58th Annual Report on Research 2013 Under Sponsorship of the ACS Petroleum Research Fund

In the last year, PRF DNI-supported research has focused on the conversion of alcohols closely related derivatives into trifluoromethyl groups. This method allows for the preparation of new fluorinated compounds from alcohol-based petroleum reformats without resorting to the traditional four-step reaction sequences. Fluorinated functional groups, including the trifluoromethyl group (CF₃), serve important roles in medicinal, agrochemical and materials chemistry by perturbing the (bio)physical properties of the parent molecule to which the CF₃ group is attached. Thus, the development of new chemicals methods to install fluorinated functional groups is critical for accessing new therapeutics and biological probes to improve human health, new agrochemical agents, and new materials to improve the quality of living. The synthesis of trifluoromethyl-containing compounds is underdeveloped, and limits the ability of a chemist to access target compounds. Since 2008, many creative and useful metal-catalyzed trifluoromethylation reactions have been developed. However, many simple and desired transformations have not been achieved. One such gap in knowledge involves the conversion of readily available alcohols into trifluoromethyl groups, which typically requires a four-step reaction sequence that consumes a chemist's time, and which generate extensive quantities of organic waste. To overcome these limitations, the work supported by the PRF DNI award has involved the development of one- and two-step strategies for converting alcohols to trifluoromethyl-based analogs.

Cu-Mediated Trifluoromethylation of Benzylic Xanthates

The trifluoromethylation of benzylic alcohols (1) was accomplished in a two-step sequence involving conversion of the alcohols to xanthates (2) followed by trifluoromethylation using a reagent system based on Cu⁰ 4. The reaction transformed a wide variety of benzylic xanthates with many useful and common functional groups, including halides, alkyl, aryl and silyl ethers, esters, –NO₂, –CF₃, and –CN, as well as N- and S-based heterocycles (27 examples). The method is limited to substrates that do not possess conjugated electron donating groups at the 4-position, and that are not sterically hindered at the R¹position.

Mechanistic studies indicate that the reaction likely involves a radical-cationic intermediate. Stoichiometric reactions of proposed intermediates, suggest that the reaction of Cu⁰ with 4 generates CuOTf and CuCF₃, and that both Cu-based species are required for the transformation. The establishment of a linear free energy relationship confirmed the buildup of cationic charge at the transition state for trifluoromethylation, and inhibition of the reaction by several radical scavengers confirmed the existence of a radical-based mechanism. Combined, these data suggest that the reaction proceeds viaa radical cationic intermediate.

Several factors encourage the development of a 2^nd generation system that overcomes limitations of the previously described method. First, the cost and atom economy of 4, the use of superstoichiometric Cu⁰, and the high molecular weight of the xanthate leaving group are not ideal in terms of cost for the process, as well as the waste stream generated by the reaction. Second, a more general method is desired that can successfully convert substrates that bear conjugated electron donating groups at the 4-position, and that can convert substrates with sterically hindered at the R¹ position. To overcome the aforementioned limitation, the group is actively pursuing the development of a catalytic variant of the proposed transformation that would employ only stoichiometric quantities of inexpensive and atom-economical trifluoromethylation reagents. Results of these ongoing studies should be published in the next project period.

Impact of PRF DNI Award

The PRF DNI award has positively affected Dr. Altman's career, as well as multiple group members involved in the project. Generally, this award has provided postdoctoral and volunteer research assistants with pportunities to conduct research in the general area of synthetic organometallic fluorine chemistry. Specifically, the researchers were intimately involved in developing the chemical method, conducting synthetic chemistry to prepare substrates and mechanistic probe molecules, and conducting mechanistic studies of the transformation. Most notably, the researchers were challenged to think critically to solve chemical problem involving activation of 5, and to probe the mechanistic underpinnings of the transformation. The support provided by the PRF award has positively impacted the research group by providing an opportunity to pursue exciting, basic research in the area of organofluorine chemistry. The results described in this report provide a solid foundation for ongoing and future work in the group. The findings that have been uncovered through support of the PRF program will continue to drive an exciting area of research in Dr. Altman's group for years to come, which should provide valuable synthetic tools for accessing new fluorinated analogs of compounds directly from petroleum reformats.