Utopia Point Bayesian Optimization Finds Condition-Dependent Selectivity for N-Methyl Pyrazole Condensation.

Area of Science:

• Organic Chemistry
• Computational Chemistry

Background:

• The Knorr pyrazole condensation is typically acid-catalyzed.
• Controlling regioselectivity in pyrazole synthesis can be challenging.

Purpose of the Study:

• To identify reaction conditions for highly selective formation of N1 and N2-methyl-3-aryl pyrazole isomers.
• To explore a wide chemical space for optimizing the Knorr pyrazole condensation under basic conditions.

Main Methods:

• Utopia Point Bayesian Optimization (UPBO) was employed to navigate vast reaction parameter spaces.
• Investigated condition-dependent equilibria of reaction intermediates.

Main Results:

• UPBO successfully identified conditions for selective synthesis of N1 and N2 isomers.
• Discovered that selectivity arises from pre-dehydration intermediate equilibrium.
• A reversibly formed hemiaminal intermediate was key for N2 isomer pathway.

Conclusions:

• UPBO enables efficient optimization of conversion and selectivity without high-performance computing.
• The study provides a novel approach to controlling regioselectivity in pyrazole synthesis.
• Understanding intermediate equilibria is crucial for directing reaction outcomes.