Pedagogía crítica

To further investigate the unique antioxidant ability of 5-HQ, a subset of the x-HQ series was used. This subset of compounds uses 1-naphthol as a starting point, and probes the addition of a heterocyclic nitrogen atom into the naphthalene scaffold as a function of position. Therefore, the molecules examined here are 1-naphthol, 4-HQ, 5-HQ and 8-HQ. As can be seen from the structures below, (Fig. 1.12) all molecules are similar in structure, with the location of the heterocyclic nitrogen, relative to the hydroxyl, being the only difference. OH OH N OH N OH N 1-naphthol (-2.07) 4-hydroxyquinoline (-4.84) 5-hydroxyquinoline (-1.71) 8-hydroxyquinoline (-4.34)

Figure 1.12 – Investigative set of 1-naphthol analogues. Note the position of the heterocyclic nitrogen (red). Relative Log(Z) values are in brackets.

The important aspects of this data set are (1) the large retardation in activity of 4-HQ and 8-HQ when compared to 1-naphthol, and (2) a slight increase in activity of 5-HQ when compared to 1-naphthol. These differences were thought to be electronic in nature, and so the electronic environment of all four compounds was probed, using the optimised structures that were produced as part of the BDE calculations.

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An analysis using several descriptors of the electronic environment of these compounds failed to illuminate the unique activity of 5-HQ compared to the rest of the x-HQ series. Standard descriptors such as E(HOMO), E(LUMO) and the polarity of the O-H and C-O bonds of the hydroxyl group of these compounds were tried, and were subsequently unsuccessful, in elucidating the source of the enhanced 5-HQ activity.

Given that the molecules of interest here are built upon a naphthalene scaffold, they contain two fused aromatic rings. This allows for an effective diffusion of charge across the molecule. From the comparison of Log(Z) values for these four compounds, it appears as though the location of the heterocyclic nitrogen atom is of vital importance.

This is demonstrated in the comparison between 4-HQ and 5-HQ. In both molecules, the endocyclic nitrogen is on the opposite side of the molecule to the OH group. The only structural difference between 4-HQ and 5-HQ is that, in 4- HQ, the nitrogen is located on the same ring as the hydroxyl; in 5-HQ, the nitrogen is on the other ring. This reasoning became the basis of the development of a novel descriptor, which evaluates the polarity of each ring in a fused aromatic ring system. This descriptor, of which no previous evidence can be found, involves the summation of the electrostatic potentials of the atoms on the ring containing the hydroxyl group. An example is shown in Fig. 1.13.

When the electrostatic charge of the ring with the hydroxyl group is examined for 4-HQ, 5-HQ and 1-naphthol, values of -0.279, -0.147 and -0.141 are obtained, which was suggestive of discrimination. In order to determine whether the relationship between this descriptor and antioxidant activity existed for the entire x-HQ series, these values were calculated and plotted against Log(Z), Fig 1.14.

Figure 1.13 – Example of the separation of charges into electrostatic charges of the ring with the hydroxyl (Red). The charges on the atoms that straddle the rings are not involved in the calculation of this descriptor. The charges of the hydrogen atoms are included. R2 = 0.8807 -7 -6 -5 -4 -3 -2 -1 0 -0.35 -0.3 -0.25 -0.2 -0.15 -0.1 S(Estat) Lo g( Z)

Figure 1.14 – Plot of electrostatic parameter against Log(Z). 8-HQ has been omitted due to the presence of the intramolecular hydrogen bond ‘leaking’ charge across the rings. 2-HQ as included due to the fact that the hydrogen bond in this compound is between atoms on the same ring.

As can be seen from Fig 1.14, a strong correlation was achieved between this descriptor and antioxidant ability, Log(Z). A rationalisation for this effect is that, with less electrostatic charge on the hydroxyl-containing aromatic ring, the

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immediate environment contains a greater capacity to delocalise the lone electron produced following homolytic bond cleavage.

A possible alternative rationalisation, involving the withdrawal of electrostatic potential away from the oxygen, and as such weakening the O-H bond, is not valid here, as a difference in polarity of this bond did not show significant correlation with Log(Z), as mentioned previously.

1.3.5 Summary

BDE has been shown here to correlate strongly to a kinetic experimental measurement of antioxidant ability, Log(Z). BDE is most effective when the effects of intramolecular hydrogen bonding have been accounted for. The enhanced activity of 5-HQ, compared to the other members of the hydroxyquinoline series, was also examined; a novel descriptor was developed, and this illustrated that the enhancement is due to electronic effects present in the fused aromatic ring system.

Following from the investigations presented here, it would be expected that further work would possibly involve several streams. Firstly, to expand the number of compounds examined by both Log(Z) and BDE, involving different classes of compounds such as anthocyanins, flavonols and various other polyphenols of botanical origin, which are of current interest. Many of these natural compounds include intramolecular hydrogen bonding, and so this work could improve predictions of antioxidant ability from calculated BDE alone. Secondly, a fundamental study, experimentally and computationally, of the effects of the intermolecular hydrogen bonding by the solvent to the reagents could be carried out. Experimentally, by changing the solvent composition and/or temperature, the intramolecular hydrogen bonds - where formed - could be controlled to some degree. This could lead to either reduced or enhanced hydrogen bonding, depending on the specific circumstances. Computationally,

molecular dynamic simulations could be carried out to further characterise the nature of the intermolecular, and intramolecular, hydrogen bonding.

Chapter 2

ESI-MS and quantum chemical investigations