Open AccessRapid Evaluation of the Mechanism of Buchwald–Hartwig Amination and Aldol Reactions Using Intramolecular 13C Kinetic Isotope Effects
Author(s) -
Victor Wambua,
Jennifer S. Hirschi,
Mathew J. Vetticatt
Publication year - 2020
Publication title -
acs catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.898
H-Index - 198
ISSN - 2155-5435
DOI - 10.1021/acscatal.0c04752
Subject(s) - amination , chemistry , intramolecular force , aldol reaction , kinetic isotope effect , catalysis , kinetic resolution , reaction mechanism , combinatorial chemistry , computational chemistry , organic chemistry , enantioselective synthesis , physics , deuterium , quantum mechanics
A practical approach is introduced for the rapid determination of 13 C kinetic isotope effects that utilizes a "designed" reactant with two identical reaction sites. The mechanism of the Buchwald-Hartwig amination of tert -butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional inter molecular 13 C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental 13 C KIEs are determined using an intra 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.