Wellcome to this video playlist about the
best methods for converting aliphatic alcohols
into alkyl fluorides.
In this first part I'll show you some examples
of the use of hydrogen fluoride as deoxyfluorinating
reagent. This is the least expensive reagent
available, but, unfortunately, only highly
reactive alcohols can be converted into fluoride
with this reagent. More powerful and versatile
deoxyfluorinating reagents are presented in
Parts 2-5 of this playlist.
So, what can alkyl fluorides be used for?
Few examples have been reported of their use
as synthetic intermediates, because alkyl
fluorides are weak electrophilic alkylating
reagents only, and often way too expensive,
because of the difficulties of their preparation.
Moreover, some alkyl fluorides are exceedingly
toxic, and this toxicity does not necessarily
correlate with their reactivity, and is difficult
to infer from their structure. One group of
toxic organofluorine compounds are fluoroacetic
acid and any compound that will be metabolized
to fluoroacetic acid, for instance primary
linear alkyl fluorides with an even number
of carbon atoms. Fluoroacetic acid is metabolized
into an inhibitor of the enzyme aconitase,
which is critical for the citric acid cycle.
There are, however, several other chemically
stable but highly toxic organofluorine compounds,
and new fluorinated compounds should be treated
with great care, in particular if these are
volatile.
The reaction on this slide shows how unreactive
alkyl fluorides are, even benzylic fluorides.
Benzyl bromides, for instance, quaternize
quinuclidine at 25 °C about two million times
faster than a benzyl fluoride at 100 °C.
The main use of fluoroorganic compounds is
in the development of new drugs and agrochemicals,
one reason being that fluorine is sufficiently
small to act as bioisostere of hydrogen. Because
the carbon-fluorine bond is very strong and
can usually not be cleaved homolytically,
replacement of metabolically labile C-H bonds
by C-F bonds will usually block metabolic
hydroxylation at this site, and enhance the
in-vivo half-life of the compound. Trifluoromethyl
groups are chemically and metabolically quite
stable, and are used in medicinal or agrochemistry
as inert, hydrophobic substituent.
Fluoroorganic compounds are also used as refrigerants,
as propellants, and as inhalation anesthetics.
The radioactive isotope F-18 is a positron
emitter with a half-life of 110 min, and is
used as radiotracer in positron emission tomography.
The direct deoxyfluorination of alcohols by
hydrogen fluoride proceeds by the same mechanism
as that of the other hydrogen halides. Protonation
of the hydroxyl group converts it into a good
leaving group, that can be substituted by
fluoride either by SN2 or by intermediate
formation of a carbocation. Typical side reactions
are ether formation and elimination. The resulting
olefins sometimes add hydrogen fluoride, but
are usually polymerized.
Because fluoride is a very small anion, actually
the smallest besides hydride, the electrostatic
field on its van der Waals surface is extremely
strong. This leads to strong bonds to protons
and to solvent molecules, what diminishes
the reactivity of fluoride as nucleophile.
Eliminations and ether formation are therefore
more prevalent in reactions with hydrogen
fluoride than with the other hydrogen halides.
Because of the short, strong bond between
protons and fluoride, hydrogen fluoride is
a weak acid, only slightly more acidic than
acetic acid. Its high dielectric constant,
however, facilitates the formation of carbocations
from alcohols or olefins. Hydrogen fluoride
has the same dielectric constant as formamide,
and is therefore a good solvent for ionic
compounds.
The main advantages of hydrogen fluoride as
deoxyfluorinating reagent are its low price
and the fact that the only byproduct of the
reaction is water.
Unfortunately, only few alcohols undergo clean
transformation into the corresponding alkyl
fluorides by treatment with hydrogen fluoride.
Only readily carbocation-forming alcohols,
such as allylic, benzylic or tertiary alcohols,
are suitable starting materials, and yields
are often low.
Although hydrogen fluoride does not cleave
peptide bonds, it is very destructive to living
tissue, and must be handled with great care.
The lethal concentration, at which 50% of
the test animals die within one hour, is only
about 0.2%, and in many industries the large
scale use of neat hydrogen fluoride is being
phased out, due to safety concerns. Moreover,
hydrogen fluoride corrodes glass.
A further disadvantage of this reagent is
its high tendency to cause polymerization
reactions, what may be one of the reasons
for the low yields of most deoxyfluorination
reactions with hydrogen fluoride.
Because neat hydrogen fluoride is not easy
to handle safely, a number of alternative
reagents have been developed. None of them,
however, is significantly better suited for
transforming alcohols into fluorides.
Here are two early attempts to convert butanol
into butyl fluoride with HF. At room temperature
no reaction occurred, and the starting alcohol
was recovered unchanged. At 100 °C and under
pressure, however, still no butyl fluoride
but mainly fluorine-free oligomers of butanol
were formed, probably ethers and oligomerized
butene.
With the more reactive cyclobutanol a 20%
yield of cyclobutyl fluoride could be achieved
by treatment with an excess of hydrogen fluoride,
but mostly ethers and butadiene were obtained.
The cyclobutyl cation readily rearranges into
cyclopropylmethyl and allyl cations, and some
of the byproducts observed resulted from these
rearranged cations.
Tert-butanol, however, can be converted into
tert-butyl fluoride. Nevertheless, the yield
attained in this older article was only 55%.
Despite the excess of hydrogen fluoride, some
of the starting alcohol underwent elimination
to isobutylene, and probably also oligomerization.
Fluorinated steroids were hot in the sixties,
both as potential antiinflammatories and as
oral contraceptives. In this example a steroid-derived,
allylic alcohol was converted into the corresponding
fluoride by treatment with anhydrous hydrogen
fluoride. Although a selective deoxyfluorination
without allylic rearrangement could be achieved,
the yield was low. No elimination of the secondary
alcohol occurred.
In this instance the yield was a bit better
than in the previous example, but still only
50%. Here the displacement occurred with retention
of configuration, because of the intermediate
formation of a cyclopropylmethyl cation.
The inventors did not explain how the manganese
dioxide influenced this reaction, and only
stated that its use was beneficial. Manganese
trifluoride or tetrafluoride were probably
not formed, because these are strong electrophilic
fluorinating reagents, that would also fluorinate
olefins and ketones.
Treatment of this deactivated, benzylic alcohol
with neat, anhydrous hydrogen fluoride at
room temperature yielded the expected fluoride
in 53% yield. At higher temperatures, however,
the displacement of chlorine atoms by fluorine
became significant, and would have been complete
if the reaction had been allowed to proceed
for longer. Treatment of trichloromethylbenzene
with hydrogen fluoride is the standard procedure
for preparing trifluoromethylbenzene.
Not all benzylic alcohols can be converted
into benzylic fluorides by treatment with
hydrogen fluoride. Most will just undergo
polymerization by Friedel-Crafts alkylation.
So, what are the potential side reactions?
As already mentioned, hydrogen fluoride is
well suited to cause elimination of hydroxyl
groups and to polymerize the resulting olefins.
For example, hydrogen fluoride is used in
the so-called 'alkylation unit' of some refineries
as catalyst for oligomerizing low molecular
weight alkenes. Although hydrogen fluoride
is only a weak acid, its high dielectric constant
promotes ionization and makes it a useful
catalyst and solvent for Friedel Crafts acylations
and alkylations.
Further potential side reactions are the addition
of hydrogen fluoride to double and triple
bonds, and, as we saw on the previous slide,
the displacement of other halides and leaving
groups by fluoride.
The next video is about the use of dialkylaminosulfur
trifluorides as deoxyfluorinating reagents.
These are more versatile and much better suited
for converting alcohols into fluorides, so,
don't miss it out.
