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Guest Post On SN1/SN2/E1/E2 (3): Step 1 – The Nucleophile

Following from Adam’s last guest post on the SN1/SN2/E1/E2 (“The Leaving Group“) here is part 3 of the series!  – James

Step One: What is the nature of the nucleophile? by @azmanam

Last time, we talked about the quick check on the nature of the leaving group. Today, we’ll discuss how the nature of the nucleophile helps our chemical differential diagnosis. If it’s all about the electrons, and if concentrating more and more electron density into a smaller and smaller volume makes a molecule less stable, then we can use this information to help us assess the nature of the nucleophile.

Reviewing the four possible mechanisms, the nucleophile plays a big role in the reaction. It is the piece with all the electron density. It is the molecule which will be attacking the electrophile to form the new bond. It is the actor in these reactions, and we need to be able to assess its strength before we can decide the appropriate mechanism.

Let’s look at the ‘2’ mechanisms first: the SN2 and the E2. In these reactions, the nucleophile directly attacks the electrophile to start out the mechanism. It either directly attacks the electrophilic carbon atom or the β-hydrogen atom, but it has to have enough inherent energy to be strong enough to directly attack the electrophile.

The opposite is true in the ‘1’ mechanisms. In the SN1 and E1, the nucleophile does not directly attack. Instead, the nucleophile has to wait around until the leaving group decides to leave, and only then will the nucleophile attack the much more unstable carbocation. If the nucleophile doesn’t have the inherent energy to directly attack, it must be a considerably weaker nucleophile compared to the ‘2’ mechanisms.

So we can already say that ‘strong’ nucleophiles will be evidence for the ‘2’ mechanisms, and ‘weak’ nucleophiles will be evidence for the ‘1’ mechanisms. But it’s a bit more nuanced than that, because sometimes the nucleophile attacks the electrophilic carbon, and sometimes it attacks the β-hydrogen. Sometimes it acts as a nucleophile, and sometimes it acts as a base.

So what makes something a ‘strong’ or a ‘weak’ nucleophile, and what makes it act more as a nucleophile or as a base? Both variables are continuums, and there are many shades of gray, but we can discuss some generalities which will help us diagnose this reaction.

Electrons do not like to be confined. It makes the electrons more unstable, and the molecule more unstable. ‘Strong’ nucleophiles and bases are characterized by lots of electron density (usually so much electron density that it has a full negative charge) in a very small volume. You may remember this trend from the acid/base chapter characterizing strong bases. In general, nucleophile strength parallels base strength. So in general strong nucleophiles will also be strong bases. Here are some molecules we would characterize as strong nucleophiles/strong bases:

Of course, there are some exceptions, not every strong base will also be a strong nucleophile, and vice versa. So what factors might make something strong in one category, but weak in another? And why is there a difference anyway? It’s subtle, but there is a difference because basicity is a thermodynamic property (the acid/base equilibrium favors the weaker base), but nucleophilicity is a kinetic property (the rate at which a nucleophile reacts with an electrophile).

Steric hindrance makes a molecule a weaker nucleophile. In order for a nucleophile to attack an electrophilic carbon atom, it has to get close enough to that carbon atom in the interior of the molecule, and bulky nucleophiles have a harder time doing that. The prototypical non-nucleophilic base is potassium tert-butoxide, KOtBu. With the full negative charge localized on the single oxygen atom, it is a strong base, but the steric bulk from the methyl groups makes t-butoxide a rather poor nucleophile. Other non-nucleophilic bases include NaH, LDA, and DBU.

The conjugate bases of the mineral acids make good nucleophiles, but terrible bases. Br and I are all pretty good nucleophiles, but pretty bad bases. Other molecules with a negative charge on a single atom, but a strong conjugate acid make good nucleophiles, but weak bases. The cyanide anion, the azide anion, and thiolates also make a great nucleophile, but tend to be a poor base.

So if negative charges concentrated in a very small volume make a molecule a ‘strong’ nucleophile and base, the opposite characteristics will make something a ‘weak’ nucleophile and base: neutral charges, electron density spread over a large volume (say, through resonance), and very low conjugate acid pKas.

Neutral alcohols, neutral carboxylic acids, neutral thiols, and even carboxylate anions (with the electron density stabilized through resonance) make weak nucleophiles and weak bases. These molecules do not have the strength to directly attack an electrophile, so they must wait around until the leaving group decides to leave and form a very unstable carbocation before the nucleophile can attack.

So remember, it’s all about electron density – does this nucleophile have a lot of electron density (maybe even a full negative charge) concentrated in a very small volume? Or are the electrons more stable or spread out over a larger volume? Learning these trends will help us figure out what evidence we get about our diagnosis from the nucleophile. The nucleophile will fall into one of four categories: strong nuc/strong base, strong nuc/weak base, weak nuc/strong base, weak nuc/weak base. And the different categories are evidence for and against different possible mechanisms. Let’s start a chart. We’ll fill in more of this chart as we assess the electrophile and the solvent, but we’ll start with the nucleophile:

Nuc Category  Evidence For Evidence Against
Strong nuc/strong base    SN2, E2    SN1, E1
Strong nuc/weak base SN2 SN1, E1, E2
Weak nuc/strong base   E2    SN1, SN2, E1
Weak nuc/weak base SN1, E1 SN2, E2

Let’s answer one interesting question before we finish for the day: Why wouldn’t a strong nuc/weak base be evidence for SN2 and E1? And why wouldn’t a weak nuc/strong base be evidence for SN1 and E2? Because the nucleophiles are the actors in these reactions. To be a ‘1’ reaction, the nucleophile has to wait around long enough for the leaving group to spontaneously leave on its own. If the nucleophile is strong enough to invoke one of the ‘2’ mechanisms without having to wait around for the carbocation, that mechanism will dominate – it won’t give the electrophile enough time to form the carbocation. It doesn’t have to. It has plenty of excess energy – more than enough to go straight to the ‘2’ mechanism.

A word of caution: even though some of the nucleophiles are only evidence for one mechanism, we still must assess all the evidence before we make a diagnosis. Do you remember the episode of House where Dr. House teaches the diagnosis class for a day? He opens class by announcing that 3 patients enter the clinic complaining of leg pain. What should they do? The first eager med student shoots his hand up and says ‘ice, rest, and elevate.’ Dr. House acknowledges that most leg pain is a result of minor sprains and strains, but if the doctor gives that advice to these three patients, within 24 hours they will all be dead. The point of the story is we need all the symptoms and all the evidence from those symptoms before we attempt a diagnosis.

Next time, we’ll learn how to read the electrophile and figure out what evidence the electrophile gives us.

Next Post: 3½ Steps To Any Substitution Or Elimination Reaction, Part 2: The Electrophile

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