The Golden Age of Computer-Assisted Structure Elucidation (CASE)

Computer-assisted structure elucidation (CASE) is the method of using software to generate all possible molecular structures consistent with a particular set of spectroscopic data. CASE works mainly with nuclear magnetic resonance (NMR) spectroscopy data resulting in elucidations of increasingly complex structures. With a computer, the process of identifying a structure from experimental data is faster, unbiased, and can generate millions of potential structures in a short time.

The history of CASE

First published in 1968, CASE described how to use computers with data from infrared spectroscopy to elucidate a structure of an unknown. As time went on, scientists realized infrared data was very limited, so they turned to NMR. In its early days, NMR was based on 1D spectra, which contained notably more structural information than infrared spectra. However, due to their lack of correlation data, there remained significant ambiguities as to how atoms were connected.

The next major milestone was in the 1990s when 2D NMR became routinely available to researchers. 2D NMR was a great way to obtain significantly more structural information using the same instrumentation as that required for 1D Fourier transform (FT) NMR. It offered a way to find exactly how atoms are connected, opening the door to the development and evolution of modern CASE algorithms.

CASE algorithms have been continuously improved to be able to handle any situation that may arise, such as non-standard or missing correlations, symmetry and experimental ambiguity. More recently, synergies with advancements in theoretical predictions of chemical shifts have helped CASE become what it is today.

The helpful CASE

CASE is now a well-established method for solving the structure of an unknown. With the existence of advanced algorithms, CASE allows a scientist to select which generated structure is correct. Some believe that when structures are generated, the problem is solved. However, this is a misunderstanding. The software will usually give you a few tens or hundreds of possible structures, but if the data are not sufficiently constraining, the result may be up to a few million structures. The problem isn’t fully solved until a scientist has a reliable means of identifying the single most probable structure – and that’s where additional verification tools and calculations are incorporated into CASE.

CASE helps find answers to questions humans aren’t able to solve. When a structure is found and confirmed using CASE software, the scientist’s results are further validated. For example, CASE helps natural product researchers determine the complex structures of their isolates out of millions of possible candidates. CASE also helps synthetic chemists when they complete a reaction and fail to get the result they wanted or expected. CASE can help determine the structure of unknowns with minimal experimental data to help the chemist find out what actually happened in their flask.

The proactive and reactive CASE

Although we have accurate methods for predicting NMR spectra, to distinguish between the top 1% of structural candidates generated with CASE, powerful computations such as density functional theory (DFT) are sometimes necessary. However, compared to the situation without CASE, this saves weeks and even months of unnecessary computation on the less likely structures, offering the optimal result much faster. CASE has and will always be a tool that can be used for structural revision and verification, meaning scientists can go back to look at structures they elucidated and confirm their accuracy using CASE.

CASE can also be used in combination with other experimental methods of structure elucidation, an example being X-ray crystallography and atomic force microscopy (AFM). AFM allows scientists to build up a picture of a molecule using an atomic force microscope and, based on the top structural candidates from CASE, determine which molecule is correct. This is not easy to do using AFM on its own, as it doesn’t always give a great picture of a given molecule.

The future of CASE

The future of CASE is bright, and it will likely become a big part of emerging scientists’ work. CASE should be utilized in schools and universities to teach students how to elucidate structures with NMR. While the theory behind manual pen-on-paper elucidations is important, scientists who use CASE will be able to quickly and significantly advance their science. Computers are incredibly reliable in quickly solving complex challenges, so they are an essential part of a modern laboratory.

My vision for CASE: All scientists will use it. Much like people use a computer for everyday activities, CASE should be used for all structure elucidations.