11.1. Writing out a synthesis

In this chapter, we’ll learn about designing a synthesis that involves more than the one or two reactions we’ve seen before.  First, we need to see that we have to write things up differently.  I recommend reviewing sections 7.1. and 7.2. before going further.

When a pharmaceutical company wants to make a new drug, or a technology company needs to prepare an advanced material with unusual properties, it often requires a carefully designed series of reactions to synthesize it.  This sequence of reactions is called a multi-step synthesis.  For example, even a common pharmaceutical such as naproxen requires several synthetic steps to make it:

This is the normal way in which organic chemists present a multi-step synthesis.  You should notice that:

  • The reactions are not balanced
  • Some details of the reactions (such as solvents and reaction time) are often not included
  • No mechanisms are given.

The synthesis shows the reactions (or synthetic steps) strung together in order, with just the main aspects of each reaction shown.  This would normally include the key reagents (such as NaHSO3), written above and/or below the reaction arrow.  This presentation focuses on the main part of the organic molecule, and how it “evolves” as new groups are added (or removed, as with the Br in the second step above); it allows to see the molecule growing until it attains the final product structure.

Given that we have spent a lot of time focusing on the details of individual reactions and their mechanisms, this minimalist description may initially seem baffling.  It is not that these details are unimportant; the chemists who designed this synthesis undoubtedly considered the details of each step, including the mechanisms, when they optimized each reaction for commercial production.  [Author note: This was in fact the focus of my full-time job, when I worked for 12 years in fine chemicals R&D during the 1980s/90s.]

When chemists want to look at a complete multi-step synthesis, they want to see the big picture, without getting distracted by the details.  This allows chemists to compare different overall approaches that might be radically different, and decide which one is likely to be the most efficient and effective.  What general approach was used?  What are the main starting materials, and how were the key bonds put together?  Are there any unusual reactions?  Is there a lot of “busy work” which could be done more efficiently?

In section 7.2., I explained that planning a synthesis is rather like planning a long road trip, where we need to decide the general route to take, rather than getting bogged down in individual right and left turns.  Will we take a more northerly route that is a little faster and shorter, or choose a slightly longer southern route that takes us through some beautiful mountains?  Are we planning to visit a friend along the way?  Likewise, in a synthesis, we may be weighing up the virtues of high yield and efficiency against other factors; perhaps another route would allow us to use a raw material made by our own company?  In an academic paper, perhaps we want to show off some elegant new reaction we have developed?  Or we may be focused on reducing waste by using an environmentally benign synthesis – which will often end up as the most cost-effective process overall.

The important thing to understand here is that we need a strategy for designing a multi-step synthesis.  When faced with a synthesis problem, many students may just reach for the reactions that remember, without considering whether these are the best ones to use.  Of course you could set out on a trip to Paris by just driving down a road you know, but you’re unlikely to see the Eiffel Tower at the end!  In the same way, random reactions won’t work – you need to make sure that the synthesis steps you choose actually lead you towards the product you’re trying to make.  And there are some general guidelines that will help you get there, which we will describe in detail in the next section.