The Williamson Ether Synthesis

All About The Williamson Ether Synthesis

In the last post, we discussed the acid-base properties of alcohols. Two posts ago, we said that acid-base reactions are often used to “set up” substitution and elimination reactions of alcohols.  In this post, we’ll talk about what is probably the best example of this last point –  the Williamson Ether Synthesis.
Spoiler: It’s basically just an S_N2 reaction between RO(-) and an alkyl halide, but there are lots of little wrinkles. Read on!

Table of Contents

1. What Is The Williamson Ether  Synthesis?
2. Why Do We Use R–O(–) and  not R–OH As The Nucleophile?
3. Which Alkyl Halides Work Well In The Williamson Ether Synthesis?
4. Starting With An Alcohol: Good and Bad Choices of Base
5. How Do We Choose The Solvent In The Williamson Ether Synthesis?
6. Summary: The Williamson Ether Synthesis
7. (Advanced) References and Further Reading

1. What Is The Williamson Ether Synthesis?

The Williamson Ether Synthesis is an old reaction, dating back to 1851, but hasn’t been surpassed. There just isn’t a simpler way out there to make an ether.

It’s a type of reaction we’ve already seen many times before – an S_N2 reaction between a deprotonated alcohol [“alkoxide”] and an alkyl halide that forms an ether. (See article: The S_N2 Mechanism)

Note that we’re forming and breaking a bond on carbon here – the textbook sign of a substitution reaction.

That’s the standard reaction. It works. But just by looking at a Williamson that “works”, we only get half the picture. In the rest of this post we’re going to look at some ways the Williamson can go wrong, and answer the following questions:

• Why RO- and not ROH as the nucleophile?
• Which alkyl halides work well, and which don’t?
• If we start with an alcohol (ROH) and add a base to get RO- , how do we choose a good base to use?
• How do we choose our solvent?

Let’s dig in.

2. Why Do We Use RO^– and Not ROH As The Nucleophile?

The first thing you might notice about the Williamson is the fact that we use the alkoxide (RO^–) in addition to the alcohol (ROH) in the reaction. You might ask, why bother?

Won’t ROH react with an alkyl halide the same way RO^–does and still give us an ether?

The answer comes back to what we talked about two posts ago: the conjugate base is always a better nucleophile. The reaction of RO^– with an alkyl halide is always going to be much faster than the reaction of ROH because of the higher electron density on the nucleophile (oxygen).  That’s why we use RO^– . (See post: What Makes a Good Nucleophile?)

The most common way to present the Williamson is to show the alkoxide added in the presence of the alcohol.

It’s also possible to start with the alcohol,  add a base to give RO^– , and then add the alkyl halide [note the shaded section]. We’ll talk about that below.

3. Which Alkyl Halides Work Well In The Williamson Ether Synthesis? (and which don’t) 

Here’s where we come back to concepts from midway through Org 1 that resurface in this chapter on alcohols.

The Williamson Ether synthesis is an S_N2 reaction. Remember that since the S_N2 reaction proceeds through a single step where the nucleophile performs a “backside attack” on the alkyl halide, the “big barrier” for the S_N2 reaction is steric hindrance. 

The rate of the S_N2 reaction was highest for methyl halides, then primary, then secondary, then tertiary (which essentially don’t happen at all). The same pattern exists for the Williamson Ether reaction.

Methyl and primary alkyl halides are excellent substrates for the Williamson.

[one exception: the very hindered tert-butoxide anion (t-BuO-) is slower to perform the S_N2 reaction than its other alkoxide counterparts. This alkoxide, also being strongly basic, may instead start to produce elimination (E2) byproducts when primary alkyl halides are used, especially if heated].

Because alkoxides are strong bases (recall the pK_a of alcohols is in the range 16-18), competition with elimination [E2] pathways becomes a concern once the alkyl halide becomes more sterically hindered.

For this reason trying to perform a Williamson on a secondary alkyl halide is a bit more problematic than it is for a primary alkyl halide.

One way to attempt to get the S_N2 to be favoured over the E2 is to use a polar aprotic solvent (such as acetonitrile or DMSO) that will increase the nucleophilicity of the alkoxide. If heat is applied, however, the E2 will most likely dominate.

One substrate that fails completely with the Williamson is tertiary alkyl halides. This should be no surprise, since a backside attack on a tertiary alkyl halide encounters tremendous steric hindrance. Instead of substitution, elimination reactions occur instead, via the E2 mechanism (See post: The E2 Mechanism)

4. Starting With An Alcohol And Adding Base – What Works?

As mentioned above, the most common way to present the Williamson is to show the alkoxide base being added to the alkyl halide in the presence of its conjugate acid as solvent.

However, it’s also possible to start with the alcohol, add base (generating the alkoxide) and then add the alkyl halide.

The question here is, what base should we use?

First of all, it goes without saying that the base must be strong enough to actually deprotonate the alcohol. Using something like Cl- or RCO₂– (acetate) is not going to do the job. Ideally, we’d like something at least as strong a base as alkoxide, or stronger.

Secondly, we need to worry about side reactions. It might help to reflect on how these reactions are run. We typically start with a flask of our alcohol solvent, add base, and then add our alkyl halide. Then, when the reaction is complete, we isolate the product. That means that after the base does its deprotonation, its conjugate acid is still swimming around in solution, and therefore has the potential to react with our alkyl halide (screwing things up).

Here’s an example of a bad choice of base:

NaNH₂ is certainly a strong enough choice of base to deprotonate the alcohol. However, after that’s done, we have NH₃ in solution, and that’s a good enough nucleophile to react with the alkyl halide, giving us amine byproducts in our reaction. Not ideal!

How can we do this the right way? It’s possible to make the alkoxide directly from the alcohol, simply by adding sodium or potassium metal, which liberates hydrogen. Hydrogen is a perfectly innocuous byproduct as far as the alkyl halide is concerned – it will not act as a competing nucleophile, and being a gas, simply bubbles out of solution. After alkoxide formation we can then add our alkyl halide.

A different (but more common) way to do this is to add sodium or potassium hydride (e.g. NaH or KH). This has the same effect as adding sodium or potassium metal – forms the alkoxide and also H₂ – and has the extra bonus of not being strongly reducing, a potential concern if we’re dealing with a complicated starting material that is easily reduced.

5. How Do We Choose Our Solvent In The Williamson Ether Synthesis?

As mentioned above, our normal choice of solvent is the conjugate acid of the alkoxide. [There are exceptions – we might choose to try a polar aprotic solvent if competition with E2 is a concern].

The question is, “why” ? Have you figured it out?

Imagine we were to decide to add sodium ethoxide to propanol, and then add our alkyl halide. What might happen?

This will set up an equilibrium! Our “sodium ethoxide” won’t stay that way for long –  it can deprotonate propanol to give sodium propoxide, along with ethanol. We can theoretically have a mixture of sodium ethoxide and sodium propoxide in solution, which could lead to a mixture of ether products. Again, not ideal.

Why give ourselves this headache? It’s pointless. For that reason, we greatly simplify matters if we just use the alcohol solvent that is the conjugate acid of the alkoxide. 

6. Summary:  The Williamson Ether Synthesis

That’s all there is to say about the Williamson for today. In the next post, however, we’re going to think about this reaction backwards. Starting with a given ether, how can we plan to synthesize it by using a Williamson reaction?

Next Post – The Williamson Ether Synthesis: Planning

Notes

(Advanced) References And Further Reading:

1. XLV. Theory of ætherification.
   Alexander Williamson (1850) , The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science, 37:251, 350-356,
   DOI: 080/14786445008646627
   The original Williamson paper.
2. Equilenin 3-Benzyl Ether
   M. Hoehn, Clifford R. Dorn, and Bernard A. Nelson
   The Journal of Organic Chemistry 1965 30 (1), 316-316
   DOI: DOI: 10.1021/jo01012a520
   One of the reactions in this paper is a classic Williamson reaction – protection of the alcohol in dehydroestrone as a benzyl ether, using benzyl chloride.
3. Total Synthesis of (+)-7-Deoxypancratistatin: A Radical Cyclization Approach
   Gary E. Keck, Stanton F. McHardy, and Jerry A. Murry
   Journal of the American Chemical Society 1995 117 (27), 7289-7290
   DOI: 1021/ja00132a047
   In modern organic synthesis, the Williamson reaction is used for the protection of reactive alcohols in a substrate. Common protecting groups include methoxymethyl (MOM) and 2-methoxyethoxymethyl (MEM). MOM protection is employed in this total synthesis by Prof. Keck and coworkers.