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Interestingly, the products obtained from 9-monosubstituted anthracenes 46a-j were dependent upon the reaction conditions. This can be illustrated by methyl substituted compound 46b (Figure 4.5). At the lower temperature (70 ˚C) the expected kinetic product 127bK was formed exclusively (the so called ‘ortho’ adduct), while at higher temperature the thermodynamic product 127bT (‘meta’ adduct) was formed

predominantly (5:1 after 8 h). The 1H NMR of the thermodynamic product 127bT, exhibits the signal for Ha as a singlet at 4.77 ppm while for the kinetic product

127bK it is a triplet at 3.84 ppm due to coupling with the bridgehead methylene group (Figure 4.6). This coupling was readily observable in the COSY spectrum (Figure 4.7).

132

Figure 4.6: 1H NMR of 9-methyl anthracene adduct 127b at 70 oC (kinetic product) and 110 oC (thermodynamic: kinetic product, 5:1)

Figure 4.7: COSY of 9-methyl anthracene adduct 127b showing coupling between Ha and the methylene group in the thermodynamic and kinetic product

HaT HaK

CH2T

CH2T CH2K CH2K

133 The formation of the thermodynamic product 127bT when the reaction was carried out at 110 ˚C suggests that the Diels-Alder reaction is reversible under these

conditions. The factors that control regiochemistry in Diels-Alder reactions are well known. For example, the reaction of methoxybutadiene 154 with acrolein 155

favours the ‘ortho’ adduct 156 and electron donating substituents at the 9-position of

anthracene 46b-j would be expected to do the same. The regioselectivity can be explained by analysing the energy gaps of the HOMO/LUMO molecular orbital combinations and the coefficients of the atomic orbitals on these HOMO’s and LUMO’s, (Figure 4.8). For 154 and 155 the most important interactions occur

between the HOMO of the diene and the LUMO of the dienophile (8.5 eV difference in energy). The LUMO of the diene and HOMO of the dienophile energy gap is much higher (13.4 eV) and as such is less important in the analysis of regiochemistry. Best overlap occurs when orbitals of the similar size can interact. Thus for 154 and 155 the ‘ortho adduct’ is predicted and observed. Alternatively, the same regiochemical outcome can be predicted by a stepwise (non-concerted) mechanism.

134 The reactions of 46b (Me), 46c (CH2OH), 46f (CHO), after 7 h showed formation of the products 127bK, 127cK and 127fK respectively (kinetic) while 46d (OMe), 46g

(C(O)Me), and 46i (Br) showed mixtures of the two products 127 K:T (127d = 4:1,

127g = 2:1, 127i = 16:1) and 127h (CO2H) and 127j (NO2) showed no products. Compounds 46a, 46k and 46l only furnish one product (due to the symmetry of the molecule) while 46m formed an inseparable mixture of regioisomers (each showing an exo and endo product) giving rise to a 1:2:2:2 mixture of isomers. Heating all the 9-monosubstituted substrates at 110 ˚C between 24-78 h furnished the thermodynamic products only 127b-jT. For each substrate the two products could be easily distinguished by both the chemical shifts of protons Ha, Hb, and Hc and their coupling patterns. For the products T, Ha was typically 1.0 ppm higher than in K, while the bridge diastereotopic methylene protons were widely separated (0.6-0.9 ppm) in T compared to those in K (0.2-0.5 ppm) (Figure 4.9).

Figure 4.9: Thermodynamic T versus kinetic K products

Comp. Subs. 1H NMR 127b-jK ppma of Hb-Hc ppma 1_{H NMR 127b-jT} ppma of Hb-Hc ppma 46b Me Hb = 2.41, Hc = 2.09, 0.32 Hb = 2.60, Hc = 2.01, 0.59 46c CH2OH Hb = 2.29, Hc = 2.00, 0.29 Hb = 2.71, Hc = 2.15, 0.56 46d OMe Hb = 2.30, Hc = 2.06, 0.24 Hb = 2.96, Hc = 2.17, 0.79 46f CHO Hb = 2.37, Hc = 2.21, 0.16 Hb = 2.94, Hc = 2.35, 0.59 46g C(O)Me Hb = 2.35, Hc = 2.22, 0.13 Hb = 3.08, Hc = 2.33, 0.75

135 46h CO2H b b Hb = 3.14, Hc = 2.55, 0.59 46i Br Hb = 2.26, Hc = 2.18, 0.08 Hb = 3.26, Hc = 2.55, 0.71 46j NO2 b b Hb = 3.40, Hc = 2.79, 0.61 a_{Measured by 400 MHz} 1_{H NMR.} b_{No product detected.}

Table 4.2: Chemical shifts of Hb and Hc in 127b-jK and 127b-jT

In frontier molecular orbital terms there are two effects of placing an electron withdrawing substituent on a diene when reacting with an electron poor dienophile. Firstly, the energy gap between the most important HOMO/LUMO interaction is larger (meaning slower reaction) but the difference between the energies of the two different HOMO/LUMO interactions is less than for a conventional diene/dienophile interaction. For diene 46h the gap is 9.5 eV and 10.4 eV respectively (compared with 8.5 and 13.4 eV for 154 and 155). The closer difference in energy suggests that both interactions might become important in any analysis of regiochemistry of 46h. The second is that the polarisation of the orbital coefficients will be significantly altered. Combining both of these effects can lead to loss of regiochemistry. For strongly electron withdrawing substituents, ‘meta’ compounds can become the fastest formed,

with both kinetic and thermodynamic control providing the same product (Figure 4.10).

136 Thus, the results (Table 4.2) can be explained by a combination of these factors. For the highly electron withdrawing groups (46j, NO2) only ‘meta’ products are isolated after prolonged reaction times, for intermediate electron withdrawing groups (46g, C(O)Me or 46i, Br) mixtures of regioisomers are detected at 70 ˚C (less selective

reactions) but ‘meta’ products are detected at higher temperatures. For electron

donating substituents (46b, Me) the reactions are fast and even after 8 h significant formation of the ‘meta’ adducts is occurring.

Special mention should be made of the reactions with 9-methoxyanthracene (46d) which was reacted 80% pure (contaminated with anthracene). The 1H NMR of the reaction at 70 ˚C shows two adducts, the expected kinetic adduct 127dK and the

anthracene adduct 127a. After prolonged heating at 110 ˚C the thermodynamic

adduct 127dT and anthracene adduct 127a were isolated, (Figure 4.11). However, it proved impossible to separate the adducts 127a and 127dT by chromatography and as such this derivative was not pursued any further as it was unlikely to lead to efficiencies in any industrial process. However, significant reaction occurs at room temperature after only 10 minutes (40% conversion of 46d) which indicates that the 9-methoxy anthracene derivative 127d is the most reactive.

137 1.75 1.85 1.95 2.05 2.15 2.25 2.35 2.45 2.55 2.65 2.75 2.85 2.95 3.05 3.15 f1 (ppm) 0. 3 3 1. 3 8 0. 9 2 0. 2 8

Figure 4.11: 1H NMR of 9-methoxy anthracene adduct 127d at 70 oC and 110 oC