(556e) Nearcritical Water for Facile Deprotection Reactions and Benign Urea Production

Hart, R., Georgia Institute of Technology
Cope, E., Georgia Institute of Technology
Pollet, P., Georgia Institute of Technology, Specialty Separations Center
Liotta, C. L., Georgia Institute of Technology
Eckert, C., Georgia Institute of Technology

Protection and deprotection reactions represent a majority of all reactions performed in the multi-step syntheses of pharmaceuticals and fine chemicals. By using nearcritical water as a solvent and in situ catalyst for carrying out deprotection reactions the processing of pharmaceuticals and fine chemicals becomes simpler and safer for the environment. The model deprotection reaction studied here is the deprotection of tert-butyl carbamates (N-Boc). The Boc protecting group is commonly used to shield amines from unwanted reactions, and the deprotection traditionally employs harsh acids such as HCl, H3PO4, and trifluoroacetic acid. The excess acid must be neutralized, resulting in the formation of salts that must be separated from the reaction mixture. Nearcritical water is capable of dissolving organic compounds and acting as a sufficient acid catalyst for carrying out the deprotection reactions. However, unlike the traditional acids, neutralization is easily achieved by cooling the mixture down to room temperature. Our investigations have also revealed that the deprotection of N-Boc aniline proceeds through multiple pathways, one of which involves the formation of diphenylurea. Presented here is the kinetic study and mechanistic elucidation for the deprotection of N-Boc aniline, allowing for the development of a continuous flow process. Additionally, we discuss the targeted production of diphenylurea by manipulating the phase behavior of the reaction mixture.