Synthesis and Diels-Alder Reactivity of 4-Fluoro-4-Methyl-4H-Pyrazoles.
4H-Pyrazoles are emerging scaffolds for "click" chemistry. Late-stage fluorination with Selectfluor® is found to provide a reliable route to 4-fluoro-4-methyl-4H-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4H-pyrazole (MFP) manifested 7-fold lower Diels-Alder reactivity than did 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP), but higher stability in the presence of biological nucleophiles. Calculations indicate that a large decrease in the hyperconjugative antiaromaticity in MFP relative to DFP does not lead to a large loss in Diels-Alder reactivity because the ground-state structure of MFP avoids hyperconjugative antiaromaticity by distorting into an envelope-like conformation like that in the Diels-Alder transition state. This predistortion enhances the reactivity of MFP and offsets the decrease in reactivity from the diminished hyperconjugative antiaromaticity.
['Abularrage|Nile S|NS|', 'Levandowski|Brian J|BJ|', 'Raines|Ronald T|RT|']
D060326:Chemistry Techniques, Synthetic D061565:Cycloaddition Reaction D005461:Fluorine D005978:Glutathione D007700:Kinetics D008958:Models, Molecular D008968:Molecular Conformation D015394:Molecular Structure D009930:Organic Chemicals D011720:Pyrazoles D013237:Stereoisomerism D013816:Thermodynamics D014466:Ultraviolet Rays
4H-pyrazole hyperconjugation antiaromaticity click chemistry cycloaddition