Functionalization of pyrimidine and purine into RNA bases in water/ammonia ices via radical substitution reactions†

Pyrimidine and purine represent immediate precursors of the four RNA bases, cytosine, uracil, adenine, and guanine. These can be, in principle, synthesized by replacing hydrogen atoms in given positions in pyrimidine and purine with NH₂ and/or OH substituents with subsequent H atom migrations from OH to the neighboring “bare” N atom in the ring creating the carbonyl moiety. Electronic structure ωB97XD/6-311G(d,p) and G3(MP2,CC) calculations of the potential energy profiles for these functionalization reactions show that they are plausible and involve moderate barriers for the radical addition and H atom elimination steps. The OH-for-H substitution reaction steps are the most facile and have lower barriers on purine (submerged by ∼4 kJ mol⁻¹) than on pyrimidine (10–19 kJ mol⁻¹). The NH₂-for-H substitution reactions are more energetically demanding, with their barriers ranging between 33 and 54 kJ mol⁻¹ and no significant differences have been found between pyrimidine and purine. In the gas phase, the critical reaction step is the H shift from O to the neighboring N in the ring following OH-for-H substitution, with barriers as high as 126–154 kJ mol⁻¹. These barriers can be greatly reduced with the direct involvement of 1–2 protic solvent molecules (e.g., H₂O, methanol, and NH₃) in ices, to only ∼30–50 kJ mol⁻¹, thus making H migrations comparable in terms of the energy demands with the NH₂-for-H substitution reaction steps. Minimal barriers have been found with the participation of two solvent molecules in the H transfer process. The barriers with the involvement of only one solvent molecule are slightly higher than those with the involvement of two molecules and the increase in the number of solvent molecules directly taking part in the reaction to three and four raises the barriers significantly. For the reactions in water ice, the H transfer transition state structures prominently involve transient hydronium (H₃O⁺) and Zündel (H₅O₂⁺) ions in the hydrogen migration process. The presence of implicit solvent taken into account through SCRF calculations does not significantly affect the reaction energetics and barrier heights for radical substitutions but slightly reduces the H shift barriers, where this effect is found to be most pronounced (up to ∼20 kJ mol⁻¹) inside ammonia ice.