Retrosynthetic Analysis

Creative chemistry
Chemistry is above all a creative science. Nearly all that you have learned so far in this book
has had one underlying aim: to teach you how to make molecules. This is after all what most
chemists do, for whatever reason. Small amounts of many drugs can be isolated from plants
or Marine animals; much greater quantities are made by chemists in laboratories. A limited
range of dyes can be extracted from plants; many more vivid and permanent ones are made
by chemists in the laboratory. Synthetic polymers, created by chemists, have replaced more
expensive and less durable alternatives like rubber. Despite the bad press it has received, the
use of PVC as insulating material for electric wires has prevented numerous fi res and saved
many lives. Food is healthier and people live longer because well-designed and controlled
pesticides allow agriculture to supply copious quantities of disease-free food to the shelves of
our shops, markets, and supermarkets. Most of the improvements in the quality of life over
the last 50 to 100 years can be traced to new molecules created by chemists. But, faced with
the challenge of making a new compound, how do chemists go about deciding how to make
it? Synthetic planning starts with the product, which is fi xed and unchangeable, and works
backwards towards the starting materials. This process is called retrosynthesis, and the art of
planning the synthesis of a target molecule is called retrosynthetic analysis. The aim of this
chapter is to introduce you to the principles of retrosynthetic analysis: once you have read
and understood it you will be well on the way to designing your own organic syntheses.
Retrosynthetic analysis: synthesis backwards

Most of the chemistry you have learned so far has concentrated on reactions (questions like
‘What do you need to add to X to get Y?’) or on products (questions like ‘What will happen
if X and Y react together?’). Now we’re looking at starting materials (questions like ‘What X
and Y do you need to react together to make Z?’). We’re looking at reactions in reverse, and
we have a special symbol for a reverse reaction called a retrosynthetic arrow (the ‘implies’
arrow from logic). A scheme with a retrosynthetic arrow (margin) m a retrosynthetic arrow
eans ‘Z could be made from X plus Y’.
Here’s a very simple fi rst example. This compound is used as an insect repellent. As it’s an
ester, we know that it can be made from alcohol plus acyl chloride, and we can represent this
using a retrosynthetic arrow.
The aromatic amide amelfolide is a cardiac antiarrhythmic agent. Because we see that it is an
amide, we know that it can be made quite simply from p-nitrobenzoyl chloride and 2,6-
dimethylaniline—again, we can represent this using a retrosynthetic arrow. Mentally
breaking a molecule into its component parts like this is known as disconnection, and it’s
helpful to indicate the site of the disconnection with a wiggly line as we have here.
Disconnections must correspond to known, reliable reactions

The chemists who fi rst made amelfolide chose to make it from an amine and an acyl chloride
because they knew that this reaction, a standard way of making an amide, had a very
good chance of success. They chose to disconnect the C–N bond because this disconnection
corresponds to a reliable reaction in a way that no other possible disconnection of this
molecule does.
Now that you’ve seen the principle of retrosynthetic analysis at work, you should be able to
suggest a reasonable disconnection of the compound in the margin, known as daminozide.
You probably spotted immediately that daminozide is again an amide, so the best
disconnection is the C–N bond, which could take us back to acyl chloride and
dimethylhydrazine. This time we’ve written ‘C–N amide’ above the retrosynthetic arrow as a
reminder of why we’ve made the disconnection and we advise you to follow this practice.
Now, in fact, there is a problem with this acyl chloride—it would be unstable as it can cyclize
to an anhydride. But this poses no problem for the synthesis of daminozide—we could just
use the anhydride instead, since the reaction should be just as reliable. A better retrosynthesis
therefore gives the anhydride and indeed this is how daminozide is made.
Synthons are idealized reagents
In the synthesis of daminozide an anhydride is used out of necessity rather than out of
choice, but it often turns out that there are several alternative reagents all corresponding to the
same disconnection. Paracetamol, for example, is an amide that can be disconnected either
to amine + acyl chloride or to amine + anhydride.
Which reagent is best can often only be determined by experimentation—commercially,

paracetamol is made from para-aminophenol and acetic anhydride largely because the by
product, acetic acid, is easier to handle than HCl. In a retrosynthetic analysis, we don’t really
want to be bothered by this sort of decision, which is best made later, so it’s useful to have a
single way of representing the key attributes of alternative reagents. We can depict both
anhydride and acyl chloride in this scheme as an ‘idealized reagent’—an electrophilic acetyl
group MeCO+.
We call such idealized reagents synthons. Synthons are fragments of molecules with an
associated polarity (represented by a ‘ + ‘ or ‘–’) which stand for the reagents we are going to
use in the forward synthesis. They are not themselves reagents, although they may
occasionally turn out to be intermediates along the reaction pathway. By disconnecting bonds
to synthons rather than to actual reagents we can indicate the polarity of the bond-forming
reaction we are going to use without having to specify details of the reagents.
We can apply these ideas to the synthesis of the herbicide 2,4-D (2,4-dichlorophenoxyacetic
acid). The most reasonable disconnection of an ether is the C–O bond because we know that
ethers can be made from alkyl halides by substitution with an alkoxide anion. We don’t at
this stage need to decide exactly which alkyl halide or alkoxide to use, so we just write the
synthons.
Once the retrosynthetic analysis is done, we can go back and use our knowledge of chemistry
to think of reagents corresponding to these synthons. Here, for example, we should certainly
choose the anion of the phenol as the nucleophile and some functionalized acetic acid
molecule with a leaving group in the á position.
We can then write out a suggested synthesis in full from start to fi nish. It isn’t reasonable to
try to predict exact conditions for a reaction: to do that you would need to conduct a thorough
search of the chemical literature and do some experiments. However, all of the syntheses in
this chapter are real examples and we shall often give full details of conditions to help you
become familiar with them.
Choosing a disconnection
The hardest task in designing a retrosynthetic analysis is spotting where to make the
disconnections. We shall offer some guidelines to help you, but the best way to learn is
through experience and practice. The overall aim of retrosynthetic analysis is to get back to
starting materials that are available from chemical suppliers, and to do this as effi ciently as
possible.
We have already mentioned that disconnections must correspond to known reliable reactions
and it’s the most important thing to bear in mind when working out a retrosynthesis.
When we disconnected the ether 2,4-D we chose to disconnect next to the oxygen atom
because we know about the synthesis of ethers. We chose not to disconnect on the aryl side of
the oxygen atom because we know of no reliable reaction corresponding to nucleophilic
attack of an alcohol on an unactivated aromatic ring.
In all the retrosynthetic analyses you’ve seen so far there is a heteroatom (N or O) joining the
rest of the molecule together, and in each case we made the disconnection next to that N or O.
This guideline works for esters, amides, ethers, amines, acetals, sulfi des, and so on because
these compounds are often made by a substitution reaction. Chlorbenside is used to kill ticks
and mites. Using Guideline 2 we can suggest a disconnection next to the sulfur atom; using
Guideline 1 we know that we must disconnect on the alkyl and not on the aryl side.
We can now suggest reagents corresponding to the synthons and propose a synthetic scheme.
The next example is the ethyl ester of, and precursor to, cetaben, a drug that can be used to
lower blood lipid levels. It is an amine, so we disconnect next to the nitrogen atom.
The alkyl bromide is available but we shall need to make the aromatic amino-ester and the
best disconnection for an ester is the C–O bond between the carbonyl group and the
esterifying group.

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What is retrosynthetic analysis and why is it important in organic chemistry?

What are some guidelines for choosing where to make disconnections in a retrosynthetic analysis?

Creative chemistry

Retrosynthetic analysis: synthesis backwards

Disconnections must correspond to known, reliable reactions

Which reagent is best can often only be determined by experimentation—commercially,

become familiar with them.

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