Synthesis of quaternary phosphonium N-chloramine biocides for antimicrobial applications

Abstract

We synthesized a phosphonium N-chloramine biocide which has distinctively higher antimicrobial efficacy than the previously developed ammonium counterpart.

Synthesis of Gemini‐QA N‐Chloramine Biocides for Antibacterial Applications

“…Obvious chemical shift change was observed on 1 H NMR spectra once precursors 8 a ‐ 11 a were transformed into N ‐chloramines 8–11 via chlorination, which well conformed to our previous reports . For instance, the signal of CH 3 ‐ and ‐CH 2 ‐ (adjacent to the imide N ) of 8 a shifted downfield from 1.36 ppm to 1.43 ppm and 3.55 ppm to 3.63 ppm respectively (Figure ), which probably was due to the electron‐withdrawing effect of the newly produced N ‐Cl bond.…”

“…Next, quaternization reactions between excess DMH bromides and N, N, N’, N’ ‐tetramethylethylenediamine (TMEDA) were conducted in acetonitrile under gentle reflux, attempting to minimize the formation of monoalkylated byproduct . However, the reaction system to produce precursor 8 a got heavily cloudy after reflux overnight, which was quite different from previously reported mono‐quaternization reaction phenomenon . It means that 8 a probably bears quite poor solubility in CH 3 CN under reflux, resulting in lots of white precipitates formed.…”

“…Synthesis route of target Gemini‐QA N ‐chloramines 8–11 was depicted in Scheme . First of all, bromides 12–15 were prepared by N ‐alkylation of commercial 5, 5‐dimethylhydantoin (DMH) according to our previous reports . Next, quaternization reactions between excess DMH bromides and N, N, N’, N’ ‐tetramethylethylenediamine (TMEDA) were conducted in acetonitrile under gentle reflux, attempting to minimize the formation of monoalkylated byproduct .…”

“…Such precursor 8 a‐11 a were then dissolved in minimal DI water and passed through the anion exchange resin (Cl − ) to give the Cl − form counterparts. Subsequent chlorination were performed by being treated with t ‐butyl hypochlorite at room temperature. The solvent of t ‐BuOH‐H 2 O, residual t ‐butyl hypochlorite (bp 78 °C) and the sole by‐product of t ‐BuOH could be removed effortlessly under vacuum, affording final N ‐chloramines 8–11 in quantitate yield.…”

“…However, N ‐chloramines usually bear relatively poor aqueous solubility once produced from precursors, which may greatly shadow its outstanding antibacterial efficacies . As a result, “composite” ionic N‐ chloramines (Figure ), including QA N ‐chloramine 1 , pyridinium N ‐chloramine 2 , QP N ‐chloramine 3 and carboxybetaine N ‐chloramine 4 were developed to overcome the solubility problem for practical applications. Interestingly, besides the pretty good aqueous solubility, drastically promoted antibacterial efficacy were achieved for these ionic N‐ chloramines.…”