The cofactor riboflavin is biochemically synthesized by a constitutionally intricate process in which two molecules of 6,7-dimethyl-8-ribityllumazine react with each other to form one molecule of the cofactor and one molecule of 5-amino-6-(ribitylamino)uracil. Remarkably, this complex molecular transformation also proceeds non-enzymatically in boiling aqueous solution at pH 7.3. Four different mechanistic pathways for this transformation (nucleophilic catalysis, hydride transfer, hydrogen atom transfer, and a nucleophilic addition mechanism) have now been analyzed by density functional theory [M06-2X/def2-TZVPP/CPCM//M06-2X/6-31+G(d,p)/IEFPCM]. On the basis of these computational results, a so far unpublished nucleophilic addition mechanism is the lowest energy pathway yielding riboflavin. The previously proposed mechanism involving nucleophilic catalysis is higher in energy but is still a viable alternative for an enzyme-catalyzed process assisted by suitably positioned catalytic groups. Pathways involving the transfer of a hydride ion or of a hydrogen atom are predicted to proceed through higher energy transition states and intermediates.
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