Kinetics of Nucleophilic Substitution of Compounds Containing Multiple Leaving Groups Bound to a Neopentyl Skeleton

Ammonium salt derivatives with a neopentyl moiety are remarkably stable against Hofmann elimination, but the neopentyl moiety slows nucleophilic substitution, complicating their synthesis. To identify the best leaving group for the synthesis of the ammonium salts, we prepared six 1,1,1-tris(X-methyl)ethane derivatives, where X is chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate (triflate), and studied the kinetics of their reactions with sodium, cesium, or tetramethylammonium azide in deuterated dimethylsulfoxide (DMSO) at 100 °C by NMR spectroscopy. Iodide and bromide were found to be more reactive than p-toluenesulfonate and methanesulfonate. As expected, the best leaving group for nucleophilic substitution was triflate. Despite the usual high reactivity and instability of primary alkyl triflates, neopentyl triflate can be used as a stable but sufficiently reactive reactant for nucleophilic substitution on neopentyl skeletons.

For 5 minutes, MsCl (2.6 mL, 33 mmol) was added dropwise, and the mixture was stirred at 0 °C. After 1.5 hours, reaction completion was confirmed by NMR. The mixture was extracted between CH2Cl2 and 1M HCl (both 50 mL). The organic phase was dried with MgSO4 (0.5 g). The crude product (1.97 g) was purified by column chromatography (25 g silica gel) eluting with hexane/EtOAc 1/3. Fractions with the product were collected and evaporated on a rotary evaporator at room temperature and then dried at room temperature using an oil rotary pump.
The product was obtained as a colorless oil, in 34% yield (1.0 g). IR (

2-Methyl-2-((tosyloxy)methyl)propane-1,3-diyl bis(4-methylbenzenesulfonate)
(4).   was dissolved in pyridine (10 mL). This solution and SOCl2 (9.7 mL, 133 mmol) were simultaneously added dropwise to pyridine (17 mL) cooled to 0 °C. After addition, the mixture was warmed to room temperature and then to 50 °C in an oil bath. After 1 hour, the mixture was warmed to 115 °C and kept under stirring for 4 hours. The reaction mixture was monitored by TLC using hexane/EtOAc 1/3 mixture for the starting compound. The substances were detected by immersing the TLC plate in a basic potassium permanganate solution, followed by heating to 250 °C by a heat gun.
The reaction mixture was extracted between Et2O and 1M HCl (both 70 mL). The organic phase was diluted with another 50 mL of Et2O and subsequently extracted with brine (70 mL). The organic phase was dried with MgSO4 (0.5 g), filtered, and evaporated at room temperature on a rotary evaporator. The product was dried at room temperature using an oil rotary pump. The product was obtained as a colorless oil, in 81%

Preparation of tetramethylammonium and cesium azides Preparation of cesium azide
Sodium azide (2.60 g, 0.040 mol) was dissolved in water (50 mL) and poured into a strong cation exchanger column DOWEX 50W (60 mL, H + form). The column was washed with water until the solution was weakly acidic. Cesium carbonate (5.2 g, 0.016 mol) was dissolved in water (100 mL), and the aqueous solution of hydrazoic acid was slowly poured into this solution. The solution was evaporated on a rotary evaporator at 50 °C. The product was dried at 70 °C using an oil rotary pump. The product was obtained as a white solid in 97% yield (5.48 g).

Preparation of tetramethylammonium azide
Sodium azide (3.12 g, 0.048 mol) was dissolved in water (50 mL) and poured into a strong cation exchanger column DOWEX 50W (60 mL, H + form). The column was washed with water until the solution was weakly acidic. Tetramethylammonium bromide (5.0 g, 0.032 mol) was dissolved in water (50 mL) and  Figure S15: Composition of the reaction mixture in reaction of (MsO)3Np (2) with an excess of NaN3 in time Figure S16: Composition of the reaction mixture in reaction of (TfO)3Np (3) with an excess of NaN3 in time S13 Figure S17: Composition of the reaction mixture in reaction of I3Np (5) with an excess of NaN3 in time Figure S18: Composition of the reaction mixture in reaction of Br3Np (6) with an excess of NaN3 in time S14 Figure S19: Composition of the reaction mixture in reaction of Cl3Np (7) with an excess of NaN3 in time Figure S20: Composition of the reaction mixture in reaction of (TsO)3Np (4) with an excess of CsN3 in time S15 Figure S21: Composition of the reaction mixture in reaction of (TsO)3Np (4) with an excess of (Me4N)N3 in time Figure S22: Composition of the reaction mixture in reaction of I3Np (5) with an excess of CsN3 in time S16 Figure S23: Composition of the reaction mixture in reaction of I3Np (5) with an excess of (Me4N)N3 in time Figure S24: Variation of concentration of (MsO)3Np (2) and NaN3 as a function of time S17 Figure S25: Variation of concentration of I3Np (5) and NaN3 as a function of time Figure S26: Variation of concentration of Br3Np (6) and NaN3 as a function of time S18 Figure S27: Variation of concentration of Cl3Np (7) and NaN3 as a function of time Figure S28: Variation of concentration of (TsO)3Np (4) and CsN3 as a function of time S19 Figure S29: Variation of concentration of (TsO)3Np (4) and (Me4N)N3 as a function of time Figure S30: Variation of concentration of I3Np (5) and CsN3 as a function of time S20 Figure S31: Variation of concentration of I3Np (5) and (Me4N)N3 as a function of time S21 Figure S32: A log-log graph depicting relationship between half-lives and rate constants of each X3Np Figure S33: Graphs of half-lives: Acompound I3Np (5) with NaN3, CsN3, and (Me4N)N3; Bcompound (TsO)3Np (4) with NaN3, CsN3, and (Me4N)N3