Prebiotic thiol-catalyzed thioamide bond formation

Abstract

Thioamide bonds are important intermediates in prebiotic chemistry. In cyanosulfidic prebiotic chemistry, they serve as crucial intermediates in the pathways that lead to the formation of many important biomolecules (e.g., amino acids). They can also serve as purine and pyrimidine precursors, the two classes of heterocycle employed in genetic molecules. Despite their importance, the formation of thioamide bonds from nitriles under prebiotic conditions has required large excesses of sulfide or compounds with unknown prebiotic sources. Here, we describe the thiol-catalyzed formation of thioamide bonds from nitriles. We show that the formation of the simplest of these compounds, thioformamide, forms readily in spark-discharge experiments from hydrogen cyanide, sulfide, and a methanethiol catalyst, suggesting potential accumulation on early Earth. Lastly, we demonstrate that thioformamide has a Gibbs energy of hydrolysis ( $\Delta G_r^{\circ }$ ) comparable to other energy-currencies on early Earth such as pyrophosphate and thioester bonds. Overall, our findings imply that thioamides might have been abundant on early Earth and served a variety of functions during chemical evolution.

Keywords: Hydrogen cyanide; Origin of life; Proto-metabolism; Thioformamide.

Fig. 1

Carbon-13 NMR spectra for reducing spark discharge experiment (${\text{H}}_2-{\text{N}}_2{-}^{13}{\text{CO}}_2$). Spectrum A shows the spark discharge mixture. Spectrum B shows the spark discharge mixture after 48 h of incubation with methanethiol at room temperature. Identifiable carbon compounds are labeled; the omitted region did not contain peaks. Peaks further downfield represent carbon nuclei with a poorer electron density (e.g. carbonyl and nitrile carbons), while those further upfield correspond to carbon nuclei with a greater electron density (e.g. alkyl and alkenyl carbons). The peak corresponding to the carbonyl carbon of thioformamide is highlighted in blue

Fig. 2

Carbon-13 NMR spectra for neutral spark discharge experiment (${\text{N}}_2{-}^{13}{\text{CO}}_2$). Spectrum A shows the spark discharge mixture. Spectrum B shows the spark discharge mixture after 48 h of incubation with methanethiol. Identifiable carbon compounds are labeled; the omitted region did not contain peaks. Peaks further downfield represent carbon nuclei with a poorer electron density (e.g. carbonyl and nitrile carbons), while those further upfield correspond to carbon nuclei with a greater electron density (e.g. alkyl and alkenyl carbons). The peak corresponding to the carbonyl carbon of thioformamide is highlighted in blue

Fig. 3

Carbon-13 NMR spectra for reactions of cyanide and sulfide with methane- and ethanethiol. Spectrum A shows the methanethiol-catalyzed formation of thioformamide at pH 7; spectrum B corresponds to this reaction at pH 11. Spectrum C shows the ethanethiol-catalyzed formation of thioformamide at pH 7; spectrum D shows the reaction at pH 11. The peak corresponding to the carbonyl carbon of thioformamide is highlighted in blue

Fig. 4

Carbon-13 NMR spectrum for the formation of thioformamide from hydrogen cyanide and sodium thiophosphate. The peak observed in these reactions (${\delta }^{13}C$ = 193.6 ppm) is identical to those in the reactions of cyanide, sulfide, with an alkyl thiol catalyst

Fig. 5

Carbon-13 NMR spectrum for the formation of thionicotinamide from 3-cyanopyridine and sulfide with a methanethiol catalyst. Reactions were carried out for 72 h at room temperature. Peaks corresponding to the carbons on the pyridine ring are labeled in both (A and B). Unlabelled peaks in spectrum B correspond to carbons on the 3-cyanopyridine ring. In the presence of the thiol-catalyst, a near complete conversion of 3-cyanopyridine was observed (spectrum A). In the absence of the catalyst, some conversion is still observed, but not to the same extent (spectrum B)

Fig. 6

Proposed mechanism for the formation of thiol-catalyzed thiolysis of nitriles. Two subsequent nucleophilic attacks yield a thiolimine which tautuomerizes to form a thioamide. The reaction is illustrated here with HCN to yield thioformamide as the end product

Fig. 7

Gibbs energy of reaction ($\mathrm{\Delta }{G}_r^{\circ }$) for the hydrolysis of thioformamide to yield either thioformic acid or formamide. Gibbs energy values were computed with B3LYP/6-311++g(3df,3pd)/scrf=(iefpcm,solvent=water)

Fig. 8

Gibbs energy of reaction ($\mathrm{\Delta }{G}_r$) for the hydrolysis of thioformamide to yield formamide. Here, a value of ${10}^{-7}$ M is used as an estimate for the ${\text{H}}_2\text{S}$ concentration on early abiotic Earth under a weakly reducing atmosphere [20]. Steady-state concentrations of formamide are a function of temperature and pH; values here represent a temperature of 50$_{}^{\circ }$C and a pH range of 4 to 10 [19]

Fig. 9

We demonstrate in this work that thioformamide can be formed from HCN and ${\text{H}}_2\text{S}$ with a thiol-catalyst (highlighted in blue). Thioformamide also reacts with the HCN trimer aminomalononitrile to form purine precursors [2]