Nucleophilic aromatic substitution on electron-rich aniline derivatives via transient polarity inversion with N-centered radical (cationic) substituents

• Applicant: Dr. Jan Seliger
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2023 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527488163

The goal of this research project is the development of a robust protocol for the nucleophilic aromatic substitution on aniline derivatives. These electron-rich substrates are unreactive towards nucleophiles under conventional conditions. To unlock this reactivity, transient polarity inversion on the arene substrate with reversibly generated nitrogen-centered radicals and radical cations is proposed as the key strategy. Preliminary DFT calculations predict substantially reduced activation energies (delta delta epsilon * = -17 to -40 kcal/mol) for nucleophilic aromatic substitutions on anilino, carbox-, and sulfonanilidyl radicals, as well as anilinium, N-phenyliminium, and carbazolium radical cations with a chloronucleofuge in the para-position and benzoate as the model nucleophile. The nitrogen-centered radicals may be generated by reversible (formal) homolysis of the N-H bonds present in corresponding precursors by MS-PCET or HAT, and the nitrogen-centered radical cations are accessible by single-electron oxidation of closed-shell parent compounds. To this end, both photoredox catalysis and chemical oxidants are considered, and a systematic screening of various reaction parameters will be carried out to identify suitable conditions. If successful, the scope of the reaction will be investigated with respect to substitution patterns and functional groups tolerated on the arene, as well as applicable nucleofuges and nucleophiles, with particular emphasis on complex and biologically active compounds. The targeted transformation represents a promising new synthetic strategy that could be used in the preparation of natural products and pharmaceutical agents. In addition, valuable insights are expected into how the reactivity of nitrogen-centered radicals and radical cations can be tamed for use in unconventional ways. Based on this, the future development of further methodologies is conceivable.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Robert Knowles, Ph.D.