Chemists identified necessary conditions for successful synthesis of small molecules

February 09, 2021

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).

Immanuel Kant Baltic Federal University

Related Nitrogen Articles from Brightsurf:

Chemistry: How nitrogen is transferred by a catalyst
Catalysts with a metal-nitrogen bond can transfer nitrogen to organic molecules.

Illinois research links soil nitrogen levels to corn yield and nitrogen losses
What exactly is the relationship between soil nitrogen, corn yield, and nitrogen loss?

Reducing nitrogen with boron and beer
The industrial conversion of nitrogen to ammonium provides fertiliser for agriculture.

New nitrogen products are in the air
A nifty move with nitrogen has brought the world one step closer to creating a range of useful products -- from dyes to pharmaceuticals -- out of thin air.

'Black nitrogen'
In the periodic table of elements there is one golden rule for carbon, oxygen, and other light elements.

A deep dive into better understanding nitrogen impacts
This special issue presents a selection of 13 papers that advance our understanding of cascading consequences of reactive nitrogen species along their emission, transport, deposition, and the impacts in the atmosphere.

How does an increase in nitrogen application affect grasslands?
The 'PaNDiv' experiment, established by researchers of the University of Bern on a 3000 m2 field site, is the largest biodiversity-ecosystem functioning experiment in Switzerland and aims to better understand how increases in nitrogen affect grasslands.

Reducing reliance on nitrogen fertilizers with biological nitrogen fixation
Crop yields have increased substantially over the past decades, occurring alongside the increasing use of nitrogen fertilizer.

Flushing nitrogen from seawater-based toilets
With about half the world's population living close to the coast, using seawater to flush toilets could be possible with a salt-tolerant bacterium.

We must wake up to devastating impact of nitrogen, say scientists
More than 150 top international scientists are calling on the world to take urgent action on nitrogen pollution, to tackle the widespread harm it is causing to humans, wildlife and the planet.

Read More: Nitrogen News and Nitrogen Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to