I was preparing for my first exam in organic chemistry and came across this question.

Draw a water molecule that is hydrogen bonded to the best anticipated hydrogen bond acceptor.
2-amino-N-(3-hydroxyphenyl)acetamide, PubChem CID: 20238693

I was thinking that it would be one of the oxygens, because of its greater electronegativity compared to nitrogen. However, I'm having a little trouble distinguishing which oxygen.

I'm leaning towards the alcohol group. My reasoning is that there is less steric hindrance preventing solvation, but I am not sure.

  • $\begingroup$ But also, the ketone oxygen is sp2 hybridized. Would this have an effect to increase the polarity of the bond? $\endgroup$ – Brandon Zhu Sep 28 '18 at 3:51
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    $\begingroup$ There is no ketone in this compound the functional group is an amide. $\endgroup$ – Martin - マーチン Sep 28 '18 at 13:01

As a general rule of thumb, a nitrogen is usually a better hydrogen bond acceptor than an oxygen. There is a brief overview on Wikipedia with a couple of values and where they were derived from.

This makes sense intuitively, too. Ammonia is a stronger base than water as it is a better proton acceptor. An amine is a stronger base than an alcohol.

In your example, 2-amino-N-(3-hydroxyphenyl)acetamide, there are three functional groups (or four if you want to count the aromatic ring, too): a primary amine, a secondary amide, and a phenolic alcohol.

The phenolic alcohol is rather acidic and not such a good hydrogen bond acceptor, as some of the lone pairs are in conjugation with the aromatic ring.
The amide is also a delocalised system, which makes the nitrogen pretty unavailable for hydrogen bonding. For this functional group, if it were separate, the π-orbital would be the HOMO, and this is where the protonation/ proton-accepting will happen; due to the delocalisation this is less so the case. An amide usually is not a good hydrogen-bond acceptor.
The amine is primary, which means there is much space around it and it can directly interact with the solvent. This is a good hydrogen-bond acceptor.

Therefore neither oxygen will be the best hydrogen-bond acceptor.

  • $\begingroup$ Thank you! That makes sense. I was a little confused about the relative strength of hydrogen bond acceptors/donors so that helped a lot. $\endgroup$ – Brandon Zhu Sep 28 '18 at 13:43
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    $\begingroup$ As per the answer, it of course correct since this was an exercise from a book. But in real live the matter is more complex. In a polar solvent, the molecule will probably be ionized with a $\ce{-NH3^+}$ group and a $\ce{-O^-}$ group. Then the best hydrogen bonding group will be the phenoxide. Still, the ionization will not be complete, etc. It is a pity that the books for teaching new chemists do not pay any attention to the details. $\endgroup$ – Raoul Kessels Sep 28 '18 at 16:11

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