The DP4 probability is one of the most sophisticated and popular approaches for the stereochemical assignment of organic molecules using GIAO NMR chemical shift calculations when only one set of experimental data is available. In order to improve the performance of the method, we have developed a modified probability (DP4+), whose main differences from the original DP4 are the inclusion of unscaled data and the use of higher levels of theory for the NMR calculation procedure. With these modifications, a significant improvement in the overall performance was achieved, providing accurate and confident results in establishing the stereochemistry of 48 challenging isomeric compounds.

The influence of the reference standard employed in the calculation of (13)C NMR chemical shifts was investigated over a large variety of known organic compounds, using different quantum chemistry methods and basis sets. After detailed analysis of the collected data, we found that methanol and benzene are excellent reference standards for computing NMR shifts of sp(3)- and sp-sp(2)-hybridized carbon atoms, respectively. This multi-standard approach (MSTD) performs better than TMS in terms of accuracy and precision and also displays much lower dependence on the level of theory employed. The use of mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level is recommended for accurate (13)C NMR chemical shift prediction at low computational cost.

The calculations of NMR properties of molecules using quantum chemical methods have deeply impacted several branches of organic chemistry. They are particularly important in structural or stereochemical assignments of organic compounds, with implications in total synthesis, stereoselective reactions, and natural products chemistry. In studying the evolution of the strategies developed to support (or reject) a structural proposal, it becomes clear that the most effective and accurate ones involve sophisticated procedures to correlate experimental and computational data. Owing to their relatively high mathematical complexity, such calculations (CP3, DP4, ANN-PRA) are often carried out using additional computational resources provided by the authors (such as applets or Excel files). This Minireview will cover the state-of-the-art of these toolboxes in the assignment of organic molecules, including mathematical definitions, updates, and discussion of relevant examples.