Several of the name reactions we have investigated in this series
have involved functional group interconversion, and in this
tutorial we are going to learn another. This particular interconversion is quite challenging,
it is the conversion of a carboxylic acid into an alkyl halide, usually a bromide or iodide,
involving the loss of one carbon atom, which is eliminated as CO2. It has been appreciated by
chemists for a long time that carboxylic acids are plentiful in nature, such as fatty acids,
whereas alkyl halides are not, and therefore such a conversion would be quite valuable.
The method of choice for this transformation is the one devised by the German husband-and-wife
team of Heinz and Cläre Hunsdiecker. They patented their work in 1939, and published it in 1942 in
the Chemische Berichte. It consists of heating a silver carboxylate in the presence of bromine,
or less commonly, iodine. This leads to the alkyl halide with the accompanying decarboxylation.
The mechanism of the reaction is quite interesting, and is known to involve free
radicals. First of all, the silver carboxylate must be made, which can be prepared by mixing
the carboxylic acid with silver oxide. Removal of water leads to the isolation of the silver salt.
These salts must be handled in the dark because they are very photosensitive, leading to silver
metal. Indeed, this “photoreduction” chemistry was the basis for the first applications of black and
white photography using silver bromide. Silver carboxylates react with halogens like bromine
to form acyl hypohalites, in this case the acyl hypobromite. The driving force for the reaction
is provided by the formation of silver bromide, AgBr, which is highly insoluble and precipitates.
Now, given that oxygen-bromine bonds are quite weak, these acyl hypobromites tend to break.
However, both oxygen and bromine are highly electronegative, and neither atom wants to
give up a pair of electrons, which is the case in many polar dissociations. What happens instead
is that they split the pair evenly, each ending with 7 electrons in their outer shells, and are
therefore both radicals. Carboxylate radicals slowly decarboxylate in the following manner,
thereby producing an alkyl radical. So if the carboxylate and bromine radicals were to
recombine, they would form the starting material, but if CO2 has been lost, we are left with this
other radical pair which can instead recombine to form the alkyl halide. The reaction can produce
primary, secondary, or tertiary alkyl halides, and also aryl bromides, via this mechanism.
In the latter case, the potential side reaction is electrophilic bromination of the benzene ring,
especially if the aromatic ring is very electron rich.
The reaction in general works best for bromides, less well for iodides, and poorly for chlorides.
Looking again at the more generalized reaction, a common side reaction is the recombination of the
alkyl and carboxyl radicals to form an ester, whereby two equivalents of the original alkyl
groups are combined. This may be a useful product, and it is sometimes referred to as
the Simonini reaction, but in most applications it is a nuisance,
so it is important to use a slight excess of bromine so as to minimize formation of the ester.
From a practical standpoint, the Hunsdiecker reaction has not found many
industrial applications and it remains primarily a lab tool.
One of the problems when scaling up is the cost of silver salts and the stoichiometric amount of
silver bromide waste produced. In addition, bromine is a corrosive and toxic liquid,
and is therefore not an attractive reagent for large scale operations.
However, there have been many modifications of this decarboxylative bromination. Some methods use
even more toxic salts than silver, like mercury or lead carboxylates. These alternatives are even
less practical than the original Hunsdiecker protocol. However, some procedures use only
catalytic amounts of silver salts, and use alkyl hypohalites as oxidizing or halogenating agents.
As an example, let’s highlight the work of Professor Chaozhong Li,
from the Shanghai Institute of Organic Chemistry, published a few years ago in
the Journal of the American Chemical Society. His method involves the use of tert-butyl
hypochlorite instead of bromine as the halogenating agent, and therefore
forms tert-butanol as a co-product, plus the alkyl chloride. The silver salt, a complex of silver
trifluoromethanesulfonate and phenanthroline, does not precipitate out as silver chloride, but simply
promotes the reaction without being consumed. It is therefore a catalyst, and it can be used
in only 5 mole percent. This procedure is quite general for alkyl chlorides, though it is not yet
known whether it can be extended to bromides and iodides. The mechanism is also not understood yet,
as the reaction is quite new, but the method sets the stage for the use of catalytic silver, and
therefore hopefully more practical applications. Thus, the Hunsdiecker reaction is still being
studied and extended, and is more than ever an important tool in modern organic synthesis.