Alcohols, Epoxides and Ethers

By James Ashenhurst

Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration

Last updated: September 24th, 2020 |

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 SN2 reaction that was covered several chapters ago. That’s the thing with organic chemistry – things you learn in the early stages of the course often come back in different forms later in the course.

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.

Here’s a summary of what we cover today:

synthesis of ethers from alkenes and alkyl halides via carbocation intermediates attack by alcohols good for tertiary ethers

Table of  Contents

  1. How To Make Ethers of Tertiary Alcohols When The Williamson (SN2) 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 (SN2)  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.

how to make di t butyl ether cannot do through williamson since e2 elimination will occur

Let’s think about this for a second. Back when we covered substitution reactions, we learned that the SN2 was best for primary alkyl halides and poorest for tertiary alkyl halides, due to steric hindrance.

But there was a different substitution reaction we learned that was actually superior for tertiary alkyl halides versus primary alkyl halides – the SN1 – and it had to do with the greater stability of tertiary carbocations versus secondary versus primary carbocations.

ether synthesis recall tertiary carbocations more easily formed than secondary or primary carbocations so lets take advantage of this to make tertiary ethers

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

In fact, we encountered carbocations not only in SN1 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?).

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

Sure!

taking advantage of teritary carbocation formation to make ethers either through addition to alkenes or loss of halide from tertiary alkyl halide

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 solvent. After removal of a proton, we’re left with our ether.

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 SN1 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. However you can click here to see the mechanism of these three reactions

examples of making tertiary ethers from carbocations eg from tertiary alkyl bromide sn1 or from alkenes or from alkene addition hydride shift

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.

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, here’s the NaBH4 mechanism

ether formation avoiding rearrangements with oxymercuration and treatment with nabh4

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 SN1 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


(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.
     194020, 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 SN2 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. SN1 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 20th 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.

Comments

Comment section

15 thoughts on “Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration

  1. In the 3rd figure the structure of the primary carbocation is wrong (it’s actually that of a secondary one, identical to the structure in the middle).

  2. Seeing how the formation of ether starting from an alkene is analogous to hydration of alkene, is it safe to say that treating an ether with H2SO4 can lead to an alkene under certain conditions (weak nucleophile, tertiary carbocation etc)?

    1. It would be a lot like oxymercuration: alkene would coordinate to the metal, and alcohol would attack the most substituted carbon. Except now you have an alkylpalladium species, and this will do beta-hydride elimination, resulting in a new double bond. So it will form an enol ether (if an alcohol is the nucleophile) or a ketone (if water is the nucleophile). For an example see the Wacker oxidation. https://www.organic-chemistry.org/namedreactions/wacker-tsuji-oxidation.shtm

    1. One way would be to start with cyclohexene, add Hg(OAc)2 and then cyclohexanol, followed by NaBH4 to do the demercuration. That would be one of the cleanest ways given the tools that you have.

  3. Is acid-catalyzed ether formation via alcohol reaction possible if what I have is a haloalkene/alkenyl halide? If yes, would it have the same mechanism as with your example in No. 2?

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