Conversion of amino-terephthalonitriles to multi-substituted single benzene fluorophores with utility in bioimaging

• Published in: Organic & biomolecular chemistry 2024-01, Vol.22 (2), p.364-373
• Main Authors: Raghava, Tanya, Chattopadhyay, Anjan, Banerjee, Subhadeep, Sarkar, Nivedita
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Benzene; Charge transfer; Chemical compounds; Emission spectra; Fluorescence; Fluorine; Fluorine - chemistry; Fluorobenzenes; Fluorophores; Lipophilic; Medical imaging; Nucleophiles; Substitutes
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d3ob01761c

Substitution of two fluorine atoms of the tetrafluoroterephthalonitrile (TFTN) ring ( ortho to each other) by amine nucleophiles through S N Ar chemistry is achievable. However, tri- and tetra-substitution towards multi-substituted single benzene fluorophores (SBFs) is harder due to increased electron richness of the TFTN moiety. Tertiary amine donors promote the molecule towards such multi-substitution guided by the steric obstruction to intramolecular charge transfer to the TFTN ring. Contrarily, secondary amine substituents with better lone pair donation to the TFTN ring cannot induce the S N Ar pathway and instead promote hydrolysis of the nitrile groups of the TFTN moiety. Theoretical investigations have helped unearth the reasons for this observed difference in chemical reactivities and also explain the differences in the emission spectra. Finally, the success of the synthetic method towards multi-substitution is showcased through creation of a highly lipophilic SBF bearing an octyl unit and demonstrating its utility in in vitro cellular imaging. Amine substitution of two ortho fluorine atoms of tetrafluoroterephthalonitrile through S N Ar chemistry is easily achievable. But further fluorine substitution is only possible under forcing conditions, yielding valuable fluorophores for bioimaging.