Highly stereoselective decarboxylation of (+)-1-Bromo-1-chloro-2,2,2-trifluoropropanoic acid gives (+)-1-Bromo-1-chloro-2,2,2-trifluoroethane ((+)-Halothane) with retention of configuration

The absolute configuration of the title acid (2) has been determined to be S by X-ray crystallography. Thus, decarboxylation of 2 produces (S)-(+)-halothane with 99% retention of configuration. This behavior is compared to other stereoselective decarboxylation reactions of ?-haloacids from the literature that also give high degrees of retention of configuration when in the form of their quaternary ammonium salts, which contain one proton. The proton of the ammonium salt is necessary to protonate the anionic intermediate formed from decarboxylation. In the absence of this relatively acidic proton, we had previously found that using triethylene glycol (TEG) as both solvent and proton source for the decarboxylation reaction of acid 2 caused poor stereoselectivity. This was in contrast to 1,2,2,2-tetrafluoro-1-methoxypropionic acid (6), which showed a high degree of retention of configuration in TEG. To rationalize this differing behavior we report DFT studies at PCM-B3LYP/6-31++G** level of theory (the results were additionally confirmed with 6-311++G** and aug-cc-pVDZ basis sets). The energy barrier to inversion of configuration of the anionic reaction intermediate of acid 2 (11) is 10.23 kcal/mol. However, we find that the anionic intermediate from acid 6 (10) would rather undergo ?-elimination instead of inversion of configuration. Thus the planar transition state required for inversion of configuration is never reached, regardless of the rate of proton transfer to the anion.本研究通过X射线晶体衍射（X-ray crystallography）确定了标题酸（2）的绝对构型为S型。因此，对酸2进行脱羧反应可得到（S）-（+）-氟烷（halothane），构型保留率达99%。该反应行为可与文献报道的其他α-卤代羧酸的立体选择性脱羧反应进行对比：当这类羧酸以带有单个质子的季铵盐形式存在时，同样可实现高程度的构型保留。季铵盐上的质子可用于质子化脱羧过程中生成的阴离子中间体，该质子为反应必需组分。此前我们发现，若缺乏该相对酸性的质子，以三甘醇（triethylene glycol, TEG）同时作为溶剂与质子源开展酸2的脱羧反应，会导致立体选择性较差。这与1,2,2,2-四氟-1-甲氧基丙酸（6）的反应行为形成显著差异：该化合物在三甘醇中反应时仍可实现高程度的构型保留。为合理阐释这一反应行为差异，我们开展了基于极化连续介质模型-贝克三参数李杨帕尔泛函/6-31++G**（PCM-B3LYP/6-31++G**）理论水平的密度泛函理论（DFT）研究，研究结果进一步通过6-311++G**与aug-cc-pVDZ基组得到验证。酸2的阴离子反应中间体（11）发生构型翻转的能垒为10.23 kcal/mol。但我们发现，酸6的阴离子中间体（10）更倾向于发生β-消除反应，而非构型翻转。因此，无论质子向阴离子转移的速率如何，构型翻转所需的平面过渡态均无法形成。