Synthesis of Azatide Dipeptide Analogs and Their Stability and Reactivity in 98% w/w Sulfuric Acid

Life as we know it depends on peptide and nucleic acid polymers built from a limited set of backbone residues, yet planetary environments beyond Earth motivate consideration of alternative chemical frameworks for genetic- and protein-like polymers. In this context, we synthesize four azatide dipeptide analogs (Ala^a-Gly^a (1), Gly^a-Ala^a (2), Gly^a-Gly^a (3), and Ala^a-Ala^a (4)) as candidate backbone motifs for non-standard biologically relevant polymers. We then systematically assess their stability and reactivity in 98% w/w sulfuric acid, a solvent relevant to Venusian cloud chemistry. We assess the stability of the azatides via ¹H and ¹³C NMR spectroscopy supported with ELSD-LCMS. We monitor the stability of the compounds over periods from hours to two weeks at room temperature and at elevated temperatures (50-80 °C). All four azatides readily dissolve in 98% w/w D₂SO₄ and are generally stable at room temperature. Gly^a-Ala^a (2) shows no detectable degradation over a two-week incubation in 98% w/w sulfuric acid. The other three azatide analogs display only minor decomposition. ELSD-LCMS measurements qualitatively confirm the NMR results, revealing only minor-to-moderate loss of parent compounds after two weeks at room temperature. At higher temperatures, representative of the lower Venusian cloud deck, the stability of the azatides decreases dramatically. All four compounds undergo significant decomposition at 50 °C and completely degrade within one to two weeks at 80 °C. Our findings indicate that azatides, despite being generally stable in concentrated sulfuric acid at room temperature, lack the thermal stability that might be required to serve as viable backbone motifs for biological polymers in environments spanning the full temperature range of Venusian clouds.