In developing a tool kit for organic synthesis, we will be very interested
in gathering ways to form carbon-carbon bonds. This is because organic molecules
consist of a carbon skeleton which needs to be assembled one way or another. But
it is also important to have techniques at one’s disposal that allow for the cleavage,
or breaking, or carbon-carbon bonds. This is a great way to isolate a particular fragment of
a larger molecule for one reason or another, and we have already learned several ways to do this.
Now let’s learn one more, which focuses on a reagent called periodic acid. We’ve learned about
oxyacids in the past, so we know that the prefix “per” is referring to the number of oxygen atoms
in this compound, which has the formula HIO4, where the iodine makes seven covalent bonds,
which is possible if each of its seven valence electrons goes towards forming its own bond.
We can see that there are three double bonds to oxygen, and one more bond to a hydroxyl group,
which of course contains the acidic proton, although interestingly, in this technique we
will see periodic acid act as an oxidizing agent rather than a Bronsted-Lowry acid.
So let’s examine precisely what this does. Periodic acid is useful in oxiding polyhydroxy
compounds, meaning multiple hydroxyl groups, specifically when the hydroxyls are on
adjacent carbons. For example, take this generalized vicinal diol. If periodic acid
is introduced, the bond between these carbons will cleave, and two carbonyls will be produced,
which can be aldehydes or ketones, depending on the rest of the molecule. Periodic acid will
lose an oxygen in the process, becoming iodic acid, and a water molecule is also produced.
Now before looking at the mechanism, let’s continue to highlight specific substrates
so we can observe what occurs in each case, as there are several possibilities.
Take glycerol for example. This has three hydroxyl groups on three consecutive carbons. This will
require two equivalents of periodic acid to fully react, and we will be left with two equivalents of
formaldehyde, and one equivalent of formic acid. So as we can see, oxidation can occur more than
once depending on how many hydroxyls are adjacent. For these terminal hydroxyls, each has only one
hydroxyl next door, so oxidation takes place only once, to produce the aldehyde. But the internal
hydroxyl has two hydroxyls next door, so oxidation occurs twice, to produce the carboxylic acid.
Likewise, oxidation can take place when a hydroxyl is adjacent to a carbonyl. Instead of glycerol,
let’s use glyceraldehyde, again with two equivalents of periodic acid.
Now instead of only acknowledging hydroxyls, we can say that each oxygen-containing functional
group is oxidized a number of times that is equal to the number of neighboring oxygen-containing
functional groups. So on top we have an aldehyde, and there is a hydroxyl next door,
so it is oxidized once to give formic acid. Then there is an internal hydroxyl with one hydroxyl
and one aldehyde on either side, so it is oxidized twice to give formic acid. And then
we have a terminal hydroxyl with one hydroxyl next door, so it is oxidized once to give formaldehyde.
Now consider something like dihydroxyacetone. This has three oxygen-containing functional groups.
The hydroxyls on either end have one carbonyl next door, so these are each
oxidized once to give formaldehyde. But the ketone has two hydroxyls adjacent,
one on either side, so this must be oxidized twice, meaning this will produce carbon dioxide.
So this method of counting the number of oxygen-containing functional groups
on either side and applying that number of oxidations to a functional group
is reliable in determining what will be produced once the carbon-carbon bonds are cleaved.
By the same token, we must understand that if there are intervening carbons that have
no oxygen-containing functionality, no cleavage can occur. So if we return to glycerol but remove
the central hydroxyl, there is no reaction. There must be hydroxyl or carbonyl groups
on adjacent carbons for this to work. Now that we know precisely what kind
of transformation will occur on any substrate, let’s take a look at the mechanism so that we
can understand how this happens. Let’s take the generalized example of two adjacent hydroxyls.
Given that the iodine atom in periodic acid has seven bonds to oxygen, it is significantly
electron-deficient and therefore electrophilic. A hydroxyl can therefore attack and coordinate
to it, kicking one of these pi bonds up onto the oxygen. We can also indirectly transfer
the remaining hydroxyl proton over to the oxyanion just to get these oxygens neutralized. Then we can
do the same thing with the other hydroxyl, attack, kick this pi bond up, and shuffle the protons.
With these three hydroxyls on iodine and protons readily exchanged, it will be easy
for one of them to reform the carbonyl and kick off the other as a water molecule to get here.
Now this is the key step. This intermediate, which is called a cyclic periodate ester,
will undergo cyclization of three sigma bonds as follows. This iodine-oxygen bond will go to form a
carbonyl here, this carbon-carbon bond will cleave and form the other carbonyl, and the electrons in
this other iodine-oxygen bond will remain with the iodine to form a lone pair. This is largely
driven by the strength of carbonyls, given their substantial bond enthalpies. We have thus split
the substrate up into two fragments, producing iodic acid and a water molecule in the process.
So with the mechanism understood, we can see what a useful technique this is, in allowing
us to either break up a molecule into fragments, or open up a cyclic substrate to get a linear one.
So oxidation with periodic acid is definitely a strategy to add to our organic synthesis tool kit.