Discovery of a Difluoroglycine Synthesis Method through Quantum Chemical Calculations

Tsuyoshi Mita, Yu Harabuchi and Satoshi Maeda (2020)
Highlighted by Jan Jensen

TOC graphic. © The Authors 2020. Reproduced under the CC-BY-NC-ND 4.0 license.

In this paper the authors use DFT calculations to identify a synthetic route to difluoroglycine. 

They started by applying the single component artificial force induced reaction (SC-AFIR) method to difluoroglycine. In the SC-AFIR artificial forces are introduced between functional groups which forces them to either react or dissociate from one another. 

This yielded 288 equilibrium structures and 309 transition states. The selected NH₃ + :CF₂ + CO₂ for further study because the reaction is 1) predicted to be very exothermic (i.e. high yield), 2) has a low barrier, and 3) NH₃ and CO₂ are readily available.

:CF₂ can be generated by a variety of methods and the authors initially chose Me₃SiCF₃, which generates CF₃^-, which in turn dissociates to :CF₂ and F^-. They then generated the reaction network for NH₃ + CF₃^- + CO₂ and performed a kinetic analysis, which predicted that "the calculated yield of difluoroglycine is almost zero because the equilibrium between CF₃^- and CF₃ + F^- favours the former. As a result, CF₃CO₂^-, in which CF₃^- is directly bound to CO₂, was obtained as the main product (99.8%)."

A similar analysis was performed for NH₃ + CF₂Br^- + CO₂, which predicted a higher yield for difluoroglycine, but also a minor by-product NH₂CO₂CHF₂ due to proton transfer from NH₃ to :CF₂. Thus, to increase the yield, the authors repeated the analysis for NMe₃ + CF₂Br^- + CO₂, which predicted a >99% yield.

Finally, the predicted synthetic route was tested experimentally and the reaction conditions (such as solvent, temperature, and silane activator) optimised resulting in a 96% yield. However, it was only possible to purify the ester.

This is the first study I have seen where a synthetic route (of an admittedly very simple molecule) is predicted from DFT calculations. Hopefully the first of many. However, as the authors note "It is  undeniable that  the  experience  and  intuition of  chemists,  or even luck, contributed to appropriate choices being made."

The calculations were performed with the GRRM17 program. It appears to be free, but I don't believe it is open source.

This work is licensed under a Creative Commons Attribution 4.0 International License.