Chemical shift predictions

They are applicable to compounds in the common NMR solvents - but not in D6-benzene (or D5-pyridine). The substituent effects are additive, but don t place too much reliance on chemical shifts predicted using the table, in compounds where more than two groups are substituted next to each other, as steric interactions between them can cause large deviations from expected values. Note that Table 5.4, like all others, does not cater for solvent shifts, etc ... 

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. 

One point worth noting is that the theoretical calculation of chemical shifts predicts absolute chemical shifts, whereas experimental values are reported with respect to some convenient but otherwise arbitrary reference. Although theoretical chemical shift trends in a series of compounds may be compared with experimental trends, it can be useful to also calculate the chemical shift of a solid reference compound for comparison, while realizing that such a calculation will also be subject to some degree of inaccuracy. 

Vast tabulations of 13C chemical shift data have been assembled in computer searchable form. These databases form the basis for 13C chemical shift prediction algorithms. For the most part, carbon chemical shifts can be calculated using what is referred to as a Hierarchically Ordered Spherical Environment (HOSE) code approach [28]. To calculate a given carbon s chemical shift, the influence of each successive spherical shell is applied to the starting chemical shift for that carbon to calculate its overall chemical shift. Typically, programs will calculate shifts for 3 or 4 layers, beyond which the effects of most substituents are negligible. The spherical layers surrounding the 23-position of strychnine are shown in Fig. 10.8. 

The last section is a compilation of useful empirical additivity rules for 13C chemical-shift prediction, regardless of underlying transmission mechanisms. Peculiarities of less common substituents are cited, and, finally, substituent-induced 13C signal shifts in various cyclic compounds are discussed, with special emphasis on their use in conformational analysis I do not, however, claim completeness for this latter discussion. 

The confirmation or refuting of a structure require that there is a chemical structure postulate. Any such decision is subject to errors, in particular those imposed by chemical shift prediction errors. A more robust decision can be made if the spectrum is not only compared against the postulate (where it exists) but also a series of closely related compounds. Such a list is most likely to originate from chemical diversity software or prior chemical knowledge. 

Statistical analysis" has demonstrated that the demands placed upon the reliability of the chemical shift predictions intrinsic in this automated confirmation of structure, are greater if predicted and experimental stoichiometries cannot be compared. Furthermore, it is inevitable that high throughput environments will not yield pure compounds and the reliable identification of impurities (identified as fractional stoichiometry) will be key. 

The ability of NOE matching to identify the correct pose from a collection of decoy poses was demonstrated on three test cases involving lead-like compounds bound to small proteins. One of these test cases involves muscle fatty acid-binding protein (mFABP) and the other two involve the leukocyte function-associated antigen 11-domain (LFA-1). As these results have been presented in detail elsewhere,1151 here we only summarize the results obtained when the BMRB average chemical shifts (diamagnetic protein statistics) were used for chemical shift predictions. The compounds used for these test cases are shown in Scheme 5.1 (compound 3 contains a proprietary core, which is represented by an ellipse). 

A full assignment of the proton resonance of substituted 2-styryl-5-nitroimidazoles was carried out by the use of an addition increment method for chemical shift prediction [353]. Some 4-styryl-5-nitroimidazoles have been studied in [354],... 

No systematic study of the effect of different solvation models has been performed. A few reports have compared specific cases such as the study of cationic and anionic alanines, which shows a significant improvement in the chemical shift prediction using polarized continuum method (PCM) or better stiU a hybrid solvation approach (Section 1.4.3). However, the linear scaling correction discussed below can often account for the systematic solvent effect and so sometimes one can get away without any solvent computation at all. 

Lodewyk et al. " have extended the approach of Jain et al. to include C chemical shifts. The RMSE results for the C chemical shifts of their recommended computational models are listed in Table 2.8. Errors are larger than for proton chemical shifts, but quite reasonable results can again be had with modest computational effort. Again, it is important to note that optimization of the geometry in solution is unnecessary. Tantillo maintains a Web site compiling the recommended methods and scahng factors for H and C chemical shift prediction. 

More recently, software has been developed that predicts H, C, and N chemical shift values of proteins from either 3D stmcture files, for example, SHIFTS (6), SHIFTX (7), and SPARTA (8), or from the mere amino acid sequence using SHIFTY (9). First results have been reported on the de novo stmcture determination of proteins using fragment-based chemical shift predictions and molecular modeling (10, 11). 

Shen Y, Bax A. Protein backbone chemical shifts predicted from 30. searching a database for torsion angle and sequence homology. 

The orientation of the substituent gtoups in 1,2,4-oxadiazole substituted pyrazoles 39, formed by reaction of benzonittile oxides with an unsymmetrically substituted hydrazine, has been determined by C NMR assignments <1998JHC161>. The scope and limitations in the regioselective synthesis of 1,3,5-trisubstituted pyrazoles from / -amino enones and hydrazine derivatives were investigated by C chemical-shift prediction mles for 1,3,5-trisubstituted pyrazoles <2001H(55)331>. 

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