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Direct positive and indirect negative NO& can often be observed in the same molecule, providing a method for establishing otherwise inaccessible connectivities in complex spectra and an effective probe of conformation in solution.The nuclear Overhauser effect (NOE) is a powerful tool for structure and conformation determination, as the enhancements are inversely related to the sixth power of the interproton distance.' Careful analysis' actually reveals that certain geometrical arrangements of spins can, in small molecules, lead to negative NOES by an indirect mechanism described in the following paragraphs. (This geometric '3-spin' effect should not be confused with the correlation time dependence which leads to generalized negative enhancements in macromolecules* and in small molecules dissolved in viscous solvent^.^ In this context 'small' is dependent on field strength and solvent, but is mol. wt < c. 1500.)We report here that such negative effects are easily observed using difference techniques4 and describe two types of application: establishment of spatial connectivities between two protons, neither of which is visible in the normal spectrum, and detailed conformational analysis in molecules lacking useful coupling constants.The negative NOE can be understood through the following simple description of the 3-spin system shown in Fig. 1, where r , = rBc. In the modern4 NOE experiment one signal (H-A) is pre-irradiated for some time and the irradiation is then turned off just before the RF pulse; the result is a decrease in the intensity of H-A and an increase in H-B and H-C. Thus a decrease in the Boltzmann population difference of the H-A spin states leads to an increase in the population differences in H-B and H-C: this is the positive NOE. Double resonance is only one way of achieving this effect; CIDNP can be a n~t h e r .~ By analogy, the increased population difference at H-B should give a decreased difference at H-C, i.e. the opposite of irradiating H-B. This is a negative indirect NOE at H-C; it is in competition with the direct positive effect at H-C from H-A. The size of the negative contribution clearly depends both on the NOE at H-B when H-A is irradiated ( = fB(A)) and on the NOE at H-C when H-B is irradiated (= fc(B)). Thus, the overall indirect effect is of the form fc(A)in = -fB(A) * fc(B). [This equation also applies to the slowly tumbling case, but as fB(A) and fc(B) are * Author to whom correspondence should be addressed. both negative the indirect effect is also negative and can be identified only by its kinetic behaviour.]When the system shown in Fig. 1 is linear ( 0 = 180"), and first considering direct effects only, H-C should receive positive NOES from H-A and H-B of 0.8 and 49.2%, respectively (i.e. in the proportion 2-6:1), whilst H-B should be enhanced 25% by H-A. Thus, we expect the negative contribution of H-A at H-C to be 0.25 x 0.492 = 12.3%, and the net negative effect to be 11.5%. Clearly, as O decreases, the positive contribution of H-A increases, so that for an equilateral ...

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The recent claim that preferred conformations of aromatic methyl ethers have been detected by nuclear Overhauser enhancement (n.0.e.) difference spectroscopy cannot in most cases be supported by analysis of the resu Its.

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