Protonation Effects on the Benzoxazine Formation Pathways and Products Distribution

Author(s)

Ribeiro, Francisco W. M. ; Omari, Isaac ; McIndoe, J. Scott ; Correra, Thiago C.

• Document type: Journal article
• Source: ChemPhysChem; v. 25, n. 19, p. 214-pg., 2024-07-30.

Abstract

The effect of acidic media on the formation of the 3,4-dihydro-2H-3-phenyl-1,3-benzoxazine Bz is evaluated, focusing on the differentiation of intermediates and products formed by the distinct pathways observed in the presence and absence of acid. The use of real-time mass spectrometry (PSI-ESI-MS) coupled to tandem mass spectrometry and infrared multiple photon dissociation (IRMPD) allowed the differentiation of the species observed during the synthesis of benzoxazines in these different conditions. The results suggest that formic acid promotes the formation of aniline and phenol condensation products (IC and IIC) by protecting the aniline amino group and enhancing the formaldehyde electrophilicity. The results also suggest that although the presence of acid allow a more efficient potential energy landscape to be accessed, the last cyclization step for the formation of benzoxazines cannot be mediated by the protonation route intermediate (ROP Bz). Overall, the conclusions presented here provide important information about the synthesis of benzoxazines under acidic conditions, allowing the development of optimal reaction conditions. The formation of benzoxazines was evaluated, showing that the addition of acid promotes the condensation of aniline and phenol by enhancing formaldehyde reactivity and protecting the aniline amino group from acting as a nucleophile. Although the addition of acid favors most of the reaction steps, it is suggested that the final cyclization proceeds via a neutral pathway, thus avoiding the formation of the last iminium intermediate. image (AU)

• FAPESP's process: 19/25634-9 - Real-time reaction analysis in complex matrices by advanced mass spectrometry techniques
• Grantee: Thiago Carita Correra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/18485-1 - Mechanistic studies of haloamination reactions promoted by metallic and organic catalysts
• Grantee: Francisco Wanderson Moreira Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/06726-0 - Investigation of reactive intermediates in complex chemical and biochemical processes
• Grantee: Thiago Carita Correra
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 14/15962-5 - Reaction mechanism of asymmetric catalysts by mass spectrometry and gas-phase vibrational ion spectroscopy
• Grantee: Thiago Carita Correra
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 22/00498-8 - Multi-user equipment approved in grant 21/06726-0: ion mobility mass spectrometry system (IMS-MS)
• Grantee: Thiago Carita Correra
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 23/01180-4 - Developments of advanced methods for the evaluation of isomers by mass spectrometry of chemical and biological systems.
• Grantee: Francisco Wanderson Moreira Ribeiro
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 15/08539-1 - Multi-User Equipment approved in grant 2014/15962-5: ion trap mass spectrometer modified to perform infrared vibrational spectroscopy (IRMPD)
• Grantee: Thiago Carita Correra
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 19/16026-5 - Cyclization reactions promoted by Pd/Cu Catalysts
• Grantee: Francisco Wanderson Moreira Ribeiro
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate