Wrapup: The Key Factors For Determining SN1/SN2/E1/E2

S_N1/S_N2/E1/E2 – Summarizing The Key Factors That Determine Whether A Reaction Will Be SN1, SN2, E1 or E2

In this article we walk through the thought process that will let you determine if a given reaction goes through a S_N1, S_N2, E1, or E2 pathway.

It assumes that you know how to draw the product of a reaction if you are told what pathway is operating. If you aren’t sure how to draw the product of a reaction if you’re told it’s S_N1/S_N2/E1/E2, then I suggest going back to the individual articles on those topics for a refresher. [SN1 SN2 E1 E2]

Note that this series covers alkyl halides (and its relatives) but not alcohols. For more on alcohols, skip ahead to the alcohol chapter (Elimination reactions of alcohols)   

• Look for a good leaving group on an alkyl (sp³-hybridized) carbon.
• Determine if the carbon bearing the good leaving group is primary, secondary, tertiary or methyl.
• Identify the strongest nucleophile/base that is present.
• Note the temperature, if given (heat tends to favor elimination)
• The identity of the solvent can also indicate S_N2, particularly with weakly basic nucleophiles. With strongly basic nucleophiles (RO(-) and HO(-) ) on secondary alkyl halides, double check with your instructor which reaction pathway tends to operate (E2 or S_N2)

This article used to be called the “Quick N’ Dirty Guide to S_N1/S_N2/E1/E2″. It’s been revised to make it a little less quick and a little less dirty, but hopefully more comprehensive and useful. [Note 1]

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 You need to be logged in a MOC Member to see all the quizzes in this post. It’s inexpensive ($10/month) and many people have found it useful in preparing for their exams.  There are roughly 2700 quizzes and counting, as well as accompanying “cheat sheets” and also the Reaction Guide. 

Table of Contents

1. 1. The SN1/SN2/E1/E2 Decision
   2. Step 1: Identify a Good Leaving Group
   3. Step 2: The Leaving Group Should Be On An Alkyl (sp3-hybridized) Carbon
   4. Step 3: Identify The Carbon As Primary, Secondary, Tertiary (or Methyl)
   5. Step 4: Identify The Base/Nucleophile
   6. Step 5: The Role of Temperature
   7. Step 6: Solvent, And SN2/E2 With Secondary Alkyl Halides And Strong Nucleophiles
   8. Notes
   9. Quiz Yourself!
   10. (Advanced) References and Further Reading

1. S_N1/SN2/E1/E2 : Wrapup

(Formerly, “The Quick N’ Dirty Guide To S_N1/S_N2/E1/E2″)

Here we are at the end of our series on determining whether a reaction is S_N1, S_N2, E1, or E2. It’s time to recap all of the steps in the deductive reasoning required to determine which reaction pathway is operating.

Note that this article assumes that you are able to draw the correct  product of a reaction if you already know what the most likely reaction pathway is.  If you are already told ahead of time what mechanism is operating, then you don’t need this article. 

However, if you’re at all unsure on how to draw the product of an S_N2 or E2 reaction if you’ve been given the starting materials and reactants, then  you should to go back to articles on the various reactions for a refresher before coming back here. 

[SN1 SN2 E1 E2]

This series also assumes you know a few key concepts such as, “What Makes a Good Leaving Group?“, What Makes a Good Nucleophile?, What Factors Influence Carbocation Stability? .

With that throat-clearing out of the way…

Let’s say you’re given a reaction and are asked to draw the major product without being told what mechanism is operating.

In order to draw the major product, you’ll need to figure out what mechanism the reaction proceeds through – if the reaction proceeds at all (yes, “no reaction” is also a possibility!).

In this post, we’ll walk through the thought process necessary to arrive at a reasonable conclusion.

Once you’ve determined what mechanism is operating, then you’ll need to apply the pattern of bonds formed/broken for each reaction to give you the correct product.

2. Step 1: Identify A Good Leaving Group

The first step in determining whether a reaction proceeds through S_N1/S_N2/E1/E2 is to identify a good leaving group in the substrate (e.g. alkyl halide) where the reaction could conceivably take place.

Good leaving groups are weak bases (See article – What Makes A Good Leaving Group?).

If you recall that “the stronger the acid, the weaker the conjugate base”, it stands to reason that the halide ions (Cl^– , Br^– , I^– but not F) and sulfonates (TsO^– and MsO^–  ; see Tosylates and Mesylates) are great leaving groups.

Carboxylates (RCO₂^– ) are the conjugate bases of carboxylic acids (pK_a of about 4) and can also be decent leaving groups. Under acidic conditions (not covered in this series, but covered in the chapter on alcohols), water (H₂O) and alcohols (ROH) can be good leaving groups.

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Some prominent examples of poor leaving groups include

• Fluoride ion – the C-F bond is extremely strong (about 130 kcal/mol) and it is thermodynamically difficult to break the C-F bond.
• Hydroxy (HO) and alkoxy (RO) groups in the absence of acid
• Amines (NH₂ , NHR, NR₂) are too basic to be good leaving groups. However ammonium salts (-NR3⁺) can be good leaving groups.
• Hydride (H-) and alkyl
• Finally, cyano (CN) and thio (SR) are also generally poor leaving groups for S_N1/S_N2/E1/E2 reactions.

3. The Leaving Group Must Be On An sp³ Hybridized Carbon

While a good leaving group is a necessary condition for S_N1/S_N2/E1/E2 to take place, it’s not a sufficient condition.

The leaving group also has to be bonded to a carbon that is capable of undergoing backside attack (S_N2), capable of being a stable carbocation (S_N1/E1) or reasonably effective at stabilizing partial positive charge (S_N2/E2).

For this reason only alkyl carbons – i.e. sp³ hybridized, tetrahedral carbon – can undergo S_N1/S_N2/E1/E2, with one limited exception we’ll cover in the chapter on alkynes and sticks out like a sore thumb (see Alkynes via Elimination Reactions).

[See article – Identifying Where SN1/SN2/E1/E2 Reactions Happen ]

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Once you’ve identified a good leaving group on an sp³-hybridized carbon, you’re ready for the next step.

4. Identify the Carbon As Primary, Secondary, Tertiary or Methyl

If you’ve identified a good leaving group on an alkyl (sp³-hybridized carbon) then the next step is to classify that carbon as primary, secondary, tertiary or methyl. [See Primary, Secondary, Tertiary In Organic Chemistry].

The number of carbons directly attached to the carbon bearing the leaving group has a profound impact on its reactivity since it will affect its steric hindrance (less steric hindrance for primary, more steric hindrance for tertiary) and ability to stabilize positive charge as a carbocation (less stability for primary, more stability for tertiary).

See article: [Deciding SN1/SN2/E1/E2: The Substrate]

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At this stage, identifying the carbon bearing the leaving group  as primary, methyl or tertiary carbons will be helpful at ruling certain reactions in or out.

• If it’s methyl, it’s S_N2
• If it’s primary, it’s S_N2 unless a strong, bulky base is added. [Note 2]
• If it’s secondary, you can’t rule anything out yet.
• If it’s tertiary, rule out S_N2 due to steric hindrance (S_N1, E1, E2 all possible)

5. Identify The Strongest Base / Nucleophile

The next step is to identify the nucleophile / base that is participating in the reaction.

For our purposes, focus on the strongest base/nucleophile that is present, and ignore anything that is weaker.

By “strongest”, I generally mean focus on negatively charged bases/nucleophiles first, as they will be more likely to participate in these reactions than neutral bases/nucleophiles. [Note 3]

For example, if you see NaOEt/EtOH, focus on NaOEt  (which, ignoring sodium, we can just think of as CH₃CH₂O(-) for our purposes), since the conjugate base is always the better nucleophile.

See article: Deciding SN1/SN2/E1/E2: The  Nucleophile/Base

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The identity of the nucleophile/base is useful for separating out S_N2/E2 from S_N1/E1 pathways.

• If the substrate is primary the only exception to S_N2 is if the nucleophile/base is strongly basic and bulky. Two prominent examples are the t-butoxide ion  tBuO(-) and lithium diisopropyl amide (LDA) . (A third, more rarely seen example is the strong bulky base DBU).  All of these reagents will perform E2 instead of S_N2, giving the less substituted alkene (non-Zaitsev) product. (See article – Bulky Bases In Elimination Reactions).
• If the substrate is secondary and the nucleophile is strong but weakly basic, it’s S_N2, particularly in a polar aprotic solvent like DMF, DMSO, acetone or acetonitrile. “Weakly basic” here means the conjugate acid has a pK_a of 12 and below. So thiolates  RS(-) are “weakly basic” but hydroxide [HO(-)] and alkoxide [RO(-)] are not.
• If the substrate is secondary and the nucleophile is strongly basic, it’s E2. This is definitely the case for acetylides (the conjugate bases of terminal acetylenes, pK_a = 25) and amides (the conjugate bases of amines, pK_a = 35-38). For hydroxides (HO-) and alkoxides (RO-) confirm with your instructor.
• If the substrate is secondary and the nucleophile is weak, it’s possibly S_N1/E1. In particular look out for examples where carbocation rearrangements can occur, because these are commonly tested in this situation.
• If the substrate is tertiary and the nucleophile is weak, you’re likely looking at S_N1/E1
• If the substrate is tertiary and the nucleophile is strongly basic, then expect E2.

6. Heat Usually Favors Elimination

Sometimes the temperature is noted. If heat (or Δ) is indicated, that’s generally a clue that elimination will be taking place, since elimination reactions are promoted by heat.

With tertiary alkyl halides, E1 is generally the major pathway over S_N1 in the presence of heat.

[See article: Deciding SN1/SN2/E1/E2: The Temperature]

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With secondary alkyl halides, be alert for one possible exception to this – S_N1 reactions with rearrangements.

Generally, leaving groups on secondary alkyl carbons don’t pop off very easily. Secondary carbocations are fairly unstable, after all!

In some instances, you may see “heat” in the presence of a secondary alkyl halide, which will increase the rate of the leaving group leaving to form the secondary carbocation. This can then be followed by a hydride or alkyl shift which will generate a more stable tertiary carbocation. Again, you might want to confirm this with your instructor.

7. The Role of Solvent. Also, Secondary Alkyl Halides With Strongly Basic Nucleophiles

You may note that we haven’t really discussed solvent here.

In S_N1/E1 reactions, the nucleophile often is the solvent. So if you see a reaction where there is only “H₂O” or “EtOH” , then you already know that the reaction is being run in a polar protic solvent with a poor nucleophile.

For secondary alkyl halides with weakly basic nucleophiles, polar aprotic solvents such as DMF, DMSO, acetone, and acetonitrile are generally good indicators for S_N2 reactions, since these solvents enhance the nucleophilicity of many anions. (See article: All About Solvents)

A common dilemma arises in how to treat secondary alkyl halides with alkoxide and hydroxide nucleophiles in the presence of a polar aprotic solvent. 

Looking at the experimental data, the only conclusion to draw is that E2 is still favored over S_N2 in this situation. Check with your instructor what they do. Experimental results say E2, but there’s a lot of inconsistency.

See article: Deciding SN1/SN2/E1/E2 – Secondary Alkyl Halides With Strong Bases]

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8. Summary

Once you have a reasonable idea of what reaction pathway is operating, makes sure you have adequate practice in actually drawing the final product of these reactions. Hopefully this article has been useful in this regard, but if you need more practice, consult the original articles on substitution and elimination, or join the MOC Membership for a host of representative practice problems.

Notes

Note 1. From the original Quick N’ Dirty Guide To S_N1/S_N2/E1/E2:

“Writing this post makes me feel like a nun giving out condoms.  I realize there will be many who are reading this an hour before their exam and are completely clueless on this subject. All I have to say is, God help you. And do more fricking practice problems so you don’t put yourself in this situation next time.”

Note 2.  primary carbons that can form relatively stable carbocations (i.e. allylic/benzylic) may proceed through the S_N1/E1 pathway if only poor nucleophiles are present.

Note 3. Some competent neutral bases/nucleophiles include:

• Thiols: (R-SH, H₂S) Can be considered to be good nucleophiles, will participate in SN2 (but not E2) reactions.
• Amines: (R-NH₂, R₂NH, R₃N); will act as nucleophiles (S_N2) with primary alkyl halides; expect elimination (E2) with secondary and tertiary alkyl halides.
• Phosphines (PPh₃) : Good nucleophiles, weak bases. Expect S_N2 reactions with primary and secondary alkyl halides.

Quiz Yourself!

[Quizzes]

(Advanced) References and Further Reading

1. An Improved Decision Tree for Predicting a Major Product in Competing Reactions
   Kate J. Graham
   Journal of Chemical Education 2014 91 (8), 1267-1268
   DOI: 10.1021/ed400908g 
   From the abstract: “When organic chemistry students encounter competing reactions, they are often overwhelmed by the task of evaluating multiple factors that affect the outcome of a reaction. The use of a decision tree is a useful tool to teach students to evaluate a complex situation and propose a likely outcome. Specifically, a decision tree can help students predict a major product in substitution and elimination reactions.”
2. Comparing Nucleophilic Substitutions Versus Elimination Reactions In Comprehensive Introductory Organic Chemistry Textbooks
   Donna J. Nelson
   Proceedings of the Oklahoma Academy of Sciences 2022, 102, 105-114
   DOI: Direct link (PDF)
   A comparison of how 17 commonly used organic chemistry textbooks treat the key factors that differentiate S_N1, S_N2, E1, and E2 reactions (base strength, temperature, steric effects, nucleophilicity).