Nomenclature of Organic Compounds
Bonding in Organic Chemistry
Stereochemistry
Reactivity
Radical Reactions
Acid-Base Chemistry
Alcohols, Ethers, Epoxides, Thiols, Sulfides, Amines
Alkenes and Alkynes
Conjugated Systems
Aromatic Compounds
Aldehydes and Ketones
Carboxylic Acids and Carboxylic Acid Derivatives
Enols and Enolates
Integrated Topics
Synthesis
Biomolecules

Acidity of Carbonyls

Here are some typical pKa values describing the acidities of common carbonyls that we usually see in organic chemistry. If we look at those numbers, they are kind of all over the place. So, why exactly is that?

pKa values of various carbonyls

In this tutorial I want to talk about the pka values of different carbonyl compounds and what influences the acidity of the carbonyls.

Review of the Acid-Base Equilibrium

So, what exactly does it mean when we say that something is acidic? If we look at some sort of generic acid, like “HA” and we look at its dissociation, what we are going to see is the formation of H+ (which is our proton) and it is going to be the same for any kind of acid; and we have an A (a conjugate base) which is going to be different for different molecules. Typically, to assess the acid-base properties of a molecule we need to look at the stability of the conjugate base. The general rule of thumb is that the more stable the conjugate base is the stronger is the acid.

review of the acid-base equilibrium

There are several different factors that we are generally going to be looking at when it comes to determining the stability of our conjugate base. Those factors are:

  1. The resonance
  2. The atomic size of atoms bearing the negative charge,
  3. The electronegativity of atoms with a negative charge,
  4. Inductive effects from electron withdrawing groups, and finally,
  5. The hybridization of atoms with a negative charge.

In the case of the carbonyl compounds, the most important factor is going to be the resonance factor. So, if we take some sort of a carbonyl compound, let’s say acetophenone, and if we look at how exactly this molecule going to look like after we deprotonate it, we are going to end up with the following resonance-stabilized anionic species (enolate anion).

resonance stabilization in enolates

The nature of our base is completely irrelevant for this example. The resonance structures that we see for this enolate anion have two resonance contributors: the major and minor contributors. And as the resonance stabilization helps us to delocalize our charge, that makes our conjugate base more stable overall. This makes our original molecule more acidic than a typical alkane that has a pKa of about 55. While the pKa=19 for an acetone molecule is not particularly high, it is still acidic enough so it can be deprotonated by mild bases like alkoxides.

How would adding other groups affect the pKa and the acidic properties of our carbonyl? If we add a group that can extend the resonance stabilization of the enolate ion, it will make it more stable and by extension, make our carbonyl more acidic. For instance, let’s look at the following example:

extended resonance effect on the acidity of carbonyls

Here, we have two carbonyl groups that are stabilizing the negative charge on the enolate once it forms. This makes this molecule, which is by the way called acetophenone, fairly acidic with the pKa value around 9. Thus, clearly, adding more resonance stabilization makes our molecule more acidic. In this case, I have tree resonance structures with two major contributors compared to only two resonance structures and one major contributor we’ve seen for acetene.

Inductive effect and the acidity of carbonyls

The resonance effect is clearly important. How about the induction though? Does induction help as well?

Well, that’s where things are a little bit more interesting and somewhat more complicated! Let’s look at the example of a ketone on the left and an ester on the right:

induction vs resonance effects on the acidity of carbonyls

In the case of the ketone, the pka of my scidic protons is about 19. While in the case of an ester, the acidic proton has the pka of around 24. And although we do have an electron withdrawing group in the form of an oxygen atom here, somehow it does not make our molecule more acidic. Normally, we are used to seeing induction being a good thing and making our acids stronger. So, what’s going on here?

And to answer this question, we actually need to dig deeper into the resonance. Since the oxygen atom has delocalized electrons, this will have an effect on our resonance in the carbonyl. When we deprotonate the acetone molecule, we add one more orbital into the conjugated system, essentially, extending the already existing resonance in the carbonyl. When we do the same in an ester molecule, the picture is somewhat different. The oxygen atom already has a resonance with the carbonyl. But deprotonating the ⍺-carbon creates a competing resonance in the molecule. So, instead of extending the resonance, we create a “fork” in the resonance. And “forking” the resonance is not going to be as favorable as extending the resonance. Thus, overall, while we still see the resonance stabilization of the negative charge in the ester enolate, this resonance stabilization is not as strong as in the case of a ketone.

So, as a rule of thumb 👍 you can remember that:

  • Extending resonance is very good,
  • “Forking” the resonance is less good.

We can illustrate this phenomenon with the example above. In the first two molecules, by deprotonating the ⍺-position in the carbonyl, we extend the resonance making one smooth conjugated “tunnel” for the electrons to travel through 3 or 5 atoms correspondingly. In the last example, however, we already have a resonance in the molecule between the carbonyl and the oxygen atom (highlighted in blue). Thus, when we deprotonate the ⍺-position, we’ll create a fork in the resonance (in pink) instead of actually extending it. This makes the enolate not as stable is in the first two examples. Thus, the molecule is going to be less acidic.

Why knowing the pKa’s of carbonyls is important?

Here is the question which you probably have right now: why is it even important to bother with all of those pKa values? Whi is it important to dig deep into all these acid-base properties?

The answer here is actually very simple: the acid-base chemistry always happens first! So, whenever we are thinking about any kind of reaction, any kind of step in our reaction, we always need to consider what happens from the perspective of the proton transfer. Only after we analyze that, we can go on and look at other possible interactions that our molecule in questions might have with other participants in the reaction mixture. Otherwise, it’s incredibly easy to make an erroneous conclusion which can completely derail your entire reaction scheme. Let me illustrate with an example:

why knowing the pKa of carbonyls is important

Above, we have a reaction between acetoacetone and lithium diisopropylamine (LDA). We know that LDA is an incredibly powerful base, and it tends to deprotonate positions which are more sterically available (less sterically hindered). So, in this case we can assume that we are going to go after one of the protons on the outskirts of the molecule. However, those protons have a pKa value of about 19, while the protons in the middle of the molecule have the pKa of about 9. This drastic difference in the pKa values and acidity is incredibly important. Since the acid-base chemistry is dependent on the, well, acid-base properties of the molecule, the more acidic protons will ALWAYS be removed first regardless of the size of your base or its strength. Thus, if you didn’t pay attention to the pKa values of the enolizable protons in your molecules, you’d end up with the wrong enolate and, by extension, the wrong product in the reaction where this enolate was involved.

So, make sure that the pKa table is your very best friend and you’re always double checking the pKa values of different protons in the molecule before you actually go ahead and do the reaction.

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