Putting it together (1)

I have a lot of students ask me about how to do synthesis. Today, I’ll share with you  a 3-step method I suggest to them, and today we’ll start to go through it. It goes like this:

1. Analyze the starting material and the product – ask yourself, what bonds are formed and what bonds are broken?
2. When you’ve made your list, ask yourself – what reactions do I know that will form/break these bonds?
3. In what order do I do these reactions?

As an illustration, let’s use this synthesis question for alkynes.

Part 1. Asking “what’s new” ? 

A lot of students expect that they’ll be able to look at a synthesis problem and “just see the answer”. This is not how it works. A synthesis question is a bit like solving a Sudoku . There’s a method to it.  Before you can make headway, you have to do some arithmetic first.

Step 1 is where you do your arithmetic. It might really help if you draw out all the hidden hydrogens, because these can be hard to spot. You want to make as complete a list of the bonds that form and break as possible – including all the hydrogens.

Like this:

Part 2: Asking “what are some potential reactions?”

The next step is to ask yourself what reactions form and break these bonds. There’s no getting around the fact that you have to know what each reaction does. But there are a few general hints (that extend beyond alkynes):

• any time you’re breaking a C-C (pi) bond, it’s an addition reaction
• if you’re forming a C-C (pi) bond, it’s an elimination reaction. 
• substitution reactions form and break a bond on the same carbon
•  look for good leaving groups
• pay close attention to stereochemistry

For the reaction we’re talking about, we’re breaking two C-C (pi) bonds, which points to two addition reactions. We’re forming two C-H bonds and two C-OH bonds.

What are some addition reactions that will form these bonds? Here, you have to come up with a list of possibilities. We’re just “playing around” here.

• Hydroboration (form C-H, form C-OH)
• Hydration (form C-H, form C-OH)
• dihydroxylation (form C-OH, form C-OH)
• hydrogenation (form C-H, form C-H)

Tomorrow, we’ll go through these possibilities and figure out which ones make sense and which don’t. 
Thanks for reading! James