Wednesday, January 29, 2020

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.