Planning Organic Synthesis With “Reaction Maps”

Organic Synthesis: A Little Bit Like Planning A Trip, But With Functional Groups As “Airports” And Reactions As “Flights”. 

By this point we’ve gone over all the major classes of reaction covered in many typical first semester organic chemistry courses.: acid base, substitution, elimination, addition, free-radical reactions, even oxidative cleavage.

Our primary focus has been looking at these reactions as means of transforming one functional group into another, which is the most intuitive way to think about reactions when you’re just starting out.

Once you learn a certain number of reactions, however, you’ll find that it’s possible to think about changing one functional group to another using two, three, or even more steps.

This is exciting! It’s like the moment when you’re learning a new language and you find you are able to take individual sentences and put them together into paragraphs. [Or paragraphs into essays – choose your metaphor].

Let’s give a quick example.

Table of Contents

1. What Do You Do When A Transformation Can’t Be Done In One Step?
2. Look For Ways In Which Functional Groups Can Be Interconverted In Two Or More Steps
3. Build “Reaction Maps” To Plan Your Syntheses
4. Some Examples of Reaction Maps

1. What Do You Do When A Synthetic Transformation Can’t Be Done In One Step?

Say we’d like to take ethane and convert it into ethane thiol. [Note 1]

We don’t know how to do this directly: there aren’t any reactions we’ve learned so far that will give ethanethiol from ethane in one step. So how might we do this?

Let’s answer this by way of an analogy. Imagine you’re in Bozeman, Montana and want to get to Charlotte, North Carolina. The problem is, there aren’t any flights that go directly to Charlotte. So what do you do?

Find a connecting flight! As it turns out you can fly from Bozeman to Denver, and from Denver you can then connect to Charlotte. [Or lots of other places, for that matter].

2. Look For Ways In Which Functional Groups Can Be Interconverted In Two Or More Steps

It’s the same way with synthesis. If a direct route cannot be found, we have to start looking for a way to achieve the same transformation in two or more steps.

We learned that alkanes can be transformed into alkyl chlorides (a type of alkyl halide) through treatment with chlorine gas and light (or heat). In the series on substitution, we also saw that alkyl halides can be converted into alcohols, ethers, nitriles, and many other functional groups (including thiols) through substitution reactions.

So long as we are aware of these two reactions, the solution is simple. First, treat ethane with Cl₂ and light to give ethyl chloride. Then, treat ethyl chloride with NaSH to give ethane thiol.

To continue the travel metaphor, it can be helpful to think of functional groups as cities on a map, and reactions as “flights” that connect those cities. Some cities, like Bozeman, will have few connecting cities; others, like Denver, will be veritable hubs.  Similarly, some functional groups, like alkanes, will have few connecting reactions, while others – like alkyl halides – will have many.

In the next few posts, this is how we’re going to think about organic synthesis. We’ll go through some of the functional groups we’ve explored so far, and map out the reactions we’ve learned. As we go along, we’ll find that we’ll be able to make progressively longer and more interesting “journeys” between functional groups.

3. Building “Reaction Maps” To Plan Organic Syntheses

Making maps is the best way I know to put all the reactions of organic chemistry in perspective and to help navigate an introduction to organic synthesis.

We’re not going to care so much about finding the “shortest” journeys, although that would be a nice bonus. The key thing will be just to get to the desired destination. Later on, after a lot of practice, one gets much better at picking the fastest routes between starting materials and final products.

PS Here’s the map I put together in a hotel room in Beirut, Lebanon after reading through Cram’s “Elements Of Organic Chemistry“. Things get really fun when you can trace routes that start with one functional group and go through a circuitous path back to the original functional group.

4. Some Examples of Reaction Maps

In various posts we’ve put together some useful reaction maps for various kinds of functional groups. Check these out.

• Alcohol Reactions Roadmap
• Alkyne Reactions Roadmap
• Reactions of Organometallics
• Reactions of Benzene and Aromatic Compounds
• Reactions of Alkenes
• Reactions of Alkyl Halides

There is also a collection of Reaction Maps available on the MOC store that gather together all the key reactions from a typical Org 1/Org 2 course. It’s $15. Available here.

Note 1. If you’re ever annoyed that people stand too close to you on the bus, making a vat of ethanethiol with sloppy lab technique will solve that problem for you.