Carbonyls: 10 key concepts (Part 2)

by James

in Aldehydes, Carboxylic acids, Esters, Functional Groups, Ketones, Organic Chemistry 2, Where Electrons Are

If you’re on the typical college cycle, chances are you’re taking Org II right now. As you are by now well aware [more aware than you wish you were, I can hear some of you say]  one of the main focii of Org II is on the many different facets of carbonyl chemistry. Following on the heels of the previous post, here are five further important points to keep in mind when studying the chemistry of these species. [Note – these will be included in the second carbonyl summary sheet, currently in preparation]. Without further ado…

6. Carbonyls make adjacent alkyl groups more acidic. How much more acidic? Consider ethane. For all practical purposes, ethane is inert to base: the pKa of its hydrogens is 50. But when you exchange one of the protons of ethane for a carbonyl group (say, -COOCH3) something phenomenal happens. The acidity changes by a factor of 10 ^25. That is an incredible number to wrap your head around.  The difference in chemical reactivity between different species can be incredibly, mind-bogglingly vast. We are not talking about the difference in quarterbacking ability between Peyton Manning and Dan Marino here, or even the comparative basketball skill set of LeBron James and Verne Troyer. The differences in reactivity* are truly cosmic:  like comparing the width of your armspan to the length of the Milky Way galaxy.

1-acidity

What’s going on here? Simply put,  the carbonyl π system provides a “sink” for the carbanion to donate electron density, setting up a sharing of negative charge between the α-carbon and the carbonyl oxygen. The key structural feature is not so much the resonance, although that is a factor – [the lower pKa of propene (42) is a good example of resonance stabilization] The reason why the carbonyl stabilizes the carbanion so much is that the negative charge becomes localized on a much more electronegative atom (oxygen), which is better able to stabilize negative charge.

*just to be clear: reactivity = the position of the equilibrium, between acid and conjugate base – not relative energies. To get the relative energies, you’d have to solve  ΔG = –RT(lnK) for each and compare.

7. The more electrophilic the carbonyl, the more acidic its α-protons. 

The stabilization afforded by the carbonyl group depends on how electron-poor it is. Placing a highly electronegative grouping like CF3 adjacent to the carbonyl makes the carbonyl much more electrophilic, which makes it better able to stabilize negative charge. On the other hand, carbonyls with electron-donating groups attached (like amides) do not stabilize negative charge nearly as well. This translates to lowered acidity of the alpha proton.

2-acidity

These effects are additive, by the way. With this principle in mind, you should be able to identify rank the following dicarbonyl compounds on the basis of acidity.

3-acidity

8. Carbonyls also activate alkenes toward nucleophilic attack. 

 Ethene (ethylene) reacts well with electrophiles like Br2 and mCPBA, but when combined with a nucleophile like diethylamine, no reaction happens. This is in spite of the fact that the reaction would actually be thermodynamically favorable: you’re trading a C-C π bond and N-H single bond  for a new C-H single bond and a C-N single bond. The reason for this lack of reactivity, just as it was for #6, is that the resulting carbanion that would result from nucleophilic attack is highly unstable. 

4-attack

Replace a hydrogen with a carbonyl derivative, however, and suddenly the alkene becomes a lot more frisky. Again, the reason is the ability of the electrophilic carbonyl group to stabilize the newly generated negative charge.  The immediate product of conjugate addition is an enolate, which can then be quickly protonated, depending on reaction conditions. The key point is that the carbonyl stabilizes the intermediate of the reaction, which allows it to proceed.

5-attack

9. The reactivity of an α,β-unsaturated carbonyl is proportional to the stability of its enolate. 

Let’s say you’re asked to rank the reactivity of the following α,β-unsaturated carbonyl derivatives toward nucleophiles:

6-acidity

By knowing the relative donation ability of each substituent at the carbonyl (e.g. NEt2 > OEt > CH3 > CF3) you can rank the stability of the enolates that will be generated through conjugate addition. Since nucleophilic addition is the rate-limiting step of this reaction, you will therefore know the relative rate of addition. 

The intersection between α,β-unsaturated carbonyls and enolates has led to all kinds of innovative discoveries in chemistry. [Not on the exam: The Baylis-Hillman reaction].

Just remember: addition to an α,β-unsaturated carbonyl gives you an enolate intermediate.

[FYI, there is another, subtle effect with α,β-unsaturated carbonyls that I don’t have time to get into right now: the gamma protons are acidic. ]

10. Enolates are nucleophiles. They come up in reactions again and again. By understanding their relative stability, you also understand their relative reactivity.

My 3rd year organic chemistry teacher, Prof.  Szarek, had us say the following out loud in class, as a group, several times a lesson, until we finally got this fact drilled into our heads: 

The enolate is a nucleophile.”

If you’re studying Org II right now, you can hopefully think of 3 or 4 examples off the top of your head where you see the enolate… adding to different electrophiles.

– the Aldol reaction

– the Claisen condensation

– the Michael reaction

– enolate alkylation

What about relative reactivity? Recall the order of carbonyl α-proton acidity:

7-acidity

The reactivity of a nucleophile is inversely proportional to its stability. Makes sense, right? The less stabilized it is, the more reactive it should be. Another way of putting it: the higher the pKa of the carbonyl compound, the more reactive the resulting enolate will be.

8-reactiivty

Say it loud, say it proud: the enolate is a nucleophile.

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{ 4 comments… read them below or add one }

Louis

Nice web site you have here Jim. Good discussion on the enolate ion. In biochemistry these types of reactions are commonplace, including 2 amide bearing amino acids, Q and N.

What about the possibility of the loss of a proton (say to the surrounding cytosol) leaving behind an anionic N capable of donating an electron pair into the carbonyl? In this way you could also create a negative oxygen with N in a double bond with the connecting carbon. Perhaps an acid/base catalytic framework could support this.

For example consider a protein salt link. Say lysine (K+) is close by and can provide a stabilizing positive charge to the enolate-like negatively charged oxygen atom. Would it be more likely that the enolate ion, normally unstable, is now more stable in the enolate form? What about the loss of a proton from the amine N, as mentioned above, and then donating the residual electrons into resonace with the carbonyl resulting in a stabilized N=C-O- ….. K+ salt link? Do you think this is possible? Which one would you predict most likely, or none at all? Just thought I’d throw this out – might help me get a better handle on this – I know it can’t be too complex but my organic chemistry is a bit rusty.

I need to do some further research on this, perhaps simple thermodyanmics could provide the answer. A simple NH3+ … -O-R bond is in the neighborhood of 4 kJ/mol – so wonder too how this might effect the two potential enolate type negative anions.

Just a thought. I am currently looking at this problem with an N sitting approxiately 2.5 Ang away from a lysine.

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ray clarke

About the diethylaminoethyl (ibuphenpropanamide )lithium enamine/enolate and its reaction with a haloalkane or haloarene. A fantastic intermediate for addition to the nitrogen atom of the amide?? What say you? Ray

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Amrutha

Could you please explain ‘Carbonyls make adjacent alkyl groups more acidic’ in a different way? I don’t understand how they are related to the acidic nature of adjacent or alpha carbons.

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Mudit

The stronger an acid is, the weaker is its conjugate base. So, any characteristic which stabilizes a conjugate base, increases the acidity of its conjugate acid.

When the alkyl group adjacent to the carbonyl carbon loses H+ and gains a negative charge, this charge is effectively held by the carbonyl oxygen due to resonance. As oxygen is more electronegative than carbon, it stabilizes the charge better than carbon does. In contrast, ethane is pretty much non acidic because it cant stabilise the negative charge that comes with loss of H+

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