Radical Carbonylation with [¹¹C]Carbon Monoxide Promoted by Oxygen-Centered Radicals:  Experimental and DFT Studies of the Mechanism

Abstract

Photoinitiated carbonylation of alkyl iodides with [11C]carbon monoxide (11C t1/2=20.4 min) is enhanced by ketones that have lowest-lying excited triplet state of npi* character. For example, adding 5 mol % of acetophenone increases radiochemical yields from 3 to 59% in brief 6-min long reactions. Similar or higher yields were achieved by adding di-tert-butyl peroxide. Since radicaloid npi* exited-state ketones and tert-butoxyl radicals have similar reactivity, the photosensitization proceeds most likely via a H-atom transfer mechanism rather than via energy transfer. We propose a mechanism that can account for the enhancement as well as for the formation of observed byproducts. The energy profile obtained by DFT calculations support the feasibility of the mechanism, and observed experimental differences in reactivity could be well rationalized by the calculated data. NBO calculations were performed to further analyze the obtained energetics. Various [carbonyl-11C]esters and some [carbonyl-11C]amides were synthesized in good radiochemical yields from primary and secondary alkyl iodides illustrating the utility of dialkyl peroxides to accelerate the carbonylations. These findings have potential in elaborating new synthetic protocols for the production of 11C-labeled tracers for positron emission tomography.

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…157–159 Detailed mechanistic studies suggest key roles for solvent in initiating radical sequences and facilitating formation of acyl iodide intermediates. Despite the apparently limited functional group tolerance, this method represents a novel and appealing approach for 11 C-carbonyl labeling.…”

A Simple, Rapid Method for the Preparation of [11C]Formaldehyde

“…Consequently, there exists a need for new reaction development to focus on methods to incorporate [ 11 C] in skeletal positions of target molecules and several research groups have developed or adapted synthetic methods for [ 11 C]-incorporation into benzene rings, carbocycles, and heterocycles as well as non-pendant locations. [3] By using carefully designed organic reactions, each of these has expanded the types of radiotracers that can be accessed.…”

C-11 Radiochemistry in Cancer Imaging Applications

“…The [ 11 C]CO, alkyl iodide or alkyl/aromatic amine and suitable solvent were trapped in the high-pressure reactor and irradiated by the mercury lamp at the optimized wavelength and photoirradiation intensity to afford the target [ 11 C-carbonyl] amides with 50 -70% radiochemical yields (decay-corrected) and 65 -90% [ 11 C] CO conversion rate in a reaction time of 5 -7 minutes [204]. The same strategy was also used to make [ 11 C-carbonyl] esters, ketones, and carboxylic acids [218][219][220][221][222]. Although there have been no published reports of the synthesis of carbon-11 radiotracers for imaging cancer using this technique, the reported rapid synthesis times and high specific activities suggest that it will be a valuable approach in the future to the Carbon-11 labeling of target structures which are not compatible with Grignard synthesis.…”