Ketone Enolization with Sodium Hexamethyldisilazide: Solvent- and Substrate-Dependent E–Z 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 Et 3 N/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 Me 3 SiCl/Et 3 N requires warming to −40 °C whereas Me 3 SiOTf reacts within seconds. In situ enolate trapping at −78 °C using preformed NaHMDS/Me 3 SiCl mixtures is effective in Et 3 N/toluene yet fails in THF by forming (Me 3 Si) 3 N. Rate studies show enolization via mono-and disolvated dimers in Et 3 N/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, 2methylcyclohexanone, causes a fundamental change in the mechanism to a trisolvated-monomer-based enolization in THF.

Highly Reactive Hydrocarbon Soluble Alkylsodium Reagents for Benzylic Aroylation of Toluenes using Weinreb Amides

“…A common strategy to increase the solubility and enhance the reactivity of polar organometallic reagents and s‐block metal amides is the use of Lewis donor additives [19] . In this regard, Collum has assessed the constitution of sodium amides NaHMDS (HMDS=1,1,1,3,3,3‐hexamethyldisilazide) and NaDA (DA=diisopropylamide) in several solvents in the presence of a variety of donor additives and investigated their reactivity in organic transformations such as dehydrohalogenation and metalation [12, 20, 21] . Recently we have shown that NaTMP (TMP=2,2′,6,6′‐tetramethylpiperidide) combined with the tridentate donor PMDETA ( N,N,N′,N′′,N′′‐ pentamethyldiethylenetriamine) and B(O i Pr) 3 can promote the regioselective borylation of non‐activated substrates, offering in some cases complementary selectivities to those observed using transition‐metal catalysed protocols [22] .…”

A Sodium Sodate as Precursor for Lanthanide Bis(4-R-benzoxazol-2-yl)methanide Single-Molecule Magnets

“…Observations in the solid state frequently differ from the behavior in solution. − Therefore, we further analyzed the dynamics of 1 in solution to determine to which extent the solvent-separated ion pair is maintained. The corresponding sodium analogue 1 ′ was prepared and characterized in the same way for comparison purposes.…”

Highly Reactive Hydrocarbon Soluble Alkylsodium Reagents for Benzylic Aroylation of Toluenes using Weinreb Amides

“…[19] In this regard, Collum has assessed the constitution of sodium amides NaHMDS (HMDS = 1,1,1,3,3,3-hexamethyldisilazide) and NaDA (DA = diisopropylamide) in several solvents in the presence of a variety of donor additives and investigated their reactivity in organic transformations such as dehydrohalogenation and metalation. [12,20,21] Recently we have shown that NaTMP (TMP = 2,2',6,6'-tetramethylpiperidide) combined with the tridentate donor PMDETA (N,N,N',N'',N''-pentamethyldiethylenetriamine) and B-(OiPr) 3 can promote the regioselective borylation of nonactivated substrates, offering in some cases complementary selectivities to those observed using transition-metal catalysed protocols. [22] The reactions are driven by the strong metalating power of the NaTMP/PMDETA combination which can also promote catalytic hydrogen isotope exchange of non-activated arenes, including toluene when using C 6 D 6 as the deuterium source.…”