Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration

When The Williamson Doesn’t Work: Synthesis of Tertiary Ethers From Alkenes, SN1 Reactions, and  Alkoxymercuration

In the last two posts we’ve been discussing the Williamson synthesis of ethers. As we saw, our discussion was essentially a complete re-hash of everything we’d already said about the S_N2 reaction that was covered awhile back.

That’s the fun* thing about organic chemistry – things you learn in the early stages of the course often come back in different forms later in the course. (*your definition of “fun” may vary)

Today’s post is similar in that we’re just going to be going back to old reactions we’ve already seen and look at them in a new light.

In this post, we’ll cover making ethers via S_N1 reactions and also through oxymercuration.

Table of  Contents

1. How To Make Ethers of Tertiary Alcohols When The Williamson (S_N2) Isn’t An Option?
2. Synthesis of Ethers via SN1 Reactions
3. Three Examples of Ether Formation Involving Addition of a Tertiary  Alcohol To A Carbocation
4. Avoiding Carbocation Rearrangements With Alkoxymercuration
5. Summary: Synthesis of  Ethers via SN1 (and related) Reactions
6. (Advanced) References and Further Reading

1. How To Make Ethers of Tertiary Alcohols When The Williamson (S_N2)  Isn’t An Option?

We ended the last post by posing a question.  How do we synthesize ethers like this one below (di-t-butyl ether) ?

We saw that when we attempt to form ethers like this through a Williamson reaction, it fails miserably – giving us elimination products (via an E2) rather than the desired ether. (See article: Williamson Ether Synthesis)

Let’s think about this for a second. Back when we covered substitution reactions, we learned that the S_N2 was best for primary alkyl halides and poorest for tertiary alkyl halides, due to steric hindrance. (See post: The S_N1 Mechanism)

But there was a different substitution reaction we learned that was actually superior for tertiary alkyl halides versus primary alkyl halides – the S_N1 – and it had to do with the greater stability of tertiary carbocations versus secondary versus primary carbocations. (See post: The S_N1 Mechanism)

2. Synthesis of Ethers via Reactions of Alcohols With Alkenes or Alkyl Halides

In fact, we encountered carbocations not only in S_N1 reactions but in another type of reaction as well. If we take an alkene and add acid, recall that we end up forming a new C-H bond on the least substituted carbon of the alkene and we form a carbocation on the more substituted carbon of the alkene (remember Markovnikov’s rule?). (See article: Markovnikov’s Rule)

This might get you to thinking – can we use either of these reactions to form ethers, via a carbocation intermediate?

Sure!

We can form this carbocation two ways.

If we dissolve an alkyl halide in the appropriate alcohol solvent, eventually the leaving group will leave, forming the carbocation – which is then trapped by the alcohol solvent. After removal of a proton, we’re left with our ether. This is a classic S_N1 reaction.

Alternatively, if we start with an alkene in an appropriate alcohol solvent, and treat with a strong acid – ideally a strong acid with a poorly nucleophilic counter ion [ yes to H₂SO₄ and TsOH as acids, generally no to HCl, HBr, and HI] the carbocation will likewise be generated, which is then trapped via the same pathway as before.

3. Three Examples Of  Ether Formation Involving Addition Of  an Alcohol To A Tertiary  Carbocation

Let’s look at three examples. The first one is a typical S_N1 reaction. The second one is an alkene addition reaction. The third one is alkene addition… with a twist!

[Note – I didn’t put the mechanisms of these reactions in because we’ve talked about these mechanisms so many times before. To see them,  hover here or click this link.

 click here to see the mechanism of these three reactions] 

4. Avoiding Carbocation Rearrangements By Using Alkoxymercuration

“Oh yes”, you might be saying at this point, like someone who suddenly finds themselves awkwardly face-to-face with an old ex-boyfriend or ex-girlfriend. “Rearrangements.” Yes, rearrangements again!

Anytime we deal with carbocation intermediates, rearrangements are going to be something to watch out for. If we form, for example, a secondary carbocation adjacent to a tertiary or quaternary carbon, expect a hydride or alkyl shift (respectively) that will result in a more stable carbocation.

There is, however, a way out!

In particular, there’s a way we can form ethers from alkenes in a way that doesn’t involve a carbocation intermediate. It’s also a reaction we’ve seen before: oxymercuration. (See post: The Three-Membered Ring Pathway)

Oxymercuration involves dissolving the starting alkene in an alcohol solvent and adding a source of mercury(II) like Hg(OAc)₂ . A “mercurinium” ion is formed, which is then attacked at the most substituted position by one of the molecules of alcohol solvent.

After removal of a proton, we’re left with the product of “oxymercuration”. The mercury can then be removed by treatment with sodium borohydride (NaBH₄). We often don’t cover the mechanism, but if you’re curious, hover here or click this link.

Note that we’ve succeeded in adding “CH₃OH” in this example across the alkene without any rearrangement occurring.

5. Summary:  Synthesis of Ethers Through SN1 (And Related) Reactions

To summarize, we’ve revisited three methods today for ether synthesis:

• Ether synthesis via S_N1 reaction of tertiary alkyl halides
• Ether synthesis via acid catalyzed addition of alcohols to alkenes
• Oxymercuration of alkenes in alcohol solvent

These serve as a useful alternative to the Williamson in cases where we want to build ethers of secondary and tertiary alcohols.

Now that you’ve covered the basics of ether synthesis, the world is your oyster. Just wait until you learn about all the exciting things we can do with ethers now that we know how to make them.

The next post in this series is going to be so exciting, I’m having a very difficult time restraining myself from spilling the beans. Yet, I must.

Excitement awaits!

Next Post – Ether Synthesis Via Alcohols And Acid

Notes

(Advanced) References and Further Reading

1. Solvomercuration-demercuration of representative olefins in the presence of alcohols. Convenient procedures for the synthesis of ethers
   Herbert Charles Brown and Min-Hon Rei
   Journal of the American Chemical Society 1969, 91 (20), 5646-5647
   DOI: 1021/ja01048a042
   Original paper by Prof. H. C. Brown on ‘solvomercuration’-demercuration to synthesize ethers by Markovnikov addition of the alcohol, without rearrangement. What is noteworthy in reading this paper is that the reaction is fast – the mercuration takes about 10 minutes, after which the basic NaBH₄ solution is added. It takes about 2 hours for demercuration to complete.
2. DL-Serine
   Herbert E. Carter and Harold D. West.
   Org. Synth. 1940, 20, 81
   DOI: 10.15227/orgsyn.020.0081
   The first step of this process is an alkoxymercuration reaction of methyl acrylate with Hg(OAc)₂ in methanol. (Interestingly, it goes anti-Markovnikov due to the electron-withdrawing effect of the adjacent methyl ester). The mercury is then replaced with bromine (via Br2) and the resulting alkyl halide then undergoes S_N2 with NH₃, giving the amino acid.
3. Activation of olefins via asymmetric Brønsted acid catalysis
   Nobuya Tsuji, Jennifer L. Kennemur, Thomas Buyck, Sunggi Lee, Sébastien Prévost, Philip S. J. Kaib, Dmytro Bykov, Christophe Farès, Benjamin List
   Science 2018: Vol. 359, Issue 6383, pp. 1501-1505
   DOI: 10.1126/science.aaq0445
   Prof. Benjamin List (now at Max Planck Institute, Germany) is a key contributor to the field of organocatalysis. In this paper, he describes the use of a bulky chiral Brønsted acid for asymmetric, intramolecular ether synthesis. By using this acid, one face of the intermediate cation that is formed from protonation of the olefin will be blocked, thus favoring a selective addition.
4. Catalysts for forming Diethyl Ether
   Inventors: Cheng Zhang, Victor J. Johnson
   Assignee: Celanese International Corp.
   Publication Date: 18, 2014
   Pub. No.: US 20140275636A1
   This describes an industrial process for diethyl ether synthesis, which is done using a heterogeneous catalyst.
5. Single stage synthesis of diisopropyl ether – an alternative octane enhancer for lead-free petrol
   Frank P. Heese, Mark E. Dry, Klaus P. Möller
   Catalysis Today 1999, 49 (1-3), 327-335
   DOI: 1016/S0920-5861(98)00440-4
   This paper shows that the mechanism for formation of symmetrical ethers from secondary alcohols (e.g. isopropanol) is more complex, as bimolecular dehydration can compete with other pathways (e.g. S_N1 or elimination-addition). Diisopropyl ether is sometimes used as a solvent but requires even more care with handling and storage compared to other ethers, as it is even more prone to formation of explosive peroxides.
6. Process for Preparing Diisopropyl Ether
   Inventor: Hanbury John Woods
   Assignee: Gulf Oil Canada Limited
   Publication Date: 16, 1977
   Pub. No.: US 4,042,633
   A patent on an industrial process for preparing diisopropyl ether from isopropanol. This is also done with a heterogeneous catalyst (Montmorillonite clay in this case).
7. Reactions of phenols and alcohols over thoria: Mechanism of ether formation
   Karuppannasamy, K. Narayanan, C. N. Pillai
   J. Catalysis 1980, 66 (2), 281-289
   DOI: 10.1016/0021-9517(80)90032-9
   Under forcing conditions, phenol can dehydrate to diphenyl ether, but this proceeds through an unusual mechanism.
8. Stable carbocations. Part 275. The dodecahedryl cation and 1,16-dodecahedryl dication. Proton and carbon-13 NMR spectroscopic studies and theoretical investigations
   George A. Olah, G. K. Surya Prakash, Wolf Dieter Fessner, Tomoshige Kobayashi, and Leo A. Paquette
   Journal of the American Chemical Society 1988, 110 (26), 8599-8605
   DOI: 1021/ja00234a004
9. Stable carbocations. Part 267. Pagodane dication, a unique 2.pi.-aromatic cyclobutanoid system
   K. Prakash, V. V. Krishnamurthy, Rainer Herges, Robert Bau, Hanna Yuan, George A. Olah, Wolf Dieter Fessner, and Horst Prinzbach
   Journal of the American Chemical Society 1986, 108 (4), 836-838
   DOI: 10.1021/ja00264a046
   One of the big challenges in synthetic organic chemistry in the late 20^th century was the synthesis of the Platonic hydrocarbon dodecahedrane (C₂₀H₂₀). Many groups all over the world attacked this problem from many angles, and the eventual ‘winner’ was Prof. Leo Paquette (Ohio State University). Prof. Horst Prinzbach (U. Freiburg, Germany) approached this by attempting to isomerize the hydrocarbon ‘pagodane’ (so called because of the shape). Both dodecahedrane and pagodane give solutions of stable carbocations in superacidic media, and quenching these solutions in cold methanol yields the methyl esters.