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Alcohols, Epoxides and Ethers

By James Ashenhurst

Epoxide Ring Opening With Base

Last updated: November 9th, 2022 |

Ring-opening of epoxides with basic nucleophiles

  • Epoxides are cyclic ethers with considerable ring strain (about 13 kcal/mol)
  • Epoxides undergo reaction with nucleophiles under basic conditions at the least substituted end of the epoxide
  • If a chiral center is at this carbon, its stereochemistry will be inverted.
  • Nucleophiles that will add to epoxides include hydroxide ion (HO-) alkoxides, Grignard reagents, organolithium reagents, and LiAlH4 (among others)
  • A simple way to remember this is to think of epoxide opening under basic conditions as proceeding much like an SN2 reaction.

reaction of epoxides under basic conditions via sn2 reaction with naoh and h2o attack at least substituted position occurs with inversion other nucleophiles possible

Table of Contents: 

  1. Opening Epoxides With Base: How it Works
  2. The Role of Solvent
  3. Understanding Separate Quench Steps: 1) Add this 2) THEN add this!
  4. What Doesn’t Work: Poor Nucleophiles
  5. Notes
  6. (Advanced) References and Further Reading

1. Opening Epoxides With Base: How It Works

In the last post we discussed the reactions of epoxides under acidic conditions and saw how they resembled the “3-membered ring” family of alkene mechanisms. We left off by noting that the reaction of the epoxide (shown above)  with NaOH in H2O gave a different product than that obtained through H3O+.  Therefore it must go through a different mechanism. 

Our question is, how does this reaction work?

Noting the fact that the nucleophile (HO-  ) attacks the epoxide at the least substituted position (C2) and results in inversion of stereochemistry at this position, our best evidence is consistent with this reaction proceeding through the familiar SN2 mechanism followed by a transfer of proton from the weakly acidic solvent (H2O) to the alkoxide (RO – ) providing a neutral alcohol.

-opening of epoxide under basic conditions follows sn2 mechanism followed by protonation giving neutral alcohol

Along the same lines,  if epoxides are treated with alkoxides (RO- ) in alcohol solvent, they lead to essentially the same reaction. Here’s an example with NaOCH3. Note that the proton must come from CH3OH here.

opening of epoxides with alkoxides ro occurs via sn2 reaction inversion at least substituted carbon

2. The Role Of Solvent

Now – at the end of the last post, we mentioned that acids are incompatible with some strong nucleophiles because they will be destroyed by irreversible protonation [classic example: Grignard reagents and water]. Should we be worried about NaOH in H2O or NaOCH3 in CH3OH?  No!  These are examples of bases in equilibrium with their conjugate acids.

It’s fine to have NaOH in the same reaction vessel with H2O since the reaction is reversible.

role of solvent is that alkodie and hydroxide are in equilibrium with neutral species so basicity is preserved nucleophilicity not diminished

However, if we move to more strongly basic nucleophiles, such as Grignard reagents (RMgX), organolithium reagents (R-Li) or hydrides (H-) we should be concerned, because the conjugate acids of each of these species (pKa of about 50 for alkanes, and about 38 for H2) are much weaker acids than ROH (pKa 16-18).

[A good rule of thumb for “reversibility” of an acid base reaction is a pKa difference of 8 or less – see A Handy Rule of Thumb for Acid-Base Reactions].

That means that if these strong bases come into contact with ROH, an irreversible acid-base reaction will occur. We thus obtain an alkoxide (RO-)  which is insufficient in strength to deprotonate alkanes or H2.

strong bases such as grignrads organolithiums nanh2 h- not compatible with water as solvent so must involve second quench step which protonates resulting alkoxide

Bye-bye nucleophile!

3.  Understanding Separate Quench Steps: 1) Add this  2) THEN, add this!  

What this means in practice is that we just move the protonation step to the end, in a process sometimes called a “quench”. Note how each of the following reactions has a Step 1) and a Step 2).

Step 1 is addition of nucleophile. After the reaction is done, we add our source of proton (Step 2) to quench. Note that there are many reagents commonly written for this process – H2O, H3O+, H+, NH4Cl, “acid workup” just to name a few. They all mean the same thing!

Here are some examples of reactions of epoxides with strongly basic nucleophiles. Grignard reagents , organolithium reagents, and hydride (e.g. LiAlH4 , a source of H- ).

with more basic nucleophiles opening epoxides quencgh step is separate happens during workup such as h+ or nh4cl etc

Is there anything else? [yes – there are other nucleophiles which will react with epoxides, but they are seldom seen at this level. However I have added them in Note 1 at the bottom].

4. What Doesn’t Work: Poor Nucleophiles

Just like any SN2 reaction, for this pathway to work, we really must be dealing with a decent nucleophile. Poor nucleophiles, especially neutral species like H2O, ROH, and RCOOH simply won’t cut it.

In order for epoxides to react we need either to use strongly acidic conditions (good for weak nucleophiles) or basic conditions (HO- , RO- , RMgBr, RLi, LiAlH4).

by themselves poor nucleophiles like roh water carboxylic acids do not open epoxides not strong enough

This concludes our exploration of epoxides and ethers. However we still have a lot to talk about regarding alcohols – and certainly we aren’t done with examples of SN1 and SN2 reactions. That’s coming up next.

Next Post – Making Alkyl Halides From Alcohols

Notes

Related Articles

Note 1. Some other nucleophiles which react with epoxides but are rarely seen in introductory organic chemistry. Note that the second and third examples don’t show the source of proton (H+) that adds to the oxygen, but it can be added afterwards in a  “quench” step.

other nucleophiles that open epoxides include cyanide ion thiolate and azide

(Advanced) References and Further Reading

  1. —The velocities of combination of sodium derivatives of phenols with olefine oxides
    David Runciman Boyd and Ernest Robert Marle
    J. Chem. Soc., Trans., 1914, 105, 2117-2139
    DOI:     10.1039/CT9140502117
    This and the accompanying paper are early examples of ring-opening of epoxides with alkoxides.
  2. —The velocities of combination of sodium derivatives of phenols with olefine oxides. Part II
    David Runciman Boyd and Miss Doris Feltham Thomas
    J. Chem. Soc., Trans., 1919, 115, 1239-1243
    DOI:     10.1039/CT9191501239
  3. CYCLOHEXENE IMINE
    Iain D. G. Watson, Nicholas Afagh, and Andrei K. Yudin
    Org. Synth. 2010, 87, 161
    DOI:     10.15227/orgsyn.087.0161
    The first reaction in this procedure from Organic Syntheses is the ring-opening of cyclohexene oxide with sodium azide. As Prof. Yudin shows, this reaction is a useful precursor for the synthesis of N-H aziridines, the nitrogen analog of epoxides.
  4. The Reaction of Dimethylmagnesium and of Diethylmagnesium with Cyclohexene Oxide
    Paul D. Bartlett and C. Manly Berry

    Journal of the American Chemical Society 1934 56 (12), 2683-2685

    DOI: 10.1021/ja01327a045This is an early example of ring-opening of epoxides with Grignard reagents.

  5. The stereochemical course of epoxide ring opening by allylic grignard reagents
    Hugh Felkin, Georges Roussi
    Tetrahedron Lett. 1965, 6 (46), 4153-4159
    DOI: 10.1016/S0040-4039(01)99581-4
    This is a more advanced (and perhaps less relevant) paper, attempting to resolve whether allylic Gringard reagents go through an SN2’ reaction. This could be resolved easily with isotopic labeling and 13C NMR.
  6. Acid- and base-catalyzed ring-opening reactions or a sterically hindered epoxide
    Herbert Mayr, Rainer Koschinsky, Elfriede Will, and Englbert Bauml
    The Journal of Organic Chemistry 1987, 52 (7), 1342-1344
    DOI:     1021/jo00383a033
    A nice paper describing the different products obtained when opening a hindered epoxide under acidic vs. basic conditions. Prof. Mayr (LMU, Germany) is well known for his extremely rigorous work in physical organic chemistry, where he has developed scales for quantifying electrophilicity and nucleophilicity.
00 General Chemistry Review
01 Bonding, Structure, and Resonance
02 Acid Base Reactions
03 Alkanes and Nomenclature
04 Conformations and Cycloalkanes
05 A Primer On Organic Reactions
06 Free Radical Reactions
07 Stereochemistry and Chirality
08 Substitution Reactions
09 Elimination Reactions
10 Rearrangements
11 SN1/SN2/E1/E2 Decision
12 Alkene Reactions
13 Alkyne Reactions
14 Alcohols, Epoxides and Ethers
15 Organometallics
16 Spectroscopy
17 Dienes and MO Theory
18 Aromaticity
19 Reactions of Aromatic Molecules
20 Aldehydes and Ketones
21 Carboxylic Acid Derivatives
22 Enols and Enolates
23 Amines
24 Carbohydrates
25 Fun and Miscellaneous
26 Organic Chemistry Tips and Tricks
27 Case Studies of Successful O-Chem Students

Comments

Comment section

30 thoughts on “Epoxide Ring Opening With Base”

  1. what is the epoxides ring opening with aluminum butoxide?
    How does aluminum butoxide catalyze this reaction?

    Reply

  2. Hi, what would happen if an epoxide is reacted with NaBH4 in the presence of EtOH, would the NaBH4 act as a nucleophile and then the EtOH would attatch? Thanks

    Reply

    1. Generally not. Even though it would release ring strain, you’d be going from a very weak base (Br-) to a much stronger base (O- ) if bromide ion opened the epoxide. Furthermore, even if it did, the reverse reaction would easily occur – recall that epoxides are formed from the closure of deprotonated halohydrins!
      https://www.masterorganicchemistry.com/2015/01/26/epoxides-the-outlier-of-the-ether-family/
      You really need the presence of an acid to stop the reaction at the halohydrin stage.

      Reply

  4. When using a strong base in the presence of an epoxide such as the one in the example presented would it be possible for an E2 reaction to occur as opposed to an Sn2? Couldn’t an alkoxide deprotonate a carbon adjacent to the epoxide, kicking off the electrons to the oxygen and forming a pi-bond?

    Reply

  6. Excellent work sir. I want to ask that LiAlH4 in the presence of AlCl3 , will it be able to break the epoxide ?(as we don’t have bronsted protonating source for the last step! )

    Reply

  7. Hi nicely explained. I have one query what if i want to attach a cysteine to glycidyloxypropyltriemthoxysilane using just sodium hydroxide as the solvent ? will it work?

    Reply

  8. Hi James, thanks for your post! I was wondering if you could help me solve this problem: I am a rookie in synthetic chemistry and I was trying to get rid of some hemiacetals in my epoxy product. I tried hydrolysis in acid solution. It turned out the epoxide hydrolyzed as well. Would you suggest anything that could help?

    Reply

    1. Hemiacetals should go away by themselves unless you have a very electronegative group adjacent to the carbonyl or if you are forming a cyclic hemiacetal. This doesn’t answer your question but hydrolysis of an acetal in the presence of an epoxide is probably not going to work. You might need to reconfigure your synthetic scheme, perhaps protecting the alcohol so that it doesn’t form the hemiacetal in the first place.

      Reply

    1. I’m not certain how to answer your question without a diagram. If you’re looking for selectivity between opening two epoxides, that will be difficult to achieve with NaOH unless there is a clear steric or electronic preference favoring one attack versus the other.

      Reply

  10. What about reactions of epoxides like 1,2 epoxy cyclohexane with PCl5, say ?? How to approach them, plz do tell..

    Reply

    1. That’s not really the opening of an epoxide with a base. There, you’re trying to coordinate the epoxide oxygen to the electrophilic phosphorus, forming a transient ion pair that will release chloride ion and open the epoxide. Kind of beyond the scope of what we deal with here.

      Reply

  11. Hi,
    I have a product from a oxido-reductase enzyme that I suspect has an epoxide group, rather than another type of oxidation. I have done NMR and mass spectrometry, both fit with the epoxide hypothesis, but I would really like to use another method to confirm. This webpage has been helpful. What I would like to do is a methanolysis reaction. My plan is to dissolve the compound after lyophilizing in dry methanol. Then prepare a solution of 1 N H2SO4 in dry methanol, and add enough to result in a final concentration of 0.2 N H2SO4. That should label the epoxide with a OCH3 group. According to the paper below it should be done after 1 h at room temperature.

    I can then analyse the result by GC-MS, and/or NMR.

    As I am not a hard-core organic chemist, I want to know if I am overlooking something.

    Reply

  12. Hello,
    I’m a mechanical engineer and my chemistry knowledge is poor, so sorry in advance if my question is silly. I’m conducting an experiment and attach some polymer chains with amine groups to a surface with epoxide group without doing anything special and just in potassium phosphate buffer (PH 7.4). Now imagine, after a point, I want to disable the epoxide groups and stop any reaction between my polymer chains and the surface (perhaps by closing the epoxide ring ??) while my polymer chains are still there. So my question is if it’s possible and how?
    Thanks
    thanks

    Reply

  15. This is probably a stupid question. From my understanding, for an epoxide, the more substituted carbon would bear more positive charge. Why wouldn’t the nucleophile attack the more substituted carbon instead? Is it something has to do with steric hindrance?

    Reply

    1. Hi – not a stupid question at all. You are right that the more substituted carbon would bear more positive charge. However, when we have a relatively strong nucleophile (such as RO- , HO-, Grignard reagents, or LiAlH4) what turns out to be more important is steric hindrance.

      Think of it like an SN2 reaction, where the least substituted carbon will react most quickly.

      When a weaker nucleophile is involved (such as H2O) we need to add an acid catalyst. In this case, the reaction will primarily occur on the carbon best able to stabilize positive charge. In this respect it is somewhat like an SN1 reaction, although it still occurs with inversion of configuration in this case.

      Hope this helps! James

      Reply

  17. Excellent post!
    I’ve a doubt though. What if I tried to add a tertiary alcohol to an asymmetrical epoxide. Since they are the most weakly acidic alcohols, would they follow a basic mechanism (sn2)? would the outcome depend on the solvent or medium used? Would they even react in the first place? If they did, would they prefer to undergo a C-O bond cleavage thereby forming a stable carbocation? I’m really confused on this, it would be a lot of help if I could get this cleared…
    Thanks

    Reply

    1. This post covers opening epoxides with base. Adding a neutral tertiary alcohol does not fall into this category. You’d need to form the conjugate base of the tertiary alcohol – say, for example, sodium t-butoxide. Sodium t-butoxide can act as a nucleophile to attack the least substituted position of an epoxide and open it, just like other alkoxides do.

      Carbocations are not relevant to this discussion because they don’t form under these basic conditions.

      Reply

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