Understanding the molecular mechanism and regioselectivity in the synthesis of celecoxib via a domino reaction: A DFT study

• The celecoxib synthesis via a domino reaction was theoretically studied using DFT.
• [3 + 2] cyclisation step presents a complete regioselective fashion.
• Mechanism and activation barriers are not considerably affected by solvent.
• The experimental outcomes can nicely be explained using DFT reactivity indices.

The molecular mechanism and energetic of the domino reaction involved in the synthesis of celecoxib, a well-known anti-inflammatory drug, were theoretically studied at the DFT-B3LYP/6-31G* level. The first reaction in this domino process, which is also the rate-determining step, is a complete regioselective [3 + 2] cycloaddition (32CA) reaction associated with the nucleophilic attack of C5 carbon atom of enamine 7 on the C3 carbon atom of nitrile imine 6, leading to cycloadduct 8. The second reaction is a rapid acid/base catalysed stepwise elimination reaction of the morpholine 9 from cycloadduct 8 affording celecoxibe 3. The results also show that neither molecular mechanism of reaction nor activation barriers are considerably affected by the inclusion of solvent. The calculated relative Gibbs free energies as well as local reactivity indices obtained using the calculated Parr functions explain the complete regioselective fashion provided by the 32CA reaction under consideration in excellent agreement with the experimental findings.

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