Impact of Multiple Hydrogen Bonds with Fluoride on Catalysis: Insight from NMR Spectroscopy

Hydrogen-bonding
interactions have been explored in catalysis,
enabling complex chemical reactions. Recently, enantioselective nucleophilic
fluorination with metal alkali fluoride has been accomplished with
BINAM-derived bisurea catalysts, presenting up to four NH hydrogen-bond
donors (HBDs) for fluoride. These catalysts bring insoluble CsF and
KF into solution, control fluoride nucleophilicity, and provide a
chiral microenvironment for enantioselective fluoride delivery to
the electrophile. These attributes encouraged a 1H/19F NMR study to gain information on hydrogen-bonding networks
with fluoride in solution, as well as how these arrangements impact
the efficiency of catalytic nucleophilic fluorination. Herein, NMR
experiments enabled the determination of the number and magnitude
of HB contacts to fluoride for thirteen bisurea catalysts. These data
supplemented by diagnostic coupling constants 1hJNH···F– give
insight into how multiple H bonds to fluoride influence reaction performance.
In dichloromethane (DCM-d2), nonalkylated
BINAM-derived bisurea catalyst engages two of its four NH groups in
hydrogen bonding with fluoride, an arrangement that allows effective
phase-transfer capability but low control over enantioselectivity
for fluoride delivery. The more efficient N-alkylated BINAM-derived
bisurea catalysts undergo urea isomerization upon fluoride binding
and form dynamically rigid trifurcated hydrogen-bonded fluoride complexes
that are structurally similar to their conformation in the solid state.
Insight into how the countercation influences fluoride complexation
is provided based on NMR data characterizing the species formed in
DCM-d2 when reacting a bisurea catalyst
with tetra-n-butylammonium fluoride (TBAF) or CsF.
Structure–activity analysis reveals that the three hydrogen-bond
contacts with fluoride are not equal in terms of their contribution
to catalyst efficacy, suggesting that tuning individual electronic
environment is a viable approach to control phase-transfer ability
and enantioselectivity.