Synthesis of a series of amino acid derived ionic liquids and tertiary amines: green chemistry metrics including microbial toxicity and preliminary biodegradation data analysis

Abstract

A series of L-phenylalanine ionic liquids (ILs), L-tyrosine ILs, tertiary amino analogues and proposed transformation products (PTPs) have been synthesised. Antimicrobial toxicity data, as part of the green chemistry metrics evaluation and to supplement preliminary biodegradation studies, was determined for ILs, tertiary amino analogues and PTPs. Good to very good overall yields (76 to 87%) for the synthesis of 6 ILs from L-phenylalanine were achieved. A C 2 -symmetric IL was prepared from TMS-imidazole in a one-pot two-step method in excellent yield (91%). Synthesis of the L-tyrosine IL derivatives utilised a simple protection group strategy by using an extra equivalent of the bromoacetyl bromide reagent. Improvements in the synthesis of the α-bromoamide alkylating reagent from L-phenylalanine were achieved, directed by green chemistry metric analysis. A solvent switch from dichloromethane to THF is described, however the yield was 15% lower. Antimicrobial activity testing of L-phenylalanine ILs, L-tyrosine ILs, tertiary amino analogues and PTPs, against 8 bacteria and 12 fungi strains, showed that no compound had a high antimicrobial activity, apart from an L-proline analogue. In this exceptional case, the highest toxicity (IC 95 = 125 and 250 µM) was observed towards the two Gram positive strains Staphylococcus aureus and Staphylococcus epidermidis respectively. High antimicrobial activity was not found for the other bacteria or fungi strains screened. The limitations of the antimicrobial activity study is discussed in relation to SAR studies. Preliminary analysis of biodegradation data (Closed Bottle Test, OECD 301D) is presented. The pyridinium IL derivative is the preferred green IL of the series based on synthesis, toxicity and biodegradation considerations. This work is a joint study with Kümmerer and co-workers and the PTPs were selected as target compounds based on concurrent biodegradation studies by the Kümmerer group. For the comprehensive biodegradation and transformation product analysis see the accompanying paper.

Environmental Impact of Ionic Liquids: Recent Advances in (Eco)toxicology and (Bio)degradability

“…To prove the presupposed idea, various studies with new amino‐acid‐based ILs have been performed, including those with bacteria and fungi. For example, Jordan et al . have evaluated the antimicrobial activity of a series of l ‐phenylalanine ILs, l ‐tyrosine ILs, and tertiary amino analogues with 8 bacteria and 12 fungi strains.…”

“…Other approaches have been applied to upgrade the synthesis of ILs, for example, the use of benign solvents or solventfree processes, the use of recyclable solvents, the design and creationo fs afer chemical products that are harmless and biodegradable, and ar eduction in waste production.F or example, variousauthors have synthesized new ILs from renewable sources, such as nicotinic acid, [38] choline, [39] sugars, [40] and amino acids. [41] Furthermore, new generationso fs alts, such as deep eutectics olvents (DESs) show good performance in chemical reactions. The synthesis of DESs simply involves mixingt wo cheap componentsw ith low environmental impact together www.chemsuschem.org to form ae utectic mixture without the need for any additional solvents.…”

“…Amino acid derivatives are one of the mostu sed classes of compounds in this context.T op rove the presupposed idea, variouss tudies with new amino-acid-basedI Ls have been performed, including those with bacteria and fungi. For example, Jordan et al [41] have evaluated the antimicrobiala ctivity of as eries of l-phenylalanine ILs, l-tyrosineI Ls, and tertiary amino analogues with 8b acteria and 12 fungi strains.N one of the compounds has high antimicrobiala ctivity,a part from an l-proline analogue. Among the selected strains,t he Gram-positive S. aureus and S. epidermidis strains are the most sensitive to the tested ILs.…”

An Overview on the Toxicological Properties of Ionic Liquids toward Microorganisms

“…However, the level of toxicity can be reduced by introducing an aryl group instead of an alkyl or allyl group in the cation . Furthermore, cations like morpholinium and cholinium have been found to be the least toxic, and can be used to design inherently safe ILs, especially when combined with short polar side chains and nontoxic anions . The oxygenated group in the cation also decreases toxicity as it contributes to hydrophilicity.…”

“…[84] Furthermore, cations like morpholinium and cholinium have been found to be the least toxic, and can be used to design inherently safe ILs, especially when combined with short polar side chains and nontoxic anions. [26,[85][86][87][88] The oxygenated group in the cation also decreases toxicity as it contributes to hydrophilicity. Mustahil et al [87] reported new antimicrobial surface active ILs with cations named pyrrolidinium, imidazolium, pyridinium, piperidinium, morpholinium, and cholinium, and lauroyl sarcosinate as an anion.…”