Controlling Reductive Elimination from Novel I(III) Salts Using a SECURE Method

Authors

• Joseph W. Graskemper, University of Nebraska-LincolnFollow

First Advisor

Stephen G. DiMagno

Date of this Version

8-2010

Document Type

Thesis

Citation

A thesis presented to the faculty of the Graduate College in the University of Nebraska in partial fulfillment of requirements for the degree of Master of Science

Major: Chemistry

Under the supervision of Professor Stephen G. DiMagno

Lincoln, Nebraska, August 2010

Comments

Copyright 2010, Joseph W. Graskemper. Used by permission

Abstract

Positron Emission Tomography (PET) is a valuable clinical, research, and diagnostic technique for human and animal organ imaging. The current market for PET in the United States is $500 million per year and is projected to be $5.4 billion per year globally by 2015. To synthesize labeled radiotracers, we are most interested in using ¹⁸F as the isotope of choice because it is a nearly ideal positron emitting radionuclide.

Electron-rich aromatic substrates can be particularly difficult to fluorinate. We show that reductive elimination of I(III) diaryliodonium salts provide increased fluorination of electron-rich aromatic substrates. Modest yields of fluorinated product were initially observed due to the lack of regioselectivity in the reductive elimination process. It seemed clear that a better directing group would be needed if extremely electron-rich rings are to be fluorinated in high chemical (or radiochemical) yields using diaryliodonium salts. The use of [2.2]paracyclophane as a directing ligand has been shown by computational and experimental data to provide an increase in steric demand above the plane of the aromatic ring; therefore, destabilizing a reductive elimination transition state. This effect is sufficiently large to provide stereoelectronic control of unidirectional reductive elimination (SECURE) for most nucleophiles; however, benzyne chemistry was observed when fluorine and 2,2,2-trifluoroethoxide were used as nucleophiles.

To address the benzyne issue, we have shown that the choice of a judiciously substituted cyclophane substituent on I(III) can provide perfect regioselectivity for reductive elimination of iodocyclophanes and fluorination of electron-rich arenes. This work constitutes the first example of regiospecific fluorination of electron-rich aromatic rings using diaryliodonium fluorides. We believe this discovery paves the way for the synthesis of highly elaborated radiotracers from Ar₂IF salts.

Advisor: Stephen G. DiMagno