The paper by Liberatore et al. is an interesting study showing the instability of GenX, a perfluorooctanoic acid alternative, in aprotic polar solvents such as acetonitrile, acetone, and dimethyl sulfoxide.(1) The authors discussed the reasons for the instability and possible chemical processes, but we would like to raise some further points. The authors proposed that proton dissociation, autodecarboxylation, and solvent-mediated proton transfer lead to the decomposition of GenX in aprotic solvents. However, proton dissociation can also occur in protic solvents (e.g., methanol and water) and GenX (pK_a = 2.84), which is a strong acid like other per- and polyfluoroalkyl substances, appears to be mostly dissociated in aqueous solutions.(2) Furthermore, hydronium ions formed from water in the presence of protons can transfer protons to other molecules (Figure 1A). Thus, these processes do not appear to be important because GenX showed almost no decomposition in aqueous solutions. Figure 1. Schemes of the (A) proposed water-mediated proton transfer in a GenX aqueous solution, (B) general reaction of the carbocation of carbonyl compounds with nucleophiles under acid catalysis, and (C) direct addition of nucleophiles to carbonyl compounds. Taking acetone as an example, we find it is reasonable to assume that the oxygen atom in the carbonyl group is first protonated by an acid catalyst under acidic conditions (Figure 1B). However, solvent-mediated proton transfer occurs and a resonance-stabilized carbocation is generated. As a result, the Lewis acidity of the carbonyl compound may be increased, allowing a nucleophile to attack the carbonyl carbon. Although the carbanion produced by GenX decarboxylation is relatively stable, it is considered a potent nucleophile. This carbanion may react with the carbocation of protonated acetone. In addition, even if the formation of a carbocation is rare under these conditions, if the carbanion produced from GenX causes an attack on the carbonyl carbon of acetone, then an addition reaction can occur (Figure 1C). This occurs because even if GenX causes the transfer of a proton to acetone, the amount of protonated acetone is very small compared with the total amount of acetone as a solvent. In fact, the trichloromethyl anion produced by the decarboxylation of trichloroacetate salt is used as a nucleophile in chemical reactions.(3) However, in the authors’ experiments, only Fluoroether E-1 was produced, at almost 100%, even when acetone was used, and no products of an addition reaction were observed in acetone. Therefore, it seems difficult to reconcile the proposed mechanism from the observations of the authors. Future studies, including molecular dynamics simulations to study the decarboxylation mechanism, will be required.(4) The authors declare no competing financial interest. The authors declare no competing financial interest.
This correspondence is a part of a research project funded by the Japan Society for the Promotion of Science (20H03930). This article references 4 other publications.

中文翻译：

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评论“毒理学研究中HFPO-DA（“ GenX”母体酸）的溶剂适用性”

Liberatore等人的论文。是一项有趣的研究，显示了全氟辛酸替代品GenX在非质子传递极性溶剂（如乙腈，丙酮和二甲基亚砜）中的不稳定性。（1）作者讨论了这种不稳定性的原因和可能的化学过程，但我们希望提出一些进一步的观点。作者提出质子解离，自脱羧和溶剂介导的质子转移导致GenX在质子惰性溶剂中分解。但是，质子解离也可能发生在质子溶剂（例如甲醇和水）和GenX中（p K _a= 2.84），它是一种强酸，像其他的全氟烷基和多氟烷基物质一样，似乎在水溶液中大部分会解离。（2）此外，在质子存在下由水形成的水合氢离子可以将质子转移到其他分子上（图1A） ）。因此，这些过程似乎并不重要，因为GenX在水溶液中几乎没有分解。图1.（A）在GenX水溶液中水介导的质子转移的方案，（B）羰基化合物的碳阳离子与亲核试剂在酸催化下的一般反应，以及（C）亲核试剂直接添加到羰基化合物中的方案。以丙酮为例，我们发现可以合理地假设羰基中的氧原子首先在酸性条件下被酸性催化剂质子化（图1B）。然而，发生溶剂介导的质子转移，并产生共振稳定的碳正离子。结果，可以增加羰基化合物的路易斯酸度，从而允许亲核试剂攻击羰基碳。尽管通过GenX脱羧产生的碳负离子是相对稳定的，但它被认为是有效的亲核试剂。该碳负离子可能与质子化丙酮的碳正离子反应。此外，即使在这些条件下很少形成碳正离子，但如果GenX产生的碳负离子对丙酮的羰基碳造成侵蚀，则可能会发生加成反应（图1C）。发生这种情况的原因是，即使GenX导致质子转移到丙酮上，与作为溶剂的丙酮总量相比，质子化丙酮的量也非常小。实际上，通过三氯乙酸盐的脱羧反应生成的三氯甲基阴离子被用作化学反应中的亲核试剂。（3）然而，在作者的实验中，即使使用丙酮，也仅生成了几乎100％的氟醚E-1，并且在丙酮中未观察到加成反应的产物。因此，似乎很难从作者的观点中调和所提出的机制。需要进行进一步的研究，包括研究脱羧机理的分子动力学模拟。（4）作者宣称没有竞争性的财务利益。作者宣称没有竞争性的经济利益。在丙酮中未观察到加成反应的产物。因此，似乎很难从作者的观点中调和所提出的机制。需要进行进一步的研究，包括研究脱羧机理的分子动力学模拟。（4）作者宣称没有竞争性的财务利益。作者宣称没有竞争性的经济利益。在丙酮中未观察到加成反应的产物。因此，似乎很难从作者的观点中调和所提出的机制。需要进行进一步的研究，包括研究脱羧机理的分子动力学模拟。（4）作者宣称没有竞争性的财务利益。作者宣称没有竞争性的经济利益。
该信件是由日本科学促进会（20H03930）资助的研究项目的一部分。本文引用了其他4个出版物。