Thioimidazolium Salts as a Platform for Nonvolatile Alkylators and Degradable Antiseptics

Abstract

A collection of thioimidazolium salts were synthesized and used as a new class of nonvolatile alkylating agents. Their nonvolatility prevents exposure during use or handling and are thus drastically safer than conventional alkylating agents. We discovered that thioimidazolium iodide salts cannot release volatile compounds in the solid state, but instead only decompose when molten. Since decomposition proceeds via alkyl iodide elimination, S N 2 of iodide on the thioimidazolium cation is constrained in the solid state, and instead can occur only upon melting when ions are mobile. By smart design of these alkylators, the melting point and thus the decomposition temperature of these salts can be increased from 106 to 169 °C and release negligible volatile organic compounds prior to melting. Thioimidazolium-bis(trifluoromethanesulfonyl)imide (TFSI) ionic liquids act as a completely nonvolatile and air-stable TFSI-based alkylating agent and can be used for high-throughput synthesis of TFSI ionic liquids without solvent. Alkyl groups from methyl to dodecyl can be transferred to a nucleophile and the product purified by sublimation of the thione byproduct, which can then be recycled. We also found that thioimidazolium salts with a dodecyl chain are bactericidal, yet can hydrolyze in water to form benign neutral products, and thus wont accumulate in the environment. These results demonstrate that thioimidazolium salts are a designable platform for the pursuit of safer and more environmentally friendly alkylating and antiseptic agents.

Not‐So‐Innocent Anions Determine the Mechanism of Cationic Alkylators

“…We have been developing a new class of highly tunable and non‐volatile cationic alkylating agents based on thioimidazolium ionic liquids [25, 26] . In contrast with oxonium, ammonium, or sulfonium analogues, thioimidazoliums are more easily derivatizable and often milder alkylating reagents.…”

“…[22][23][24] We have been developing an ew class of highly tunable and non-volatile cationic alkylating agentsb ased on thioimidazolium ionic liquids. [25,26] In contrastw ith oxonium,a mmonium,o r sulfonium analogues, thioimidazoliums are more easily deriva-tizable and often milder alkylating reagents. For example, alkyl groups attached to the sulfur atom are exclusively transferred to an ucleophile under mild reaction conditions leaving all other positions unaffected, thus allowing for their derivatization without compromisingp roduct formation.O ur preliminary investigations showedt hat electron deficient thioimidazolium cations have weaker S-R bonds and correspondingly faster alkylation reactions [25] and that exchanging the iodide counteranion with the much less nucleophilic bis(trifluoro-methane)sulfonimide (TFSI) decreased the rate constant by 100-fold for reactions with pyridine.…”

Unexpected Intrinsic Lability of Thiol-Functionalized Carboxylate Imidazolium Ionic Liquids

“…These results underline an active role played by the imidazolium cation in triggering the decomposition process. It is worth mentioning that imidazolium 2-thiones attracted some interest recently for the preparation of nonvolatile alkylating agents [23,24].…”

Oxidative Cyclization of 4‐(2‐Mercaptophenyl)‐Substituted 4H‐1,2,4‐Triazolium Species to Tricyclic Benzothiazolium Salts

“…A similar method was recently applied in preparation of fused azoles‐thiazolines from alkylthiocyanato‐functionalized azolium precursors [50] . However, 2‐alkylthioimidazolium salts are generally prepared by reacting the imidazolium precursor with S 8 to give the thioimidazolium species which subsequently is alkylated [51–54] . The same alkylation approach has been utilized in preparation of 3‐methylthio‐substituted 1,2,4‐triazolium salts [55,56] …”

“…[50] However, 2alkylthioimidazolium salts are generally prepared by reacting the imidazolium precursor with S 8 to give the thioimidazolium species which subsequently is alkylated. [51][52][53][54] The same alkylation approach has been utilized in preparation of 3-methylthiosubstituted 1,2,4-triazolium salts. [55,56]…”