Quantum chemical exploration of the mechanism of Robinson-Gabriel reaction

One of the important methods of generating oxazoles is the Robinson-Gabriel reaction. Quantum chemical density functional methods have been used in this work to investigate the mechanism of the reaction. The barrier for the cyclization step of the reaction has been estimated to be 31.4 kcal/mol for oxazole in the absence of any catalyst. The transition state involves participation of explicit water molecule. The same reaction under hemiaminal condition requires marginally less barrier 28.2 kcal/mol. In the acidic medium (with water participa-tion), the barrier is significantly reduced to 9.5 kcal/mol when the protonation happens at the amide center. Protonation at keto carbon is less favorable but such a condition helps the cyclisation in a barrier less process. Additionally, it was also found that the water molecules play an essential role during the reaction, even in the acidic condition.