00:01
So, let’s have a brief look at the reactivity
of carboxylic acid derivatives as a general
group. This is the order of reactivity starting
with the least reactive on the right hand
side and going to the most reactive on the
left hand side. And this, to be honest with
you, is a crucial element when it relates
to the biology. As you know, proteins have
a primary structure which consists of amino
acids joined by a series of amide bonds to
each other. And so, therefore, this is rather
a good job that they are the least reactive,
otherwise you would be getting a relatively
easy, simple hydrolysis of these amide bonds
of your proteins.
00:38
As it happens, specific enzymes are usually
required to break these down; enzymes known
as peptidases or amidases. If we move from
right to left, we can see that the degree
of reactivity goes along in terms of nucleophilic
addition elimination reactions as carboxylic
acid, followed by carboxylic ester, followed
by carboxylic acid, followed by anhydride
until finally we get to the most reactive,
an acid chloride. In fact, acetyl chloride
is so reactive that it is otherwise known
as a lachrymator.
01:12
What happens is that fumes of acetyl chloride
in a laboratory, if they are exposed to the
mucous membranes like, for example, in the
eyes, can react with the water and generate
quantities of hydrochloric acid and also of
the acetic acid and this is irritant and causes
you to cry, hence the term lachrymatory, that’s
how reactive they are.
01:35
These are the types shown in that rectangle
that you tend to use where you can, in order
to carry out an actylation reaction, as they
are, generally speaking, the easiest to work
with and afford you the largest yields. The
reactivity, as you can appreciate, depends
on the electrophilicity of the carbon-oxygen
double bond. And so, what I’d like to do
before we go on is draw your attention to
the electronegativity of the groups attached
to the carbonyls.
02:03
In the case of the chlorine, we know that
it is electronegative because it is in group
7. And so, this… what this does is render
the delta positive on the carbon even more
pronounced and even more delta positive than
on, for example, the carboxylic acid. So,
aside from just affording us a good leaving
group as the chloride, it also actually makes
that carbonyl carbon more electrophilic than
in the case of either the carboxylic ester
and certainly, in the case of the amide.
02:30
So, let’s have a look. How do we make these
things, at the end of the day, since obviously,
a carboxylic acid in itself is not particularly
useful from a synthetic perspective very often,
how do we actually make these things? So,
I am going through, here, just a few reactions
as to how you can convert a carboxylic acid
into an ester, an acid chloride, an acid anhydride
and also, an amide.
02:54
So, in the first instance, conversion into
an ester can be accomplished by dissolving
the carboxylic acid up usually in an alcohol
of choice. In this case, we have shown the
OR group in green, this could be an ethoxy
group and this could be a propoxy group, it’s
largely irrelevant. And this is known as a
Fischer Esterification. So, you add a catalytic
amount of H+ in the form of maybe a mineral
acid like hydrochloric acid and it converts
the carboxylic acid into the ester.
03:25
Now, this is okay if it’s possible in your
reaction to be able to heat the thing up under
reflux, but if this is going to cause problems
with other parts of the molecule then there
are simpler ways and coupling reagents and
something otherwise known as the Mitsunobu
reaction, which if you are really interested
about how esters are formed, you may wish
to read up about.
03:44
Making acid chlorides is also can be a little
bit on the tricky side, but this is facilitated
in the same way that alcohols can be converted
to haloalkanes by thionyl chloride or SOCl2.
03:58
Another way of converting these is via PCl5,
this is phosphorous pentochloride. Again,
care should be taken when working with either
of these compounds as they can produce toxic
fumes.
04:10
In the third scenario, an acid anhydride,
this is where we have taken two acids, put
them together and removed water. This can
be facilitated in a number of ways, one of
those is actually by reacting a carboxylic
acid directly with an acid chloride generating
hydrochloric acid and the associated acid
anhydride. However, the way I have shown here
is to use phosphorous pentoxide which is a
very strong dehydrating agent which removes
water from those two carboxylic acids forming
the acid anhydride.
04:43
And finally, amide formation. Now, I have
shown a very basic way of generating an amide
from a carboxylic acid. You take an amine,
which we will see in the next lecture, and
then you heat it up, usually in the presence
of an acid catalyst, and you dehydrate it.
05:01
The conditions for this are sometimes really,
really unpleasant, in terms of the actual
temperatures you have to achieve and the length
of time you have to get it under reflux.
05:11
When you are talking about synthesising polypeptides
from a biological perspective, there are far
better ways of doing it than this, but this
just demonstrates the basic principles by
which OH-, in this case, can be lost from
the carboxylic acid and an amine can be put
in its place. If you are interested in looking
at polypeptide synthesis and coupling agents,
then I recommend that you look at dicyclohexylcarbodiimide,
that is a basic one and although also, EDCI
and [Unaware 00:27:11] as another.