Peter D. Kennewell Lehigh University Bethlehem, Pennsylvania 18015
Applications of the Nuclear Overhauser Effect in Organic Chemistry
In recent years the use of chemical shifts and coupling constants derived from nuclear magnetic resonance spectra, nmr, as tools for the establishment of chemical structure has become so established that a discussion of nmr spectroscopy has become an integral part of most undergraduate courses. This widespread use is not negated by the fact that much of the mathematics of the quantum mechanical basis of nmr is often very difficult for the non-mathematically inclined students to comprehend. The use of double resonance to specifically designate coupled protons provides a valuable, readily appreciated extension of the simple theory. I n recent years, a further technique has been described from which it is possible to define protons which are in close molecular proximity to one another but which are not necessarily coupled. This is the Nuclear Oveihauser Effect (NOE) and the purpose of this paper is to show how the NOE can be used to determine the configurations and conformations of organic molecules. Anet and Bourn (1) first described the application of the NOE to organic compounds in 1965 and since that date a rapidly increasing variety of applications have been appearing. Expressed very briefly, the NOE arises because magnetic nuclei which are in close proximity to each other cause a mutual effect on the relaxation processes of each nuclei. Relaxation processes are of paramount importance in the establishment, maintenance and appearance of nmr signals (8) and may be classified as spin-lattice of spin-spin relaxation processes. I t is the spin-lattice relaxation process with which we are concerned in discussing the NOE. This relaxation arises because the molecular motion of the magnetic nuclei of the atoms of the molecules which make up a sample produce fluctuating magnetic fields within the sample. The total fluctuating magnetic field can be regarded as being composed of many individual oscillating components any one of which may match the frequency of precession which a nucleus within the sample makes around an applied field Ho. When this happens relaxation from an excited spin state to a lower spin state of the nucleus will be induced. A relaxation time TIis used to express the efficiency of this process; a large value of TIindicates an inefficient relaxation mechanism and is found in highly purified solids, whilst small values of T,(< 1 see) are associated with non-viscous liquids and gases. TIis markedly reduced by the presence of paramagnetic ions or molecules, e.g., oxygen, which induces local magnetic fields which are very much greater (lo3) than those due to nuclear magnetic moments. It h&r; been shown (3) that the major relaxation mechanism affecting TI involves dipole-dipole interactions between the nuclear magnetic dipoles. Fur278
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ther, this interaction is critically dependent upon the separation of the two dipoles [a(l/r6)] and thus in suitable cases, to be descrihed, the interaction can be attributed to particular nuclei. If the molecule under investigation is dissolved in a magnetically inert solvent, i.e., one in which, in particular, neither fluorines nor protons are present, the dipolar interactions can be made almost intramolecular. Further, in the light of what was said earlier about the effect of paramagnetic species, such species must be removed. I n practice this means that the samples must be efficiently degassed to remove oxygen, although we shall see especially favorable cases in which neither of these conditions are required. The method by which these intramolecular relaxation processes can be detected arises from a further extension of the theory mentioned above. I t can be shown that if two protons A and B are so placed that they and only they contribute to the relaxation processes of each other, then saturation of the B nuclei will lead to an enhancement of the signal due to A by 50Y0 and vice-versa. The use of double resonance experiments to simplify complex splitting patterns is a common feature of the analysis of such spectra. Here we are using the technique not to make the spectrum appear simpler, although this may also happen, but rather to see an increase in the intensity of one or more peaks in the spectrum. Experimentally, the techuique consists of standard double resonance experiments in which one of the protons or groups of protons is irradiated and the rest of the spectrum is observed by means of a frequency sweep.. Integration then shows any increase in the intensities of any of the signals. Applications of the NOE which have so far appeared in the literature may be divided into those involving the precise assignments of nmr signals to particular protons and those which have been concerned with the elucidation of the structures of complex molecules. Thus in their original article Anet and Bourn (1) studied &!-dimethyl acrylic acid I. The signals due to the methyl groups in I appear as 2 doublets (J = 1.3 Hz) at 1.97 ppm and 1.42 ppm; t.he lower field signal being assigned to methyl group b which would be deshielded by the cis carbonyl group (4). The a proton appears at 5.66 ppm as a septet due to almost equal coupling to both methyl groups. Irradiation of either methyl group collapses this septet to a quartet, but, more significant,ly, irradiation of t,he doublet at 1.42 ppm causes an increase of 17'% in the integrated intensity of the vinyl signal while no such increase occurs on irradiation of the signal at 1.97 ppm. Since the cis methyl group is much closer to the vinyl proton than the trans methyl group, this definitely es-
tablishes that the higher field signal is due to methyl group a. An exactly analogous result was found with dimethyl formamide I1 in which only irradiation of higher field signal caused an increase in the in tens it,^ of the formyl proton. These authors point out that while instrumental effects may give misleading results a differential effect as noted here for I and I1 is unambiguous.
Another example involving an NOE between a t butyl group and a proton in close molecular proximity to it occurs in 1,4-di-tbutyl-naphthaleneVI (NOE between t-butyl group and the 5-H and RH) (9).
@ VI
Martin and Nouls (5) have shown that NOE's can be of use in assigning the signals due to the methyl group in the nmr spectrum of the overcrowded aromatic hydrocarbon, 1,2,3,4-tetramethylphenanthrene 111. NOE's were observed between a multiplet due to 5-H and only one methyl group signal which must therefore be assigned to C-4(CHa). Similarly C-l(CHa) could be assigned to the only peak which gave an NOE with C-lO(H). The methyl group signals in citral a and b (partial structure IV) could likewise be assigned on the basis of
an NOE with the vinylic proton which was only seen for the methyl group cis to this proton (6). Important though these applications are, it is in the field of structure elucidation in which the NOE has had its greatest effect. The first such example of this use involved the determination of the structure of the ginkgolides, a class of CXosubstances isolated from the leaves of Ginkgo biloba L (7). Extensive chemical and spectral analysis established V as the basic structure of these compounds and a remarkable NOE was observed between the tbutyl group and protons I, J, E and F. Irradiation of the tbntyl signal caused an increase in intensity of the signals due to I, J, E and F even when the sample was dissolved in trifluoroacetic acid. This must mean that the t-butyl group prevents the approach of solvent molecules to protons. J, I, E and F and requires the t-hutyl group to exist in close proximity to them. This directly establishes the preferred conformation of ring B and the quasi-equatorial arrangement of the t-butyl group. This same group later used the NOE to confirm the structure assigned from chemical and physical investigations to the natural product futeonone (8).
Lansbury and coworkers (10) have used the NOE as part of their extensive studies of the 7,12-dihydropleiadenes. In particular they have shown that NOE's occur between diaxial protons in CT and CI1 and used this to confirm previous studies on the conformational analysis of 7-methoxy-7,12-dihydropleiadeneVII. Conformer VIIb shows a NOE between the axial protons but no such effect occurs in VIIa. At -20' separate signals can be seen for both isomers; the use of the NOE allows the signals due to conformer (h) to be definitely identified and thus also the conformer ratio. The observation of an NOE between the 1-met,hyl group and the 7 equatorial proton enabled the configurational isomers 7-hydroxy-11-methyl-12(7H)-pleiadene VIII and 12-hydroxy-11-methyl-7-(12HbpleiadeneI X to be distinguished. Spectral studies of poncitrin established the partial structure X for this material and the correct assemblage
of these groups, XI, was evident when NOE experiments showed that the 0-methyl group was in close proximit,~ to both C-4 and C-6 (11). In an analogous manner the configuration of the ethylidene side chain in the alkaloid Volume 47, Number 4, April 1970
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essentially unchanged while the integration increases. A combination of the two effects results in an increase in the peak integration value and a decrease in the band width. Eliel (16) has used the NOE to distinguish between cis and trans 2-methoxy-4,4,6-trimethyl-3,3-dioxanes
dehydrovoachalotine XI1 (192) was established by the observation of an NOE between the side chain methyl group and 15 (H). The existance of NOE's between 4-(CHa) and the nrotons on C-2 and C-6 and between 10-CH3 and 2-H combined with the absence of such an effect between 4-Me and 1(H) and between 10-Me and 5-H, establishes the solution conformation of dihydrotamaulipin-A acetate as that shown inXIII (15).
.~
~~~
xv.
XTV. . -. . ,--..
Saturation of one of the 2 singlet methyl groups led to a 12% increase in signal height of the H-2 proton in XIV while no effect was found in XV. In the latest example of this technique to appear to date, Hart and Davis (17) have determined the solution conformation of the nucleosides, 2',3'-isopropylideneadenosine and 2'-3' isopropylideneguanosine XVI, by observing NOES between 5-H and 1'-H, 2'-H and 5'H. Such interaction is possible for the anti conformation XVa but not for the syn conformer XVIb. It can therefore be concluded that while the examples of the use of the NOE are at present limited, the future holds the promise that many diverse and useful applications will be forthcoming. Acknowledgment
Mr. W. P. Fives is thanked for many interesting conversations and Dr. N. D. Heindel for critically reading this manuscript. Literature Cited (1) ANET, F. A . L.,A N D BOURN,A. J . R., J. Am. Chem, Soo., 87, 5250 (1'365). (2) J * c n ~ m . L. A., "Ap~%Iieationsof Nuclear Magnetic Resonance Speotroseopy in Organic Chemistry." Phrgamon Press, London, 1959, p. 8. (3) A s n ~ o * A ~ ,,. "The Principles of Nuclear Magnetism." Oxford Press. Oxford, 1961, p. 264. L.NF.. , A N D SHOOLBRY. J. N.,"NMR Spectra (4) BHAC.\,N. S.. J O ~ ~ N B O Ca,talog." Varian Assooiates, Pda Alto, California, 1961, (5) M*n.rrw, R. H.. A N D N o u l s , J. C . . T e l r o l d m n Lrtlers, 2727 (1968). (6) O ~ x ~ s u nhl.. u , T E ~ A O M.. X ATORI, , K., A N D TIKEDA. I
