Prediction of chemical shifts

Consultation of tables containing chemical shifts of and C atoms based on their chemical environment is something we do a lot of initially. However, as our assignment skills develop and mature we find that this practice is required less often. Many software packages that are commercially available at the time of this writing are able to predict and C chemical shifts on the basis of a user-supplied chemical structure. However, these software packages are of only limited utility once we encounter greater molecular complexity. 

An important caveat is that chemical shifts can often lead to incorrect assignments of resonances. Chemical shifts are influenced by many factors e.g., chemical shifts reflect not only the electronegativity of nearby atoms but also bond hybridization as manifested through constraints imposed by molecular geometry, and proximity to aromatic and other electron-rich systems. 

In carrying out the assignment of observed resonances to atoms in a molecule of knovm structure, we must balance the urge to use chemical shift arguments with a healthy skepticism of the many ways in which chemical shifts may be influenced by less-than-obvious factors. That is, avoid whenever possible using small differences in chemical shifts to make resonance assignments. 

With that said, it should also be stated that chemical shifts are the single most accessible and readily useful aspect of the spectrum of a typical organic molecule. Identification of entry points is often done by using simple chemical shift arguments and little if any corroborating information is expected, given a unique and well-isolated chemical shift. 

For example, the H resonance of a carboxylic acid proton or an aldehyde proton is typically in the range of 9-10 ppm, far dovmfield and well-separated from the other resonances in the H spectrum. In the chemical shift range, carbonyls are similarly found well down-field (at 160-250ppm) of the other resonances in the spectra of most organic compounds. 

Ab-initio calculations are particularly usefiil for the prediction of chemical shifts of unusual species . In this context unusual species means chemical entities that are not frequently found in the available large databases of chemical shifts, e.g., charged intermediates of reactions, radicals, and structures containing elements other than H, C, O, N, S, P, halogens, and a few common metals. 

NMR calculations are based on a given molecular geometry, which means that an experimental 3D structure must be available, or it has to be previously calculated. Because a rigid structure is used for the calculations, different chemical 

Using semi-einpirical methods, which are also based on approximate solutions of the Schrodingcr equation but use parameterized equations, the computation times can be reduced by twu orders of magnitude. HyperChem from Hypercubc, 

A good source of information regarding the scientifre background of ab-initio and semi-empirical calculations are the manuals that accompany commercial software. Some of the documentation is available for evaluation on the Internet, 

A useful empirical method for the prediction of chemical shifts and coupling constants relies on the information contained in databases of structures with the corresponding NMR data. Large databases with hundred-thousands of chemical shifts are commercially available and are linked to predictive systems, which basically rely on database searching [35], Protons are internally represented by their structural environments, usually their HOSE codes [9]. When a query structure is submitted, a search is performed to find the protons belonging to similar (overlapping) substructures. These are the protons with the same HOSE codes as the protons in the query molecule. The prediction of the chemical shift is calculated as the average chemical shift of the retrieved protons. 

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Figure 10.2.5. Example of a local RDF descriptoT for proton 6 used in the prediction of chemical shifts (e = 20 A...

The most obvious feature of these C chemical shifts is that the closer the carbon is to the electronegative chlorine the more deshielded it is Peak assignments will not always be this easy but the correspondence with electronegativity is so pronounced that spec trum simulators are available that allow reliable prediction of chemical shifts from structural formulas These simulators are based on arithmetic formulas that combine experimentally derived chemical shift increments for the various structural units within a molecule... 

Currently there is only one product that adopts this approach and this is NMRPredict from Modgraph. It is based on the work by Prof. Ray Abraham at the University of Liverpool (UK). This approach calculates chemical shifts for a range of low energy conformers and averages them to give a net chemical shift. This approach seems to offer the most accurate prediction of chemical shift but the disadvantage is that it is very slow (particularly for conformationally flexible molecules). 

Despite the successful prediction of chemical shifts for a great structural variety of carbocations some difficulties have been encountered for vinyl cations.47 The effect of electron correlation, basis sets and geometry on calculated NMR spectra of vinyl cations has been studied in some detail also for the parent vinyl cation in its linear form.48 Comparative experimental and computational NMR studies, however, have... 

Advanced Chemistry Development Inc. has built a sizeable proton chemical shift database derived from published spectra (most commonly in CDCI3 solution). Their H NMR predictor programme accesses this database and allows the prediction of chemical shifts. Whilst this software takes account of geometry in calculating scalar couplings, in predicting chemical shifts it essentially treats the structure as planar. It would therefore seem doomed to failure. However, if closely related compounds, run at infinite dilution and in the same solvent, are present in the database, the conformation is implied and the results can be quite accurate. Of course, the results will not be reliable if sub-structures are not well represented within the database and the wide dispersion of errors (dependent on whether a compound is represented or not) can cause serious problems in structure confirmation (later). ACD are currently revising their strict adherence to HOSE codes for sub-structure identification and this will hopefully remove infrequent odd sub-structure selections made currently. 

Calculations of chemical shielding and EFG parameters for crystalline materials have become a valuable tool for the interpretation of solid-state NMR data. With the advent of powerful computational resources and methods that allow calculations to be performed within a reasonable time, quantum chemical first-principles approaches are nowadays feasible and of very great applicability to NMR. Former studies dealt with the prediction of chemical shifts and other NMR parameters from... 

Several tables for the prediction of chemical shifts for substituted CH3, CH2, and CH groups have been updated. Earlier tables for substituted CH groups in particular have not been satisfactory. 

Though these codes failed to characterize uniquely the molecular structure54), they are useful for ordering structures as basis for systematic searches for regularities in molecular data 55), fragment56) and ring S7) search, for recognition of structural similarity 54> in molecules, for the prediction of chemical shift in NMR-data, etc. 

Hybridisation of the carbon atom has a significant effect on the chemical shift sp3-hybridised carbon absorbs at high field (0-60 p.p.m. downfield from TMS), sp2-carbon at low field (80-200 p.p.m.) and sp-carbon at intermediate values. The precise position of absorption of a particular atom is largely determined by the electronic effects of any substituents, and the fact that these are approximately additive enables fairly accurate predictions of chemical shifts to be made, provided that similar compounds of known structure are available for reference purposes. 

Table 14.1. Prediction of chemical shift of c/s-l,2-dimethylcyclohexane in the frozen state, using the cyclohexane shift of 5c = 27.6 and substituent effects (e.g. Ref. 6, p. 316)...

A study of a large number of B chemical shifts in mono-halogenodecaboranes has provided a good basis for the prediction of chemical shifts in the disubstituted compounds. Thus, if AcrA and AcrB are the A-shifts in the monohalogenodecaboranes, then the A-shift in the related dihalogenodecaborane, Acrc, is given by ... 

The discussions in this section briefly described the use of local descriptors. Another application of local descriptors is the characterization of atoms in nuclear magnetic resonance (NMR) spectroscopy. This is described later with an application for the prediction of chemical shifts in H-NMR spectroscopy, where protons were represented by their local RDF descriptors. 

The prediction of chemical shifts in H-NMR spectroscopy is usually more problematic than in C-NMR. Experimental conditions can have an influence on the chemical shifts in H-NMR spectroscopy and structural effects are difficult to estimate. In particular, stereochemistry and 3D effects have been addressed in the context of empirical H-NMR chemical shift prediction only in a few specific situations [81,82]. Most of the available databases lack stereochemical labeling, assignments for diastereo-topic protons, and suitable representations for the 3D environment of hydrogen nuclei [83]. This is the point where local RDF descriptors seemed to be a promising tool. 

A study of closely related compounds, however, often reveals secondary influences on nitrogen chemical shifts. Poranski and Moniz ° have shown that the chemical shifts of aliphatic nitro-compounds (Table III) depend on the inductive effect of substituent groups. Simple empirical rules for the prediction of chemical shifts in the system R R R CN02 have been devised, where R = H, NO2, Cl or alkyl.The contribution of the shift from CH3, RCH2 and Cl are additive and, with a further modification of the expression—... 

As expected, substituent effects on <5 C and S H in the chalcogenophene series led to a qualitative determination of four different substituent classes depending on the heteroatom, and its interaction with the substituent. This method allows the prediction of chemical shifts <90MRC397>. 

Figure 6.12 shows for the same set of molecules the performance of various DFT schemes for the prediction of chemical shifts [167]. As it is seen the DFT results are less satisfactory than those obtained with the more traditional schemes for treating electron correlation. Some improvements compared to HF-SCF are noted, especially for the challenging cases, but the DFT calculations do not reach the same accuracy as the corresponding MP2 calculations. 

The first chemical applications to show the importance of electron correlation effects for NMR chemical shift calculations dealt with the chemistry of boranes and carboranes, which has often been a fertile area for theoretical insights. Since NMR is one of the main tools for establishing molecular structures in this area, there is accordingly great interest in the accurate prediction of chemical shifts for these compounds. Biihl and Schleyer [13] found that uncorrelated calculations are sufficient in most... 

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