Theoretical Study of Structural and Thermodynamic Properties for Ibuprofen Synthesis Mechanism

Ibuprofen ((R,S)-2-(4- (2-methylpropyl) phenyl) propanoic acid), a non-steroid derived from 2-arylpropionic acid, is one of the most widely used (in its racemic form) in the treatment of fever, pain, and inflammation. Initially its synthesis, patented by Boots Pure Drug Company(known by BOOTS route), involved several steps, substantial formation of inorganic salts and low atomic efficiency. Subsequently, an alternative route was developed, by partnership between Boots and Hoechst Celanese (The BHC route). This route is characterized by three steps only, having a high atom economy and a low-waste production. The objective of this study was to evaluate the ibuprofen synthesis considering both routes. The mechanism was studied from the energetic point of view, in addition, the chirality of ibuprofen was analysed using of chiroptic methods. Thermodynamic properties were calculated using G4MP2 method. The energy profile of the BHC route (ΔG = -17,36 kcal/mol) was described by few steps in comparison with the BOOTS route. Timedependent density functional theory (TDDFT) was employed for theoretical calculations of electronic circular dichroism (ECD). The chiral properties of the enantiomers were evaluated at the CAMB3LYP/GTLargeXP level of theory and quantitative agreement between the theoretical prediction and experiment was observed. All calculations were carried out with the GAUSSIAN 09 program.