Impact of solvent interactions on¹H and¹³C chemical shifts investigated using DFT and a reference dataset recorded in CDCl₃and CCl₄

Abstract

1H and 13C chemical shifts of 35 small, rigid molecules were measured under standardized conditions in chloroform-d and in tetrachloromethane. The solvent change mainly affects carbon shifts of polar functional...

Perspectives on Nuclear Magnetic Resonance Spectroscopy in Drug Discovery Research

“…Density functional theory (DFT) is a QM method used to understand the electronic structure for optimizing the geometries of molecules. DFT calculations can provide accurate chemical shift and coupling constant predictions which are required to differentiate between similar structures. , Chemical shift calculations using gauge-invariant atomic orbital protocol (GIAO) is the most common application of DFT for NMR observables. Other NMR parameters are also being routinely probed via this methodology for structure elucidation.…”

The accuracy limit of chemical shift predictions for species in aqueous solution

“…7,19 Even if the target species along with a local solvent environment is sampled by AIMD simulations, as has been done for N-methylacetamide (NMA) in water 19 the residual error from averaging over QM-based snapshot calculations is quite large when using an empirical reference, on the order of 1 ppm for the amide proton. Alternatively, NMR calculations on geometry optimized structures of TMS or DSS are established and frequently used in the literature, [20][21][22][23] allowing for a direct referencing approach mimicking an internal standard. However, fitting the reference to experimental data 7,21 as well as secondary or multi-standard methods 24,25 are usually preferred 26 as they lead to more accurate shift calculations due to improved error compensation.…”

DELTA50: A Highly Accurate Database of Experimental 1H and 13C NMR Chemical Shifts Applied to DFT Benchmarking

“…One of the earliest and most comprehensive compound sets comprising 80 structures of proton ( 1 H) chemical shifts was curated by Rablen et al [ 1 ] in 1999 and later augmented by Tantillo and coworkers [ 3 ] with the inclusion of carbon ( 13 C) chemical shift data ( Figure 1 a) and an additional 24 compounds in a separate probe set ( Figure 1 b). Although the test and probe sets of Rablen and Tantillo have been used for several benchmarking studies [ 1 , 3 , 50 , 56 ] with various density functionals, basis sets, and solvent effect studies, they are not without challenges: (1) relativistic effects from elements in rows three and beyond of the periodic table must be included for accurate δ C predictions of carbons bound to the heavy atom ( Figure 1 c) [ 57 ]; (2) molecules such as furfural ( Figure 1 c) and dimethyl acetal exhibit multiple low-lying conformers in solution whose Boltzmann-weighting factors are highly dependent on the level of theory employed; (3) compounds such as methanol and indole contain hydrogen bond donors that will exhibit concentration-, pH-, and temperature-dependent chemical shifts in solution; (4) aromatic, olefinic, and alkynyl compounds may also exhibit concentration-dependent chemical shifts due to aggregation from π–π stacking [ 58 , 59 ]; and 5) experimental data were not measured in a single solvent system (instead, either CDCl 3 or CCl 4 was used, which may yield significant differences [ 60 ]). Experimental NMR chemical shift data used by Rablen and Tantillo were from eight sources [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ] with sample concentrations for carbon NMR spectra, which at times reached up to 10% weight/volume (solid) or volume/volume (liquid).…”