A Primer On Organic Reactions
By James Ashenhurst
The Three Classes of Nucleophiles
Last updated: March 21st, 2019
I know I’ve said this before, but a whole lot of organic chemistry can be boiled down to “nucleophile attacks electrophile“.
A nucleophile is a compound that can donate a pair of electrons to (you guessed it) an electrophile, which results in the formation of a chemical bond.
If you look closely at nucleophiles, you’ll see that they fall into three broad categories. That’s what today’s post is about: seeing these patterns.
1) Lone Pairs
This is probably the easiest class of nucleophiles to understand, because of the parallels to basicity. After all, what is an acid-base reaction but the combination of a lone pair on an atom with a proton?
There are several key trends to keep track of when assessing the strength of lone pairs as nucleophiles.
- The nucleophilicity increases as the charge of the atom it is attached to decreases. A simpler way to put this is, “the conjugate base is always a stronger nucleophile”.
- The nucleophilicity increases as you increase the basicity. So as you go across the periodic table from right to left, nucleophilicity also increases. [H3C(-) > H2N(-) > HO(-) > F(-) ).
- Nucleophilicity increases as you go down the periodic table. So comparing halides, I(-) > Br (-) > Cl (-) > F(-)
Of course you might be able to spot a contradiction here: iodine is more polarizable than fluorine, but it is also less basic. So when these two trends collide, what wins? The wishy washy answer is that “it depends”. Solvent is a key variable here. In polar protic solvents, nucleophilicity increases with polarizability, because hydrogen bonds form a shell around the less polarizable atoms and decrease their nucleophilicity. In polar aprotic solvents, this is not an issue, so basicity is the most important variable. [Ultimately, when trends collide, however, the final arbiter is experiment].
EDIT: Alert reader Prasanna reminds me that these trends hold for SN2 reactions, but trend #3 is less important for reactions where the nucleophile is adding to unsaturated carbon (carbonyls and aromatics). One of the challenges of understanding nucleophilicity is that it is highly dependent on the electrophile.
2) π bonds.
π bonds can also be thought of as nucleophiles: they donate a pair of electrons as well, but in this case the pair is shared between two atoms. This not only covers double bonds, but also triple bonds (alkynes) as well as aromatics and even enols and enolates (in Org 2).
The key trend that determines nucleophilicity of π bonds is the presence of donor groups. By donor groups I mean an atom that can share electrons with the double bond to help stabilize it after it has donated its pair of electrons to the electrophile. This should hopefully make sense: after all, when a double bond reacts with an electrophile, the result is a carbocation (a high-energy species). Electron-donor groups help to stabilize the carbocation through donation of electrons. Anything which makes the carbocation more stable is going to lower the activation energy for the reaction and make it faster.
3) Sigma bonds.
Finally, the pair of electrons in a sigma bond can, on occasion, also act as nucleophiles. This third important class of nucleophiles is probably more subtle and less commonly encountered than the previous two, but you might recognize it when you see it. Here are some examples:
Note that in order for a sigma bond to act as a nucleophile, we have to break that sigma bond. Therefore, the #1 most important factor governing the nucleophilicity of sigma bonds is the leaving group. In two of those cases, the sigma bond is attached to a negatively charged atom that will become neutral once the bond is broken. In the third case (the hydride shift) we’re changing from a very unstable secondary carbocation to a more stable tertiary carbocation.
Did this post miss anything? Anything I should have covered? Leave a comment!