Rapid Evaluation of the Mechanism of Buchwald-Hartwig Amination and Aldol Reactions Using Intramolecular C Kinetic Isotope Effects.

A practical approach is introduced for the rapid determination of C kinetic isotope effects that utilizes a "designed" reactant with two identical reaction sites. The mechanism of the Buchwald-Hartwig amination of -butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional molecular C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental C KIEs are determined using an molecular KIE approach. This rapid methodology for KIE determination requires substantially less material and time compared to traditional approaches. Details of the Buchwald-Hartwig amination mechanism are investigated under varying synthetic conditions, namely a variety of halides and bases. The enantioselectivity-determining step of the l-proline catalyzed aldol reaction is also evaluated using this approach. We expect this mechanistic methodology to gain traction among synthetic chemists as a practical technique to rapidly obtain high-resolution information regarding the transition structure of synthetically relevant reactions under catalytic conditions.