Williamson Ether Synthesis: Planning

Planning A Williamson Ether Synthesis: Avoiding The Pitfalls

• The Williamson Ether synthesis proceeds through an S_N2 mechanism
• When planning the synthesis of an ether through the Williamson, remember that S_N2 reactions work well for primary and methyl alkyl halides and fail for tertiary alkyl halides.
• Also, S_N2 reactions do not work at all with alkenyl or aryl halides.
• This means that in certain cases there are definitely “right” and “wrong” ways to plan the synthesis of ethers using the Williamson.

Table of Contents

1. The Williamson Ether Synthesis: Thinking Backwards
2. The Mechanism of The Williamson Ether Synthesis
3. Planning A Williamson: Two Simple Examples
4. Where Planning A Williamson Can Go Wrong
5. Summary: Avoid Planning S_N2 Reactions On Tertiary or Aryl Halides

1. The Williamson Ether Synthesis: Thinking Backwards

In the last post we introduced the Williamson ether synthesis,  one of the most straightforward ways we know of to make an ether. If you’ve been in the trenches long enough, you would have also noticed that it’s actually nothing that new –  the Williamson is just “rebranding” of a reaction we’ve seen before,  the S_N2 reaction between an alkoxide (RO- ) and an alkyl halide (R-X). (See post: The S_N2 Mechanism)

[Side note: when Williamson reported the reaction in 1850 he didn’t know what an S_N2 was – scientists didn’t even know what electrons were, for that matter – which again goes to show that the science of organic chemistry developed through a lot of empirical observations first, and the theory developed later.]

Often we’ll be in the position of having to plan the synthesis of an ether using the Williamson [this happens to be a very popular exam question]. Today we’re going to apply what we know about this reaction to think backwards.  This will be good training for the many occasions later in the course where you’ll be asked to plan syntheses of increasingly complex molecules.

Here’s what we’re going to talk about today:

• Review the mechanism of the Williamson ether synthesis
• Show two easy examples of planning a Williamson
• Show two more difficult examples of planning a Williamson, and how to avoid the most common mistakes

2. The Mechanism of the Williamson Ether Synthesis

As we said above, the Williamson is just an S_N2 reaction between an alkoxide and an alkyl halide.  Here’s the mechanism.

“X” here is just a good leaving group, such as Cl, Br, I, OTs, or OMs. I like to show specific examples instead of “X”, so in the images below, I’ll be using Br, but keep in mind that they work perfectly well if you use any of those other leaving groups I just mentioned in the preceding sentence. Just don’t use F.

What are the most important points to recall about S_N2 reactions?

• It’s a very simple reaction: a bond forms at carbon and a bond breaks on the same carbon.
• Because it proceeds through a backside attack of the nucleophile on the alkyl halide, the “big barrier” (h/t Steven) is “steric hindrance”. The rate decreases as the alkyl halide goes from methyl to primary to secondary to tertiary
• S_N2 reactions don’t proceed at all with tertiary alkyl halides. They also don’t work with alkenyl or alkynyl halides (i.e.  where the halogen is attached directly to a C-C double or triple bond).

Keeping these factors in mind,Williamson Ether syntheses involving a tertiary alkyl halide or alkenyl halide will fail.

3. Planning The Williamson: Two Simple Examples 

Let’s take the first example (diethyl ether) and work backwards. How can we make this molecule through an S_N2 reaction?

We need a nucleophile (alkoxide) and an electrophile (alkyl halide) to combine in a substitution reaction to form diethyl ether.  So let’s “break” one of the C-O bonds of diethyl ether and tack a good leaving group (Br in this example) on the end.

Notice that it’s symmetrical. No matter what C-O bond you choose to form in the process of the S_N2 reaction, you should end up with the same starting materials.

In this example we have an S_N2 between ethoxide ion and an ethyl halide.  This is the only possible way to use the Williamson to make this molecule. This is a perfectly good S_N2 reaction because the electrophile is a primary alkyl halide.

Our next example is ethyl methyl ether (“methoxyethane”). Note here that unlike diethyl ether, this is not a symmetrical molecule.

Therefore there are two possible C-O bonds we could form in an S_N2 reaction that generates the ether.

Let’s call them A (green) and B (blue). Imagine what starting materials would be necessary for the S_N2 that forms bond A, and then think about what starting materials would be necessary for the S_N2 that forms bond B. We call this “retrosynthetically” (reverse-synthesizing, if you will) breaking these bonds.

• Possibility A leads us to a reaction between methoxide (CH₃O^– ) and a primary alkyl halide (ethyl bromide in this example).
• Possibility B leads us to a reaction between ethoxide (CH₃CH₂O^–) and a methyl halide (methyl bromide here).

Both of these S_N2 reactions should work perfectly well. So there’s really no “wrong” way to make this molecule via the Williamson here.

4. Where Planning A Williamson Can Go Wrong

In the preceding examples there was really no “wrong” way to plan the synthesis of our ethers via the Williamson synthesis. It’s not always so straightforward.

Let’s look at t-butyl ethyl ether, for example. As with methyl ethyl ether, there are two possible ways to “disconnect” our desired product into starting materials. Let’s call them Path A and Path B.

• Possibility A involves the S_N2 between ethoxide (CH₃CH₂O^–) and t-butyl bromide.
• Possibility B involves the S_N2 between t-butoxide [(CH₃)₃CO^– ]and ethyl bromide.

Do you notice something wrong here? One of these S_N2 reactions is NOT going to work.

• Possibility A, the S_N2 involving a tertiary alkyl halide is a no-go. In fact, what would happen instead would likely be an E2 reaction (elimination).
• On the other hand, Possibility B (anS_N2 on the primary alkyl halide ) would work just fine.

So there’s definitely a “right way” and a “wrong way” to build this molecule using the Williamson. If you’re planning an S_N2 that involves a tertiary alkyl halide, you’re doing it wrong. 

Let’s look at another example, Phenyl methyl ether.

As before, let’s break it down into two possibilities.

• Possibility A involves the S_N2 of methoxide (CH₃O^–) with phenyl halide.
• Possibility B involves the S_N2 of phenoxide (PhO^–) with methyl halide.

Which S_N2 is going to work better?

If you said possibility B, you’re right. Again, Possibility A doesn’t work because we’d be trying to perform an S_N2 on an sp² hybridized carbon. These aren’t effective. The S_N2 is a reaction that is only effective on sp³ hybridized carbon atoms.

5. Summary: Avoid Planning S_N2 Reactions On Tertiary or Aryl Halides

The bottom line here is that you should plan the synthesis of an ether using a Williamson the same way you’d plan any S_N2.

Choose to break down your ether in a way that allows you to employ, ideally, a methyl or primary alkyl halide. Avoid any syntheses that require employing a tertiary or alkenyl halide.

We didn’t really involve secondary alkyl halides here. They are borderline for a Williamson and it’s not as clear a choice.

This begs the question. What happens if we have to synthesize an ether like this one?

Clearly the Williamson is out. So what do we do?

The answer, as we’ll see in the next post, will involve more déja vu from Org 1.

Think about it for a little while. The oxygen is attached to tertiary carbons.

Can you think of a reaction which prefers tertiary carbons as a starting material (versus primary)?

Answer next time.

Next Post: Synthesis of Ethers (2) – Back To The Future!

Notes