BFU chemists identified necessary conditions for successful synthesis of small molecules
The development of the so-called small molecules is a promising field of the pharmaceutical industry. Small molecules are organic compounds with a small molecular mass. They are often based on heterocycles–carbon rings that also include atoms of nitrogen and other elements. The synthesis of small molecules is much cheaper than the development of drugs based on antibodies or other biological molecules; however, their properties are still understudied. Even the slightest modifications can change the characteristics of a small molecule and open a whole new range of its practical applications. Therefore, many research teams working in the field of chemical pharmacology improve synthesis methods to create libraries of small molecules and evaluate their biological properties. In the future, this data can be used to develop new drugs.
A team of chemists from Immanuel Kant Baltic Federal University and Saint Petersburg State University have been focusing on the synthesis of new small molecules for a long time. For example, several years ago the researchers successfully developed a method of hydrated imidazoline ring expansion (HIRE). Hydrated imidazolines are based on an imidazole heterocycle (with two nitrogen and three carbon atoms) with three more rings of different composition attached to it. The reaction created by the chemists provided for the formation of bonds with at least three bigger heterocycles, thus leading to the expansion of the initial imidazole ring. However, further studies showed that sometimes the same reaction can cause one of the tetracyclic imidazoline rings to break. In this case, the reaction product (an ethylenediamine derivative) contains no expanded heterocycles and is less useful in pharmacology because it doesn’t always produce necessary results.
The team decided to focus on the factors that promote the synthesis of expanded heterocycles. They suggested that the success of the reaction depended on the differences in the electronic properties of substituent groups. Specifically, they assumed that such differences determined the migration of the substitutes from one atom in the cycle to another. To better understand the nature of this dependency, the chemists synthesized 13 ethylenediamine derivatives. An ethylenediamine derivative is an organic substance that contains two amino groups. The derivatives were placed in alkaline solutions at different temperatures: from room temperature to 90°?.
The experiment showed that the nature of the bond between the substituent group and a nitrogen atom determines the reaction speed. If a substitute acts as an electron acceptor, i.e. pulls the electron pair that it has in common with nitrogen closer, the structure of the compound immediately changes. In some cases, it took a substituent group less than 30 seconds to migrate from one atom to another. On the contrary, the compounds with electron-donating substitutes that pushed the electron pair forward reacted slowly, and the reactions required increased temperatures. In two cases, no migration of substituent groups took place at all.
“In this study, we used relatively simple compounds as models to better understand the reaction processes in heterocyclic molecules that are in high demand in the industry. We are already using the obtained data to synthesize small molecules with expanded heterocycles from reaction by-products”, said Mikhail Krasavin, D.Sc.. in Chemistry, Research Professor at the Institute of Living Systems (BFU), and the Head of the Department of the Chemistry of Natural Products (SPbSU).
Featured image: Graphical abstract by Lavit et al.
Reference: Kseniya Lavit, Elena Reutskaya, Sergey Grintsevich, Alexander Sapegin, Mikhail Krasavin, Zooming in on the hydrated imidazoline ring expansion: Factors influencing the rate of N →N′ aroyl migration in N-aroyl-N-(hetero)aryl ethylenediamines, Tetrahedron Letters, Volume 61, Issue 42, 2020, 152423, ISSN 0040-4039, https://doi.org/10.1016/j.tetlet.2020.152423. (https://www.sciencedirect.com/science/article/pii/S0040403920309011)
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