ID and 2D INADEQUATE

So far we have discussed homonuclear 2D H,H-shift correlation spectroscopy (H,H-COSY) as well as heteronuclear 2D C,H-shift correlation spectroscopy (C,H-COSY, or C,H-HSC). Let us now consider homonuclear 2D C,C-shift correlation spectroscopy. 

Suppose we could devise a 2D NMR technique to map out all one-bond C-C couplings. What would be the value of such data A moment s reflection should convince you that this information would provide the carbon-carbon connectivity (the carbon backbone) of the entire molecule This is the single most useful piece of information in the elucidation of organic structure. But how can we accomplish it  

Recall how we could use the small 13C satellites present in a H spectrum to determine the magnitude of one-bond C-H coupling constants (Section 8.6.1). Now we will need to use I3C satellites in the proton-decoupled /SC spectrum to map out all 13C-13C one-bond couplings This will not be easy, however, because the probability of having two 13C nuclei bonded together in a molecule is 1% of 1%, or 1 in 10,000. 

QUATE multiplet corresponding to signal 4 in the 13C spectrum of 2-chlorobutane. Because the two one-bond coupling constants are nearly equal (ca. 35 Hz between tetrahedral carbons Section 9.3), the two doublets are barely resolved, appearing instead as one doublet at lower resolution. 

If all the individual one-bond JC-c values in a compound could be determined, and the multiplets thereby correlated, we would have the precious C-C connectivity information we are seeking. Unfortunately, for all but the most simple structures, this has proven impossible because of the close similarity in the J values. But do not despair There is a 2D version of INADEQUATE that provides exactly the correlations we seek, even when all the J values are too close to resolve  

---

Fig. 5.2. One-bond 13C—13C coupling constants (in Hz) of stigmasterol (A) and 1,4-andro-stadiene-3,11,17-trione (B) measured at 100.6 MHz and 70 °C in pyridine-d5 (700 mg/2.5 mL). (A) ID and 2D INADEQUATE experiments were performed with i = 6 msec, digital resolution 0.21 Hz/point.17(C7-C8) cannot be observed because the AS value is only 0.1 ppm. The long 7, value for C-10 resulted in a poor signal to noise ratio which prevented the observation of 7(10-C. 5). (B) 1 D INADEQUATE experiments r = 5 msec, digital resolution 0.33 Hz/point. 1/(C6-C7) and 7(0,2 C13) cannot be observed because the A<5 values are only 0.22 and 0.01 ppm, respectively [595].

EXAMPLE 13.4 Describe the appearance of a ID and 2D INADEQUATE signed for a methoxy carbon, OCH3. 

Today, a number of one- and two-dimensional NMR experiments are available for the detection of homonuclear Li, Li and Li, Li couplings. Aside from the COSY experiment, the double quantum filtered COSY (COSY-DQF), the TOCSY, and the ID and 2D INADEQUATE experiments [24] have been successfully employed. An attractive feature of all these experiments is their sensitivity for small scalar interactions which give rise to crosspeaks even if line splittings in the corresponding ID spectra are not resolved. This was first demonstrated with COSY experiments for a paramagnetic nickel complex [82] and for quadrupolar nuclei in the case of boron-11 [83]. 

The principle of multiple selective excitation has been incorporated into a few ID and 2D experiments, the schemes of which are shown below (fig. 1). Depending on the experiment, either a DANTE pulse train (ID TOCSY [2]), frequency selective 180° pulses (ID NOE [3], ID INADEQUATE [4], ID C/H COSY [5] and 2D TOCSY-COSY [6]) or frequency selective 90° pulses (2D HMBC [11]) are applied to selectively perturb and uniquely label selected spins. Besides the DANTE pulse , composed itself of a series of non-selective rectangular pulses, Gaussian-shaped 180° and... 

INADEQUATE, ID and 2D NMR experiments to demonstrate direct C-C connectivity INEPT, insensitive nuclei enhanced by polarization transfer... 

SELINQUATE (Berger, 1988) is the selective ID counterpart of the 2D INADEQUATE experiment (Bax et al., 1980). The pulse sequence is shown in Fig. 7.4. Double-quantum coherences (DQC) are first excited in the usual manner, and then a selective pulse is applied to only one nucleus. This converts the DQC related to this nucleus into antiphase magnetization, which is refocused during the detection period. The experiment has not been used widely because of its low sensitivity, but it can be employed to solve a specific problem from the connectivity information. 

TOPHAT-shaped 90° pulses are used in other cases as the best compromise with respect to the excitation profile, the phase homogeneity and length. Depending on the type of the detected spin-spin interaction - being either scalar or dipolar coupling - each selected spin is initially perturbed only once (ID TOCSY, ID INADEQUATE, ID C/H COSY, 2D TOCSY-COSY and 2D HMBC), or for several times (ID NOE). With each of the selected spins initially perturbed only once the inherently smaller transient NOEs would be detected in the latter case, whereas with the multiple excitation of a selected spin within the NOE build-up period the stronger steady-state NOEs are more or less approximated. 

A series of ID NOE experiments confirmed the following proximities HI to H2 H2 to H5, H6, and H7 and H3 to H8. (a) Propose as complete a structure as you can for this compound and assign all NMR data, (b) Confirm or reconstitute your structure so it is consistent with the 2D INADEQUATE spectrum of the compound tabulated below ... 

Vinaxanthone (991) (Fig. 13.21) was isolated by Yokose and Seto in 1991 from the soil microbe, Penicillium vinaceum, and shown to be a novel phospholipase C (PLC) inhibitor, with an /C50 value in the low micromolar range (658). PLC is an enzyme that hydrolyzes phosphatidylinositol biphosphate (PIP) in the cellular membrane, and is involved in the signal transduction cascade and pathways affecting cell proliferation. Encountering difficulty in the structure elucidation process due to both the low solubility and highly substituted nature of 991, the authors used a series of NMR techniques including 2D-INADEQUATE and selective ID-INADEQUATE experiments to solve the structure. 

The rearrangement of the cage hydrocarbon diazo-nium ion [1] in the presence of water could lead to three possible alcohol products [2], [3] and [4]. Only two alcohol products were obtained from this reaction in isolated yields of 38% and 7%. The structures of these two products could only be determined by the 2D INADEQUATE experiment due to the hydrocarbon nature of their structures, and therefore, the lack of any distinguishing details in the proton spectra. Each compound also had the same number of methylene, methine and quaternary carbons, thus precluding the utilization of structure determination by simple ID spectroscopy. 

Figure 5.83A shows the broad-band decoupled spectrum of 5a-androstane while the ID-INADEQUATE spectrum of 5a-androstane is presented in Figure 5.83B. The doublets due to C-10 and C-8 have been expanded in Figure 5.83C. Thus the C-10 signal (set of upright and inverted peaks) shows couplings with C-1, C-19, C-9, and C-5. Similarly, the C-8 signal shows couplings with C-7, C-9, and C-14. The 2D-INADEQUATE spectrum shown in Figure 5.83D shows the ID-INADEQUATE spectrum at the base and the peaks for the coupling carbon atoms located on different horizontal lines, making their identification very easy in the 2D plot.

Figure 5.83. (A) Broad-band decoupled spectrum of 5a-androstane. (B) ID-INADEQUATE spectrum. (C) region of C-8 and C-10 expanded to show up couplings. (D) 2D-INADEQUATE spectrum of 5a-androstane showing the couplings lying on separate horizontal lines with the peaks located symmetrically on either side of a diagonal, thus greatly facilitating identification.

An expansion of the aliphatic region from the 2D-INADEQUATE spectmm of low-MW poly(a- C-styrene) is shown in Figure 43(a) where correlations between C -C atoms from the directly coupled fragments are shown in region 1. Correlations between one of the C to a and to from a styrene unit added in the normal H-T fashion are also seen in regions 2 and 3. In the ID-NMR spectmm at the top, the resonance from the a carbon near 40 ppm (off-scale resonance) is... 

The simplest situation is represented by most 1-dimensional (ID) models in which the distributions are taken to represent variability, and where there are adequate data to characterize the distributions. More complicated situations may involve ID modeling with data that are inadequate or problematic (e.g., because of availability of only summary statistics), or the inclusion of uncertainties in 2-dimensional (2D) models. 

Fig. 1. Pulse sequences modified for multiple selective excitation. I ID TOCSY, II het-eronuclear ID NOE, III ID INADEQUATE, IVa heteronuclear ID COSY (optimized to detect Jch), IVb heteronuclear ID COSY (optimized to detect "Jch), V 2D TOCSY-COSY, Via 2D HMBC (designed to detect heteronuclear long-range couplings "Jch only), VIh 2D HMBC (extended pulse sequence to detect both heteronuclear long-range "Jch and...

Most of the carbon-carbon coupling constants published recently have been measured using 2D 13C-detected INADEQUATE spectra.39-44 ID INADEQUATE experiments were used less frequently43 45 due to potential overlap problems. The measured coupling constants are usually used to resolve stereochemical problems and also compared with theoretical values. 

---