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

Abstract

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.

Selective Arylation of RNA 2′‐OH Groups via SNAr Reaction with Trialkylammonium Heterocycles

“…We tested the stability of DMTMM in pure methanol (CD 3 OD), and its half‐life was >3 weeks at room temperature (Figure S15), confirming that this class of reagent reacts very poorly even with a much less hindered alcohol than the 2′‐OH of RNA. In addition, research has shown that most trialkylamines are poorer leaving groups than halides, [46] while in the present case with RNA they are considerably more reactive. We wondered whether the cationic charge of DMTMM might enhance reaction by increasing its local concentration near polyanionic RNA; however, addition of tetraethylammonium chloride (10–100 mM) as a cationic competitor had little effect on yields in arylation of a test RNA strand, whether or not the reagent was cationic (Figure S16).…”

Facile synthesis of new N-(aminocycloalkylene)amino acid compounds using chiral triflate esters with N-Boc-aminopyrrolidines and N-Boc-aminopiperidines

“…28 A triate group is an excellent leaving group used in nucleophilic substitution reactions and has been shown to be signicantly superior to other leaving groups in the Walden inversion, where the inversion of a stereogenic centre in a chiral molecule takes place. 29,30 It is known that the reaction of enantiopure a-halocarboxylic acid esters with amines is accompanied by extensive racemization of a-amino esters; with a-methanesulfonyloxy and a-toluenesulfonyloxy carboxylic acid derivatives, both racemization and elimination products are formed due to the drastic conditions. 31 Therefore, triate esters with primary and secondary amines are known to give N-substituted a-aminocarboxylates in the S N 2 reaction, resulting in good chemical as well as optical yields.…”

N-(2-Tetrafluoro(trifluoromethyl)-λ6-sulfanyl(CF3SF4)-ethyl) Amines: The Influence of the CF3SF4 Group on Lipophilicity and pKa

“…The report of successful utilization of 2-pentafluorosulfanylethyl triflate in displacement reactions by Paquin suggested the utilization of the superior leaving group trifluoromethansulfonate (triflate) (Scheme ). The triflate leaving group is a highly reactive and consequently has limited stability . Triflate 3 was obtained as a yellow oil precluding ready single-crystal diffraction studies.…”

“…The triflate leaving group is a highly reactive and consequently has limited stability. 18 Triflate 3 was obtained as a yellow oil precluding ready single-crystal diffraction studies.…”