Alcohols, Epoxides and Ethers
Opening of Epoxides With Acid
Last updated: January 17th, 2023 |
Opening Epoxides With Aqueous Acid
- Epoxides can undergo ring-opening with nucleophiles under acidic conditions.
- In this reaction, the epoxide oxygen is protonated first, making it a better leaving group
- In the second step, the nucleophile tends to attack the more substituted carbon, which breaks the weakest C-O bond.
- The best analogy is that it is a lot like the Markovnikov opening of bromonium or mercurinium ions.
Table of Contents
- Formation of trans-Diols Through Opening of Epoxides With Aqueous Acid
- The Mechanism For Opening of trans-Diols With Acid Is Similar To Opening Halonium Ions
- Other Nucleophiles: Alcohols and HX
- Acid Only Helps The Reaction If The Nucleophile Is Compatible With Strong Acid
- What About Opening of Epoxides With Base?
- (Advanced) References and Further Reading
In the last post, we saw some examples of how epoxides are considerably more reactive towards breakage than are ordinary ethers. For example, aqueous acid [often abbreviated “H3O+”] will open an epoxide under MUCH milder conditions than an “ordinary” ether such as diethyl ether, because epoxides have considerable ring strain [about 13 kcal/mol].
Looking more closely at the reaction, we also noted two interesting patterns:
- the nucleophile attacks at the “more substituted” position of the epoxide (C-1, below)
- inversion of stereochemistry occurs at this position, but not at the other position (note that the C-O bond at C-2 below is a “wedge” in both starting material and product ).
It should be noted that in the absence of acid, no reaction occurs. So clearly the H+ plays a key role.
What could be going on?
By analogy to the reaction of ethers with acid, the first step must be reaction of the most basic site on the molecule – the epoxide oxygen – with acid, giving us a protonated epoxide. This will function as a much better leaving group than does the unprotonated epoxide. [Recall that the conjugate acid is always a better leaving group]
The next step must then be reaction of the best nucleophile present in solution – H2O, in this case – with our protonated epoxide. And this occurs at the most substituted position, always with inversion of stereochemistry. So it must be performing a “backside attack” at this carbon, as we observe in SN2 reactions. A final deprotonation gives us the neutral product.
Hold on for a second. If you remember the key lesson of the SN2 – that it is disfavoured by steric hindrance – this might seem weird. If this was a “pure” SN2, reaction, wouldn’t we expect the attack to occur as the “least substituted” position?
Clearly something else must be going on here!
Thankfully, you’ve likely encountered reactions like this before! If you think back to the chapter on alkenes, you might see that the protonated epoxide bears an uncanny resemblance to two other reactive intermediates you met in that chapter: “halonium” ions, and “mercurinium” ions, both 3-membered rings bearing a positive charge:
If you think back to how these species reacted with nucleophiles, it was always at the more substituted position with inversion of stereochemistry. In fact, there is a whole family of alkene addition reactions that proceed this mechanism that we called the “3-membered ring pathway“. Halohydrin formation is a perfect example:
So in essence, the addition of nucleophiles to protonated epoxides is just another example of the “3 membered ring pathway” of alkenes!
Changing the solvent from water to an alcohol will result in the alcohol adding instead. For example if we were to use CH3OH as solvent instead of water, then our product would contain OCH3 joined to the most substituted position.
Hydrohalic acids [HCl, HBr, and HI] can also work well, forming halohydrins.
Now, you might think – if epoxides are made more reactive by treating with acid, then can’t we extend this to other nucleophiles too? For example, what about NaOH, or NaNH2, or even Grignard reagents?
Herein lies the dilemma. Acidic conditions are only compatible with nucleophiles that are protonated reversibly. [in other words, nucleophiles whose conjugate acids are strong acids – think pKa < 0 ]. [Note 2]
Can you see a little problem with adding NaOH to a solution of aqueous acid? What do you think might happen?
Kaboom. Well, that’s an exaggeration. But the acid will protonate NaOH irreversibly, giving us H2O [recall that acid-base reactions are fast]. Similarly, you can imagine what happens on adding NaNH2 to acid or Grignard reagents to acid: the nucleophile is protonated, giving us the conjugate acid.
There’s still one mystery to solve. From the last post you might recall that if we just add NaOH – no acid – to the epoxide we met above, we get a different product altogether.
Note how the stereochemistry at C-2 is completely different than with acid.
What might be happening here? Any thoughts? Hint – it’s a reaction we’ve talked about before, and even mentioned in this post.
We’ll talk about this in the next post.
Next Post – Opening Of Epoxides With Base
Note 1: Why does the nucleophile attack the more substituted carbon?
- In our protonated epoxide, although oxygen bears a positive formal charge, in reality positive charge density mostly resides on carbon [recall that oxygen is more electronegative than carbon].
- Recall that positive charge is best stabilized by carbon in the order tertiary > secondary > primary. So in our case, the tertiary carbon atom will bear more positive charge. The tertiary carbon will be more electron-poor (electrophilic)
- The length of the C-O bonds will NOT be equal – the C-O bond to the tertiary carbon is longer and weaker than that of the secondary carbon.
Bottom line: the tertiary carbon is more electrophilic (electron poor) and the C-O bond on the tertiary carbon is weaker, longer, and easier to break.
- Mechanisms Of Epoxide Reactions
E. Parker and N. S. Isaacs
Chemical Reviews 1959, 59 (4), 737-799
This review is old but starts with the basics in discussing reactions of epoxides. Both acidic and basic (nucleophilic) reactions are covered.
- Synthetic Methods and Reactions; 681. Nafion-H-Catalyzed Hydration and Methanolysis of Epoxides
George A. Olah, Alexander P. Fung, David Meidar
Synthesis 1981; 1981 (4): 280-282
In this instance, NafionTM-H (a polymeric resin developed by DuPont and subsequently modified to the superacidic “-H” form by Prof. Olah) can be used as a catalyst to promote the hydrolytic ring-opening of epoxides to 1,2-diols.
- Friedel-Crafts Alkylations of Arenes with Mono- and Bis(trifluoromethyl)oxiranes in Superacid Medium: Facile Synthesis of α-(Trifluoromethyl)- and α,α-Bis(Trifluoromethyl)-β-Arylethanols
K. Surya Prakash, Pablo J. Linares-Palomino, Kevin Glinton, Sujith Chacko, Golam Rasul, Thomas Mathew, and George A. Olah
Synlett 2007, (7), 1158-1162
Under Brønsted acid conditions, epoxides can be used as electrophiles in Friedel-Crafts reactions.
- Hot Water-Promoted Ring-Opening of Epoxides and Aziridines by Water and Other Nucleopliles
Zhi Wang, Yong-Tao Cui, Zhao-Bing Xu, and Jin Qu
The Journal of Organic Chemistry 2008, 73 (6), 2270-2274
The title has that typo, which makes me a bit suspicious. On the other hand, this is a JOC article, so it should be reliable. Turns out that hot water can hydrolyze epoxides to diols, no catalyst needed!Epoxides can undergo ring-opening under both acidic and basic conditions – i.e. under electrophilic and nucleophilic reaction conditions. To take this one step further, in acidic conditions, epoxides can be activated by both Brønsted and Lewis acids. Lewis acid catalysis is more common, and is described in the following publications:
- Titanium isopropoxide-mediated nucleophilic openings of 2,3-epoxy alcohols. A mild procedure for regioselective ring-opening
Maurice Caron and K. B. Sharpless
The Journal of Organic Chemistry 1985, 50 (9), 1557-1560
- Asymmetric Catalysis of Epoxide Ring-Opening Reactions
Eric N. Jacobsen
Accounts of Chemical Research 2000, 33 (6), 421-431
Prof. Jacobsen (Harvard) has made a career out of developing and studying asymmetric reactions. One of his notable contributions is the development of a Cr(salen) catalyst for the asymmetric ring-opening of epoxides, and the story of the development of this chemistry is described here.
- Epoxide opening with tert-butyldimethylsilyl cyanide-zinc iodide. Evidence for a stepwise process in the opening of a sterically hindered epoxide
Paul G. Gassman and Leonard M. Haberman
The Journal of Organic Chemistry 1986, 51 (25), 5010-5013
This is a study of an unusual but interesting reaction developed in the labs of the late Prof P. G. Gassman (U Minnesota). The reaction of epoxides with TMSCN (an organic-soluble and easier-to-handle substitute to traditional cyanide reagents such as KCN) and catalytic ZnI2 gives 1,2-isocyano alcohols. This paper is a mechanistic investigation of this reaction.
- CONVERSION OF EPOXIDES TO β-HYDROXY ISOCYANIDES: trans-2-ISOCYANOCYCLOHEXANOL
Paul G. Gassman and Thomas L. Guggenheim
Org. Synth. 1986, 64, 39
An Organic Syntheses procedure for the ring-opening of epoxides to 1,2-isocyano alcohols.