Note that our calculations recover the posited slight endothermicity of the neutral phosphorylation reaction, in close agreement with experimental estimates (2.7 kcal/mol computed for α-ribose in the field-free situation here, vs. the experimental value of 5.1 kcal/mol deduced from thermodynamic cycles), providing confidence in the accuracy of the selected level of theory. Overall, our calculations suggest that under standard bulk aqueous conditions, phosphorylation should not occur, in line with experimental observations. In the microdroplet experiments performed by Zare and co-workers, however, H 3 PO 4 is present in millimolar concentrations so that the reaction medium can be expected to be fairly acidic (pH ∼ 3) -and that is even before any pH-altering interface effects are taken into account. Under such reaction conditions, one can expect a non-negligible fraction of the ribose molecules to be protonated at any given time. In its protonated form, ribofuranose should dissociate fairly easily in a carbocation and water. This dissociation will be particularly favored if the carbocation is formed in the 1' position, since a resonance-stabilized oxocarbenium species is generated in this manner.