Kinetics and Mechanism of Allantoin Racemization

The kinetics and mechanism of racemization of allantoin have been examined; racemization proceeds via two independent pathways that can be separately monitored. One pathway involves proton exchange at C5 with solvent. The other pathway occurs via intramolecular attack of N8 on C4 to form a symmetrical bicyclic intermediate, which can decompose to form either enantiomer of allantoin. The intramolecular pathway proceeds more rapidly from the allantoin anion than from neutral allantoin. This result is explained by conformational analyses based on experimental NMR data and computational results, which suggest that the ureido arm of anionic allantoin adopts a cis-conformation, allowing intramolecular attack. Neutral allantoin adopts a trans-conformation. The proton exchange pathway is buffer-catalyzed and also proceeds more rapidly at basic pH, although it is suggested that the reaction occurs from neutral allantoin. The relatively slow rate of racemization, particlarly at physiological pH, suggests that nonenzymatic racemization of allantoin is not a viable mechanism for the in vivo generation of (S)-allantoin.