Right. Amide formation from esters.
If you recall a couple of slides ago, I talked
about the biological input or importance of
this because activation of certain amino acids
by transesterification is important for them
to then be converted into amides and we will
see this in Module IV when we start looking
at the biology behind it.
In this particular case, I am sharing a relatively
simple addition elimination reaction. In the
case of methylamine or methylamine, depending
on which side of the water you are from, and
you have the lone pair of nitrogen again attacking,
in this case, the carbonyl carbon, opening
it up and, in this case, kicking off a methoxide
ion. Now, this in itself is not a reaction
which would necessarily always go to completion
and you can tell this by the fact you have
an arrow going in one direction and an arrow
going in the other direction, which suggest
that this is in equilibrium. And so, you should
be trying to remove the amide acid that is
formed to push the equilibrium in the direction
of the desired product.
It should be stressed that esters cannot be
formed from amides, although having said this
from a chemical perspective, it’s not possible,
but in biology, enzymes do achieve this and
as I said, we will see more of that a little
It is also possible to reduce esters to alcohols.
This reduction can take place through the
use of a hydride transfer reagent such as
lithium aluminium hydride or lithal, for short,
followed by proteination to remove the lithium
salt. As you can see, the ester is converted,
first, to an aldehyde and then in this case,
back down to the primary alcohol. It is also
possible to reduce amides to amines using
the same technique, although indeed, another
reducing agent [Unaware 00:33:10] is also
possible to reduce this as well.
Note, we are converting the carbonyl into
an alcohol in the first instance, which forms
an amine, which is then reduced even further.
So, in this particular case, we have converted
our amide carbonyl into a CH2 group, as you
can see in the bottom right hand corner. So,
care must be taken and indeed, there are a
number of text books available when you actually
have got multiple functional groups that you
only want to reduce one or other, but not
usually both or maybe several of them. So,
you have to be careful to select your reagents
in order to make sure that you have achieved
the desired outcome in your reaction.
So, in summary, substitution reactions, and
this is what we started off with, involves
nucleophilic attack and a carbonyl carbon
with a reasonable leaving group in the form
of that denoted by Z. This opens up that SP2
hybridised carbonyl carbon, generates a tetrahedron
intermediate and then the negative charge
on the oxygen kicks back in, reforms the carbonyl
and discharges the Z leaving group, shown
here as Z-.
There are a number of different substituents
which forms the category of Z, in this case,
but when you are trying to substitute in that
position, you need to make sure your nucleophile
is a worse leaving group than your Z, whatever
that may be.
So, Z- must be a better leaving group than
the nucleophile, otherwise the reverse reaction
can take place. The nucleophile must also
be strong enough to actually attack whichever
the carboxylic acid derivative you are looking
at. It also must be an electrophile good enough
to react with the nucleophile in the first
place and this is where the amide falls down.
Bearing in mind, if we go back to the structure
of the amide, you actually have the lone pair
of the nitrogen donating back into the carbonyl
carbon and decreasing the size of the dipole.
And so, finally, this is a scheme which shows
not just how carboxylic acid derivatives can
be formed, which is in the first part in the
center, but also on the right hand side, the
reactions and the inter conversions that can
take place. And my recommendation is that
you actually study this and make sure you
are familiar with those interconversions.
Even if you are not necessarily 100 percent
certain about the particular mechanisms, you
should be aware of how acid chlorides can
be converted to a wide variety of different
other carboxylic acid derivatives and vice