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Enantioselective synthesis of ammonium cations


Control of molecular chirality is a fundamental challenge in organic synthesis. Whereas methods to construct carbon stereocentres enantioselectively are well established, routes to synthesize enriched heteroatomic stereocentres have garnered less attention1,2,3,4,5. Of those atoms commonly present in organic molecules, nitrogen is the most difficult to control stereochemically. Although a limited number of resolution processes have been demonstrated6,7,8, no general methodology exists to enantioselectively prepare a nitrogen stereocentre. Here we show that control of the chirality of ammonium cations is easily achieved through a supramolecular recognition process. By combining enantioselective ammonium recognition mediated by 1,1′-bi-2-naphthol scaffolds with conditions that allow the nitrogen stereocentre to racemize, chiral ammonium cations can be produced in excellent yields and selectivities. Mechanistic investigations demonstrate that, through a combination of solution and solid-phase recognition, a thermodynamically driven adductive crystallization process is responsible for the observed selectivity. Distinct from processes based on dynamic and kinetic resolution, which are under kinetic control, this allows for increased selectivity over time by a self-corrective process. The importance of nitrogen stereocentres can be revealed through a stereoselective supramolecular recognition, which is not possible with naturally occurring pseudoenantiomeric Cinchona alkaloids. With practical access to the enantiomeric forms of ammonium cations, this previously ignored stereocentre is now available to be explored.

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Fig. 1: Nitrogen stereocentres.
Fig. 2: General enantioselective ammonium recognition.
Fig. 3: Dynamic behaviour of ammonium cations.
Fig. 4: Enantioselective synthesis of ammonium cations.

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Data Availability

Full crystallographic details in CIF format have been deposited in the Cambridge Crystallographic Data Centre database (deposition numbers: CCDC-1987042–1987058; 1987061–1987068; 1987165–1987180; 2047299–2047303). All other data are available from the corresponding author upon request.


  1. Knouse, K. W. et al. Unlocking P(V): reagents for chiral phosphorothioate synthesis. Science 361, 1234–1238 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hayakawa, Y., Hyodo, M., Kimura, K. & Kataoka, M. The first asymmetric synthesis of trialkyl phosphates on the basis of dynamic kinetic resolution in the phosphite method using a chiral source in a catalytic manner. Chem. Commun. 1704–1705 (2003).

  3. Bergin, E. et al. Synthesis of P-stereogenic phosphorus compounds. Asymmetric oxidation of phosphines under Appel conditions. J. Am. Chem. Soc. 129, 9566–9567 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Pitchen, P., Duñach, E., Deshmukh, M. N. & Kagan, H. B. An efficient asymmetric oxidation of sulfides to sulfoxides. J. Am. Chem. Soc. 106, 8188–8193 (1984).

    Article  CAS  Google Scholar 

  5. Liu, G., Cogan, D. A. & Ellman, J. A. Catalytic asymmetric synthesis of tert-butanesulfinamide. Application to the asymmetric synthesis of amines. J. Am. Chem. Soc. 119, 9913–9914 (1997).

    Article  CAS  Google Scholar 

  6. Wedekind, E. Zur charaktersitik stereoisomerer Ammoniumsaize. J. Chem. Soc. 32, 3561–3569 (1899).

    CAS  Google Scholar 

  7. Wedekind, E. & Wedekind, O. Über die Aktivierung einer cyclischen asymmetrischen Ammoniumbase. Chem. Ber. 40, 4450–4456 (1907).

    Article  Google Scholar 

  8. Fröhlich, E. & Wedekind, E. Über asymmetrische ammoniumsaize des p-anisidins. Chem. Ber. 40, 1009–1013 (1907).

    Article  Google Scholar 

  9. Lehn, J.-M. Nitrogen inversion. Fortschr. Chem. Forsch. 15, 311–377 (1970).

    Article  CAS  Google Scholar 

  10. Dolling, U.-H., Davis, P. & Grabowski, E. J. J. Efficient catalytic asymmetric alkylations. 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis. J. Am. Chem. Soc. 106, 446–447 (1984).

    Article  CAS  Google Scholar 

  11. Brown, D. R., Lygo, R., McKenna, J., McKenna, J. M. & Hutley, B. G. The preferred steric course of quaternisation of 1-alkylpiperidines. J. Chem. Soc.1967 1184–1194 (1967).

    Google Scholar 

  12. Brois, S. J. Aziridines. XI. Nitrogen inversion in N-haloaziridines. J. Am. Chem. Soc. 90, 506–508 (1968).

    Article  CAS  Google Scholar 

  13. Montanari, F., Moretti, I. & Torre, G. Asymmetric introduction at trivalent nitrogen. Optically active 2-methyl-3,3-diphenyloxaziridine, a compound with molecular asymmetry due solely to the nitrogen atom. Chem. Commun. 1968, 1694–1695 (1968).

    Google Scholar 

  14. Mannschreck, A. & Seitz, W. Separation of invertomers (diastereoisomers) of diaziridines. Slow inversion at tervalent nitrogen atoms. Angew. Chem. Int. Edn Engl. 8, 212–213 (1969).

    Article  CAS  Google Scholar 

  15. Prelog, V. & Wieland, P. Über die Spaltung der Tröger’schen Base in optische Antipoden, ein Beitrag zur Stereochemie des dreiwertigen Stickstoffs. Helv. Chim. Acta 27, 1127–1134 (1944).

    Article  CAS  Google Scholar 

  16. Wilen, S. H., Qi, J. Z. & Williard, P. G. Resolution, asymmetric transformation, and configuration of Troeger’s base. Application of Troeger’s base as a chiral solvating agent. J. Org. Chem. 56, 485–487 (1991).

    Article  CAS  Google Scholar 

  17. Pope, W. J. & Peachey, S. J. Asymmetric optically active nitrogen compounds. Dextro- and laevo-benzylphenylallylmethylammonium iodides and bromides. J. Chem. Soc. 75, 1127–1131 (1899).

    Article  CAS  Google Scholar 

  18. Havinga, E. Spontaneous formation of optically active substances. Biochim. Biophys. Acta 13, 171–174 (1954).

    Article  CAS  PubMed  Google Scholar 

  19. Kostyanovsky, R. G., Lyssenko, K. A., Krutiusa, O. N. & Kostyanovsky, V. R. Isomorphism of chiral ammonium salts Ph(All)N+Et(Me)X·CHCl3. Mendeleev Commun. 19, 19–20 (2009).

    Article  CAS  Google Scholar 

  20. Torbeev, V. Y., Lyssenko, K. A., Kharybin, O. N., Antipin, M. Y. & Kostyanovsky, R. G. Lamellar racemic twinning as an obstacle for the resolution of enantiomers by crystallization: the case of Me(All)N+(CH2Ph)Ph X- (X = Br, I) salts. J. Phys. Chem. B 107, 13523–13531 (2003).

    Article  CAS  Google Scholar 

  21. Tanaka, K., Okada, T. & Toda, F. Separation of enantiomers of 2,2′-dihydroxy-1, 1′-binaphthyl and 10,10′-dihydroxy-9,9′-biphenanthryl by complexation with n-alkylcinchonidinium halides. Angew. Chem. Int. Edn Engl. 32, 1147–1148 (1993).

    Article  Google Scholar 

  22. Toda, F., Tanaka, K., Stein, Z. & Goldberg, I. Optical resolution of binaphthyl and biphenanthryl diols by inclusion crystallization with N-alkylcinchonidium halides. Structural characterization of the resolved materials. J. Org. Chem. 59, 5748–5751 (1994).

    Article  CAS  Google Scholar 

  23. Du, H. et al. A new method for optical resolution of BINOL by molecular complexation with (S)-5-oxopyrrolidine-2-carboxanilide. Tetrahedr. Lett. 43, 5273–5276 (2002).

    Article  CAS  Google Scholar 

  24. Deng, J. et al. Resolution of omeprazole by inclusion complexation with a chiral host BINOL. Tetrahedron Asymmetry 11, 1729–1732 (2000).

    Article  CAS  Google Scholar 

  25. Schanz, H. J., Linseis, M. A. & Gilheany, D. G. Improved resolution methods for (R,R)- and (S,S)-cyclohexane-1,2-diamine and (R)- and (S)-BINOL. Tetrahedron Asymmetry 14, 2763–2769 (2003).

    Article  CAS  Google Scholar 

  26. Roy, B. N. et al. A novel method for large-scale synthesis of lamivudine through cocrystal formation of racemic lamivudine with (S)-(−)-1,1′-Bi(2-naphthol) [(S)-(BINOL)]. Org. Process Res. Dev. 13, 450–455 (2009).

    Article  CAS  Google Scholar 

  27. Ratajczak-Sitarz, M., Katrusiak, A., Gawrońska, K. & Gawroński, J. Racemate resolution via diastereomeric helicates in hydrogen-bonded co-crystals: the case of BINOL-diamine complexes. Tetrahedron Asymmetry 18, 765–773 (2007).

    Article  CAS  Google Scholar 

  28. Jin, S., Dong, Q., Wang, D. & Zhou, W. Six hydrogen bond directed supramolecular adducts formed between racemic-bis-β-naphthol and N-containing aromatic bases. J. Mol. Struct. 1013, 143–155 (2012).

    Article  ADS  CAS  Google Scholar 

  29. Tayama, E. & Tanaka, H. An efficient optical resolution of nitrogen-centered chiral beta-hydroxy-tetraalkylammonium salts via complexation with (R)-BINOL. Tetrahedr. Lett. 48, 4183–4185 (2007).

    Article  CAS  Google Scholar 

  30. Tayama, E., Otoyama, S. & Tanaka, H. Resolution of nitrogen-centered chiral tetraalkylammonium salts: application to [1,2] Stevens rearrangements with N-to-C chirality transmission. Tetrahedron Asymmetry 20, 2600–2608 (2009).

    Article  CAS  Google Scholar 

  31. Shirakawa, S. et al. Tetraalkylammonium salts as hydrogen-bonding catalysts. Angew. Chem. Int. Ed. 54, 15767–15770 (2015).

    Article  CAS  Google Scholar 

  32. Pike, S. J., Lavagnini, E., Varley, L. M., Cook, J. L. & Hunter, C. A. H-bond donor parameters for cations. Chem. Sci. 10, 5943–5951 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hunter, C. A. Quantifying intermolecular interactions: guidelines for the molecular recognition toolbox. Angew. Chem. Int. Ed. 43, 5310–5324 (2004).

    Article  CAS  Google Scholar 

  34. Taylor, R. & Kennard, O. Crystallographic evidence for the existence of C—H···O, C—H···N, and C—H···Cl hydrogen bonds. J. Am. Chem. Soc. 104, 5063–5070 (1982).

    Article  CAS  Google Scholar 

  35. Lacour, J., Vial, L. & Herse, C. Efficient NMR enantiodifferentiation of chiral quats with BINPHAT anion. Org. Lett. 4, 1351–1354 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Lacour, J., Londez, A., Goujon-Ginglinger, C., Buss, V. & Bernardinelli, G. Configurational ordering of cationic chiral dyes using a novel C(2)-symmetric hexacoordinated phosphate anion. Org. Lett. 2, 4185–4188 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Michon, C., Gonçalves-Farbos, M.-H. & Lacour, J. NMR enantiodifferentiation of quaternary ammonium salts of Tröger base. Chirality 21, 809–817 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Steed, K. M. & Steed, J. W. Packing problems: high Z′ crystal structures and their relationship to cocrystals, inclusion compounds, and polymorphism. Chem. Rev. 115, 2895–2933 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Spackman, M. A. & Jayatilaka, D. Hirshfield surface analysis. CrystEngComm 11, 19–32 (2009).

    Article  CAS  Google Scholar 

  40. Gavezzotti, A. Are crystal structures predictable? Acc. Chem. Res. 27, 309–314 (1994).

    Article  CAS  Google Scholar 

  41. Gavezzotti, A. & Fillipini, G. Geometry of the intermolecular X–H···Y (X, Y = N, O) hydrogen bond and the calibration of empirical hydrogen-bond potentials. J. Phys. Chem. 98, 4831–4837 (1994).

    Article  CAS  Google Scholar 

  42. Mullin, J. W. in Ullman’s Encylopedia of Industrial Chemistry Vol. 10 (ed. Elvers, B.) 582–630 (Wiley-VCH, 2012).

  43. Kulchat, S. & Lehn, J.-M. Dynamic covalent chemistry of nucleophilic substitution component exchange of quaternary ammonium salts. Chem. Asian J. 10, 2484–2496 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Lee, I., Park, Y. K., Huh, C. & Lee, H. W. Nucleophilic substitution reaction of benzyl bromide with N,N‐dimethylaniline: significance of equilibrium cross‐interaction constant. J. Phys. Org. Chem. 7, 555–560 (1994).

    Article  CAS  Google Scholar 

  45. Bordwell, F. G. & Hughes, D. L. Rate-equilibrium relationships for reactions of families of carbanion nucleophiles with N-benzyl-N,N-dimethylanilinium cations and with alkyl chlorides, bromides, and iodides. J. Am. Chem. Soc. 108, 7300–7309 (1986).

    Article  CAS  Google Scholar 

  46. Abboud, J.-L. M., Notario, R., Bertran, J. & Sold, M. in Progress in Physical Organic Chemistry (ed. Taft, R. W.) (Wiley, 1993).

  47. Keith, J. M., Larrow, J. F. & Jacobsen, E. N. Practical considerations in kinetic resolution reactions. Adv. Synth. Catal. 343, 5–26 (2001).

    Article  CAS  Google Scholar 

  48. Brands, K. M. J. & Davies, A. J. Crystallization-induced diastereomer transformations. Chem. Rev. 106, 2711–2733 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Flack, H. D. On enantiomorph-polarity estimation. Acta Crystallogr. A 39, 876–881 (1983).

    Article  Google Scholar 

  50. Genov, G. R., Douthwaite, J. L., Lahdenperä, A. S. K., Gibson, D. C. & Phipps, R. J. Enantioselective remote C–H activation directed by a chiral cation. Science 367, 1246–1251 (2020).

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Wang, Y., Sun, J. & Ding, K. Practical method and novel mechanism for optical resolution of BINOL by molecular complexation with N-benzylcinchoninium chloride. Tetrahedron 56, 4447–4451 (2000).

    Article  CAS  Google Scholar 

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We acknowledge funding from The Royal Society to M.O.K in the form of a University Research Fellowship (UF150536) and equipment grant (RGS\R2\180467) award. Durham University is acknowledged for providing a doctoral studentship (M.P.W.). J.M.P acknowledges support from the Laidlaw Undergraduate Research and Leadership programme in the form of a scholarship. The Royal Society is also acknowledged for providing M.E.L. with funding for a summer studentship. We thank our colleagues at Durham University and beyond, as well as members of the Kitching group, for input and advice during the preparation of this manuscript.

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Authors and Affiliations



The project was conceived by M.O.K. and M.P.W. Experiments were devised by M.O.K. and M.P.W. M.P.W., J.M.P. and M.E.L. carried out starting material synthesis for the project. M.P.W. carried out experimental work to develop the enantioselective recognition, dynamic studies and enantioselective syntheses. X-ray crystallography was conducted by M.P.W. and D.S.Y. The manuscript was prepared by M.O.K. and M.P.W. with input from all authors.

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Correspondence to Matthew O. Kitching.

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The authors have filed a patent on this work (GB2017799.4).

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Extended data figures and tables

Extended Data Fig. 1 Recognition screening.

Addition of recognition species (0.5 equiv) to 60 mM solution (CDCl3) of (rac)-1b. Recognition was monitored by observing changes in chemical shift and increased multiplicities of 1H resonances of salt (rac)-1b.

Extended Data Fig. 2 Crystal structure of ternary complex 2b.

a, The asymmetric unit (P43). b, Viewed along the b axis. c, Viewed along the c axis.

Extended Data Fig. 3 BINOL–halide network.

The (R)-BINOL and bromide counterions of complex 2d are shown as a van der Waals surface (teal), displaying the chiral hydrogen-bond network that encapsulates the ammonium cation (S)-1d.

Extended Data Fig. 4 Control reactions.

a, Table of control reactions, demonstrating the requirement for correct balance of temperature, alkylating agent and concentration for optimal results. b, Analysis of both the solid and solution phases of the reaction mixture. Both phases show bias towards the (S) enantiomer of the quaternary ammonium cation.

Extended Data Fig. 5 Ammonium hexafluorophosphate salts.

a, X-ray crystal structures of enantioenriched hexafluorophosphate salts (S)-1t and (R)-1t. b, Evaluation of the stereochemical stability of (S)-1t and (R)-1t by exposing both enantiomers to conditions previously used to racemize ammonium halide salts, while also observing minimal changes to their optical activity after 24 h.

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Walsh, M.P., Phelps, J.M., Lennon, M.E. et al. Enantioselective synthesis of ammonium cations. Nature 597, 70–76 (2021).

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