Sunday, September 8, 2019

DAST: The First Deoxyfluorination Reagent


Reported by a chemist at Dupont in 1975, DAST (Dietylaminosulfur trifluoride) became a stable to gaseous SF4 (Wen-Li Hua, Xiang-Go Hu, & Hunter, 2017) . This gaseous reagent, SF4, is extremely toxic and corrosive. Hence, DAST appeared as an alternative in liquid form. The excellence of DAST than SF4, DAST is easier to be handled as it doesn't require much higher temperatures.

Nevertheless, it was soon found that DAST also has some weaknesses. If it undergoes heating, it can decompose and produce SF4 as we already knew that this substance is toxic and corrosive. If it undergoes further heating, it can explode into undefined gases and black char (Heureux, et al., 2010). 

Then, Deoxofluor was developed. From differential scanning calorimetry (DSC), Deoxofluor has the same decomposition temperature with DAST, yet it degrades slower so it is considered safe.

Do you know? Soon after DAST and Deoxofluor conducted in larger scale, it is found to be unsafe. The preparation process was problematic. First, the purification of the crude using vacuum distillation is dangerous as they are explosive. Secondly, after the manufacturing, the shipping regulation is very strict. Thirdly, these reagent is also not stable in color. Fourthly, during the use, both may generate free HF which is very volatile, highly toxic, extremely corrosive to the skin and other tissues including bones (Heureux, et al., 2010).

Nonetheless,  DAST remains the most popular deoxyfluorination reagent because of its availability and general scope (Nielsen, Ugaz, Li & Doyle, 2015). Deoxyfluorination is a reaction of introducing fluorine atom into a molecule through the substitution of alcohol functional group. The reaction with DAST proceeds with inversion. It goes with SN2 reaction as the alcohol functional group is a poor leaving group, the alcohol then is converted into weaker base by being attached with the electrophilic sulfur atom. Then, the nucleophile, the fluorine atom with negative charge, attacks from the backside of the carbon atom which is the electrophile. It attacks from the backside since the leaving group which is attached with the electrophile blocks the approach of the nucleophile from the frontside. That's why it simply goes with inversion through SN2 reaction.


In deoxyfluorination, DAST also has limitation. It may produce side products. If the substrate has double bond, it may undergo elimination. And if the substrate has carbonyl group, it may be difluorinated. Therefore, several new reagents has been developed to improve the selectivity.  


Reference:
Heureux, A. L., Beaulieu, F., Bennett, C., Bill, D. R., Clayton, S., Mirmehrabi, M., … Couturier, M. (2010). Aminodifluorosulfinium Salts : Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling †,‡, 3401–3411. https://doi.org/10.1021/jo100504x
Nielsen, M. K., Ugaz, C. R., Li, W., & Doyle, A. G. (2015). PyFluor: A Low-Cost, Stable, and Selective Deoxy fl uorination Reagent, 9571–9574. https://doi.org/10.1021/jacs.5b06307
Wen-Li Hua, Xiang-Guo Hu, L. H. (2017). Recent Developments in the Deoxyfluorination of Alcohols and Phenols : New Reagents , Mechanistic Insights , and Applications, 4917–4930. https://doi.org/10.1055/s-0036-1590881

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