-plane hydrogen bonding. The transition state model with the urea and amine was used to define a database search with the computer program CAVEAT to identify structures suitable for linking the amine and urea/thiourea moieties in the transition state. On the basis of a group of structures identified from this search, a flexible but conformationally biased linker was designed to connect the two catalytic moieties. The molecule having the amine and thiourea moieties connected by this linker was synthesized and was shown to catalyze proton exchange between methanol and deuterated acetone. The catalyst was about 5-fold more efficient than the amine and thiourea as separate molecules and relative to a similar but less conformationally biased catalyst.

Original languageEnglish (US)
Pages (from-to)7755-7760
Number of pages6
JournalJournal of Organic Chemistry
Volume70
Issue number19
DOIs
Publication statusPublished - Sep 16 2005

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All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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