Deciding SN1/SN2/E1/E2 – The Solvent

Secondary Alkyl Halides With Strongly Basic Nucleophiles. The “Ask Your Instructor” Edition

• In the previous four articles in this series, we covered how to identify where an SN1/SN2/E1/E2 reaction could take place, and then discussed the various roles of the substrate (primary, secondary, tertiary), the nucleophile/base, and temperature.
• We’ve seen that secondary alkyl halides with poorly basic nucleophiles (such as RS(-), N3)(-), (-)CN and halides) tend to give SN2 products, particularly in polar aprotic solvents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, and acetonitrile.
• Following the consequences of each of these variables only leaves us with one tricky situation we need to deal with:
  What about secondary alkyl halides with strongly basic nucleophiles like hydroxide (HO^– ) and alkoxide (RO^–).

• The chemical literature is pretty clear that these reactions result in mostly elimination (E2). Additionally, most textbooks state that elimination (E2) is favored – even in polar aprotic solvents, which tend to favor substitution reactions with poorly basic nucleophiles.
• However, that doesn’t mean that this topic is taught consistently among all schools or instructors. There are certainly examples of instructors giving exam questions where the expected answer is that this reaction gives substitution. (S_N2).
• For that reason, I strongly suggest asking your instructor their opinion on what happens when a strongly basic nucleophile reacts with a secondary alkyl halide (and whether or not a polar protic or polar aprotic solvent will affect this!)  and prepare accordingly.

[0-summary image]

Table of Contents

1. 1. The Question Many Instructors Avoid: Secondary Alkyl Halides With A Strongly Basic Nucleophile
   2. What Do Experiments Say? (E2)
   3. What Do Textbooks Say? (E2… mostly)
   4. Some Potentially Ambiguous Exam Questions
   5. Bottom Line: Ask Your Instructor
   6. Notes
   7. Quiz Yourself!
   8. (Advanced) References and Further Reading

1. The Question Many Instructors Avoid: Secondary Alkyl Halides With A Strongly Basic Nucleophile

You’re in an exam. You’re given the following question.

What do you draw as the answer?

Let’s start by walking through the process for narrowing down whether a reaction is S_N1/S_N2/E1/E2:

• LG – Identify a good leaving group (Cl)
• sp³ – Ensure that it’s on an sp³-hybridized carbon (it is)
• 123– Identify that carbon as primary, secondary or tertiary (secondary). This doesn’t rule out anything.
• N – the nucleophile is NaOCH₃ (potassium methoxide).  It’s a strong nucleophile due to the negative charge on oxygen, but also a strong base. (For our purposes,  anything equally basic to HO(-) or RO(-) qualifies as a strong base.  That rules out S_N1/E1
• T – the temperature is not indicated. If heat were indicated, elimination would be likely.

Since S_N1 and E1 have been ruled out, we’re left with S_N2 and E2 here. We have no further clues.

What’s the product? 

• If the question is, “what would happen in an actual reaction flask”, the answer is elimination (E2). [Ref] How would you know this? You would have to be told explicitly either by your instructor or by your textbook, because this is an experimental observation, not something that could be predicted from first principles.
• If the question is, “what answer would you give on an exam?” then I would say, “ask your instructor, because the answer to this specific type question is not always taught consistently. It could be S_N2 or E2.”

As far as the way that organic chemistry is taught in North America, there is no greater question I know of that has as much variance as the question of “secondary alkyl halide with strongly basic nucleophile”.

Small sample size, maybe, but there’s a lot of variation in the answers.  And many instructors just flat-out avoid asking this question.

Welcome to the “ask your instructor” edition of the S_N1/S_N2/E1/E2 decision!

2. What Do Experiments Say? (E2!)

When I was just starting grad school, I was trying to do a substitution reaction (S_N2) on a secondary alkyl halide as part of my research project with a fairly basic nucleophile (a Gilman reagent, to be precise).

My product was almost exclusively elimination (E2). Very little of my desired S_N2 product was formed.

When I showed the results to my boss, his reaction was “yeah, the S_N2 is a pretty crappy reaction on secondary alkyl halides”.

This initially came as a shock. After all, I’d spent so much time in sophomore organic chemistry learning the various factors that determined whether a reaction was S_N1/S_N2/E1/E2. Surely they wouldn’t spend all this time teaching us the S_N2 if it wasn’t useful in the real world, would they?

Well… yes. In the real world, the S_N2 can be a great reaction for primary alkyl halides, but for secondary alkyl halides, it only tends to work well if the nucleophile is poorly basic, like RS(-), N₃(-), (-)CN, and halide ions.  We covered this in the post on nucleophiles – see article.  In addition, a polar aprotic solvent like DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), acetonitrile or acetone will assist the rate of S_N2 reactions. 

However, as soon as the nucleophile becomes strongly basic (such as with alkoxides, hydroxide, and acetylides, or Gilman reagents) elimination (E2) becomes the dominant pathway.

Here is the results of an early study on 2-bromopentane. [Ref]

Even at room temperature it’s 82% alkene (elimination). As the temperature is increased, the proportion of elimination products also increases. (See article – Elimination Reactions Are Favored By Heat).

The absolute best case I could find was isopropyl bromide with sodium ethoxide in ethanol / H₂O, which gives a 47% yield of S_N2 product (and only 21% in pure ethanol). 

This is as good as it gets! 

Even changing out one of the methyl groups for ethyl (i.e. to make 2-bromobutane) makes the yield drop considerably to the 20% range.

Cyclic alkyl halides aren’t any better. Cyclohexyl bromide, for example, gives about a 1% yield of SN2 product:

You might think you can improve the yield of S_N2 by using a polar aprotic solvent like dimethyl sulfoxide (DMSO). But in that case the yield of substitution product drops from 47% (in ethanol/H₂O)  to about 3%.

The bottom line here is that yes, indeed,  reactions of secondary alkyl halides with hydroxide and alkoxides give predominantly E2 products. [Note 1]

3. What Do The Textbooks Say? (E2… mostly)

Given to the amount of angst that S_N1/S_N2/E1/E2 questions cause students in introductory organic chemistry, one might reasonably expect that the issue of competing SN2/E2 reactions with secondary alkyl halides would get significant coverage.

From what I see, textbooks do not discuss this issue in any great depth. It gets a sentence, or perhaps a short paragraph.

Here’s what some of the more popular organic chemistry textbooks have to say on the topic of “secondary alkyl halide + strongly basic nucleophile”.

• Klein (1st, p. 378) – E2 (major), S_N2 (minor). “When the substrate is both a strong nucleophile and a strong base, bimolecular mechanisms will dominate (S_N2 and E2).”
• McMurry (OpenStax): For secondary alkyl halides… E2 elimination predominates if a strong base is used.  Reference
• Clayden – shows a chart where strongly basic, unhindered nucleophiles (e.g. RO(-) ) give E2. Weakly basic nucleophiles (e.g. RS(-) give S_N2).
• Solomons (12th) – E2 major.  “With secondary halides, however, a strong base favors elimination because steric hindrance in the substrate makes substitution more difficult.”  Gives the example of isopropyl bromide with NaOH. 79% E2, 21% S_N2.
• Wade  (8th, p. 272) – “with a strong base, either the S_N2 or E2 reaction are possible”.  Nothing more specific than that.
• Streitweiser (4th ed. p. 232) – gives an example (secondary alkyl halide with alkoxide) that gives an 85:5 ratio of E2 to S_N2.

So from this relatively small sample, textbooks generally say that secondary + strongly basic nucleophile favors E2, but there is a considerable amount of hedging.

4. Clear Up This Question With Your Instructor Ahead of Time

Instructors want to see that you understand that S_N2 reactions result in  inversion of configuration.

For that reason, expect to see examples of S_N2 reactions on secondary alkyl halides containing a chiral center.

Hopefully, they’ll do this using questions involving a poorly basic nucleophile like RS(-), N₃(-), (-)CN or a halide.

But they might not!  Be prepared for a situation where the use hydroxide or an alkoxide to demonstrate this point:

This is from “Organic Chemistry” by John D. Roberts et. al., 1971. I love John Roberts (the father of NMR), but question the choice of nucleophile to demonstrate S_N2 here. 

Despite the fact that the literature is pretty unambiguous that E2 is dominant, and textbooks are generally on the side of E2, sometimes instructors don’t explicitly tell you whether or not E2 or S_N2 is favored for cases with a secondary alkyl halide and a strongly basic nucleophile.

That means you might have to guess the product on your own.

You should ask your instructor ahead of time whether or not reactions like the ones below give predominantly E2 or S_N2 products.

Here’s the first example. Substitution or elimination?

The bulky base (t-butoxide) tends to only give S_N2 with methyl halides, but you should get a definitive answer from your instructor on the expected product with ethoxide.  (The answer key gave both answers as elimination). 

Another example. Substitution or elimination as major product?

In this case the stereochemistry of the leaving group is specified, and the solvent is polar aprotic (acetone). If you weren’t told ahead of time that these reactions favor elimination, there’s a good case to be made that this could be S_N2. (The answer key said E2). Check this with your instructor! 

Below is another example where the stereochemistry is specified. Is this substitution or elimination?

In this case the answer key also said elimination.

5. Summary: All I Can Really Say Is, “Ask Your Instructor”.

At some point before your big midterm on substitution vs elimination reactions, you should try to pin down your instructor on this question.

“Is S_N2 ever the major product with a strongly basic nucleophile like hydroxide or alkoxide?”.

A simple, one-sentence question. Feel free to use any of the examples in this section to make your point.

That way, at least you’ll be told explicitly what to expect.

Notes

In previous versions of this article, I have said that secondary alkyl halides with strongly basic nucleophiles tend to give S_N2 products with polar aprotic solvents. After doing a deep dive into the old chemical literature, I find that there is really zero evidence for this view. Therefore, I am now advising that the major products of these reactions should be E2 in all circumstances. For not having fixed this earlier, I apologize.

Note 1. One example that does work for the formation of ethers on secondary alkyl halides, but kind of a special case, is here.

It works because  RO(-) is the conjugate base of phenol (pK_a = 10) which is roughly as acidic as a thiol. So elimination isn’t as much of a concern as it would be with the more basic hydroxide and alkoxide ions.

Note 2. Table of results from a 1948 study by Ingold et. al. The results are not presented in a way that is easy to digest, but the key value is top left, where isopropyl bromide at 45°C in 60% EtOH/40% H₂O gives a mixture that is 53% alkene (olefin) and presumably 47% substitution product. All other results with isopropyl halides are worse.

Quiz Yourself!

[quizzes]

(Advanced) References and Further Reading

1. Mechanism of elimination reactions. Part VII. Solvent effects on rates and product-proportions in uni- and bi-molecular substitution and elimination reactions of alkyl halides and sulphonium salts in hydroxylic solvents
   K. A. Cooper, M. L. Dhar, E. D. Hughes, C. K. Ingold, B. J. MacNulty and L. I. Woolf
   J. Chem. Soc. 1948, 2043-2049
   DOI: 10.1039/JR9480002043
   For the reaction of isopropyl bromide with hydroxide ion in ethanol at 55°C, the reaction gives 29% SN2 products and 71% E2 products (see table V).  (The amount of SN2 can be increased to 46% by adding 40% H2O by volume).
2. Mechanism of elimination reactions. Part X. Kinetics of olefin elimination from isopropyl, sec.-butyl, 2-n-amyl, and 3-n-amyl bromides in acidic and alkaline alcoholic media
   M. L. Dhar, E. D. Hughes and C. K. Ingold
   J. Chem. Soc. 1948, 2058-2065
   DOI: 10.1039/JR9480002058
   This article studies the SN2/E2 ratios of various secondary alkyl halides such as 2-bromobutane and 2-bromopentane and finds that they almost exclusively (>80%) give E2 products.
3. The Reaction of Primary and Secondary Alkylaryl and Alkyl Sulfonates with Potassium t-Butoxide in Dimethyl Sulfoxide
   Carl H. Snyder and Aida R. Soto
   The Journal of Organic Chemistry 1964 29 (3), 742-745
   DOI: 10.1021/jo01026a055
   Study on SN2/E2 ratios in primary and secondary alkyl sulfonates. In this article the authors state that essentially no SN2 products are isolated from the reaction of secondary alkyl sulfonates (e.g. ROTs) with KOtBu in dimethyl sulfoxide.
4. Hydroxide-Promoted Elimination Reactions: Alkyl Halides as Substrates†
   Manfred Schlosser, Claudio Tarchini
   Helvetica Chim. Acta. 1977, 60, 3060-3068
   DOI: 10.1002/hlca.19770600858.
   Secondary alkyl halides are shown as giving almost exclusively elimination products here.
5. Solvation of ions. XIV. Protic-dipolar aprotic solvent effects on rates of bimolecular reactions. Solvent activity coefficients of reactants and transition states at 25°.
   R. Alexander, E. C. F. Ko, A. J. Parker, and T. J. Broxton
   Journal of the American Chemical Society 1968 90 (19), 5049-5069
   DOI: 10.1021/ja01021a002
   Rates of 78 SN2 and E2 reactions for primary and secondary alkyl halides in various solvents. In this article the yield of the SN2 reaction of isopropyl bromide with NaOCH₃ in DMSO is given as 3% as measured by vapor phase chromatography (97% elimination).
6. How Alkyl Halide Structure Affects E2 and SN2 Reaction Barriers: E2 Reactions Are as Sensitive as SN2 Reactions
   Paul R. Rablen, Brett D. McLarney, Brandon J. Karlow, and Jean E. Schneider
   The Journal of Organic Chemistry 2014 79 (3), 867-879
   DOI: 10.1021/jo4026644
   A more recent article about competition between SN2 and E2 reactions.
7. https://www.sciencedirect.com/science/article/abs/pii/S0040402001972503