Deciding SN1/SN2/E1/E2 (2) – 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 S_N1/S_N2/E1/E2 – The Substrate]

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

• For example, if a substrate is primary, 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 the nucleophile or base. ( 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 strongest one. ( 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 pK_a Table ].

So if you see NaOCH₂CH₃ in the presence of CH₃CH₂OH or tBuO(-) in the presence of t-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 solvents which 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 polar protic solvents such as water, alcohols, carboxylic acids and even ammonia. These solvents are capable of participating in substitution/elimination reactions.

• Polar protic solvents such as water, alcohols, and even NH₃can 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 S_N1/S_N2/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 with strong nucleophiles/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 a leaving group from 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!)