Aggregation and Solvation of Sodium Hexamethyldisilazide: Across the Solvent Spectrum

Abstract

We report solution structures of sodium hexamethyldisilazide (NaHMDS) solvated by >30 standard solvents (ligands). These include: toluene, benzene, and styrene; triethylamine and related trialkylamines; pyrrolidine as a representative dialkylamine; dialkylethers including THF, tert-butylmethyl ether, and diethyl ether; dipolar ligands such as DMF, HMPA, DMSO, and DMPU; a bifunctional dipolar ligand nonamethylimidodiphosphoramide (NIPA); polyamines N,N,N′,N′-tetramethylenediamine (TMEDA), N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDTA), N,N,N′,N′-tetramethylcyclohexanediamine (TMCDA), and 2,2′-bipyridine; polyethers 12-crown-4, 15-crown-5, 18-crown-6, and diglyme; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]­hexacosane ([2.2.2] cryptand); and tris­[2-(2-methoxyethoxy)­ethyl]­amine (TDA-1). Combinations of 1H, 13C, 15N, and 29Si NMR spectroscopies, the method of continuous variations, X-ray crystallography, and density functional theory (DFT) computations reveal ligand-modulated aggregation to give mixtures of dimers, monomers, triple ions, and ion pairs. 15N–29Si coupling constants distinguish dimers and monomers. Solvation numbers are determined by a combination of solvent titrations, observed free and bound solvent in the slow exchange limit, and DFT computations. The relative abilities of solvents to compete in binary mixtures often match that predicted by conventional wisdom but with some exceptions and evidence of both competitive and cooperative (mixed) solvation. Crystal structures of a NaHMDS cryptate ion pair and a 15-crown-5-solvated monomer are included. Results are compared with those for lithium hexamethyldisilazide, lithium diisopropylamide, and sodium diisopropylamide.

Ketone Enolization with Sodium Hexamethyldisilazide: Solvent- and Substrate-Dependent E–Z Selectivity and Affiliated Mechanisms

“…Complexation of the starting ketone to the NaHMDS dimer was detected by a shift in the carbonyl absorbance ( 8 = 1712 cm –1 ; 8 - d 3 = 1704 cm –1 ) only in toluene, Et 3 N/toluene, TMEDA/toluene, and very low MTBE concentrations in MTBE/toluene. Similar perturbations in the carbonyl absorbances are documented for ketone–lithium amide complexes. ,, A monotonic 2 Hz rise in the 29 Si– 15 N coupling constant resulting from incremental additions of ketone 8 to [ 15 N]­NaHMDS/Et 3 N/toluene affirmed the complexation . Enolization rates at −78 °C were modulated for maximal convenience using 8 and its deuterated analog ( 8 - d 3 ) .…”

“…Dimeric NaHMDS dominates in poorly coordinating solvents . As found previously in lithium amide chemistry, these weak solvents can promote dimer-based mechanisms, the simplest of which is shown in eqs –.…”

“…In total, the data demand a full ionization of observable monomer κ 3 - 7 as in Mechanism C (eqs –). We had observed solvent-separated ion pair formation in the spectroscopic studies of NaHMDS but were not able to spectroscopically distinguish them from free ions, which are suggested to be present in low concentrations based on dissociation constants of ion pairs. , An ion pair-based pathway (Mechanism B) and free ion-based pathway (Mechanism C), however, would display distinctly different rate laws. The free ion-based enolization is illustrated in Scheme .…”

“…NaHMDS and [ 15 N]­NaHMDS were prepared as white crystalline solids from hexamethyldizilazane and sodium metal . There is no evidence the added precautions to purify NaHMDS for structural and mechanistic studies alter reactivity when compared with commercial samples.…”

“…The preeminent organosodium reagent that has not been ignored by the synthetic community is sodium hexamethyldisilazide (NaHMDS). − It is soluble, stable, and commercially available in toluene and tetrahydrofuran (THF). NaHMDS is used in both academic and industrial laboratories on micro-to-plant scales. , Nevertheless, whereas crystallographers have characterized a number of synthetically relevant NaHMDS solvates, solution structural and even computational studies were nearly nonexistent. , Hoping to nudge researchers to consider a broader range of conditions, we determined the aggregation and solvation states of NaHMDS in over 30 mono-, di-, and polyfunctional solvents . Emblematic solution structures 1 – 7 germane to the mechanistic studies described herein are shown in Chart .…”