Functionalization of Aromatic Organic Molecules by Anhydrous Flourides and by Reductive Elimination of Iodine(III)

Solution phase reactivity of nucleophilic fluoride reagents is attenuated by ion-pairing interactions. 1H-19F HOESY competition experiments permit generation of a fluoride ion affinity scale in the weak-binding regime. Direct DFT calculations of ion pair interaction energies as well as calculated cation electrostatic potential maps can be used to predict solution phase ion pairing tendencies for closely related ammonium cations. It was found by studying the decomposition of tetra-substituted ammonium cations by fluoride that: 1) rates of E2 decomposition is faster than the SN2 pathway; 2) aryl substituents destabilize the cations; 3) steric strain tends to promote decomposition. This led us to prepare anhydrous trineopentylmethylammonium fluoride as a fluorinating regent with superior thermal stability. We show that the reagent combination of PhIF2/TBAF* is a convenient and effective dehydrating agent for anhydrous fluoride salts. In conjunction with 19F NMR spectroscopy, this reagent combination can be used as a rapid, convenient, general, and exquisitely sensitive aquametry method. Fluorination via reductive elimination of diaryliodonium salts is investigated. Use of non-polar solvents suppresses disproportionation and leads to significant improvements in total fluorination yields. Fluoride promotes aryl ligand exchange processes of diaryliodonium species, which lowers the apparent regioselectivity of aryl fluoride extrusion from diaryliodonium fluorides under stoichiometric conditions, but this problem disappears at low fluoride ion concentration. A computational study shows that the regioselectivity is determined by transition state stability. We also show that 18F-DOPA can be synthesized in good yield with our improved procedures. Diaryliodine(III) species can also be used to functionalize arenes with a variety of nucleophiles. Aryl azide formation is found to be a robust reaction that is insensitive to change of solvent, and which offers fast access to various azido aromatic compounds. Lastly, we show that an increase in steric demand above the plane of the aromatic ring leads to a high degree of regioselectivity in reductive elimination reactions of Ar2I(III) salts. This effect is sufficiently large to provide stereoelectronic control of unidirectional reductive elimination (SECURE). Adviser: Stephen G. DiMagn