What Makes A Good Nucleophile?

As I said yesterday, in a substitution reaction, the nucleophile is the species that gives up a lone pair of electrons to the electrophile.

Let’s talk about the factors that affect nucleophilicity.
First, nucleophilicity and basicity are very similar. One difference is that nucleophile strength is measured by how fast it reacts, whereas acid-base strength is measured by equilibrium (pKa).  Also, substitution reactions are much more subject to steric hindrance than acid-base reactions. It’s OK to think of nucleophilicity as correlating with basicity, with two exceptions (cases 3 and 4, below).

For now, let’s just think of nucleophiles as lone pairs on atoms.(Note 1). Imagine comparing two compounds, and asking “which of these is most nucleophilic?”.

So what would make one atom more likely to give up its lone pair of electrons than another? There are at least four factors.

1. Charge.“The conjugate base is always a better nucleophile”. HO- is a better nucleophile than H2O. NH2(-) is a better nucleophile than NH3. HS(-) is a better nucleophile than H2S. The greater the negative charge, the more likely an atom will give up its pair of electrons to form a bond.
2. Electronegativity. Nucleophilicity increases as you go to the left along the periodic table.

H3C(-) > H2N(-) > HO(-) > F(-)

This makes sense when you think about it, electronegativity – “greed for electrons” – is the opposite of nucleophilicity – “giving away electrons”.

3. Hydrogen bonding solvents (polar protic solvents) 

This causes the most confusion, because it is solvent-dependent. In polar protic solvents (e.g. water and alcohols, any solvent with OH) nucleophilicity increases as you go down the periodic table (F- < Cl- < Br- < I – ). In polar aprotic solvents (e.g. DMSO, acetone) the order is reversed, and the most basic nucleophiles are also the most nucleophilic. (F- > Cl – > Br – > I – ).

Why is this? Because hydrogen bonding has a dramatic effect on nucleophilicity. In hydrogen bonding solvents (polar protic solvents) the most basic nucleophiles (e.g. F-) are surrounded by an entourage of solvent molecules. It might help for you to think that this makes them far more “sterically hindered” than they would normally be, and they are less reactive.

By contrast, the least basic nucleophiles  (e.g. I-) get involved with less hydrogen bonding, and are less hindered – therefore more nucleophilic.

4. Steric bulk

Remember the Pavlovian association between “t-butyl” and “steric hindrance”  I mentioned earlier? Here it comes again!

The bulkier the groups that are adjacent to a nucleophilic atom, the slower the reaction will be (and hence the poorer the nucleophile).

Phew! that’s a lot. Here’s a little table that should help to make sense of things.

Tomorrow: What makes a good leaving group?

Thanks for reading! James

P.S. Note 1   (Pi bonds – found in alkenes and alkynes – can act like nucleophiles too, but that’s a subject for later).