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Spectral Interpretation. General Process for Structure Elucidation of an Unknown. Nat. Prod. Rep. , 1999, 16, 241-248. Spectral Interpretation. General Process for Structure Elucidation of an Unknown. Normally the molecular formula is derived from a combination of 13 C NMR, DEPT and MS data.

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Spectral interpretation

Spectral Interpretation

General Process for Structure Elucidation of an Unknown

Nat. Prod. Rep., 1999, 16, 241-248


Spectral interpretation

Spectral Interpretation

General Process for Structure Elucidation of an Unknown

  • Normally the molecular formula is derived from a combination of 13C NMR, DEPT and MS data.

  • Using IR, UV and 13C NMR the functional groups can be proposed

  • 1H NMR coupling data or 2D NMR correlations are used to assemble substructures

  • The substructures are then combined into ‘working structures’ using all possible combinations of the substructures

  • Check structures for consistency with the 2D-NMR data and MS fragmentations etc.

  • 13C chemical shifts of the surviving structure(s) are then compared with literature, database or predicted values to confirm the 2D structure of the molecule.

  • To determine the relative stereochemistry of the molecule, 1H coupling constant (J) and Nuclear Overhauser (NOE) data is used

Need to Verify as early as possible if the structure has already been identified

  • Don’t want to waste time and effort re-discovering a compound

  • Done by using a combination of molecular formula, substructure and chemical structure databases

Nat. Prod. Rep., 1999, 16, 241-248


Spectral interpretation

NMR Spectroscopy

Possible Strategy using only C-C correlations

heteroatoms can be inferred from 13C chemical shifts

  • Requires high concentrations because of low sensitivity of 2D INADEQUATE

  • Because of 1JCC variability may need to collect multiple 2D INADEQUATE experiments

  • Requires longer time than other methods, still need HMBC or NOE to bridge heteroatoms

Nat. Prod. Rep., 1999, 16, 241-248


Spectral interpretation

NMR Spectroscopy

Possible Strategy using H-H and H-C correlations

  • COSY sees 2,3 & 4 bond correlation which leads to confusion

  • Impossible to distinguish between 3 and 3-bond correlations in HMBC

  • - Angular dependence of 3JHH and 3JCH means that some expected cross peaks will not appear in the COSY and HMBC spectra

  • Lower resolution in indirect 13C dimension

Nat. Prod. Rep., 1999, 16, 241-248


Spectral interpretation

NMR Spectroscopy

Typical Experiments and Connectivity Information used in Structure Elucidation


Spectral interpretation

NMR Spectroscopy

Summarizing the available NMR results is an important first step.

  • Also a source of problems if data is missing from the summary.

  • Don’t ignore the spectral data or rely completely on your peak lists or summary data

J. Nat. Prod. 2002, 65, 693-703


Spectral interpretation

NMR Spectroscopy

Need to Generate Molecular Connectivity Diagrams of the compound

  • effectively summarizes all the experimental NMR data

  • numerous possible connectivities, increases with the complexity of the compound

Magn. Reson. Chem. 2003; 41: 359–372


Spectral interpretation

NMR Spectroscopy

Proposed Structure Needs to Be Consistent with ALL the observed data

  • a single unaccounted for peak, or a missing peak predicted by the structure may indicate a wrong structure.

  • especially if some components of the structure rely on a single observation or correlation

Magn. Reson. Chem. 2001; 39: 762–764


Spectral interpretation

NMR Spectroscopy

Proposed Structure Needs to Be Consistent with ALL the observed data

  • missing peak predicted by the structure may indicate a wrong structure.

Corrected Structure

Original Structure

Assignment change resolved missing NOE problem

Org. Lett., Vol. 6, No. 23, 2004


Spectral interpretation

NMR Spectroscopy

Validate or Verify Accuracy of Structure by Consistency with Databases

  • is the structure and experimental chemical shift assignments consistent with predicted chemicals shifts based on the experimental structures

Correct Structure

J. Chem. Inf. Comput. Sci. 2002, 42, 241-248


Spectral interpretation

NMR Spectroscopy

Validate or Verify Accuracy of Structure by Consistency with Databases

  • is the structure and experimental chemical shift assignments consistent with predicted chemicals shifts based on the experimental structures

Correct Structure


Spectral interpretation

NMR Spectroscopy

Numerous Examples of Incorrect Structures in the Literature

Example:

Verified by total synthesis

Incorrect

Correct

key HMBC correlations

Angew. Chem. Int. Ed. 2005, 44, 1012 – 1044


Spectral interpretation

NMR Spectroscopy

Numerous Examples of Incorrect Structures in the Literature

  • coupling correlation not always sufficient to properly determine a structure

  • NOEs can provide critical correlations that are not evident simply from coupling

key NOE correlations

J. Nat. Prod. 2004, 67, 1996-2001