How to Plan a Synthesis.....(part 1)

The ideas collected here are based on the work of  E.J.Corey (Nobel Prize 1990) who was one of the pioneers at trying to design strategies for the synthesis of complex organic molecules.
 

"Retrosynthesis" means planning a synthesis backwards, by starting at the product, the "target" and taking it back a step at a time to simple, available starting materials or precursors.  In general students dislike these problems because it requires "thinking backwards", good problem solving skills, and a good knowledge of their organic reactions. In order to "plan" a synthesis, we can break the target down by making a series of "disconnections" - these steps are the reverse of synthetic steps or reactions.

Why do you think most students struggle with synthesis questions ? 

By now you will probably have written at least one exam that had a lot of reactions on it.... and many of you will have gone into the exam thinking you knew your reactions, but still got a grade you were less than happy with.

Part of the reason for this is shown by the following cartoon that depicts a typical student response to various organic question types......

	Forward thinking
	Fill the gap, forwards or backwards
	Think backwards, but lots of help
	Think backwards with no help !

The MORAL ?
 

An instructor will probably expect that you know your reactions inside out and literally back to front. An idea that may help you to prepare for this is treating reactions as a "triangle" of information that connects the starting material, the product and the reagent.

How to Plan a Synthesis.....(part 2)

Throughout this page we will collect some simple ideas to keep in mind:

• Most reactions occur at or adjacent to FUNCTIONAL GROUPS.
• FUNCTIONAL GROUPS characterize the reactivity of molecules.

• functional group interconversions (e.g. R-Br to R-OH)
• carbon-carbon bond forming reactions (e.g. reactions of Grignard reagents)

• Recognize the FUNCTIONAL GROUPS in the TARGET.
• Ask yourself how you could make this functional group.
• Use disconnections that correspond to known and reliable reactions.
• Repeat steps these steps to reach available starting materials.

• Write out the plan according to the analysis adding reagents and conditions
• refine plan based on practical results and or a rational order

• Make synthesis as short as possible.
• Use disconnections that correspond to known and reliable reactions.
• Disconnect C-X or C-C bonds.
• The reactions of alcohols, aldehydes / ketones and carboxylic acids are some of the most important.
• If possible aim for the greatest simplification by disconnecting at the middle of molecules, at branch points or rings from chains or use symmetry (if there is any)
• There are rarely unique solutions, but some are better than others
• As simple as it sounds COUNT CARBONS !

What is the functional group ?

Scenario 1 Lets first consider "disconnecting" the R group by breaking the C-C bond at the functional group.
This would correspond to the reaction of an organometallic reagent (which is equivalent to the carbanion, R-) with methanal (which has an electrophilic C)
Scenario 2 Alternatively we could "disconnect" an H atom by breaking a C-H bond at the functional group.
This would correspond to the reaction of a reducing agent such as lithium aluminum hydride with an aldehyde:

Let's think about disconnections in general. When we break a bond, most likely we will be considering heterolytic reactions involving nucleophiles and electrophiles, so we need to "consider" which fragment is the nucleophile and which is the electrophile. Consider both options, but typically one will make much more sense than the others provided you know how to recognize nucleophilic and electrophilic centers.

In order to become good at synthesis problems practice is the best tactic. (it also helps you learn your reactions)
 

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