Alcohols, Epoxides and Ethers
Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration
Last updated: November 17th, 2022 |
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 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 SN1 reactions and also through oxymercuration.
Table of Contents
- How To Make Ethers of Tertiary Alcohols When The Williamson (SN2) Isn’t An Option?
- Synthesis of Ethers via SN1 Reactions
- Three Examples of Ether Formation Involving Addition of a Tertiary Alcohol To A Carbocation
- Avoiding Carbocation Rearrangements With Alkoxymercuration
- Summary: Synthesis of Ethers via SN1 (and related) Reactions
- (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. (See article: Williamson Ether Synthesis)
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. (See post: The SN1 Mechanism)
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. (See post: The SN1 Mechanism)
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?). (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?
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 SN1 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 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. 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 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.
Next Post – Ether Synthesis Via Alcohols And Acid
(Advanced) References and Further Reading
- 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
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.
Herbert E. Carter and Harold D. West.
Org. Synth. 1940, 20, 81DOI: 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.
- 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
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.
- 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.
- 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
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.
- 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).
- Reactions of phenols and alcohols over thoria: Mechanism of ether formation
Karuppannasamy, K. Narayanan, C. N. Pillai
J. Catalysis 1980, 66 (2), 281-289
Under forcing conditions, phenol can dehydrate to diphenyl ether, but this proceeds through an unusual mechanism.
- 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
- 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
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.
18 thoughts on “Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration”
If I was asked what would occur with an alkene + ethanol in the presence of HCl, would the answer be nothing, since Cl isn’t a poorly nucleophillic counter-ion like you mentioned?
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?
Without seeing the specific example, it’s hard to say.
How would you make a di-tertbutyl ether from an alkene?
In theory: catalytic acid plus the appropriate alkene plus t-butyl alcohol.
How would you make dicyclohexyl ether?
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.
Why do you say that oxymercuration is not a mechanism typically covered? UCLA teaches it in first quarter of organic chemistry and it was used as a vital reaction in many tough synthesis problems
The mechanism of the final demercuration step is often not covered.
What does Palladium catalyzed ether synthesis look like?
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
How will be the mechanism if primary alkyl halide is treated with tertiary alkoxide anion?
Likely an SN2 reaction.
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)?
The link for NaBH4 mechanism isn’t working
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).
Fixed. Thank you as always.