Alcohols, Epoxides and Ethers
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:
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
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.
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.
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?
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.
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]
“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
Note that we’ve succeeded in adding “CH3OH” in this example across the alkene without any rearrangement occurring.
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
- 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.