Chemistry of Enolates and Enols – Acidity of Alpha-Hydrogens

In the presence of carbonyl functional group, the alpha-hydrogens of a molecule exhibit acidity i.e. in the presence of a base they can be abstracted very easily to yield a carbanion.

In the presence of a base alpha-hydrogens to carbonyl functional group can be abstracted very easily to yield a carbanion
In the presence of a base alpha-hydrogens to carbonyl functional group can be abstracted very easily to yield a carbanion

The acidity of the α-hydrogen of carbonyl compounds depends on the stability of the carbanion formed (which is the conjugate base in this case). If the carbanion is more stable, the alpha-hydrogen is more acidic. The carbanion can be stabilized either with resonance – i.e. the carbanion lone pair to the oxygen of the carbonyl to form the stabilized enolate, or by inductive effect – if electron withdrawing groups are directly attached to the alpha-carbon.

Stabilization with resonance - i.e. the carbanion lone pair to the oxygen of the carbonyl
Stabilization with resonance form showing an enolate - i.e. the carbanion lone pair to the oxygen of the carbonyl
Stabilization by inductive effect - if electron withdrawing groups are directly attached to the alpha-carbon.
Stabilization by inductive effect - if electron withdrawing groups are directly attached to the alpha-carbon.

Note – Acidities of the alpha-hydrogen is measured in pKa. Lower pKa value of the hydrogen, more acidic it is.

Comparison of Acidities of Alpha – Hydrogens

Note – The pKa values are given assuming the R’ and R” groups are alkyl (mostly methyl group) and are an approximate value.

1] α-Hydrogens of Ketones vs Aldehydes

The alpha-hydrogens of ketones (pKa = 20) are less acidic as compared to aldehydes (pKa = 17). This is because the alkyl group R” of ketones pushes electrons via inductive effect on to the alpha-carbon. This would increase the electron density at the alpha-carbon to slightly destabilize the formation of the conjugate base – carbanion.

alpha-hydrogens of ketones (pKa = 20) are less acidic as compared to aldehydes (pKa = 17) due to inductive effect
alpha-hydrogens of ketones (pKa = 20) are less acidic as compared to aldehydes (pKa = 17) due to inductive effect

2] α-Hydrogens of Ketones vs Esters

The alpha-hydrogen of ketones (pKa = 20) is more acidic as compared to the alpha-hydrogens of esters (pKa = 25). The reason for this is that the ester functional group has free lone pairs on the oxygen which can participate in resonance with carbonyl group. This resonance competes with the resonance of the stabilization of the enolate resonance. Also the oxygen acts as an electron donating group via resonance and therefore makes the formation of carbanion more difficult.

alpha-hydrogen of ketones (pKa = 20) is more acidic as compared to the alpha-hydrogens of esters (pKa = 25) due to resonance with the oxygen lone pair
alpha-hydrogen of ketones (pKa = 20) is more acidic as compared to the alpha-hydrogens of esters (pKa = 25) due to resonance with the oxygen lone pair

3] α-Hydrogens of β-Diketones, β-Ketoesters and β-Diesters

Beta-diketones have extremely acidic alpha-hydrogens (pKa = 9), mainly because the formed negative charge on the conjugate base can be distributed on both the ketone groups on either side. For this reason abstraction of this proton can be achieved using even weak bases such as sodium hydroxide.

Beta-diketones have extremely acidic alpha-hydrogens (pKa = 9), mainly because the formed negative charge on the conjugate base can be distributed on both the ketone groups on either side
Beta-diketones have extremely acidic alpha-hydrogens (pKa = 9), mainly because the formed negative charge on the conjugate base can be distributed on both the ketone groups on either side

Similarly, beta-ketoesters (pKa = 11) and beta-diesters (pKa = 13) also have lower pKa values compared to the simple ketones or esters due to the additional resonance stabilization by the alternate carbonyl group.

 beta-ketoesters (pKa = 11) and beta-diesters (pKa = 13) also have lower pKa values compared to the simple ketones or esters due to the additional resonance stabilization by the alternate carbonyl group.
beta-ketoesters (pKa = 11) also have lower pKa values compared to the simple ketones or esters due to the additional resonance stabilization by the alternate carbonyl group.
 beta-ketoesters (pKa = 11) and beta-diesters (pKa = 13) also have lower pKa values compared to the simple ketones or esters due to the additional resonance stabilization by the alternate carbonyl group.
beta-ketoesters (pKa = 11)also have lower pKa values compared to the simple ketones or esters due to the additional resonance stabilization by the alternate carbonyl group.

pKa List for α-Hydrogens

The following images displays the pKa for alpha-hydrogens of different functional groups.

Note – These image is taken from http://www.chem.ucalgary.ca/courses/350/Carey/Ch21/ch21-2.html and can also be found in reference 1.In case of carboxylic acids and amides, the alpha-hydrogen is not the most acidic one and therefore the most acidic hydrogen is shown.

pKa list for alpha-hydrogens of carboxylic acids, nitro compounds, amides, aldehydes, ketones, esters, nitriles, amides and alkanes. Note - the pKa value is for the hydrogen highlighted in red and it may not be the alpha-hydrogen.
pKa list for alpha-hydrogens of carboxylic acids, nitro compounds, amides, aldehydes, ketones, esters, nitriles, amides and alkanes. Note - the pKa value is for the hydrogen highlighted in red and it may not be the alpha-hydrogen.
pKa list for alpha-hydrogens of beta-diketone, beta-ketoester, beta-diesters. Note - the pKa value is for the hydrogen highlighted in red and it may not be the alpha-hydrogen.
pKa list for alpha-hydrogens of beta-diketone, beta-ketoester, beta-diesters. Note - the pKa value is for the hydrogen highlighted in red and it may not be the alpha-hydrogen.

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References

  1. Advanced Organic Chemistry: Reactions and synthesis. By Francis A. Carey, Richard J. Sundberg
  2. Organic-Chemistry.org (accessed on February 13, 2011)
  3. http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/crbacid3.htm (accessed on February 13, 2011)
  4. http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/aldket2.htm(accessed on February 13, 2011)

This Post Has 11 Comments

  1. Mb

    Nice…stuck it!

  2. Mark Nolan

    so does this mean that greater resonance of the leaving group increases the acidity of the alpha hydrogen?

    1. Akul Mehta

      Hi Mark,
      the leaving group would be a proton. Since that has no electrons it would not be resonating. The remaining species is the carbanion. Resonance in the carbanionic species will govern the acidity of the alpha hydrogen the most. However, there are other factors which will also govern it such as the inductive effect in case any electron withdrawing groups are present near the formed carbanion in the structure. Hope that answers your question.

  3. anonymous

    do u mean that I can’t do Medicinal Chemistry at all??? In fact, I wanna do that!!

    1. Akul Mehta

      No it does not mean that. You can do medicinal chemistry but you must also understand other subjects apart from chemistry for it.

  4. anonymous

    Thanks dude…. It’s a great job… I was having loads of problems in understanding this part on enols and enolates….

    From Mauritius….
    BSc(Hons) Chemistry

    1. Akul Mehta

      You are welcome. Please remember to +1 or share the website on facebook or twitter and you can find our group or twitter page as well to get more information.

      1. anonymous

        Ok dude…
        Do you do only Organic Chemistry???

        1. Akul Mehta

          No medicinal chemistry… it involves a lot of things apart from chemistry

          1. anonymous

            can I ask a question?
            If I have done BSc(Hons) Chemistry, can I do a Master only in Medicinal Chemistry???

          2. Akul Mehta

            No not necessarily. There are many more sub-fields in chemistry such as analytical chemistry or structural biology etc. where you could apply.

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