Project Summary
Most, if not all, fluorinating reagents (electrophilic or nucleophilic) are actually made from
hydrogen fluoride (HF). However, the gaseous and corrosive nature of HF excludes it from
working laboratories where special equipment and training are not available. The complexes of
HF with organic bases like pyridine-HF complex (Olah's reagent) and triethylamine-HF complex
have been explored extensively as nucleophilic sources of fluorine, but use of these organic
bases reduce the acidity of the system and may interfere with many metal catalysts. So far there
is no HF-based nucleophilic fluorination reagent that works well in acid or transition metal
catalyzed reactions. Our primary goal is to develop a new generation of HF-based nucleophilic
fluorination reagents that is compatible with acids and metal catalysts based on a rational
design. The same strategy can also be used for new HX (X = Cl, Br, I)-based halogenation
reagents.
Hydrogen bonding, rather than an ionic interaction, has been identified as the major interaction
between HF and an organic base in complexes such as pyridine-HF (Olah's reagent). To reduce
the volatility of an HF complex (make it a liquid or solid at room temperature), we have to use a
relatively good hydrogen bonding acceptor (HBA) to complex with HF. Our hypothesis is: a
strong (good) hydrogen bonding acceptor is not necessarily a strong base (BrØnsted or
Lewis base). In this way, a compound that serves as good hydrogen bonding acceptor (better
than pyridine or triethylamine), but is less basic, is expected to form a less volatile complex. And
due to the low basicity of this HBA, the resulting HBA-HF complex will be compatible with acid
catalysts or mediators. In this manner, we may achieve unprecedented reactivity and selectivity
in HF-participating reactions.
The first part of our research is the preparation of HBA-HX complexes. We are seeking
`anomaly' HBAs, that is, good hydrogen bond acceptors but weak BrØnsted bases. The
quantitative descriptor of hydrogen bond basicity and BrØnsted basicity shown in Figure 1
(based on Laurence and co-workers' database of hydrogen-bond basicity) is our primary
guideline for the selection of suitable hydrogen bonding acceptors.
The nucleophilic fluorination reagents proposed and the methodologies for their use will enable
diverse-oriented, stereo- and regio-selective synthesis of fluoroamines, fluorohydrins,
fluoroaminoacids, fluorinated aliphatic, alkenes, cyclic and heterocyclic compounds, through
new synthetic protocols such as tandem HF-addition-metathesis, HF trapping in cationic
cascade reactions, strain-release nucleophilic fluorinations, in-situ electrophilic fluorine
formation, Markovnikov and anti-Markovnikov hydrofluorinations. A similar strategy will be used
to develop designer-HX based (X = Cl, Br, I) halogenation reagents.
One of our reagents (DMPU-HF) is already commercially available, and we will commercialize
other newly developed reagents to make our methods available to medicinal chemists
worldwide.