Hey it’s Professor Dave, let’s talk about amides.
We’ve looked at a few different carbonyl-containing functional groups and their derivatives, so
let’s look at one more, the amide.
As we recall, these consist of a carbonyl adjacent to a nitrogen atom, with the nitrogen
bonded to two other groups, either hydrogen or alkyl in some combination.
There is a lot to talk about with amides, both in the context of their synthesis, and
their role in nature, so let’s start out by getting a more sophisticated understanding
of this functional group and its properties.
Let’s start out by looking at a very simple amide, dimethyl formamide, or DMF.
This has two methyls on the nitrogen atom, and the common prefix “form” is referring
to the lack of alkyl on the other side of the carbonyl, just like with formaldehyde
or formic acid.
DMF is a common organic solvent, which is polar, aprotic, and miscible with water, so
we will encounter this in the lab quite frequently.
One of the most interesting things about amides is the energy barrier for rotation around
the C-N bond, which is substantial.
We know that sigma bonds can rotate freely, so this may seem unexpected.
But we must realize that amides have a zwitterionic resonance structure, whereby the lone pair
on the nitrogen forms a pi bond to carbon, which kicks this pi bond up to form the oxyanion.
This resonance structure is not as strongly contributing as the other, due to the presence
of formal charges, but it still contributes to the composite, which means there is partial
pi bond character between carbon and nitrogen, and this is what limits the rotation around
this bond.
This is not limited to conjecture with lewis dot structures, there is actually very strong
empirical evidence for this fact in the way of X-ray data, which invariably shows that
amides are planar about this region, just like alkenes, which is indicative of the strong
double bond character.
This is in stark contrast with amines, which are pyramidal, as the lone pair occupies one
of the vertices of a tetrahedron, which the lone pair on the nitrogen in the amide does
not do, because of resonance.
In addition, if we look at IR spectroscopy data, the carbonyl stretch for DMF shows up
at a wavenumber of around 1675, as opposed to a ketone, which shows up at 1700 or above.
This means it takes less energy to stretch the carbonyl in an amide than in a ketone,
which is indicative of the fact that the carbonyl in the ketone is localized, whereas in the
amide it is delocalized.
Chemists have calculated that the free energy barrier of rotation around this C-N bond in
DMF is around twenty kilocalories per mole, and this is rather typical of amides.
This is quite an impressive figure to have calculated, which was actually derived from
NMR data.
A typical 400 megahertz proton NMR spectrum of DMF at room temperature shows these two
methyls as two distinct signals, indicating that they are fixed in place and thus not
chemically equivalent.
But if you warm up the probe, slowly the two signals broaden, and coalesce into a singlet,
located exactly at the midpoint of the two former signals.
By measuring the behavior of the signals versus temperature, and using a complex formula derived
from the standard Bloch equations that we won’t go into here, we can obtain the activation
energy for the rotation around this bond that would be required to make these methyls chemically
equivalent.
Now that we’ve looked at DMF for a while, let’s try another amide.
How about secondary amides, whereby the nitrogen is bonded to one hydrogen and one alkyl group.
This means the amide can exist as two isomers, which can be assigned E and Z absolute configuration,
according to the Cahn-Ingold-Prelog convention that we already know.
In practice, however, most chemists simply refer to these as either cis or trans, to
indicate the relative position of the alkyl groups.
Looking at this equilibrium between the cis and trans isomers of a secondary amide, an
energy on the order of twenty kcals per mole, which could allow for free rotation around
the C-N bond, making these conformers rather than isomers.
But with cis and trans isomers of amides, the trans is much more stable for reasons
of sterics, just like we saw with alkenes, so they will exist as 90 to 99 percent as
the trans isomer, in equilibrium with small amounts of the cis isomer.
You may wonder why we are fixated on secondary amides.
Well if you have made it over to my biochemistry playlist yet, you will know that secondary
amides are the basis of proteins, as when amino acids polymerize, they will form peptide
bonds, which are secondary amides.
Biochemists have determined that of all the amino acid residues in all the proteins in
the body, less than 0.1 percent of them contain cis peptide bonds, for the reasons we have
just discussed.
But this small amount does play a definite role in protein structure, as well as the
rate at which they rotate and fold into the most stable conformation.
One other property of amides that is relevant to protein structure is their stability.
Amides are not particularly susceptible to hydrolysis, which is important since biomolecules
are surrounded by water, and we can’t have them falling apart all the time, or life could
not exist.
The half life of a typical biological amide has been estimated as seven years, which is
quite the sweet spot.
As we said, if they were a little less stable, they would fall apart too easily, but if they
were a little more stable, then it would have been too difficult for enzymes to have evolved
that are able to promote hydrolysis of peptide bonds, which would mean that metabolizing
proteins would be impossible, and there would be no way for cells to get the amino acid
building blocks needed to build all the cellular machinery.
If it takes a hundred years to digest a cheeseburger, that’s not a very good recipe for life,
so we owe a lot to the very particular stability of the amide.
Later on we will spend some time talking about protein synthesis not in the context of a
cell, but from the perspective of laboratory organic synthesis, as this is a fascinating
area of study that has progressed tremendously in the past few decades.
But for now, we can just be satisfied with an enhanced understanding of amides and their properties.