DOI: 10.1002/chem.201300062 New Chiral Zwitterionic Phosphorus Heterocycles: Synthesis, Structure, Properties and Application as Chiral Solvating Agents Andrey E. Sheshenev, [a] Ekaterina V. Boltukhina, [a] Anastasiya A. Grishina, [b] Ivana Cisar ˇova, [c] Ilya M. Lyapkalo, [b] and King Kuok (Mimi) Hii* [a] In memory of Ilya M. Lyapkalo Introduction Significant advances in asymmetric chemistry have expedit- ed demand for faster methods of analysis for enantiomeric mixtures. [1, 2] Although chiral chromatography (LC or GC) is the accepted industrial standard for quantifying enantiomer- ic purity, these methods typically require several minutes, if not hours, and the assignment of the absolute stereochemis- try can only be achieved by correlation with known com- pounds. In contrast, the use of a chiral derivatising agent (CDA) or chiral solvating agent (CSA) allows the enantio- meric ratio to be determined in a few minutes by NMR spectroscopy, [3] which is an available, automated and high- throughput technique available in modern laboratories. As an added advantage, the absolute stereochemistry of a par- ticular enantiomer can also be established by further NMR experiments. [4] CSAs form diastereomeric complexes with chiral analytes through weak intermolecular interactions, which lead to chemical-shift inequivalence in analogous nuclei. Because the technique is non-destructive, they are inherently more desirable than CDAs, which require the formation of a cova- lent bond. In general, there are two main types of interac- tions between a CSA and the analyte: 1) Host–guest interac- tions that involve the intercalation of the enantiomer within a supramolecular architecture, such as cyclodextrins, crown ethers, or peptides; and/or 2) Donor–acceptor interactions, mostly through H bonding with certain functional groups, for example, amines, alcohols, acids and sulfoxides. To date, there has only been one report of zwitterionic CSAs, comprising of a chiral imidazolinium moiety with a sulfonate or sulfamate counteranion (Figure 1). [5] These mol- ecules could provide multiple points of ionic contact for greater chiral recognition. However, because the charges are well separated, this can limit their solubility in organic sol- vents, for example, the best-performing compound III (R 1 = Ph, R 2 = 2-MeC 6 H 4 ) is not soluble in toluene. Keywords: binding constants · chir- ality · enantioselectivity · NMR spectroscopy · phosphorus hetero- cycles · zwitterions Abstract: A family of new chiral zwitterionic phosphorus-containing heterocycles (zPHC) have been derived from methylene-bridged bis(imidazolines). These struc- tures were unambiguously determined, including single-crystal XRD analysis for two compounds. The stability, acid/base and electronic properties of these dipolar phosphorus heterocycles were subsequently investigated. zPHCs can be successful- ly employed as a new class of chiral solvating agents for the enantiodifferentiation of chiral carboxylic and sulfonic acids by NMR spectroscopy. The stoichiometry and binding constants for the donor–acceptor complexes formed were established by NMR titration methods. [a] Dr. A. E. Sheshenev, Dr. E. V. Boltukhina, Dr. K. K. Hii Department of Chemistry, Imperial College London Exhibition Road, SW7 2AZ London (UK) Fax: (+ 44) 2075945804 E-mail : mimi.hii@imperial.ac.uk [b] A. A. Grishina, Dr. I. M. Lyapkalo Institute of Organic Chemistry and Biochemistry AS CR, v.v.i. Flemingovo nam. 2, 166 10 Prague 6 (Czech Republic) [c] Dr. I. Cisar ˇova Department of Inorganic Chemistry, Charles University Hlavova 2030, 12840 Prague 2 (Czech Republic) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201300062. It includes data for new compounds, experimental procedures, crystallographic details, copies of 1 H and 13 C NMR spectra. X-ray crystallographic structures are provided as .cif files, as well as the checkpoint file for the calculat- ed structure of compound 4a. Figure 1. Chiral zwitterionic imidazolinium sulfonates/sulfamates. Chem. Eur. J. 2013, 00,0–0 # 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! ÞÞ &1& FULL PAPER