Uploaded April 2023 | Updated September 2026, 2 weeks ago
How to determine the absolute stereochemistry at oxygen of a chiral secondary alcohol by NMR spectroscopy.
References:
Ikuko Ohtani, Takenori Kusumi, Yoel Kashman, and Hiroshi Kakisawa
Journal of the American Chemical Society 1991 113 (11), 4092-4096
DOI: 10.1021/ja00011a006
James A. Dale and Harry S. Mosher
Journal of the American Chemical Society 1973 95 (2), 512-519
DOI: 10.1021/ja00783a034
In asymmetric organic synthesis, frequently a stereocentre at oxygen will be synthesised and it is usually important that it is formed in high enantiomeric excess. It is also important to confirm that you have synthesised the correct absolute stereochemistry of the centre – as in the absolute chirality. Most commonly, these oxygen-based stereocentres are hydroxyl groups are as part of a secondary alcohol.
To determine enantiomeric excess (ee), any chiral derivitising agent can be used, but forming the Mosher ester is an easy option given the availability of the reagent itself in high ee. The idea is that if you have a molecule with a single or isolated hydroxyl-based stereocentre, the NMR spectrum of molecules with either configuration will be identical (or nearly identical). If you have a compound with a mixture of both configurations, you make, for example, an ester by condensation reaction with a carbonyl derivative, such as a carboxylic acid (using a coupling reagent like DCC) or acid chloride, that is known to of very high enantiopurity – as in essentially only one enantiomer – with a stereocentre as close as possible to the carbonyl itself, ideally in the alpha position. Following this procedure will synthesise two diastereomers that are distinct by NMR spectroscopy. The diastereomeric ratio (dr) can be found by determining the integrations for equivalent peaks in the NMR spectrum, from which an enantiomeric excess can be calculated for the parent alcohol. A really clear way of doing this is to use the 19F NMR spectrum instead, exploiting the -trifluromethyl (CF3) group on the Mosher ester. The signals corresponding to each diastereomer will be clean singlets and very likely to be well separated by ppm. Another common chiral derivitising agent is one of the enantiomers of menthol.
To determine the absolute stereochemistry of an unknown hydroxyl stereocentre, you need a compound which is already of high enantiomeric excess. This technique is good for structural determination of new natural products. First you split your sample of secondary alcohol and separately react a portion with each of the two enantiomerically pure Mosher acids (MTPA) using a coupling agent or via the acid chloride. This will generate two diastereomers of Mosher ester in separate flasks, and the 1H NMR spectrum should be obtained for both of them. These Mosher esters (MTPA derivatives) will have a major preferred conformation around the ester linkage. Pseudo-allylic strain (A1,3), as modelled by the Houk model, with mean the carbinol proton (C-H of the secondary alcohol stereocentre) will prefer to sit eclipsed to the carbonyl C=O bond. Furthermore, the trifluoromethyl group on the MTPA will prefer to sit antiperiplanar to the C-O “single” bond of the ester linkage due to a favourable molecular orbital interaction (hyperconjugation).
Next you look at all the chemical shift (delta) values in each diastereomer separately for the equivalent peaks in the structures, and it will be found that there are some reasonably significant differences, particularly close to the unknown sterocentre. For each corresponding signal you then compute the difference between the chemical shifts (delta delta) conventionally as those found in the (S)-MTPA derivative minus those found in the (R)-MTPA derivative. Due to the major conformers of these molecules, the two R groups on the esters will sit either close in space to the phenyl or the methoxy group of the Mosher ester-based stereocentre. Any protons in the 1H NMR spectrum that sit close to the phenyl group will be shielded by being placed inside the ring current of the aromatic system. Comparatively, any proton sitting near in space to the methoxy group will be slightly deshielded (towards a higher ppm). Hence, whether or not the delta delta value is positive or negative will tell you which R group a certain signal belongs too, and hence determine the absolute stereochemistry of the original chiral secondary alcohol. It is best practice to get as many delta delta values determined as possible to reinforce your conclusion for the alcohol’s configuration.
#chemistry #science #education
How to determine the absolute stereochemistry at oxygen of a chiral secondary alcohol by NMR spectroscopy.
References:
Ikuko Ohtani, Takenori Kusumi, Yoel Kashman, and Hiroshi Kakisawa
Journal of the American Chemical Society 1991 113 (11), 4092-4096
DOI: 10.1021/ja00011a006
James A. Dale and Harry S. Mosher
Journal of the American Chemical Society 1973 95 (2), 512-519
DOI: 10.1021/ja00783a034
In asymmetric organic synthesis, frequently a stereocentre at oxygen will be synthesised and it is usually important that it is formed in high enantiomeric excess. It is also important to confirm that you have synthesised the correct absolute stereochemistry of the centre – as in the absolute chirality. Most commonly, these oxygen-based stereocentres are hydroxyl groups are as part of a secondary alcohol.
To determine enantiomeric excess (ee), any chiral derivitising agent can be used, but forming the Mosher ester is an easy option given the availability of the reagent itself in high ee. The idea is that if you have a molecule with a single or isolated hydroxyl-based stereocentre, the NMR spectrum of molecules with either configuration will be identical (or nearly identical). If you have a compound with a mixture of both configurations, you make, for example, an ester by condensation reaction with a carbonyl derivative, such as a carboxylic acid (using a coupling reagent like DCC) or acid chloride, that is known to of very high enantiopurity – as in essentially only one enantiomer – with a stereocentre as close as possible to the carbonyl itself, ideally in the alpha position. Following this procedure will synthesise two diastereomers that are distinct by NMR spectroscopy. The diastereomeric ratio (dr) can be found by determining the integrations for equivalent peaks in the NMR spectrum, from which an enantiomeric excess can be calculated for the parent alcohol. A really clear way of doing this is to use the 19F NMR spectrum instead, exploiting the -trifluromethyl (CF3) group on the Mosher ester. The signals corresponding to each diastereomer will be clean singlets and very likely to be well separated by ppm. Another common chiral derivitising agent is one of the enantiomers of menthol.
To determine the absolute stereochemistry of an unknown hydroxyl stereocentre, you need a compound which is already of high enantiomeric excess. This technique is good for structural determination of new natural products. First you split your sample of secondary alcohol and separately react a portion with each of the two enantiomerically pure Mosher acids (MTPA) using a coupling agent or via the acid chloride. This will generate two diastereomers of Mosher ester in separate flasks, and the 1H NMR spectrum should be obtained for both of them. These Mosher esters (MTPA derivatives) will have a major preferred conformation around the ester linkage. Pseudo-allylic strain (A1,3), as modelled by the Houk model, with mean the carbinol proton (C-H of the secondary alcohol stereocentre) will prefer to sit eclipsed to the carbonyl C=O bond. Furthermore, the trifluoromethyl group on the MTPA will prefer to sit antiperiplanar to the C-O “single” bond of the ester linkage due to a favourable molecular orbital interaction (hyperconjugation).
Next you look at all the chemical shift (delta) values in each diastereomer separately for the equivalent peaks in the structures, and it will be found that there are some reasonably significant differences, particularly close to the unknown sterocentre. For each corresponding signal you then compute the difference between the chemical shifts (delta delta) conventionally as those found in the (S)-MTPA derivative minus those found in the (R)-MTPA derivative. Due to the major conformers of these molecules, the two R groups on the esters will sit either close in space to the phenyl or the methoxy group of the Mosher ester-based stereocentre. Any protons in the 1H NMR spectrum that sit close to the phenyl group will be shielded by being placed inside the ring current of the aromatic system. Comparatively, any proton sitting near in space to the methoxy group will be slightly deshielded (towards a higher ppm). Hence, whether or not the delta delta value is positive or negative will tell you which R group a certain signal belongs too, and hence determine the absolute stereochemistry of the original chiral secondary alcohol. It is best practice to get as many delta delta values determined as possible to reinforce your conclusion for the alcohol’s configuration.
#chemistry #science #education
