Direct Synthesis of Amides from Amines and Carboxylic Acids under Hydrothermal Conditions

Hydrothermal systems provide a unique habitat for the subsurface biosphere, and possibly, for the origin of life. Amides are fundamental to hydrothermal organic geochemistry and deep subsurface biology research, in large part because of their involvement in metabolism, such as in the forms of peptides and proteins, and also because of their participation in the deep nitrogen cycle and their potential role in the origin of life. Hydrothermal chemistry of amides is also of great interest to astrobiology research because it may reveal potential formation pathways of peptides and biomolecules in the space outside Earth. Here, we describe a nonmineral-catalyzed synthetic pathway for amide synthesis under hydrothermal conditions (250 °C and 40 bar, Psat). We find that a suite of amides (12 examples) are readily synthesized through a direct condensation between amines and carboxylic acids, with an amide yield of up to 90% over a timescale of hours. Time-series hydrothermal experiments were performed to obtain apparent rate constants for amide synthesis. The observed hydrothermal rate constants were significantly larger for certain amines (e.g., 0.2 h–1 for benzylamine) than for others (e.g., 0.05 h–1 for cyclohexylamine), which suggests a strong substitution effect on amide formation. An amine acylation mechanism is proposed, and also consistent with previous studies. Furthermore, amide formation is found to be strongly inhibited in high or low pH solutions (e.g., pH <2 or >12), which further supports that the condensation reaction should occur between the neutral amine and acid. Our finding of a feasible and selective hydrothermal pathway for amide bond formation may provide new insights into understanding peptides and biomolecule synthesis in relevant hydrothermal environments.