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Sept. 7, 2008, ACD/Labs NMR Software Symposium (SMASH) 2008, Santa Fe, NM, USA
Generation and Verification of Structural Hypotheses: A Systematic Approach
Mikhail Elyashberg
Abstract
The structure elucidation of new chemical compounds continues to be a major challenge, and an important problem in the domain of organic chemistry and molecular spectroscopy. The structure determination process, in general, is reduced to forming structural hypotheses and performing the subsequent verification.
Each hypothesis is the result of the comprehensive logical treatment of spectral and chemical information associated with the structure under analysis. Nowadays, the main source of spectral information is a combination of 1D and 2D NMR spectra. The information obtained from 2D NMR data can be complicated:
- Information is fuzzy by nature (2 or 3 bonds separate intervening H and C atoms in HMBC)
- Not all possible HMBC and COSY correlations are observed in spectra, i.e., the spectral information is often incomplete
- Presence of "Non Standard 2D NMR Correlations" (NSCs), i.e., nJCH,HH, n>3 frequently makes information contradictory
- Total number of NSCs and their lengths are unknown. Signal overlap leads to the appearance of ambiguous correlations. Hence information is otherwise indefinite
Therefore it is not surprising that during the interpretation of 2D NMR data several structural hypotheses are often produced, each of them fitting the experimental data and commonly other available information. Since most spectroscopists do not have the means to thoroughly examine all hypotheses, computer algorithms and software tools may be called upon to help. CASE programs can derive all logical consequences (structures) from the initial data to solve the task which the spectroscopist performs without computational assistance.
ACD/Structure Elucidator is developed in such a way that it is capable of deducing all logically admissible structural hypotheses from combined 1D and 2D NMR data, even in the case when the initial data are fuzzy, contradictory, incomplete, or indefinite. To circumvent difficulties ensuing from "bad" data properties, the program employs Fragment Mode and Fuzzy Structure Generation strategies.
In this presentation, we will briefly investigate these strategies and underline difficulties that have yet to be overcome. In addition, the impact of new fast and accurate empirical methods of NMR spectrum prediction on structure elucidation is discussed. To demonstrate the advantages of a systematic approach to structure elucidation, we will consider a series of examples taken from literature where a GIAO option of DFT approximation was used for the identification of unknowns versus ones suggested by chemists.
A general approach is suggested where the most probable structure is established as a result of the joint application of a CASE expert system in combination with both empirical and quantum-mechanical methods for chemical shift prediction.
Download the presentation (376 Kb PDF file)
Relevant Products: ACD/Structure Elucidator
Relevant Solution: NMR Laboratory
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