In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too “small” to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole–methanol and indole–water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole–methanol–water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.

中文翻译：

---

答复“关于“关于吲哚周围水和甲醇的位置和取向顺序：对溶解度的微观起源的研究”的评论。化学 化学 物理 ，2018，20，DOI：10.1039 / C7CP03698A”

G. Graziano在对我们最近发表的出版物的评论中声称，吲哚在甲醇和水中的溶解度差异可以通过在溶质大小的溶剂（在本例中为吲哚）中形成空腔所需的可逆工作来合理化。他认为，该数量与溶剂可及的表面积密切相关，与水相比，甲醇的表面积更大，因此使吲哚更易溶于前一种溶剂。G. Graziano断言，正是这种性质造成了吲哚在甲醇和水中的溶解度之间的巨大差异。此外，G。Graziano认为，在我们最初的工作中发现的甲醇和水中以及作为助溶剂的甲醇和水中吲哚的过量熵和距离分布函数的差异（Henao等，物理 化学 化学 物理 ，2016年，18，23006）太“小”，不足以说明吲哚分子的溶解度差异。通过以与原始论文所述不同的方式显示一些选定的距离分布函数，我们在这项工作中证明我们发现的差异并不小。实际上，我们得出的结论是，这些功能的差异在数量上要大于Graziano在其评论中发现的差异。其次，我们在该答复中表明，尽管溶剂可及表面积的增加可能使吲哚-甲醇和吲哚-水二元体系之间的差异合理化，因此可以合理地创造型腔，但仍不足以完全解决通过在三元体系吲哚-甲醇-水中添加极少量的甲醇来增加吲哚在水中的溶解度。换句话说，正如我们在原始论文中所述，甲醇正在积极改变溶剂化壳层，而不仅仅是被动地增加吲哚周围溶剂可及的表面积。这些额外分析的结果是，我们得出的结论是，我们对水和甲醇中吲哚的溶剂化差异的研究成功地捕获了二元和三元系统中吲哚周围两种溶剂的溶剂化壳层的差异。最后，虽然我们确实同意Graziano的计算能够抓住空腔产生的作用来解释溶解度的差异，但我们认为关于分子相互作用变化定量的结果应添加到他建议的计算中，从而得出溶解度的完整描述。甲醇正在积极改变溶剂化壳层，而不仅仅是被动地增加吲哚周围溶剂可及的表面积。这些额外分析的结果是，我们得出的结论是，我们对水和甲醇中吲哚的溶剂化差异的研究成功地捕获了二元和三元系统中吲哚周围两种溶剂的溶剂化壳层的差异。最后，虽然我们确实同意Graziano的计算能够抓住空腔产生的作用来解释溶解度的差异，但我们认为关于分子相互作用变化定量的结果应添加到他建议的计算中，从而得出溶解度的完整描述。甲醇正在积极改变溶剂化壳层，而不仅仅是被动地增加吲哚周围溶剂可及的表面积。这些额外分析的结果是，我们得出的结论是，我们对水和甲醇中吲哚的溶剂化差异的研究成功地捕获了二元和三元系统中吲哚周围两种溶剂的溶剂化壳层的差异。最后，虽然我们确实同意Graziano的计算能够抓住空腔产生的作用来解释溶解度的差异，但我们认为关于分子相互作用变化定量的结果应添加到他建议的计算中，从而得出溶解度的完整描述。我们得出的结论是，我们对水和甲醇中吲哚的溶剂化差异的研究成功地捕获了二元和三元系统中吲哚周围两种溶剂的溶剂化壳层的差异。最后，虽然我们确实同意Graziano的计算能够抓住空腔产生的作用来解释溶解度的差异，但我们认为关于分子相互作用变化定量的结果应添加到他建议的计算中，从而得出溶解度的完整描述。我们得出的结论是，我们对水和甲醇中吲哚的溶剂化差异的研究成功地捕获了二元和三元系统中吲哚周围两种溶剂的溶剂化壳层的差异。最后，虽然我们确实同意Graziano的计算能够抓住空腔产生的作用来解释溶解度的差异，但我们认为关于分子相互作用变化定量的结果应添加到他建议的计算中，从而得出溶解度的完整描述。