The binding role of hydroxyl groups

Hydroxyl groups are commonly involved in hydrogen bonding. Converting such a group to a methyl ether or an ester is straightforward (Fig. 7.5) and will usually destroy or weaken such a bond. 

There are several possible explanations for this. The obvious explanation is that the proton of the hydroxyl group is involved in the hydrogen bond to the receptor and if it is removed, the hydrogen bond is lost (Fig. 7.6). However, suppose it is the oxygen atom which is hydrogen bonding to a suitable amino acid residue  

The oxygen is still present in the ether or the ester analogue, so could we really expect there to be any effect on hydrogen bonding Well, yes we could. The hydrogen bonding may not be completely destroyed, but we could reasonably expect it to be weakened, especially in the case of an ester. 

The reason is straightforward. When we consider the electronic properties of an ester compared to an alcohol, then we observe an important difference. The carboxyl group can pull electrons from the neighbouring oxygen to give the resonance structure shown in Fig. 7.7 Since the lone pair is involved in such an interaction, it cannot take part so effectively in a hydrogen bond. 

Steric factors also count against the hydrogen bond. The extra bulk of the acyl group will hinder the close approach which was previously attainable. 

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