Hydrogen bonding and the phenolic hydroxyl group

The hydrogen bond is an electrostatic interaction between a hydrogen atom bound to an electronegative atom such as oxygen, fluorine or nitrogen, and the free electrons of other atoms. An actual covalent bond is not possible, because that would result in the presence of more than two electrons in the orbital around the hydrogen atom.

The proton of the hydroxyl group of phenol is an ideal candidate for hydrogen bonding. Shown below (2.7) are three phenol molecules, with the hydrogen bonds indicated by dotted lines.

The hydrogen bond is weaker than a shared covalent bond, and the distance between the hydrogen nucleus and the oxygen nucleus is approximately 1.5 times larger than that of the covalent bond. The presence of hydrogen bonds raises the melting and boiling points of compounds, because more energy is required to break intermolecular bonds. The presence of hydrogen bonds can alter the UV and IR spectra of a given compound.

1.4.1 Intra- and inter-molecular hydrogen bonds

Phenolic compounds may form both inter- and intra-molecular hydrogen bonds, referring to bonds that are formed between or within molecules, respectively. Intra-molecular hydrogen bonds are common between adjacent hydroxyl groups (ortho-substitution), or groups in the ortho-position relative to a carbonyl group. An example is quercetin (2.8). The B-ring of flavonoids is more stable with respect to hydroxyl groups. The hydroxyl groups on the B-ring are placed in either the ortho- or the tri-w'c configuration, both of which allow hydrogen bonding. The hydroxyl groups on the A-ring are typically in the meta-position, which precludes hydrogen bonds from forming. Catechin (2.9) may form a hydrogen bond between the hydroxyl group and the oxygen of the heterocycle.

1.4.2 Stability of the hydrogen bond ring

Intramolecular hydrogen bonding is considered to reduce the reactivity of the phenolic hydroxyl group. Thus, it reduces solubility in alcohol, and may reduce the ability to form esters and ethers. Note that the hydrogen bond results in the formation of a ring. This ring also has a level of stability. The six-member rings are more stable and stronger than the five-member rings. Compare for example O-hydroxyacetophenone (six-member ring; 2.10) to catechol (a five-member ring; 2.11).

Intermodular hydrogen bonds raise melting points and solubility. Table 2.1 lists physical properties of phenol (2.5), resorcinol (2.12) and phloroglucinol (2.13) that are influenced by hydrogen bonds.

Table 2-1. Impact of substituents on solubility

Table 2-1. Impact of substituents on solubility

phenol

resorcinol

phloroglucinol

Melting point (°C)

41

118

218

Solubility in ethanol

very good

1 g/0.9 ml

1 g/12 ml

Solubility in water

1 g/15 ml

1 g/0.9 ml

1 g/100 ml

Intermolecular hydrogen bonds make it difficult to purify phenolic compounds from mixtures, because of the interactions between different molecules, including the solvent.

Hydrogen bond formation in phenolic compounds can be summarized with the following general rules:

1. Unless they are sterically hindered, all phenolic compounds take part in hydrogen bonding.

2. Intramolecular hydrogen bonds are less stable than intermolecular hydrogen bonds. The formation of intramolecular hydrogen bonds diminishes reactivity, whereas the formation of intermolecular hydrogen bonds can complicate purification.

3. Phenolic compounds that form intermodular hydrogen bonds are typically solid at room temperature.

4. Ring structures can be formed as a result of hydrogen bonds. Six-member rings are more stable than five-member rings.

5. Some phenolic compounds can form flat hexagonal structures with the aromatic rings facing outward, and linked by hydrogen bonds. The internal space thus formed contains solvent. Such compounds are called inclusion compounds or clathrates. An example is dianin (2.14), which can form clathrates in more than 50 different solvents.

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