Centre for Systems Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4, 9747AG, Groningen, Netherlands.
Chemistry. 2022 Jul 15;28(40):e202201043. doi: 10.1002/chem.202201043. Epub 2022 Jun 1.
Dynamic combinatorial chemistry is a method widely used for generating responsive libraries of compounds, with applications ranging from chemical biology to materials science. It relies on dynamic covalent bonds that are able to form in a reversible manner in mild conditions, and therefore requires the discovery of new types of these bonds in order to progress. Amides, due to their high stability, have been scarcely used in this field and typically require an external catalyst or harsh conditions for exchange. Compounds able to undergo uncatalysed transamidation at room temperature are still rare exceptions. In this work, we describe reversible amide formation and transamidation in a class of compounds known as maleamic acids. Due to the presence of a carboxylic acid in β-position, these compounds are in equilibrium with their anhydride and amine precursors in organic solvents at room temperature. First, we show that this equilibrium is responsive to external stimuli: by alternating the additions of a Brønsted acid and a base, we can switch between amide and anhydride several times without side-reactions. Next, we prove that this equilibrium provides a pathway for reversible transamidation without any added catalyst, leading to thermodynamic distributions of amides at room temperature. Lastly, we use different preparation conditions and concentrations of Brønsted acid to access different library distributions, easily controlling the transition between kinetic and thermodynamic regimes. Our results show that maleamic acids can undergo transamidation in mild conditions in a reversible and tunable way, establishing them as a new addition to the toolbox of dynamic combinatorial chemistry.
动态组合化学是一种广泛用于生成化合物响应库的方法，其应用范围从化学生物学到材料科学。它依赖于能够在温和条件下以可逆方式形成的动态共价键，因此需要发现新型的这些键来取得进展。酰胺由于其高稳定性，在该领域中很少使用，通常需要外部催化剂或苛刻的条件才能进行交换。能够在室温下进行无催化剂的转酰胺化的化合物仍然是罕见的例外。在这项工作中，我们描述了一类称为马来酸酐的化合物中的可逆酰胺形成和转酰胺化。由于β-位存在羧酸，这些化合物在室温下的有机溶剂中与它们的酸酐和胺前体处于平衡状态。首先，我们表明这种平衡对外部刺激有响应：通过交替添加布朗斯台德酸和碱，我们可以在没有副反应的情况下多次在酰胺和酸酐之间切换。接下来，我们证明这种平衡为无需任何外加催化剂的可逆转酰胺化提供了途径，导致室温下酰胺的热力学分布。最后，我们使用不同的制备条件和浓度的布朗斯台德酸来获得不同的文库分布，轻松控制动力学和热力学状态之间的转变。我们的结果表明，马来酸酐可以在温和条件下以可逆和可调的方式进行转酰胺化，为动态组合化学的工具箱增添了一种新的方法。
