Catalytic methods for the synthesis of amides are much sought after. Silica catalysts have shown promise, but yields are generally moderate and the use of toluene, a toxic and regulated solvent, is required. Here, the Hansen Solubility Parameters in Practice (HSPiP) software package has been used along with the Yalkowsky approximation to make predictions about the solubility of a series of aliphatic and aromatic amides in less hazardous solvents. The conventional solvent toluene has been modeled, alongside potential bioderived alternatives, to find a safer and more productive reaction medium for amidation chemistry. The best candidate, 4-methylisopropylbenzene (p-cymene) was then examined experimentally against toluene in a range of silica-catalyzed reactions between carboxylic acids and amines, including both aromatic and aliphatic reactants. The increased temperatures achievable in the higher boiling p-cymene are shown to provide a significant improvement to yields compared to toluene. The low solubility of many of the amides in cold p-cymene proves an aid to separation. In general, higher polarity amides exhibit more favorable yields. In addition, tests run in a continuous flow system demonstrate the potential for further efficiency improvements by the recirculation of reactants.

中文翻译：

---

使用预测性工具优化酰胺化反应，以更安全的生物基替代品替代受管制的溶剂

人们非常追求用于合成酰胺的催化方法。二氧化硅催化剂已显示出希望，但是收率通常是中等的，并且需要使用甲苯（一种有毒且受管制的溶剂）。在这里，已将Hansen实用溶解度参数（HSPiP）软件包与Yalkowsky近似一起使用，以预测一系列脂族和芳族酰胺在危害较小的溶剂中的溶解度。已对常规溶剂甲苯以及潜在的生物衍生替代品进行了建模，以寻找用于酰胺化化学的更安全，生产效率更高的反应介质。最佳候选物4-甲基异丙基苯（p然后在羧酸和胺类（包括芳族和脂族反应物）之间的一系列二氧化硅催化反应中，对甲苯进行了实验研究。与甲苯相比，在高沸点对甲基异丙基苯中可达到的升高的温度显示出产率的显着提高。许多酰胺在冷对甲基异丙基苯中的低溶解度证明有助于分离。通常，较高极性的酰胺显示出更有利的收率。另外，在连续流系统中进行的测试表明，通过反应物的再循环可以进一步提高效率。