5-Endo-trig radical cyclizations: disfavored or favored processes?

Area of Science:

• Organic Chemistry
• Reaction Mechanisms
• Computational Chemistry

Background:

• The Baldwin-Beckwith rules classify certain radical cyclizations, like 5-endo-trig, as disfavored.
• Understanding radical cyclization mechanisms is crucial for synthetic organic chemistry.

Purpose of the Study:

• To investigate the kinetics and thermodynamics of 5-endo-trig radical cyclization.
• To computationally explore the factors influencing the selectivity between 5-endo and 4-exo cyclization modes.
• To re-evaluate the generalization of the Baldwin-Beckwith rules for radical cyclizations.

Main Methods:

• Determination of relative kinetic data for radical cyclization versus hydrogen abstraction.
• Computational studies using the UB3LYP/6-31G level of theory.
• Analysis of transition state structures and delocalization effects.

Main Results:

• The 5-endo-trig cyclization has a rate constant of 2 x 10(4) s(-1) at 298 K with a 9 kcal/mol activation energy.
• In the absence of steric effects, 5-endo cyclization is kinetically and thermodynamically favored over 4-exo cyclization.
• Substituents that delocalize the radical electron can make 4-exo pathways kinetically competitive.

Conclusions:

• 5-endo-trig radical cyclizations are not universally disfavored and can be kinetically preferred.
• The findings necessitate a revision of the Baldwin-Beckwith rules regarding these specific cyclizations.
• Computational and experimental data provide insights into controlling radical cyclization selectivity.