Hi, wellcome to Part two of my video playlist
about the best methods to convert alcohols
into alkyl bromides.
This presentation is about the use of reagents
with phosphorus-bromine bonds as deoxybrominating
reagents. These can also be used under neutral
or basic reaction conditions, and are often
the best choice if ones starting alcohol is
sensitive toward acids.
The most common phosphorus-based reagents
used for deoxybrominations are trialkyl- or
triarylphosphines and PBr3 in combination
with an electrophilic brominating reagent,
such as bromine, CBr4, or N-bromosuccinimide.
These reactions are closely related to the
Mitsunobu reaction and proceed by intermediate
formation of a pentavalent phosphorus bromide
or a phosphonium bromide. These intermediates
react with alcohols, even without any base,
to yield a pentavalent alkoxyphosphorus derivative
which decomposes into a phosphine oxide and
the alkyl bromide.
Similar intermediates are also likely to be
formed when alcohols are deoxybrominated by
PBr3 without any added base.
Both the Wittig and the Mitsunobu reaction
are mechanistically related, as I've tried
to sketch on this slide. In both reactions
an alcohol adds to a tetravalent phosphonium
salt to yield a pentavalent alkoxyphosphorus
derivative. This intermediate decomposes irreversible
to the observed products: an olefin in the
case of the Wittig reaction and a substitution
product in the case of the Mitsunobu reaction
or phosphorus-mediated deoxyhalogenations.
Phosphorus tri- and pentabromide can be prepared
directly from the elements under mild conditions,
and in numerous deoxybromination procedures
these reagents are generated in the presence
of the starting alcohol. These reagents, as
well as phosphorus oxybromide are also commercially
available, but PBr5 is not very stable, and
tends to decompose into bromine and PBr3 upon
heating above room temperature.
This is one older example where phosphorus
bromides were generated in situ from the elements
in the presence of an alcohol. No displacement
of chloride by bromide occurred.
Also in this example the phosphorus bromides
were generated in the reaction mixture from
phosphorus and bromine. The starting alcohol
was glycerol, and only the two primary hydroxyl
groups were displaced.
In this example an acid-resistant alcohol
was converted into the corresponding bromide
by treatment with less than one equivalent
of PBr3, without any base or solvent. The
product was isolated by dilution with water,
filtration, and recrystallization from ethanol.
Pentaerythritol, the starting alcohol of this
example, is neopentyl-like and therefore difficult
to deoxyhalogenate. With half an equivalent
of PBr3 at 180 °C each hydroxyl group could,
however, be displaced. Thus, PBr3 is well
suited for high-temperature reactions and
unreactive alcohols.
In this example again neither base nor solvent
were required but, despite the low reaction
temperature, isomerization to the tert-butyl
cation occurred to a small extent.
In this example the deoxybromination was performed
in the presence of a small amount of benzene
as solvent and of pyridine as base. Although
the starting alcohol was not very reactive
and despite the mild reaction conditions,
an acceptable yield was achieved. Such conditions
are particularly useful for acid-sensitive
alcohols, prone to rearrangements.
Here cinnamyl alcohol was converted into the
bromide, this time with acetonitrile as solvent
and without any base. The substitution proceeded
quickly at room temperature and without allylic
inversion.
If compared to PBr3 or PBr5, mixtures of PPh3
and brominating reagents show a better solubility
in organic solvents, and yields are sometimes
higher than with purely inorganic phosphorus
bromides. The big disadvantage of PPh3 is,
though, that this reagent and its oxide can
be difficult to remove from the product.
Concerning the choice of solvent, acetonitrile
is usually a better solvent than benzene or
dichloromethane, in particular for unreactive
alcohols, because most reactions proceed faster
in acetonitrile than in less polar solvents,
and because acetonitrile is a better solvent
and allows to work at higher concentrations.
One further alternative phosphorus source
are triaryl phosphites, as shown here. A number
of successful examples of the use of this
reagent have been reported, but there is always
the risk that aryl ethers may result as byproducts.
Beta-fluorinated alcohols, as the starting
material of this example, do not undergo SN2
reactions readily, and sulfonates of such
alcohols or the corresponding bromides or
iodides are exceptionally unreactive electrophiles.
In this example a tertiary cyclopropanol was
converted into a bromide at room temperature
in dichloromethane in the presence of one
equivalent of pyridine. These mild reaction
conditions were necessary because the starting
alcohol readily isomerized to an ethylketone,
both under acidic or basic reaction conditions,
or upon excessive heating.
So, what can go wrong?
If no bases are used, the reaction mixture
can become rather acidic, and similar side
reactions as with HBr can occur.
Then, if bases are used and the starting alcohol
is too unreactive or the reaction temperature
is too low, alkyl phosphites or phosphate
may be formed. These are rather stable and
usually do not react with bromide.
As with most other deoxyhalogenating reagents,
also phosphorus bromides can cause allylic
or propargylic rearrangements.
It has been reported a few times that when
PBr3 or PCl3 are heated strongly, fires or
explosions can occur, presumably caused by
the formation of phosphorus hydrides.
A further side reaction is the quaternization
of an excess of phosphine or of other trivalent
phosphorus intermediates by the alkyl bromide.
Then, other functional groups than alcohols
can also react with phosphorus bromides. Ketones,
for instance, can be converted into vinyl
bromides, and amides into iminium bromides
or nitriles.
Both PBr5 and PCl5 can also dealkylate amides,
to yield nitriles and alkyl halides. Tertiary
amines, however, cannot be dealkylated with
phosphorus halides, because of the low tendency
of phosphorus to form bonds to nitrogen.
Trivalent phosphorus derivatives are strong
reducing agents, and can reduce various functional
groups. These include sulfonic acids, their
salts, and sulfonyl halides.
Further groups that are usually reduced by
PBr3 or PCl3 are amine N-oxides, azides, nitro
groups, alpha-haloketones, and disulfides.
Because PBr5 and related compounds can release
bromine upon slight heating, these reagents
can also cause oxidative brominations of electron-rich
functional groups in the starting alcohol.
These include alkenes, alkynes, electron-rich
arenes and heteroarenes, such as pyrroles
or indoles, and CH-acidic compounds such as
acyl halides, esters, or ketones.
Occasionally, even electrophilic phosphorylations
of reactive arenes, alkenes or alkynes may
occur.
One rather unique reaction of trivalent phosphorus
halides is the formation of diphosphonic acids
from carboxylic acids and amides. These diphosphonic
acids are stable and very hydrophilic compounds
that will probably be lost during an aqueous
workup, unless you are specifically looking
for them.
If ones starting alcohol is also an aldehyde
or a ketone, it may not be a good idea to
use CBr4 as electrophilic brominating reagent,
because one further potential side reaction
is the olefination of aldehydes or ketones.
As shown by this example, such dibromomethylenations
can occur under surprisingly mild reaction
conditions.
The formation of a phosphorus ylide from carbon
tetrabromide requires the absence of acids,
which would protonate the CBr3 anion. Then,
a reducing agent is usually also required,
to convert the trihalomethylphosphonium salt
into the ylide. When the phosphine is used
as reducing agent, two equivalents of phosphine
are required to produce one equivalent of
ylide.
So, to prevent this reaction, the alcohol
may be first mixed with CBr4, followed by
slow addition of the phosphine.
Here is a short selection of some additional
examples to illustrate the scope of this reaction,
but many more have been reported.
Unfortunately the brominated analogs of phosgene
and SOCl2 are more difficult to prepare and
less readily available. Therefore, fewer examples
of the use of these reagents in deoxybrominations
have been reported.
Here are some references describing the generation
and use of iminium bromides as deoxybrominating
reagents. Amides do react with methylene bromide
or CBr4, thermally, photolytically, or in
the presence of some transition metal catalyst.
The resulting O-alkylated amides can activate
alcohols and bring about their conversion
into alkyl bromides.
Alternatively, amides may also be O-derivatized
by treatment with cyanuric chloride or with
oxalyl chloride. If alcohols are treated with
these activated amides in the presence of
lithium or sodium bromides, good yields of
alkyl bromides are sometimes obtained, because
bromide is a better nucleophile than chloride.
The reaction of bromine with CO to yield carbonyl
bromide does not proceed as readily as the
preparation of phosgene. It has been reported,
though, that carbonyl bromide can be generated
in sufficient amounts at room temperature
in the presence of alcohols and a silica catalyst.
Other deoxybrominating reagents include SOBr2,
which can be prepared from SOCl2 and HBr and
is commerically available.
Then, mixtures of dialkylsulfides with electrophilic
brominating reagents can also be used to convert
aliphatic alcohols into bromides, but a number
of side reactions can occur, such as oxidations
or the formation of methylthiomethyl ethers,
and the products often contain smelly and
catalyst-poisoning inpurities.
Trimethylsilyl chloride or bromide can also
be used to prepare alkyl bromides from alcohols,
but few examples have been reported.
One alternative to direct, one-step deoxybrominations
that should always be considered is the preparation
of a mesylate or tosylate, followed by SN2
displacement with bromide. Mesylate formation
proceeds under mild conditions in high yields,
and because bromide is only weakly basic,
nucleophilic substitutions with bromide do
usually not cause any unexpected side reactions.
