After putting together last week’s summary sheet on addition reactions to carbonyls, I thought it would be helpful to highlight some of the key points.
1. There is a direct correlation between pKa and leaving group ability. The weaker the base, the better the leaving group it is.
A stronger base will NEVER be displaced from a carbonyl by a weaker base. For practical purposes, if you’re drawing hydride or alkyl groups as leaving groups, you’re doing something wrong.
Hydroxide is a terrible leaving group under basic conditions because the carboxylic acid will readily deprotonate give O- . The leaving group would thus have to be O2-, which as you can probably imagine (being dibasic) is a pretty bad leaving group.
Note that acidic hydrolysis is different situation, since protonation results in creation of a much more stable leaving group (the conjugate acid) that is capable of being displaced by relatively weak nucleophiles (e.g. water). For instance, water is a better leaving group than HO- by a factor of ~10 ^16 ! [pKa of H3O+ is -1.7 ; pKa of H2O is ~15]
2. Electron withdrawing functional groups increase the reactivity of adjacent carbonyls with nucleophiles (i.e. make it more electrophilic).
Here’s a common example:
3. Pi-donors decrease the reactivity of adjacent carbonyls with nucleophiles (i.e. make it less electrophilic).
Just as with aromatics and alkenes, carbonyls can accept electrons into their pi system from atoms with available lone pairs. A more electron-rich electrophile is a poorer electrophile. As with electophilic aromatic substitution, pi-donation ability has a far greater impact than the slightly deactivating sigma-acceptor effect of the electronegative N and O functional groups. This little chart should look familiar:
Substitutents in group A (pi-donors) slow nucleophilic attack at the carbonyl carbon proportional to their donating ability. Substituents in group B have an intermediate effect, whereas substituents in group C strongly activate the carbonyl carbon towards attack.
4. For mechanisms: Carboxylic acid derivatives always protonate on the carbonyl first.
With amides, for instance, it’s tempting to protonate the nitrogen first, since you know that this is the group that is eventually going to leave. However, the fact that the lone pair of the nitrogen donates into the carbonyl means that the right-hand resonance form (with the anionic carbonyl) is more Lewis basic. Protonate the carbonyl oxygen first, then add the nucleophile to the carbonyl carbon.
5. Increasing steric bulk around a carbonyl slows down the reaction with nucleophiles. Take this series of aldehydes/ketones:
The bulkier the group, the slower the reaction will be.The reason is that the nucleophile is reacting with the pi* of the carbonyl, and the electron cloud of the bulky groups hinder nucleophilic attack. A similar decrease in reactivity occurs when you increase the steric bulk about the primary alkyl halide in an SN2 reaction.
The angle of attack, by the way, is about 105 degrees, which is known as the Burgi Dunitz Trajectory. Mention this to your prof or TA and their eyes should light up with awe, because you took the time to learn something that will definitely not be on the exam. Anyhow, steric bulk slows addition of nucleophiles to amides and esters too: