Chemical shifts isotope effects

A second example of a study exploiting chemical shift isotope effects is shown in Fig. 7.15b which reports 1II, 2H and 19F low temperature NMR spectra of the... 

Fig. 12.7 An unusually long range (10-bond) secondary D isotope shift IE on an [19F] NMR. The H/D chemical shift isotope effect due to substitution at an OH — N hydrogen bond sited ten bonds away from a para-F is 11 ppb (Hansen, P. E. et al. Acta Chim. Scandanavia 51,881 (1997))...

The preceding discussion makes clear the fact that the precise values of chemical shift isotope effects will depend on the choice of isotopic reference. Correct choice of the reference is somewhat subtle. In the context of tritium as an isotope at low abundance, pertritiated TMS would clearly be an incorrect choice partially monotritiated TMS would appear to be best. 

Having given the definition of isotope effects on chemical shifts, isotope effects can be further subdivided into intrinsic or equilibrium. In the latter case, isotope substitution many lead to a change in the chemical equilibrium due to a difference in zero-point energies as illustrated in Figure 6.3 (for an explanation, see later). 

Chemical shifts are shifted to higher field when deuterium replaces hydrogen either geminally or vicinally the stereochemical dependence of the vicinal-shift isotope effect has been investigated by means of cis- and trans-[2- H]fluorocyclohexane with spectra obtained under conditions of slow ring-inversion at — 85°C. The observed F isotope shifts (/p.p.m.) for (34) and (35) are shown. Values for (36) and (37) and the norbornyl systems (38) and (39) are also shown these were determined in order to ascertain the stereochemical dependence of the isotopic shift. The smallest... 

Carbon-13 nmr. Carbon-13 [14762-74-4] nmr (1,2,11) has been available routinely since the invention of the pulsed ft/nmr spectrometer in the early 1970s. The difficulties of studying carbon by nmr methods is that the most abundant isotope, has a spin, /, of 0, and thus cannot be observed by nmr. However, has 7 = 1/2 and spin properties similar to H. The natural abundance of is only 1.1% of the total carbon the magnetogyric ratio of is 0.25 that of H. Together, these effects make the nucleus ca 1/5700 times as sensitive as H. The interpretation of experiments involves measurements of chemical shifts, integrations, andy-coupling information however, these last two are harder to determine accurately and are less important to identification of connectivity than in H nmr. 

Figure 1.9. NMR spectra of a mixture of ethanol and hexadeuterioethanol [27 75 v/v, 25 °C, 20 MHz], (a) H broadband decoupled (b) without decoupling. The deuterium isotope effect Sch - d on chemical shifts is 1.1 and 0.85 ppm for methyl and methylene carbon nuclei, respectively...

MI1 P. E. Hansen, Isotope Effects on Chemical Shifts as a Tool in Struc-... 

A simple NMR technique, and arguably the most widely used and effective for hit validation, is the chemical shift perturbation method. In this approach, a reference spectrum of isotopically labeled target is recorded in absence and presence of a given test ligand (or a mixture of test ligands). Commonly, differences in chemical shift between free and bound protein target are observed in 2D [15N, 1H and/or 2D [13C, H] correlation spectra of a protein (or nucleic acid) upon titration of a ligand... 

Because fluorine is relatively sensitive to its environment and has such a large range of chemical shifts, considerable changes in chemical shift can be observed when a nearby atom is replaced by an isotope. For example, replacement of 12C by 13C for the atom to which the fluorine is attached, gives rise to a quite measurable shift, usually to lower frequency. A consequence of this isotope effect is the observation that the 13C satellites in a fluorine spectrum are not symmetrical about the 12C—F resonance. 

FIGURE 2.11. 19F NMR spectrum of l,6-difhiorohexane-l,l-d2, demonstrating the deuterium isotope effect on the fluorine chemical shift... 

Scheme 2.16 provides further insight regarding both a- and 3-deuterium isotope effects on fluorine chemical shifts with a series of deuterated chloro, fluoroethylenes.16... 

FIGURE 2.12. CH2F/CD2F region of the 13C NMR spectrum of 1,6-difluorohexane-1,1 -d2 demonstrating deuterium isotope effect on 13C chemical shifts... 

So if this all sounds a bit bleak, what s the good news Well, strangely, there is quite a lot. For a start, let s not forget that had the 13C nucleus been the predominant carbon isotope, the development of the whole NMR technique itself would have been held back massively and possibly even totally overlooked as proton spectra would have been too complex to interpret. Whimsical speculation aside, chemical shift prediction is far more reliable for 13C than it is for proton NMR and there are chemical shift databases available to help you that are actually very useful (see Chapter 14). This is because 13 C shifts are less prone to the effects of molecular anisotropy than proton shifts as carbon atoms are more internal to a molecule than the protons and also because as the carbon chemical shifts are spread across approximately 200 ppm of the field (as opposed to the approx. 13 ppm of the proton spectrum), the effects are proportionately less dramatic. This large range of chemical shifts also means that it is relatively unlikely that two 13C nuclei are exactly coincident, though it does happen. 

The measurement of deuterium isotope effects on chemical shifts is a useful tool for studies of tautomeric equilibrium (for details see the reviews 42 44). The deuterium isotope effect AX(D) is defined as the difference between chemical shifts in deuterated and non-deuterated sample [26]. 

The deuterium isotope effects on chemical shift consists of intrinsic isotope effect (direct perturbation of the shielding of X atom) and equilibrium isotope effect (perturbation of the equilibrium caused by the isotopic substitution). The values of deuterium isotope effects are to some extent independent of chemical shifts and allow determination of the mole fraction of the forms in equilibrium. 

T. Deuterium isotope effects on 13 C chemical shifts In the studies of proton transfer equilibrium of Schiff bases, the most informative are deuterium isotope effects measured for carbons bonded with proton donor groups (C-2 or C-7 for gossypol derivatives). For imines in which... 

Deuterium isotope effects on 1SN chemical shifts Deuterium isotope effects on 15N chemical shifts AN(D), similarly as for AC(D), can be employed in determination of mole fraction of the proton transferred form Schiff bases.44 A similar correlation between the mole fraction of NFI-form and AN(D) values was found (Figure 2). For the Schiff bases in which proton transfer takes place, the AN(D) values varied from —2 to + 5 ppm and depend on solvent and temperature. The AN(D) values of... 

Deuterium isotope effects on 15N chemical shift in CDC13 solution as well as in solid state were measured for a series of symmetrical and unsymmetrical di-Schiff bases being derivatives of fra s-l,2-diaminocy-clohexane and various aromatic ort/io-hydroxy-aldehydes [22],57 The AN (D) value determined in solid state for symmetrical di-Schiff base which was a derivative of salicylaldehyde was —1.8 ppm, which was typical of... 

The position of the proton transfer equilibrium for the Schiff bases being derivatives of rac-2-aminobutane [24] or rac-a-methylbenzylamine [25] and their adducts with dirhodium complex has been estimated in CDCI3 solution on the basis of measurements of deuterium isotope effects on 15N chemical shift.12 It was shown that adduct formation significantly influenced the position of the equilibrium which was manifested by AN(D) values. 

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