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Why is the pka of the carboxylic acid part of alpha amino acids (pka around 2.3 for most amino acids) quite a bit less than the pka of a normal carboxylic acid, say acetic acid (pka =4.76)?

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  • $\begingroup$ Look at mesomer forms of the conjugate base. The more you find the more the acid is strong. $\endgroup$ – ParaH2 Nov 15 '15 at 14:26
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The amino group in $\alpha$-amino acids is electron-withdrawing via the inductive effect. Mesomeric (resonance) effects cannot occur here because there is no conjugation of the nitrogen lone pair with the carboxyl group. There are two equivalent ways of looking at how the EWG affects the acidity:

  1. It stabilises the conjugate base via withdrawal of electron density from the negatively charged oxygens;

  2. It polarises the $\ce{O-H}$ bond further than in the unsubstituted carboxylic acid, making the proton more prone to dissociation.

Therefore, the $\mathrm{p}K_\mathrm{a}$ of glycine is $2.34$, significantly lower than the unsubstituted acid (acetic acid, $\mathrm{p}K_\mathrm{a} = 4.76$). Similar effects are seen in 2-chloroacetic acid ($\mathrm{p}K_\mathrm{a} = 2.86$).


As for the comparison between glycine and 2-chloroacetic acid, one thing to bear in mind is that glycine exists as a zwitterion at neutral pH. Therefore, the relevant acid-base equilibria are:

Glycine

For $\mathrm{p}K_\mathrm{a1}$, which you are interested in, note that the substituent is no longer merely a $\ce{-NH2}$ group but is now a $\ce{-NH3+}$ group. Despite nitrogen and chlorine having extremely similar Pauling electronegativities, the positively charged nitrogen is now more electron-withdrawing than a simple uncharged chloro substituent.

One could draw some parallels with aromatic chemistry: aniline is rather unreactive (compared to chlorobenzene) in electrophilic substitution under acidic conditions, where it is protonated. Of course, the reactivity of aromatic rings is a kinetic effect whereas $\mathrm{p}K_\mathrm{a}$ is a thermodynamic effect, but the underlying rationale is the same: $\ce{-NH3+}$ is more electron-withdrawing than $\ce{-Cl}$.

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  • $\begingroup$ Cheers for this reply, upvoted, but I'm not going to accept yet as I'm not fully convinced for the following reason: chlorine has the same electronegativity as nitrogen so why is there still a non-negligible difference in the pka of 2-chloroacetic acid and glycine. Furthermore I'd expect the former compound to be even more acidic because nitrogen pulls electron density from 3 bonds (2 hydrogens and the rest of the molecule) whereas chlorine is only pulling electron density from the molecule itself, the only moiety it is attached to. $\endgroup$ – Laksh Nov 15 '15 at 16:28
  • $\begingroup$ Furthermore, fluoroacetic acid (fluoro electronegativity > nitrogen) is still observed to be less acidic (pka 2.6) than glycine. $\endgroup$ – Laksh Nov 15 '15 at 16:34
  • $\begingroup$ Unless the substituents are extremely similar (e.g. F, Cl, Br, I), it is difficult to simply compare substituents just on the basis of Pauling electronegativity, and a direct relationship may or may not exist. Nevertheless, it is a good question and I will expand the answer a little bit because there is a second aspect of glycine that I neglected earlier. $\endgroup$ – orthocresol Nov 15 '15 at 16:38

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