The INADEQUATE Experiment

The information on carbon chemical shifts and multiplicities is invaluable for structure determination. It would be ideal if we also had a method for obtaining information directly on carbon-carbon bonding in the compound under study, since this would allow us to draw on paper at least parts of the carbon framework of the molecule. 

Carbon-13 represents only 1.1% of the total carbon nuclei present in a sample. In order to get the information we require, we need to detect the doublets due to carbon-carbon coupling. Thus we wish to observe only those molecules containing two neighbouring carbon-13 nuclei, i.e. about 10 4 of the nuclei present at the same time we have to get rid of the signal coming from those molecules containing only one carbon-13 (the great majority ). 

INADEQUATE stands for Incredible Natural Abundance DoublE QUAntum Transfer Experiment. Again, we refer you to NMR textbooks for an explanation of the principles. Here we only present the result, which is shown in Fig. 20 for the diester 2. 

Why do we see multiplets rather than singlets Firstly, we are in each case looking at signals due to C-C coupling, so each signal will be split into a doublet just as in an AX proton spin system. Secondly, the influence of the phosphorus nucleus is still there and will lead to further splitting of some of the signals. 

To see clearly what is going on, we need to expand the signals, and this is done in Fig. 21 for the methyl signal at 16.2 ppm (above) as well as for the pro-tonated aromatic carbon at 110.1 ppm (below). 

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The one-dimensional variations of the INADEQUATE experiment suppress the intense... 

The correlation signals of the INADEQUATE experiment directly build up the ring skeleton A of the compound. Elere characteristic C shifts (5c = 123.1, 137.6 148.9, 109.1) establish the existence and position of two double bonds and of one tetrahedral C-0 single bond (5c = 70.5). DEPT spectra for the analysis of the CH multiplicities become unnecessary, because the INADEQUATE plot itself gives the number of CC bonds that radiate from each C atom. 

The INADEQUATE experiment is a homonuclear NMR technique in which coupling satellites are detected after suppressing the stronger... 

Practical constraints prevent this technique from living up to its potential, even in this, the era of the superconducting probe. Until sensitivity improves by at least another order of magnitude, the INADEQUATE experiment will remain just that - inadequate by name and by nature. 

The heteronucleus-detected INADEQUATE experiment, first reported in 1981 by Freeman and co-workers, is elegantly capable of establishing the identity of adjacent neighbour carbons via [fcc couplings.21-24 Major drawbacks of the INADEQUATE experiment are extreme insensitivity and prodigious sample requirements. To an extent, the sensitivity and... 

In 2001, Knaack and co-workers56 reported an application of the INADEQUATE experiment in the course of synthesizing and characterizing a biologically active 2-[l-(4-chlorobenzyl)-lH-indol-3-yl]-2-oxo-N-pyri-din-4-yl acetamide (6). Treatment of l-(4-chlorobenzyl)-lH-indole with oxalyl chloride afforded the corresponding oxoacetyl chloride that was finally subjected to aminolysis with 4-aminopyridine to afford the final product of the reaction scheme, 6. Although the NMR data supported the N-benzyl structure, a 1,1-ADEQUATE spectrum was acquired to provide additional confirmation of the structure of 6. 

The elucidation of the structure of 5,6-dihydrolamellarin37 38 served as the development vehicle for the entire family of ADEQUATE experiments. Hence, this work also represented the first reported application of the INADEQUATE experiment. Two important 1ADEQUATE correlations were observed in the benzopyrone portion of the molecule and are shown by 28. The C19 resonance was correlated via three bonds to the C23 carbonyl. The C22 carbon was correlated via three bonds to the C3 quaternary carbon adjacent to the C23 carbonyl. 

The AB and AX systems of all 13C —13C bonds appear in one spectrum when the INADEQUATE pulse sequence (Fig. 2.48) is applied. Complete interpretation usually becomes difficult in practice due to signal overlapping, isotope shifts and AB effects (Section 2.9.4). A separation of the individual 13C— 13C two-spin systems by means of a second dimension would be desirable. It is the frequency of the double quantum transfer (d e) in Fig. 2.48 which introduces a second dimension to the INADEQUATE experiment. This double quantum frequency vDQ characterizes each 13CA — I3CX bond, as it depends on the sum of the individual carbon shieldings vA and vx in addition to the frequency v0 of the transmitter pulse located in the center of the spectrum if quadrature detection is applied [69c, 71] ... 

One way to imagine this experiment is as a carbon analogue of DQF-COSY in which both FI and F2 would be carbon axes, and theoretically this experiment is possible. For practical considerations related to obtaining complete double quantum filtration, the INADEQUATE experiment is run slightly differently. In the display of the INADEQUATE spectrum of caryophyllene oxide (Figure 5.19), we find that the F2 axis is the familiar carbon axis, which we can, of course, relate to t2 acquisition. The FI axis looks unfamiliar and requires further explanation. 

The one-dimensional variations of the INADEQUATE experiment 12,13 17, 20 suppress the intense 13C-12C main signal, so that both AX and AB systems appear for all 13C-13C bonds in one spectrum. The two-dimensional methods 12 13,17 21,22 segregate these AB systems on the basis of their indivi-... 

A number of spectacular applications in structural studies of glasses were reported employing the INADEQUATE experiment.174 175 The basic sequence and different modifications were discussed in Section 2.2.2. Smith and coworkers176 used 31P refocused INADEQUATE MAS NMR experiment for searching the length of phosphate chain and quantification of crystalline phases in ternary sodium calcium phosphate ceramic of composition (CaO)0.4(Na20)0.i(P205)o.5. 

In the cases of ZSM-12 and ZSM-22, the results of the natural abundance 29si/29si COSY and INADEQUATE 2D NMR experiments are in exact agreement with the lattice structures, the INADEQUATE experiment being particularly successful by detecting all of the connectivities (16). 

Although more distant couplings are observable, the most important are the one-bond couplings, which vary slightly for every carbon-carbon bond. Thus, a match of 7( C— " C) for any two carbons strongly suggests that they are bonded to each other. Even in complex molecules, there is sufficient variability of couplings that INADEQUATE can be used to map the complete connectivity of the carbon framework, provided that it is not broken by a heteroatom. The major drawback to the INADEQUATE experiment is its extremely low sensitivity, as it uses only 0.01% of the carbons in the molecule. The two-dimensional version is discussed in Section 6-4. 

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