Hi, wellcome to Part 2 of this video playlist
about the best methods for preparing alkyl
iodides from aliphatic alcohols.
This presentation is about the use of compounds
containing phosphorus-iodine bonds as deoxyiodinating
reagents.
The most common laboratory reagents for preparing
alkyl iodides from alcohols are mixtures of
triphenylphosphine with iodine or with another
electrophilic iodinating reagent. Alcohols
can, however, also be converted into alkyl
iodides with mixtures of elemental phosphorus
and iodine, which react to yield phosphorus
triiodide.
These reactions are closely related to the
Mitsunobu reaction. From the alcohol and the
phosphorus iodide a pentavalent alkoxy phosphorus
derivative is formed, which decomposes by
intramolecular nucleophilic substitution to
the alkyl iodide and some derivative of phosphorous
or phosphoric acid. Depending on the electrophilic
iodinating reagent chosen, the reaction mixture
will turn more or less acidic.
According to this mechanism, only anionic,
phosphorus-bound nucleophiles can compete
with iodide, but not neutral nucleophiles,
such as pyridine, imidazole, or amines. The
latter may, however, react with the alkyl
iodide if the reaction temperature is too
high.
This reaction is often performed in the presence
of one equivalent of imidazole as a weak base,
because this seems to increase the yield of
alkyl iodide. This base, however, is not stricktly
required unless the alcohol is acid sensitive.
Suitable iodinating reagents include elemental
iodine, N-iodoimides, triiodoimidazole, and
carbon tetraiodide.
As a low cost alternative to triphenylphosphine,
triphenylphosphite can also be used in this
reaction, but alkoxybenzenes may result as
byproducts.
Deoxyiodinations with phosphorus iodides usually
proceed with clean inversion of configuration.
The most important advantages of this strategy
are the mild reaction conditions and the high
yields, what makes this particularly suitable
for expensive alcohols. Furthermore, no large
excess of iodide is required, and because
of its high responsiveness to steric effects,
selective monoiodinations of polyols can be
achieved.
Main disadvantages are the high cost of the
phosphine, and the difficulty of removing
the resulting phophine oxides from the product.
Furthermore, large amounts of phosphorus-containing
waste can be difficult to dispose of.
This example is the preparation of methyl
iodide from methanol. Because methanol doesn't
cost much, an excess of the alcohol was used
to enhance the yield with respect to the iodine
used, which is the most expensive reagent
in this synthesis.
In this example a higher-boiling primary alcohol
was converted into the corresponding iodide.
Interestingly, only half an equivalent of
iodine was sufficient to attain a high yield
of product, what means that both iodine atoms
were used, the second one probably by the
same mechanism as in HI mediated deoxyiodinations.
No large excess of phosphorus was required,
making this a very affordable strategy for
the preparation of alkyl iodides.
This example is the conversion of Boc-serine
methyl ester into the iodide, which illustrates
the mildness of this strategy. Upon activation,
serine derivatives often undergo beta-elimination,
but this did not occur here, and a high yield
of the desired iodide was obtained. A chromatographic
purification was, however, required to remove
the phosphine oxide.
In this example a secondary unreactive alcohol
was converted into the iodide by treatment
with triphenylphosphite and N-iodosuccinimide,
without the use of imidazole or other bases.
Despite the low reactivity of the starting
alcohol, still a substantial amount of the
iodide was obtained. Unfortunately the authors
did not disclose what happened to the remainder
of the starting material.
When using triarylphosphites instead of phosphines
or elemental phosphorus, one potential byproduct
is the arylether. Alkyl phosphites cannot
be used, because the phosphite alkyl groups
would also be converted into alkyl iodides.
As shown in this example, the combination
of triphenylphosphine and iodine enables the
selective deoxyiodination of primary hydroxyl
groups in the presence of secondary hydroxyl
groups. Interestingly, the unreactive hydroxyl
groups did not consume any phosphine. In this
instance the use of a weak base such as imidazole
made sense, because the starting alcohol was
an acid-sensitive acetal. Carbohydrate-derived
acetals are more resistant toward acid-catalyzed
transformations than other acetals, but it
is always a good idea to try to avoid potential
problems.
So, what can go wrong?
Besides iodide-mediated reductions, one typical
side reaction of deoxyiodinations is elimination
to form olefins. Some phosphorus-based deoxyiodinating
reagents, such as methyltriphenoxyphosphonium
iodide, are in fact used for the dehydration
of alcohols to prepare alkenes. Bases generally
favor the formation of olefins, while acidic
conditions and an excess of iodide will promote
the formation of alkyl iodides.
In the examples on this slide no base was
used, but still the tertiary hydroxyl groups
underwent complete elimination.
In this example a secondary, unreactive alcohol
was converted into the iodide with inversion
of configuration. As byproduct an arene was
formed by elimination of the hydroxyl group
and an alkoxy group. High reaction temperatures
often promote elimination reactions, and may
have contributed here to the observed arene
formation.
Inherently unstable alkyl iodides, such as
the product of this reaction, will of course
be difficult to prepare in high yield. Alcohols
and alkyl halides with electron-withdrawing
groups in beta position readily undergo elimination,
and olefin formation was probably the main
reason for the low yield of this reaction.
If 1,2-diols are treated with an excess of
deoxyiodinating reagent, olefins will often
result because 1,2-diiodoalkanes are unstable
and decompose into an olefin and elemental
iodine. Unlike the other halogens, iodine
does not add to olefins to yield diiodoalkanes
because these are too strained and unstable.
The reaction on this slide is an example of
such a reductive deoxygenation of a 1,2-diol.
Only a small amount of iodoalcohol was obtained,
formed with retention of configuration. The
stereochemical outcome suggests some anchimeric
assistance by the pyrimidinone group.
If mixtures of phosphorus and iodine are used
without any additional base, the reaction
mixture may turn strongly acidic due to the
formation of phosphorous or phosphoric acid
and small amounts of HI. This may cause rearrangement
of acid-sensitive alcohols. Acidification
can be prevented by adding a base, but not
a large excess, because alkyl iodides readily
undergo elimination or substitution in the
presence of bases.
Phosphorus iodides are reducing agents, and
during the reaction, other strongly reducing
intermediates may be formed. Thus, similar
as in reactions with hydrogen iodide, the
reduction of various functional groups can
occur. In particular sulfuric and sulfonic
acid derivatives, amine oxides or pyridine
N-oxides can be reduced, and are usually incompatible
with these reagents.
The reaction on this slide shows the many
products formed from cinnamyl alcohol and
iodine and hypophosphoric acid.
Here are some more examples to give you an
idea of the scope of this reaction.
The reagents described by now, namely hydrogen
iodide and phosphorus iodides, enable the
economic preparation of iodides from a wide
variety of alcohols.
Some additional reagents have been descibed,
though, which are less versatile but may offer
some advantages in special situations. These
will be discussed in the next presentation.
See you there.
