{"doi":"10.1021/jacs.1c06529","title":"Ketone Enolization with Sodium Hexamethyldisilazide: Solvent- and Substrate-Dependent <i>E</i>–<i>Z</i> Selectivity and Affiliated Mechanisms","abstract":"Ketone enolization by sodium hexamethyldisilazide (NaHMDS) shows a marked solvent and substrate dependence. Enolization of 2-methyl-3-pentanone reveals E–Z selectivities in Et3N/toluene (20:1), methyl-t-butyl ether (MTBE, 10:1), N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDTA)/toluene (8:1), TMEDA/toluene (4:1), diglyme (1:1), DME (1:22), and tetrahydrofuran (THF) (1:90). Control experiments show slow or nonexistent stereochemical equilibration in all solvents except THF. Enolate trapping with Me3SiCl/Et3N requires warming to −40 °C whereas Me3SiOTf reacts within seconds. In situ enolate trapping at −78 °C using preformed NaHMDS/Me3SiCl mixtures is effective in Et3N/toluene yet fails in THF by forming (Me3Si)3N. Rate studies show enolization via mono- and disolvated dimers in Et3N/toluene, disolvated dimers in TMEDA, trisolvated monomers in THF/toluene, and free ions with PMDTA. Density functional theory computations explore the selectivities via the E- and Z-based transition structures. Failures of theory-experiment correlations of ionic fragments were considerable even when isodesmic comparisons could have canceled electron correlation errors. Swapping 2-methyl-3-pentanone with a close isostere, 2-methylcyclohexanone, causes a fundamental change in the mechanism to a trisolvated-monomer-based enolization in THF.","journal":"Journal of the American Chemical Society","year":2021,"id":170380,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":463781,"name":"David B. Collum","orcid":"0000-0001-6065-1655","position":1,"is_corresponding":false},{"id":463782,"name":"Ryan A. Woltornist","orcid":"0000-0001-7734-052X","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-18T23:46:24.040760Z","pmid":"34643382","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}