Tautomers: Interconversion of Isomers

Views: 81     Author: Site Editor     Publish Time: 2023-09-22      Origin: Site

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Tautomerization refers to the equilibrium system between two isomers, which can be interconverted by moving both double bonds and protons. It exemplifies a special kind of isomerism. A common example of isomerism is the ketone-enol tautomerization, such as the conversion between acetone and propene. It is crucial to understand that the two isomers are in essence the same substance but with different spatial configurations. However, due to the equilibrium system and the current technological limitations, it is impossible to separate a single isomer.

In this article, we will use two molecules we have encountered in our everyday work—a Pralsetinib intermediate (CAS No. 2778223-48-4) and a Doravirine intermediate (CAS No. 1155846-86-8), to explain tautomerization in nitrogen-heterocyclic compounds.

Basic Concepts: Bonds, Electronegativity, and pH

Bonds between atoms can be single, double, or triple. Double bonds involve two shared pairs of electrons, rigidly linking the connected atoms. In organic compounds, double bonds often exist between carbon atoms and another atom. Yet, double bonds can sometimes form between nitrogen and carbon atoms too.

The ability of an atom to attract electrons is called electronegativity. For example, the electronegativity of oxygen is higher than that of nitrogen or carbon.

pH represents the concentration of hydrogen ions (H+) in a solution, dictating its acidity or alkalinity. A lower pH signifies a higher H+ concentration, making the solution more acidic; a higher pH indicates a lower H+ concentration, rendering the solution more alkaline. pH affects the position of double bonds in organic compounds containing nitrogenous bases.

While electronegativity can influence the position of the double bond, the tautomeric balance in nitrogen-heterocyclic compounds is predominantly determined by pH.

Tautomerization of Pralsetinib Intermediate 2778223-48-4

Anyone may notice "different" structures of Pralsetinib intermediate 2778223-48-4 in their routine work. Structure A can be searched on ChemicalBook, and structure B is seen in patent CN115057822A and our COA—was there a problem with our actual production supply? In fact, it's not. A and B are the same substance. We see a difference in the structure on the heterocycle due to tautomerization.

Isomers converstion of Pralsetinib Intermediate CAS RN 2778233-48-4.

In B, the double bond is between the nitrogen and carbon atoms. In A, the double bond has moved to the carbon and oxygen atoms.

From an electronegativity perspective, this is because oxygen has a higher electronegativity than nitrogen, pulling the double bond's electrons towards itself, forming C=O rather than N=C. This makes structure A more stable than B, establishing a balance between the tautomers.

From a solvent environment perspective, under acidic conditions, oxygen is protonated, and Pralsetinib intermediate 2778223-48-4 predominantly exists as the enol form B. Under alkaline conditions, the balance leans toward the ketonic form, which corresponds to structure A.

Balancing and "Tug-of-War" Analogies of Tautomerization

Tautomers are in a kind of equilibrium between the ketonic form (like A) and the enolic form (like B), much like a "tug of war" over the double bond. The high electronegativity oxygen atom often "wins" this "tug of war" against the low electronegativity nitrogen atom, pushing the equilibrium towards the keto form.

However, the balance ratio (the equilibrium) is largely determined by the pH of the solution. The higher the H+ concentration (lower pH), the reaction is driven towards the enol form, generating more form B; the more alkaline the solution (higher pH), the reaction is pushed towards the keto form, producing more form A.

Tautomerization of Doravirine Intermediate 1155846-86-8

Similarly, for Doravirine Intermediate 1155846-86-8, structure C can be found on ChemicalBook or PubChem, and structure D is seen in patent WO2011120133A1. The heterocycle C=O in structure C and the N=C in structure D manifest the tautomeric transformation.

Isomers converstion of Doravirine Intermediate CAS RN 1155846-86-8.


In summary, tautomerization involves achieving a balance between two structures through the movement of the double bond position. This process is fundamentally governed by the concepts of double bonds, electronegativity, solvent environment, and equilibrium.