A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent
The bis-thiourea chiral solvating agent (CSA) <b>BTDA</b> enables the NMR-based determination of absolute configuration in <i>N</i>-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and a...
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2025-07-01
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| author | Virginia Rondinini Federica Aiello Federica Cefalì Alessandra Recchimurzo Gloria Uccello Barretta Federica Balzano |
| author_facet | Virginia Rondinini Federica Aiello Federica Cefalì Alessandra Recchimurzo Gloria Uccello Barretta Federica Balzano |
| author_sort | Virginia Rondinini |
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| description | The bis-thiourea chiral solvating agent (CSA) <b>BTDA</b> enables the NMR-based determination of absolute configuration in <i>N</i>-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both <sup>1</sup>H and <sup>13</sup>C NMR spectra. A dual-enantiomer approach, using (<i>R</i>,<i>R</i>)- and (<i>S</i>,<i>S</i>)-<b>BTDA</b>, generates diastereomeric complexes with the enantiopure substrate, and distinct spatial arrangements are reflected in consistent and interpretable Δδ values. The observed chemical shift differences correlate reliably with the stereochemistry of the chiral center and are further supported by ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) experiments and binding constants’ measurements, confirming the formation of stereoselective non-covalent complexes. This methodology extends the logic of Mosher’s analysis to solvating agents and remains effective even in samples containing single pure enantiomers of the amino acid derivative. The <b>BTDA</b>-based dual-CSA system thus represents a robust, non-derivatizing strategy for stereochemical assignment by NMR, combining operational simplicity with broad applicability to DNB derivatives of amino acids with free carboxyl function. |
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| spelling | doaj-art-38203be4a8a54a5a90da2a2d7a11a57a2025-07-25T13:31:46ZengMDPI AGMolecules1420-30492025-07-013014293010.3390/molecules30142930A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating AgentVirginia Rondinini0Federica Aiello1Federica Cefalì2Alessandra Recchimurzo3Gloria Uccello Barretta4Federica Balzano5Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, ItalyNational Research Council-Institute for Chemical and Physical Processes (CNR-IPCF), Via G. Moruzzi 1, 56124 Pisa, ItalyDepartment of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, ItalyDepartment of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, ItalyDepartment of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, ItalyDepartment of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, ItalyThe bis-thiourea chiral solvating agent (CSA) <b>BTDA</b> enables the NMR-based determination of absolute configuration in <i>N</i>-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both <sup>1</sup>H and <sup>13</sup>C NMR spectra. A dual-enantiomer approach, using (<i>R</i>,<i>R</i>)- and (<i>S</i>,<i>S</i>)-<b>BTDA</b>, generates diastereomeric complexes with the enantiopure substrate, and distinct spatial arrangements are reflected in consistent and interpretable Δδ values. The observed chemical shift differences correlate reliably with the stereochemistry of the chiral center and are further supported by ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) experiments and binding constants’ measurements, confirming the formation of stereoselective non-covalent complexes. This methodology extends the logic of Mosher’s analysis to solvating agents and remains effective even in samples containing single pure enantiomers of the amino acid derivative. The <b>BTDA</b>-based dual-CSA system thus represents a robust, non-derivatizing strategy for stereochemical assignment by NMR, combining operational simplicity with broad applicability to DNB derivatives of amino acids with free carboxyl function.https://www.mdpi.com/1420-3049/30/14/2930CSANMRabsolute configurationchiral analysisROESYassociation constant |
| spellingShingle | Virginia Rondinini Federica Aiello Federica Cefalì Alessandra Recchimurzo Gloria Uccello Barretta Federica Balzano A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent Molecules CSA NMR absolute configuration chiral analysis ROESY association constant |
| title | A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent |
| title_full | A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent |
| title_fullStr | A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent |
| title_full_unstemmed | A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent |
| title_short | A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent |
| title_sort | supramolecular extension of mosher s method absolute configuration assignment of i n i amino acid derivatives via bis thiourea chiral solvating agent |
| topic | CSA NMR absolute configuration chiral analysis ROESY association constant |
| url | https://www.mdpi.com/1420-3049/30/14/2930 |
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