Methoxy groups, conformational stabilization

Optimization of the valence and dihedral angles yields planar cyclic structures for the 3- to 5-ring intermediates in contrast to a chair conformation for that of the 6-ring. In the cases of n = 4, 5, 6 the oxygen atom is placed almost in the plane of the three C-atoms directly bonded to it. Therefore, an intramolecular solvation of the cationic chain end by methoxy groups which are bonded to the polymer backbone is preferred in the gas phase. The calculations show that for a non-polar solvent such as CH2C12 a decrease in stability of the cyclic intermediates exists. But this decrease does not result in a total break of the intramolecular solvation (Table 13). An equilibrium between open chain and cyclic intermediates must only be taken into account in more polar solvents, due to the competition of intra- and intermolecular solvation. 

Analyses of the C and n.m.r. spectra of 2-substituted methylenecyclo-hexanes (e.g. 2-methoxy-l-methylenecyclohexane) and 3-substituted cyclohexenes have demonstrated that a double bond stabilizes the axial or pseudoaxial con-former, respectively, when an electronegative substituent is present at the allylic position. Stabilization of the (pseudo)axial conformer by the double bond in both series is adequately explained in terms of double bond-no bond resonance [e.0. (641) <- (642)]. This effect is enhanced by a methoxy-group on the double bond, as in 2-methoxy-l-(methoxymethylene)cyclohexane. 

Computation of the conformational energies of 2-methoxytetrahydropyran, a model for the methyl aldopyranosides, gave results in agreement with experimental observations. A preference for the axial conformer was apparent, but the nature of the stabilizing factor (anomeric effect) was not resolved. Force-field calculations have been extended to include alcohols, ethers, simple acetals, and 2-methoxytetrahydropyran. 2 The preference of 2-methoxytetrahydropyran for the axial conformer was attributed to interaction of the axial lone-pair orbital on the ring-oxygen atom with the axial C—O bond of the methoxy-group, which can be represented by the resonance structure (501) (see also, Vol. 6, p. 163). 

For compoimds 16, this conformation is in slow exchange (AG = 70-88 kJ/mol at 328K in CDCI3) with the 1,2,3-alternate conformation, the latter being less stable (AG° = 2-7 kJ/mol). ° Therefore it is possible to conclude that three important factors stabilize the flattened cone structure, viz. (i) the self-inclusion of the methoxy groups in the apolar cavity driven by CH-ti interactions, (ii) the presence of three bulky groups in 2,4,6 positions at the lower rim, and (iii) the presence of the ter/-butyl groups at the upper... 

Davis and co-workers designed isophthalamide receptors with appended hydroxyl (4c) or methoxyl (4d) groups [23]. In the solid state, the hydroxyl groups of 4c formed intramolecular OI 1—0=C H-bonds with the amide carbonyls to stabilize the syn—syn conformation, which complexed Cl (K = 5,230 M ) in its cleft. On the other hand, 4d did not bind halide anions, because the methoxy groups promoted the formation of the anti-anti conformation. 

As regards product stabilities the axial methoxy-ketone (125) might be expected to be less stable than the equatorial isomer (126). It exhibits an axial preference of ca. 0.85 kcalmol" on the basis of AG° for methoxycyclohexanes and with account taken of the 3-alkyl ketone effect for (125) (126). Precedent exists for a number of 4-substituted cyclohexanones where the axial conformer or isomer is atypically the more stable, and in these instances dipole-dipole interactions between the carbonyl group and the polar substituent are postulated in order to rationalize the results. It is suggested that analogous dipole-dipole interactions may stabilize (125) with the reservation that it is difficult to quantify this effect in the present instance, on account of different rotamers with respect to the C—0(Me) bond. The possibility is also mentioned that the anomeric effect is also capable of rationalizing the greater stability of (125). 

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