CONTENIDOS

.F(1) C(4) )C(3) C(2) C(6) C<1) C(7) F(4) C(12) C(1 0(2) C(16) C(14) C(17) C(15)

Figure 4.15 -X -r a y crystal structure o f 146.

R' R R <!>1 (°) (1>2 (°) F-Ca

interspatial

distance (A)

interspatial

distance (A)

Table 4.3 - Structural data fo r crystaline 2-fluoro- a-hy drogen chalcones.

As would be expected for alpha hydrogen chalcones, the X-ray data shows the molecules to be orientated in the s-cis conformation. And in all three cases the fluorine atom is shown to be positioned anti to the carbonyl oxygen due, presumably, to electrostatic repulsions between these two highly electronegative atoms. Dihedral angles (|)1 and <J>2 all approach 180°, showing the molecules to be relatively flat, which indicates good 7i-overlap. (The X-ray data shows the configuration only in the crystalline state, o f course, and it is likely that in solution there is some rotation about the single bonds, although it is reasonable to assume that the molecule would spend most of the time in the orientation shown.)

This means that the fluorine atom is positioned relatively close to the a carbon in space (2.82, 2.86 and 2.80 A for 139, 140 and 146 respectively) and, since it is believed that in the case o f fluorine-hydrogen through-space coupling, the interaction is due to overlap between the lone pairs on the F atom and on the C atom to which the H is attached, this supports the idea that this coupling, at least, is due to a through-space interaction.

The X-ray data also shows, however, that the beta proton (and the beta carbon) is not only much too far from the fluorine to interact through space, it is also separated from it by the C=C double bond, this makes it very unlikely that a through-space interaction would take place between these two atoms. Since, due to the number o f atoms separating them, this coupling effect is equally unlikely to be the result o f a conventional through-bond interaction, it would seem that this is a very unusual type o f coupling interaction.

There are limited explanations for this unusual effect. One is that in solution, unlike the crystalline state, the molecule has sufficient rotational freedom about the CO-C=C single bond to allow it to adopt the s-trans conformation for some o f the time, and that in this conformation a through-space interaction is able to take place between the fluorine atom and Cp.

Figure 4 .1 6 - Interconversion o f s-cis and s-trans isomers in solution.

Another explanation is that some sort o f through-bond coupling is responsible; it could be that since the crystal structures seem to show the C-F bond roughly perpendicular to the C=C double bond, the through-space interaction between F and C a is transmitted through the vinyl bond to Hp. (Something similar to this is discussed above, in which a fluorine-fluorine through-space coupling is transmitted through a phenyl group.155)

Or the coupling could simply be a very long range through-bond effect, resulting from the high degree o f resonance within the chalcone molecule. Again an example o f this is discussed in the

163

introduction although the effect is not very well understood and it offers no explanation for the fact that this coupling is only possible when the fluorine is in the 2 ’ position.

In order to test the first o f these hypotheses a range o f alpha methyl chalcones were made. It is well known that alpha methyl chalcones are predominantly s-trans so if the F-Hp coupling constant in the alpha methyl compounds is the same as has been observed in alpha hydrogen

Chapter 4 Long Range NMR Couplings and Dimerisation

chalcones, that would suggest that the latter is a result o f the molecule adopting the s-trans conformation in solution.

Initially ketone 148 was made by ethyl Grignard addition to 2-fluoro-4-methoxybenzaldehyde followed by oxidation with KMnC>4 (Scheme 4.5). Condensation of chalcones from 148 was more difficult than in the case o f the alpha hydrogen chalcones and reaction was carried out by refluxing the ketone and aldehyde mixture with piperidine and acetic acid in ethanol.

F OH 1) EtMgBr 2) H+ 147, 88% KMnO H

A

Scheme 4.5 - Synthesis o f a-methyl chalcones. Yield (% ) A-Ring B-Ring P-H 5 <7hf 149 23 2-fluoro-4-methoxy 2,4-dimethoxy 7.16 0 150 20 2-fluoro-4-methoxy 2,3,4-trimethoxy 7.30 0 151 53 2-fluoro-4-methoxy 3-fluoro-4-methoxy 7.00 0 152 18 2-fluoro-4-methoxy 3,4-methylenedioxy 7.03 0 153 61 2-fluoro-4-methoxy 3-bromo-4-methoxy 7.09 0 154 40 2-fluoro-4-methoxy 4-trifluoromethyl 7.09 0 Table 4.4 - Yeilds and NMR properties o f a-methyl chalcones.

None o f these chalcones display any coupling interaction between the fluorine atom and the beta hydrogen and in all cases Hp appears as a singlet in the proton NMR. This is surprising since there is a through-space interaction between F2’ and H a in the alpha hydrogen chalcones and one would expect F2’ and CP to be significantly closer in this case.

Unfortunately no X ray data could be obtained for any o f these compounds, although the results o f nOe experiments on 151 and 153 show a 1.96 and 1.92% enhancement at H6’ respectively when irradiated at Hp. That there is such an nOe effect is consistent with the compounds adopting the s-trans conformation rather than s-cis, and the fact that the enhancement in both cases is so small is probably due to restricted rotation about the Ar-CO bond with the F and O positioned anti most o f the time.

It may be that in this conformation the F2’ and Cp atoms are so close together that steric hindrance between them forces the molecule to twist in such a way that the atoms are out o f plane and therefore cannot undergo through-space coupling. This effect is seen in compound 112 above, although in that example the through-space coupling is not eliminated, merely reduced.

It is clear, though, from these results that the coupling observed in the alpha hydrogen chalcones between the fluorine atom on the T position and the proton on the P position is not due to any direct through-space coupling. This must mean that through-bond interactions play at least some role in the observed NMR coupling. If the coupling is transmitted entirely through bonds and is a result o f the highly conjugated nature o f the chalcone molecule, similar to the effect described by England et al.,m then it remains to be seen why a similar effect is not observed between alpha and beta protons and fluorine atoms in different positions within the molecule, and also why no such coupling occurs in the equally conjugated alpha methyl chalcones. It seems more likely, at this point, that the observed effects are a combination o f through-space and through-bond interactions and the F2’ atom is coupled through space to the C=C double bond and that this effect is then transferred through bonds to the alpha and beta protons.

4.2.2 Cytotoxicities

The cytotoxicities o f these compounds were also tested and are shown below in Table 4.5.

A Ring B ring a Position Cytotoxicity

(pM )

127 3,4,5-trimethoxy 2-fluoro-4-methoxy H 1.8

128 2-fluoro 4-methyl H 9.5

129 2-fluoro 3,5-dimethoxy H 3.6

Chapter 4 Long Range NMR Couplings and Dimerisation