Sodium Isopropyl(trimethylsilyl)amide: A Stable and Highly Soluble Lithium Diisopropylamide Mimic

Abstract

The preparation, structure, physical properties, and reactivities of sodium isopropyl(trimethylsilyl)amide (NaPTA) are described. The solubilities at room temperature range from n-heptane (0.55 M), n-hexane (0.60 M), toluene (0.65 M), MTBE (1.7 M), Et3N (3.2 M), and THF (>6.0 M). The half-life to destruction in neat THF is >1 year at 25 °C and 7 days at 70 °C, which compares favorably to 2.5 months and 1.5 days, respectively, for LDA in neat THF. This study focuses on NaPTA in THF. 29Si NMR spectroscopy shows exclusively a mixture of cis and trans stereoisomeric dimers in 0.10–12 M THF in hexane. Density functional theory (DFT) computations suggest that the pK b is intermediate between dimeric sodium diisopropylamide (NaDA) and dimeric sodium hexamethyldisilazide (NaHMDS). Metalations of arenes, epoxides, ketones, hydrazones, alkenes, and alkyl halides show higher reactivities than LDA (k NaPTA/LDA = 1–30). While the rates of arene metalation are high, the lower pK b of NaPTA limits the substrates. Metalation of pseudoephedrate-based carboxamides to form disodiated Myers enolates solves several challenging technical problems.

New Frontiers in Organosodium Chemistry as Sustainable Alternatives to Organolithium Reagents

“…Another approach to improve the solubility of sodium amides without significantly compromising their reactivity has been reported recently by the same group, in which ‐SiMe 3 and ‐ i Pr groups are combined in the nitrogen center, giving sodium isopropyl(trimethylsilyl)amide. This base has similar stability in ethereal solvents to the commercially available LiDA, but with higher reactivity [40] …”

Carbon–Nitrogen Bond Formation Using Sodium Hexamethyldisilazide: Solvent-Dependent Reactivities and Mechanisms

“…1−3 This involved some minor adjustments to protocols for generating and handling sodium diisopropylamide (NaDA) 2,3 as well as developing a new reagent, sodium isopropyl(trimethyl)silyl amide (NaPTA), that manifests desirable solubilities and reactivities as a strong base. 4 Our primary approach, however, is decidedly structural and mechanistic with the faith that understanding how solvation and aggregation influence reactivity and selectivity will propel applications through a combination of serendipity in our laboratory and need-driven progress by others. Even the most prominent organosodium reagent, sodium hexamethyldisilazide (NaHMDS), 5 while garnering the attention of crystallographers, 6 had evaded spectroscopic, mechanistic, and computational scrutiny until recent studies of its solvent-dependent structure and reactivity toward enolization.…”

“…NaHMDS plays the role of a highly reactive analogue of ammonia and a preface to expanding investigations of sodium alkylsilazides. 4 Some of the transformations surveyed as opportunities for mechanistic studies piqued our interest as synthetically promising and have surprisingly little or no presence in the NaHMDS literature. The more mechanistically inclined will find the prevalence of dimer-and mixed aggregate-based reactivity surprising.…”

“…After decades of communal disinterest in organosodium chemistry, we began trying to shine a light on its potential by expanding the toolbox for generating and using organosodium species. − This involved some minor adjustments to protocols for generating and handling sodium diisopropylamide (NaDA) , as well as developing a new reagent, sodium isopropyl­(trimethyl)­silyl amide (NaPTA), that manifests desirable solubilities and reactivities as a strong base . Our primary approach, however, is decidedly structural and mechanistic with the faith that understanding how solvation and aggregation influence reactivity and selectivity will propel applications through a combination of serendipity in our laboratory and need-driven progress by others.…”

“…We describe herein a survey of the reactivity of NaHMDS toward carbon-centered electrophiles of potential interest in synthesis, accompanied by detailed structural and mechanistic studies. NaHMDS plays the role of a highly reactive analogue of ammonia and a preface to expanding investigations of sodium alkylsilazides . Some of the transformations surveyed as opportunities for mechanistic studies piqued our interest as synthetically promising and have surprisingly little or no presence in the NaHMDS literature.…”