Prediction of Optimum Conditions for New Substrates in the Willgerodt-Kindler Reaction

1 Prediction of Optimum Conditions for New Substrates in the Willgerodt-Kindler Reaction [19] 

The example shows a sequential approach to the study of discrete variations. The Willgerodt-Kindler reaction was studied with a set of para substituted acetophenones, see Schema 9. As the reaction failed with strong electron-withdrawing substituents, the study was limited to include donor, alkyl, and halogen substituents. 

An initial set of five para substitutes (H, Me, Cl, MeO, Me2N) acetophenones was selected. The experimental conditions which afforded the maximum yield were determined for each substrate by response surface methods. The optimum settings 

To characterize the substituents (the X block) a set common substituent parameters were compiled from the literature. These parameters were as (Taft inductive parameter), trp (Hammett parameter for para substituents), F and R (Swain-Lupton dual substituent parameters), Es and Esc (Taft steric parameters), van der Waals radius, L, Bv B2, B3, (Verloop sterimol parameters), MR (molar refractivity), and n (Hansch lipophilicity parameter). Data are given in Refs. [1,19] and are not reproduced here. 

Entry Subst. Predicted optimum8 Method Yields (%)  

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The reaction space linked to the experimental space and the response space, illustrated by prediction of optimum conditions for new substrates in the Willgerodt-Kindler reaction. 

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