Computer simulations are typically used as a guide so that chemists can more rapidly work out the specifics of a basic reaction idea they have in mind, similar to how a compass assists an explorer in efficiently navigating to a specific location on a map.
Researchers at ICReDD, on the other hand, went a step farther and used simulations to generate the general concept for an entirely unimagined reaction, thereby employing computations to create the map itself.
The team used a design idea derived from computational results to effectively construct a 48-reaction suite that could be useful for the advancement of new drugs.
Fluorine’s position and presence in a molecule can have a significant impact on the molecule’s pharmacological properties.
Researchers at ICReDD used quantum chemical calculations to find a way to add two fluorine atoms to a hard-to-reach spot on an N-heterocycle, which is a molecule with a carbon ring structure where at least one carbon is replaced by nitrogen.
The ability to link fluorine atoms to previously inaccessible “alpha carbon” — the carbon directly adjacent to the nitrogen in the ring structure — could lead to the development of a number of new medications.
Before conducting laboratory studies, the researchers cast a wide net by computationally evaluating the viability of several 3-component reactions using the artificial force-induced reaction (AFIR) technique.
They recreated the interaction of different pairs of tiny molecules with double or triple bonds with a difluorocarbene molecule, which acts as the source of fluorine atoms. These computer simulations demonstrated that a variety of ring-forming processes ought to be possible.
Researchers attempted one of the promising reactions identified by preliminary computational data but failed. A more concentrated, optimized estimate of the transition state energy of the reaction in issue revealed that the difluorocarbene molecule reacted with itself more easily than with the chosen starting molecules, indicating that an unwanted side reaction was likely to occur.
Researchers were motivated by this outcome to switch one of the initial components to the cyclic molecule pyridine, which they believed would be able to compete with the undesirable side reaction. This change made it possible to make the N-heterocyclic product that was desired, which had two fluorines attached to the alpha carbon.
The reaction established here is also notable since it fractures the aromatic system of electrons in the pyridine molecule, a challenging transformation due to the strong stability of aromatic systems.
Furthermore, the 3-component reaction framework was successfully implemented in the lab to a wide range of starting materials, yielding many novel compounds with distinct alpha position fluorine substitutions.
This reaction framework could be very useful for making new drugs because it has a wide range of possible reactions.
They believe their streamlined screening approach will enable them to expand the scope of their search and uncover fresh possibilities for chemical reaction design.
“Our study’s highlight is the successful demonstration of an in silico reaction screening strategy for reaction development. The computational reaction simulation suggested less-explored three-component reactions of difluorocarbene and two unsaturated molecules, which we successfully realized in experiments,” says lead author Hiroki Hayashi.
He thinks that “the AFIR method is a powerful tool for dictating new research directions in reaction discovery, and we plan to continue building a computation-based reaction development platform by integrating the computational and informatics techniques of ICReDD.”
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