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. 

1-pka

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:

2-carbonyl

3. Pi-donors decrease the reactivity of adjacent carbonyls with nucleophiles (i.e. make it less electrophilic). 

3-amide

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:

4-groups

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. 

5-protonation

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:

6-steric

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:

7-amides

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{ 3 comments… read them below or add one }

Bruce Sea

Re. 1. There is a direct correlation between pKa and leaving group ability. The weaker the base, the better the leaving group it is.
I noticed a mark next to the OH, and it being classified as a moderate leaving group. I am just curious what that dot represents. This week in fact we looked at some reactions where OH was indeed the leaving group, this seems so contradictory to what I have read before, and the conditions were basic, not excessively, but they were definitely not promoting the OH to get protonated. WHAT seemed to be the factor is the stability and lower energy of the product, and very much in comparison to the intermediates, the alkoxides, the ethylene oxide which is so strained, and the product was a neutral cyclic lactone. Its a good thing to keep in mind that such a leaving group is plausible if the products are more stable than the reactants. Perhaps not a rule, but something to consider. CHEERS>

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james

Hah – yes. The asterisk next to the OH is because under basic conditions, OH becomes O(-) and therefore as a leaving group it is O(2-), which is extremely bad.

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Ajinkya Palande

pl.Read at lest one time. i think reaction is completely depend upon reactivity of function group toward adding reactive agent therefore we conc. on functional group making or converting by using various reagent with basic chemistry rule such as reaction with gas pressure require, SN1,SN2,E1,E2, steriochemistry, neighbouring group effect, lechatlier principle etc.
when i started study by such style & thinking about functional group behaviours i getting always good results as i expected with literature help.
ln my education careers i learn & read only bookish type not by functional group wise that’s mistake by every Indian student even max. teacher also & tell us organic is volatile chemistry
i think who is best chemist who imaging, realise logically perfect no such person who got only good marks in his career
because in my country Many people got PhD but no focus on organic hart(functional group) but focus only on patent & available literature lf u think i m wrong I can give u example cinchonine very less in alcohol but in pharmacopeia soluble in alcohol but not specify which alcohol. many people tell me u r wrong
lf u suggest other people by such way that’s very helpfully to everybody
l hope u sound our voice

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