Mechanistic Studies Yield Improved Protocols for Base-Catalyzed Anti-Markovnikov Alcohol Addition Reactions

The catalytic anti-Markovnikov addition
of alcohols to simple alkenes
is a longstanding synthetic challenge. We recently disclosed the use
of organic superbase catalysis for the nucleophilic addition of alcohols
to activated styrene derivatives. This article describes mechanistic
studies on this reversible reaction, including thermodynamic and kinetic
profiling as well as computational modeling. Our findings show the
negative entropy of addition is counterbalanced by an enthalpy that
is most favored in nonpolar solvents. However, a large negative alcohol
rate order under these conditions indicates excess alcohol sequesters
the active alkoxide ion pairs, slowing the reaction rate. These observations
led to an unexpected solution to a thermodynamically challenging reaction:
use of less alcohol enables faster addition, which in turn allows
for lower reaction temperatures to counteract Le Chatelier’s
principle. Thus, our original method has been improved with new protocols
that do not require excess alcohol stoichiometry, enable an expanded
alkene substrate scope, and allow for the use of more practical catalyst
systems. The generality of this insight for other challenging hydroetherification
reactions is also demonstrated through new alkenol cyclization and
oxa-Michael addition reactions.