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Computer-Assisted Structure Elucidation (CASE): Past, Present, and Future

February 24, 2022
by Sarah Srokosz, Marketing Communications Specialist, ACD/Labs

Computer-assisted structure elucidation (CASE) is the method of using software to determine chemical structures based on spectroscopic data. In 1968, Mikhail Elyashberg and Lev Gribov published the first CASE method. Since its introduction, with significant advances in both the fields of computer science and spectroscopy, CASE has also come a long way. The first CASE systems were limited to simple small molecules. Modern CASE expert systems can now elucidate the structures of large and complex natural products in far less time than it would take even the most advanced spectroscopists.

With commercially available CASE systems such as ACD/Structure Elucidator, an increasing number of scientists are turning to these tools for a fast and unbiased answer to even their most challenging structure elucidations. While CASE systems will never fully replace a scientist, they can be of benefit to those performing structure elucidations of every level. In fact, experts believe that, similarly to how a processing software is now used in the analysis of all analytical data today, CASE will be used in every structure elucidation in the not-so-distant future.

Computer-Assisted Structure Elucidation (CASE)

The Origins of Case

The first CASE method from the 1968 publication described the use of computers to determine the structure of an unknown from infrared spectroscopy data. As the field of spectroscopy evolved and scientists began taking advantage of the increased amount of structural information in 1D NMR data, CASE algorithms also pivoted to rely more heavily on the data from 1H and 13C NMR. However, these systems were still limited to relatively small and simple structures and were not nearly as reliable as modern CASE systems.

These early CASE systems were also challenged by the output of multiple equally probable structures. Since these algorithms were based on libraries of molecular fragments and their characteristic spectral features, they turned to predicted 13C NMR spectra of candidate structures to differentiate them. The general architecture of these early algorithms is still used in today’s most powerful CASE systems.

As computer technology continued to develop, these computations were sped up, making them a more practical solution for scientists. Unfortunately, the structural data that 1D NMR offered was still too limited to make CASE an attractive option to most labs.

The arrival of 2D NMR experiments in the 1990s revolutionized the field of structure elucidation from NMR data, and CASE was no exception. These new data correlating to how atoms in a molecule are connected were able to fill in the gaps of existing CASE systems. Methods using 2D NMR data became the backbone of CASE technology, as they continue to be today.

The Role of ACD/Structure Elucidator in the History of CASE

In 1997, Professor Elyashberg approached ACD/Labs about creating a software program so that the method could be made easily available to chemists in the lab. A passion project of his lifetime, Structure Elucidator from ACD/Labs is the most peer-reviewed and arguably most powerful CASE system on the market today. In its lifetime, it has led the development of CASE technology. It has gone from a program operating on Windows 3.x or Windows 98/95 capable of solving structures of molecules with up to 20–25 heavy atoms to the high-performance software that can solve the structures of complex natural products in a matter of minutes.

In 2003, Structure Elucidator was the first CASE system reported to outperform human expertise (though it still required a non-negligible amount of human input). But in only 10 seconds, 353 candidate structures for the unknown were generated. After ranking based on predicted 1H and 13C NMR spectra, the top 12 candidates were considered and quickly narrowed down to a single candidate structure based on ROESY and mass spectrometry fragmentation data.

Structure Elucidator continues to demonstrate its exceptional ability to elucidate structures of complex molecules by taking on complex spectroscopic problems from the literature through our Elucidation of the Month posts. We also invite any scientists to bring us their most challenging datasets in our Structure Elucidator Challenge. So far, the software has a 100% success rate over the 82 challenges issued.

Professor Mikhail Elyashberg was a member of the team who pioneered Structure Elucidator and continues to be involved in its industry-leading development to this day. In 1999, Professor Elyashberg was one member of a team of four who were nationally recognized for the development of the theory and methods for calculating molecular spectra and the design of CASE expert systems.

Today, Professor Elyashberg is a co-author of over 100 scientific papers and several reference books. Most recently, he has shared Computer-Assisted Structure Elucidation (CASE): Current and future perspectives in Magnetic Resonance in Chemistry and ACD/Structure Elucidator: 20 Years in the History of Development in a special issue of the journal Molecules in honor of his 85th birthday.

The Future of CASE

CASE systems like Structure Elucidator are incrementally updated to implement methods to better handle challenges such as ambiguities in available data, non-standard correlations, and molecular symmetry. As we have seen from its past, CASE will evolve and grow more powerful alongside advances in NMR experimentation, computational chemistry, and computer science.  These advances along with the development of non-spectroscopic methods of structure elucidation and the incorporation of deep learning show great potential for the future of the already powerful method that is CASE.

There is no doubt that the future of CASE is bright. Experts including Professor Elyashberg anticipate that in the near future, CASE will be widely used by NMR spectroscopists and analysts in academic and industrial laboratories and that the “golden age” of CASE is yet to come.

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