Addressing the Miller Paradox and the Prebiotic Synthesis of Nucleobases

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In origins of life research, there is a general consensus that the prebiotic syntheses of nucleobases and sugars in the same location are problematic because reactions containing both hydrogen cyanide and formaldehyde react to produce glycolonitrile and inhibit the syntheses of nucleobases and sugars (referred to as the Miller Paradox). Here, we used a direct analysis in a real-time ionization source coupled to a high-resolution orbitrap mass spectrometer to rapidly analyze products from a set of aqueous reactions containing various concentrations and ratios of ammonium cyanide and formaldehyde. We observed that several nucleobases and nucleobase analogs were synthesized in ammonium cyanide reactions in the presence of formaldehyde, which suggests that the Miller Paradox may not be as detrimental for nucleobase (and nucleobase analogue) synthesis as previously thought.