Deciding SN1/SN2/E1/E2 (2) - The Nucleophile/Base (2024)

S_N1 / S_N2 / E1 / E2 The Nucleophile / Base

• This article assumes you understand the mechanisms of the S_N1/S_N2/E1 and E2 reactions. For review, see here [SN1] [SN2] [E1] [E2]
• S_N1/S_N2/E1/E2 reactions tend to happen on alkyl halides [see Identifying Where Substitution and Elimination Reactions Happen]
• Determining whether the alkyl halide is primary, secondary, tertiary (or methyl) helps to narrow down the possibilities [See SN1/SN2/E1/E2 – The Substrate]
• Primary alkyl halides tend to go through S_N2 reactions. Tertiary alkyl halides never go S_N2.
• Identifying the substrate alone often isn’t enough to narrow down the available possibilities, so the next step is to examine the nucleophile / base.That’s the purpose of this article!
• For our purposes, “strong” nucleophiles/bases are negatively charged and “weak” nucleophiles/bases are neutral
• A good rule of thumb is to expect S_N2/E2 with “strong‘ (i.e. negatively charged) nucleophiles/bases and expect S_N1/E1 with neutral nucleophiles/bases
• So the main focus of this article is in distinguishing S_N1/E1 from S_N2/E2, although this article will also discuss some ways of distinguishing S_N2 from E2 based on basicity.
• Many quizzes and examples below, including exceptions.

Table of Contents

1. 1. Identifying the Nucleophile / Base
   2. “Strong” (Negatively charged) Versus “Weak” (Neutral) Acids and Bases
   3. The Six Major Cases, Based On Substrate + Nucleophile/Base
   4. Secondary Alkyl Halides: The Importance of Base Strength
   5. More On The “SN1 vs E1″ and “SN2 vs E2″ Cases
   6. Do Acid-Base Reactions First
   7. Because You Can Never Have Enough Practice With Intramolecular Examples
   8. The Substrate Always Has The Final Say
   9. Summary
   10. Notes
   11. Quiz Yourself!
   12. (Advanced) References and Further Reading

1. Identifying the Nucleophile / Base

In previous articles were able to identify substrates as primary, secondary or tertiary. [See articles – Identifying Where Substitution and Elimination Reactions Happen, and SN1/SN2/E1/E2 – The Substrate]

This was helpful in being able to quickly rule out certain reactions.

• For example, if a substrate isprimary, you can generally rule out the S_N1 or E1 reactions since they go through a carbocation intermediate and primary carbocations are unstable. With few exceptions (bulky bases) primary substrates will generally go through S_N2.
• If a substrate is tertiary, you can rule out S_N2 since backside attack will be too slow due to steric hindrance impeding the nucleophile’s approach to the C-LG sigma* orbital

Once you have done this analysis, you’ll likely still have several possibilities. How can you narrow them down even further?

The next step in the deductive process is to examine thenucleophile orbase. (Remember, a “nucleophile” is just what we call a base when it’s attacking an atom other than hydrogen, such as carbon.)

See if you can identify the nucleophile or base in these reactions below. When there are multiple potential nucleophiles/bases present, choose the strongestone. (More on that in a second).

The substrate will react the fastest with the strongest nucleophile/base that is present.

The conjugate base is always a better nucleophile [See article – What Makes A Good Nucleophile?], and the conjugate base is always a stronger base [See article – How To Use A pKa Table].

So if you see NaOCH₂CH₃ in the presence of CH₃CH₂OH ortBuO(-) in the presence oft-BuOH, the negatively charged species will be the active one.

Another tip: don’t fall into the common trap of assuming that the nucleophile will always be listed on the top of the arrow. Sometimes it’s actually the nucleophile that is drawn as the reactant and the substrate is over the arrow!

It’s better to try understand what’s going on than to try to memorize simplistic (and often faulty! ) rules like “the nucleophile will always be the first thing above the arrow”.

OK. Let’s look at another, slightly more complex set of questions.

Another point which often trips students up is in failing to distinguish potential nucleophiles from various aprotic solventswhich find use in, but do not participate in, these reactions.

Polar aprotic solvents are often chosen when substitution (usually S_N2) is desired, since they are polar enough to dissolve charged nucleophiles, but cannot hydrogen-bond to them. The result is that nucleophiles in a polar aprotic solvent are relatively “free” and react faster with electrophiles, relative to their rates in polar protic solvents. [See article – Polar Protic? Polar Aprotic? All About Solvents]

Here are some common solvents to be aware of in substitution and elimination reactions. Note that they can be depicted in several different ways! (Acetonitrile, for example, can be written as CH₃CN, MeCN or just “acetonitrile”.)

At the bottom are various polarprotic solvents such as water, alcohols, carboxylic acids and even ammonia. These solventsare capable of participating in substitution/elimination reactions.

• Polarproticsolvents such as water, alcohols, and even NH₃ can potentially act as nucleophiles/bases in reactions.
• However, for our purposes, polar aprotic solvents will never be nucleophiles in S_N1/S_N2/E1/E2 reactions. [Note 1]

Note that the choice of solvent [polar protic vs polar aprotic] can have a strong influence on whether a reaction favors E2 or S_N2. We’ll cover this in a subsequent article. [See article – Deciding SN1/SN2/E1/E2 – Solvent]

Here’s another set of more challenging cases:

To summarize this section:

• There are no hard and fast rules about whether the nucleophile appears above or below the reaction arrow
• Look for negatively charged species to be your “best” nucleophiles/bases
• Know how to identify potential solvents – they will not participate in substitution or elimination, but they can influence the ratio of substitution vs. elimination products
• Sometimes the nucleophile / base is present on the substrate itself! These are examples of “intramolecular” reactions [More below]

2. “Strong” vs. “Weak” Nucleophiles / Bases

Now that we have had some practice in identifying the likely nucleophile, I am going to suggest a somewhat rough but very helpful classification that will help in distinguishing S_N1/E1 reactions from S_N2/E2 reactions.

Let’s call negatively charged nucleophiles “strong” and call neutral nucleophiles “weak“. [Note 2]

• S_N2/E2 reactions tend to occur withstrongnucleophiles/bases.
• S_N1/E1 reactions tend to occur with weak nucleophiles/bases.

The rate determining step in S_N1/E1 reactions is formation of a carbocation, which is generally only possible with secondary and tertiary substrates in highly polar, ionizing solvents like water, alcohols, carboxylic acids and mixtures thereof. Carbocations have an empty p-orbital and will readily combine even with weak Lewis bases such as water and alcohols since the carbon on the resulting product will have a full octet.

The rate determining step in S_N2/E2 requires that the nucleophile/base displace aleaving groupfrom a carbon that already has a full octet. Generally these reactions work best when the nucleophile/base is a stronger base than the leaving group.

Since alcohols, water, and carboxylic acids are relatively poor bases, many S_N2/E2 reactions with them as nucleophiles/bases are disfavored from an acid-base standpoint. [See article: What Makes A Good Leaving Group] [Note 3]

With that in mind, classify the nucleophiles below as “strong” or “weak” (there are some land mines buried in this question!)

3. The Six Major Cases, Based On Substrate + Nucleophile

You have already learned how to identify substrate as primary, secondary, tertiary.

Having identified the best nucleophile, and classifying it as strong or weak, we’re now ready to start applying this to some reactions. See how you do:

Since there are really only six major cases (not counting methyl) it might be helpful to draw up a grid like this:

The six general cases are:

• Primary / strong and primary / weak . With rare exceptions (bulky bases like KOt-Bu) these will be S_N2.
• Secondary / strong will be S_N2 or E2
• Secondary / weak will be S_N1 or E1
• Tertiary / strong will be E2 with only rare exceptions [Note 4]
• Tertiary / weak will be S_N1/E1 [Note]

Here is some more practice:

You might find it annoying that after all this work of analyzing the substrate and the nucleophile we still have multiple situations where we still can’t really nail down the dominant pathway.

Helpfully, analyzing thebasicity of some strong nucleophiles/bases will help us make some clearer distinctions.

4. Secondary Alkyl Halides: The Importance of Base Strength

The E2 reaction generally requires a strong base. Negatively charged species that are weak bases such as halides, carboxylates, cyanide, azide, or thiolates [RS(-)] generally won’t perform E2 reactions. [Note 5]

Strong bases such as hydroxide ion HO (-), alkoxides RO(-), and species more basic than them (e.g. acetylides, amide bases, hydride) are fully capable of performing E2 reactions, however.

So a reasonably good dividing line for “E2-capable” bases is around a pK_a of 12 for the conjugate acid. More basic than thiolates, in other words.

This chart might help. Note that this is specific forsecondaryalkyl halides.

For secondary alkyl halides with weakly basic nucleophiles, expect S_N2 for everything up to thiolates, and elimination for everything more basic than alkoxides. Amide bases (e.g. NH₂(-), R₂N(-), NaH, and acetylides will primarily give E2 products. (Acetylides are fine nucleophiles with primary alkyl halides, but will perform E2 reactions on secondary alkyl halides).

Depending on conditions, hydroxide and alkoxides themselves can go either way with secondary alkyl halides, We’ll cover this in more detail in a subsequent article. [See article – Deciding SN1/SN2/E1/E2 – The Solvent]

The E2 reaction on tertiary alkyl halides also requires a reasonably strong base such as hydroxide, alkoxides, or species more basic than that. (One exception – neutral nitrogen bases such as triethylamine or DBU will also perform E2 reactions)

S_N1 reactions are sometimes observed when “strong” , weakly basic nucleophiles such as (-)CN or N₃(-) are in solution with a tertiary alkyl halide under conditions that favor carbocation formation. These species are such excellent nucleophiles that they can out-compete the solvent.[Ref ]

5. More on the “SN1 vs E1” and “S_N2 vs E2″ Cases

At this point we have shown how to identify alkyl halides as primary, secondary, or tertiary, then how to identify nucleophiles as “strong” or “weak”, and then how to further narrow down negatively charged nucleophiles so as to identify which would be more likely to perform S_N2 or E2.

The two problems that remain for a comprehensive assignment of S_N1/S_N2/E1/E2 are:

• distinguishing S_N1 from E1 (the short answer is that heat favors elimination, more on that in a subsequent article – see Deciding SN1/SN2/E1/E2 – The Temperature).
• distinguishing S_N2 from E2 for secondary alkyl halides with strong nucleophiles/bases in the “borderline” region [hydroxide and alkoxides]. (My short answer here – besides “ask your instructor, because many disagree” – is that polar aprotic solvents will favor substitution, but more in Deciding SN1/SN2/E1/E2 – The Solvent).

We will deal with these in subsequent articles.

Other than that, are there any other loose ends and exceptions to tie up? Yes!

Let’s finish up by dealing with acid-base reactions, intramolecular examples, and a final word from your substrate.

6. A Reminder To Do Acid-Base Reactions First

In our rush to cover the basics of strong and weak nucleophiles, above, we only considered that a nucleophile/base would either do substitution or elimination.

There is actually a third possibility (a fourth, if you count “no reaction”).

The nucleophile/base can also perform anacid-base reaction on the substrate.

This is most likely when reasonably acidic substrates such as alcohols, thiols, terminal acetylenes and carboxylic acids are treated withstrong bases.

Acid-base reactions tend to befast, relative to substitution and elimination reactions [See article – Acid-Base Reactions Are Fast]. So it makes sense to apply them first.

The resultingconjugate base will be, as we discussed above, a superior nucleophile/base relative to its conjugate acid.

These reactions show examples of a deprotonation step followed by a substitution step. See if you can draw the products.

The corollary to “the conjugate base is a better nucleophile” is “the conjugate acid is a better leaving group”.

Addition of acids (including Lewis acids) will help turn poor leaving groups into better leaving groups.

This is most often seen withalcohols, where addition of H+ converts the poor -OH leaving group into the (much better) leaving group H₂O.

Halides can be made into better leaving groups through addition of silver salts, which irreversibly precipitate the halides out of solution.

7. Intramolecular Reactions

It always pays to look at theintramolecularvariant of every new reaction you learn, since they are a perennial favorite of exam-writers everywhere.

In an intramolecular S_N2 reaction, the nucleophile and substrate are on the same molecule. Their combination will result in a new ring.

You can never have enough practice with intramolecular reactions.

8. The Substrate Always Has The Final Say

I know this is a lot to learn. Substrates, nucleophiles, reactions. That’s one of many reasons why students find organic chemistry difficult.

Rules of thumb, checklists, and flowcharts can be very helpful for making sense of all the information you’re asked to process.

You’re probably not going to like that there is one last thing, but there is one last thing.

At the end of the analysis process you will still have to apply the appropriate bond-forming/breaking pattern to your substrate in order to be able to draw the correct product.

And sometimes… even though you have run through all the checklists… your substrate might still have (or lack) a crucial feature that results in a specific reaction being unworkable.

Here are some examples.

So by all means use flowcharts and rules of thumb, but don’t get so “locked in” on following a flowchart that you forget to actually look at the molecule itself and decide whether or not that reaction is even possible.

Your substrate always has a veto.

9. Summary

In the process of trying to decide if a reaction is S_N1/S_N2/E1/E2, there are five general steps. This article is the third of five.

We’ve previously covered Step 1 (look for alkyl halides [link]) and Step 2 (determine if the alkyl halide is primary, secondary or tertiary [link]).Step 4(solvent [link]) and Step 5 (temperature [link]) are next.

In this article, we first looked at various reactions and looked for the strongest nucleophile/base present in each case. (A nucleophile is our name for a base when it’s forming a bond with any atom other than hydrogen).

• We then made a rule of thumb in defining nucleophiles/bases bearing a negative charge as “strong”, and neutral nucleophiles/bases as “weak”.
• This gives us six key cases to analyze (primary, secondary, tertiary with strong/weak).
• Primary alkyl halides tend to undergo S_N2 reactions regardless of whether or not the nucleophile is strong or weak.
• E2 reactions generally require reasonably strong bases (as strong as hydroxide or alkoxides, or stronger).
• For secondary alkyl halides, strong nucleophiles/bases tend to perform S_N2/E2 reactions, and weak nucleophiles/bases tend to perform S_N1/E1 reactions.
• With secondary substrates, negatively charged nucleophiles that are weaker bases than hydroxide tend to do S_N2 exclusively, and negatively charged nucleophiles that are stronger bases than hydroxides/alkoxides tend to do E2 exclusively.
• Hydroxide/alkoxide ions with secondary alkyl halides is a borderline area and may go either S_N2 or E2. [More on that next]
• For tertiary alkyl halides, strong bases tend to perform E2 reactions, and weak nucleophiles/bases give S_N1/E1 products.
• When acids/bases are added to the substrate, perform the acid-base reactions first.
• By all means apply rules of thumb / flowcharts, but still be alert for substrates where an S_N1/S_N2/E1/E2 reaction might not work due to the presence or absence of certain structural features (like the lack of a beta carbon with a C-H bond making E2 impossible for instance).

Notes

Note 1. The lone pair on acetonitrile (and other nitriles) will react with carbocations in a reaction known as the Ritter reaction but that’s beyond the scope of what we’ll cover here. [link]

Note 2.The biggest quibble I have about this “strong” and “weak” designation is that neutral amines such as triethylamine are perfectly capable of performing E2 reactions.

Other nitrogenous bases such as DBU and DBN will perform elimination reactions as well.

Secondly, neutral PPh₃ is perfectly capable of performing S_N2 on some secondary alkyl halides.

Note 3.You won’t go too wrong if you think of substitution reactions as being a fancy class of acid-base reaction, which tend to be successful when reaction of a stronger base with a substrate results in a weaker base (the leaving group).

One key difference is that substitution and elimination reactions tend to be irreversible and acid-base reactions are reversible.

Note 4.One example of a “strong” nucleophile/base reacting with a tertiary alkyl halide can be found in this example of an azide ion “intercepting” the carbocation formed from Ph₃CCl in water.

Note 5.Triethylamine and other neutral basic nitrogenous compounds are the main exception.

Quiz Yourself!

[Quiz]

(Advanced) References and Further Reading

[literature]

Reference. J. Am. Chem. Soc. 1953,75, 136.