Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere

Abstract

Secondary-sphere interactions serve a fundamental role in controlling the reactivity and selectivity of organometallic and enzymatic catalysts. However, there is a dearth of studies that explicitly incorporate secondary-sphere modifiers into organocatalytic systems. In this work, we introduce an approach for the in situ systematic modification of organocatalysts in their secondary sphere through dynamic covalent binding under the reaction conditions. As a proof-of-concept, we applied boronic acids as secondary-sphere modifiers of N-heterocyclic carbenes that contained a hydroxy handle. The bound system formed in the reaction mixture catalysed the enantioselective benzoin condensations of a challenging substrate class that contains electron-withdrawing groups. Linear regression coupled with data visualization served to pinpoint the divergent origins of enantioselectivity for different substrates and decision tree algorithms served to formulate selection criteria for the appropriate secondary-sphere modifiers. The combination of this highly modular catalytic approach with machine-learning techniques provided mechanistic insights and guided the streamlined optimization process of a gram-scale reaction at low organocatalyst loading.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The influence of secondary-sphere modulation of NHCs on the benzoin reaction.
Fig. 2: Multivariate model of the enantioselectivity for 6 hour reactions across a set of electron-withdrawing aldehydes.
Fig. 3: Disentangling the effect of racemization.
Fig. 4: Binding studies of BA to NHC in THF.
Fig. 5: Cross-over experiments between the benzoin product and an additional aldehyde.

Similar content being viewed by others

Data availability

All data generated or analysed during this study are available in this published article and its Supplementary Information files, or from the corresponding author upon request. Experimental procedures, results, characterization data, spreadsheets of parameters used in the models and MATLAB scripts used for model identification are accessible online as Supplementary Information.

References

  1. Warren, J. J., Lancaster, K. M., Richards, J. H. & Gray, H. B. Inner- and outer-sphere metal coordination in blue copper proteins. J. Inorg. Biochem. 115, 119–126 (2012).

    Article  CAS  Google Scholar 

  2. Werner, A. Zur kenntnis des asymmetrischen kobaltatoms. Ber. Dtschn Chem. Ges. 45, 121–130 (1912).

    Article  CAS  Google Scholar 

  3. Werner, A. Über die raumisomeren kobaltverbindungen. Justus Liebig’s Ann. Chem. 386, 1–272 (1912).

    Article  CAS  Google Scholar 

  4. Cook, S. A. & Borovik, A. S. Molecular designs for controlling the local environments around metal ions. Acc. Chem. Res. 48, 2407–2414 (2015).

    Article  CAS  Google Scholar 

  5. Reedijk, J. Coordination chemistry beyond Werner: interplay between hydrogen bonding and coordination. Chem. Soc. Rev. 42, 1776–1783 (2013).

    Article  CAS  Google Scholar 

  6. Shook, R. L. & Borovik, A. S. Role of the secondary coordination sphere in metal-mediated dioxygen activation. Inorg. Chem. 49, 3646–3660 (2010).

    Article  CAS  Google Scholar 

  7. Baschieri, A., Bernardi, L., Ricci, A., Suresh, S. & Adamo, M. F. Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro-5-styrylisoxazoles. Angew. Chem. Int. Ed. 48, 9342–9345 (2009).

    Article  CAS  Google Scholar 

  8. Kawai, H., Kusuda, A., Nakamura, S., Shiro, M. & Shibata, N. Catalytic enantioselective trifluoromethylation of azomethine imines with trimethyl(trifluoromethyl)silane. Angew. Chem. Int. Ed. 48, 6324–6327 (2009).

    Article  CAS  Google Scholar 

  9. Nicolaou, K. C., Liu, G., Beabout, K., McCurry, M. D. & Shamoo, Y. Asymmetric alkylation of anthrones, enantioselective total synthesis of (−)- and (+)-viridicatumtoxins B and analogues thereof: absolute configuration and potent antibacterial agents. J. Am. Chem. Soc. 139, 3736–3746 (2017).

    Article  CAS  Google Scholar 

  10. Sahu, S. et al. Secondary coordination sphere influence on the reactivity of nonheme iron(ii) complexes: an experimental and DFT approach. J. Am. Chem. Soc. 135, 10590–10593 (2013).

    Article  CAS  Google Scholar 

  11. Ward, T. R. et al. Exploiting the second coordination sphere: proteins as host for enantioselective catalysis. Chimia 57, 586–588 (2003).

    Article  CAS  Google Scholar 

  12. Uraguchi, D., Ueki, Y. & Ooi, T. Chiral organic ion pair catalysts assembled through a hydrogen-bonding network. Science 326, 120–123 (2009).

    Article  CAS  Google Scholar 

  13. Meeuwissen, J. & Reek, J. N. H. Supramolecular catalysis beyond enzyme mimics. Nat. Chem. 2, 615–621 (2010).

    Article  CAS  Google Scholar 

  14. Leenders, S. H. A. M., Gramage-Doria, R., de Bruin, B. & Reek, J. N. H. Transition metal catalysis in confined spaces. Chem. Soc. Rev. 44, 433–448 (2014).

    Article  Google Scholar 

  15. Rowan, S. J., Cantrill, S. J. & Cousins, G. R. L. Dynamic covalent chemistry. Angew. Chem. Int. Ed. 41, 898–952 (2002).

    Article  Google Scholar 

  16. Bapat, A. P., Roy, D., Ray, J. G., Savin, D. A. & Sumerlin, B. S. Dynamic-covalent macromolecular stars with boronic ester linkages. J. Am. Chem. Soc. 133, 19832–19838 (2011).

    Article  CAS  Google Scholar 

  17. Bull, S. D. et al. Exploiting the reversible covalent bonding of boronic acids: recognition, sensing, and assembly. Acc. Chem. Res. 46, 312–326 (2013).

    Article  CAS  Google Scholar 

  18. Wilson, A., Gasparini, G. & Matile, S. Functional systems with orthogonal dynamic covalent bonds. Chem. Soc. Rev. 43, 1948–1962 (2014).

    Article  CAS  Google Scholar 

  19. Schaufelberger, F. & Ramström, O. Dynamic covalent organocatalysts discovered from catalytic systems through rapid deconvolution screening. Chem. Eur. J. 21, 12735–12740 (2015).

    Article  CAS  Google Scholar 

  20. Lascano, S. et al. The third orthogonal dynamic covalent bond. Chem. Sci. 7, 4720–4724 (2016).

    Article  CAS  Google Scholar 

  21. Seifert, H. M., Ramirez Trejo, K. & Anslyn, E. V. Four simultaneously dynamic covalent reactions. Experimental proof of orthogonality. J. Am. Chem. Soc 138, 10916–10924 (2016).

    Article  CAS  Google Scholar 

  22. Zhou, Y., Li, L., Ye, H., Zhang, L. & You, L. Quantitative reactivity scales for dynamic covalent and systems chemistry. J. Am. Chem. Soc. 138, 381–389 (2016).

    Article  CAS  Google Scholar 

  23. Akgun, B. & Hall, D. G. Fast and tight boronate formation for click bioorthogonal conjugation. Angew. Chem. Int. Ed. 55, 3909–3913 (2016).

    Article  CAS  Google Scholar 

  24. Moulin, E., Cormos, G. & Giuseppone, N. Dynamic combinatorial chemistry as a tool for the design of functional materials and devices. Chem. Soc. Rev. 41, 1031–1049 (2012).

    Article  CAS  Google Scholar 

  25. Teichert, J. F., Mazunin, D. & Bode, J. W. Chemical sensing of polyols with shapeshifting boronic acids as a self-contained sensor array. J. Am. Chem. Soc. 135, 11314–11321 (2013).

    Article  CAS  Google Scholar 

  26. Wong, C.-H. & Zimmerman, S. C. Orthogonality in organic, polymer, and supramolecular chemistry: from Merrifield to click chemistry. Chem. Commun. 49, 1679–1695 (2013).

    Article  CAS  Google Scholar 

  27. Wiskur, S. L. & Anslyn, E. V. Using a synthetic receptor to create an optical-sensing ensemble for a class of analytes: a colorimetric assay for the aging of scotch. J. Am. Chem. Soc. 123, 10109–10110 (2001).

    Article  CAS  Google Scholar 

  28. Baragwanath, L., Rose, C. A., Zeitler, K. & Connon, S. J. Highly enantioselective benzoin condensation reactions involving a bifunctional protic pentafluorophenyl-substituted triazolium precatalyst. J. Org. Chem. 74, 9214–9217 (2009).

    Article  CAS  Google Scholar 

  29. O’Toole, S. E. & Connon, S. J. The enantioselective benzoin condensation promoted by chiral triazolium precatalysts: stereochemical control via hydrogen bonding. Org. Biomol. Chem. 7, 3584–3593 (2009).

    Article  Google Scholar 

  30. Langdon, S. M., Legault, C. Y. & Gravel, M. Origin of chemoselectivity in N-heterocyclic carbene catalyzed cross-benzoin reactions: DFT and experimental insights. J. Org. Chem. 80, 3597–3610 (2015).

    Article  CAS  Google Scholar 

  31. Maji, R. & Wheeler, S. E. in Aromatic interactions: Frontiers in Knowledge and Application (eds Darren W Johnson, D. W. & Hof, F.) 18–38 (The Royal Society of Chemistry, Cambridge, 2017).

  32. Paul, M., Breugst, M., Neudorfl, J. M., Sunoj, R. B. & Berkessel, A. Keto-enol thermodynamics of Breslow intermediates. J. Am. Chem. Soc. 138, 5044–5051 (2016).

    Article  CAS  Google Scholar 

  33. Flanigan, D. M., Romanov-Michailidis, F., White, N. A. & Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem. Rev. 115, 9307–9387 (2015).

    Article  CAS  Google Scholar 

  34. Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91, 165–195 (1991).

    Article  CAS  Google Scholar 

  35. Verloop, A., Hoogenstraaten, W. & Tipker, J. in Drug Design Vol 7 (ed. Ariens, E. J.) 165–207 (Academic, 1976).

  36. Milo, A., Bess, E. N. & Sigman, M. S. Interrogating selectivity in catalysis using molecular vibrations. Nature 507, 210–214 (2014).

    Article  CAS  Google Scholar 

  37. Glendening, E. D., Landis, C. R. & Weinhold, F. Natural bond orbital methods. WIREs Comput. Mol. Sci. 2, 1–42 (2011).

    Article  Google Scholar 

  38. Maji, R. & Wheeler, S. E. Importance of electrostatic effects in the stereoselectivity of NHC-catalyzed kinetic resolutions. J. Am. Chem. Soc. 139, 12441–12449 (2017).

    Article  CAS  Google Scholar 

  39. Massey, R. S., Collett, C. J., Lindsay, A. G., Smith, A. D. & O’Donoghue, A. C. Proton transfer reactions of triazol-3-ylidenes: kinetic acidities and carbon acid pKa values for twenty triazolium salts in aqueous solution. J. Am. Chem. Soc. 134, 20421–20432 (2012).

    Article  CAS  Google Scholar 

  40. Niu, Y. et al. Experimental and computational gas phase acidities of conjugate acids of triazolylidene carbenes: rationalizing subtle electronic effects. J. Am. Chem. Soc. 139, 14917–14930 (2017).

    Article  CAS  Google Scholar 

  41. Companyó, X. & Burés, J. Distribution of catalytic species as an indicator to overcome reproducibility problems. J. Am. Chem. Soc. 139, 8432–8435 (2017).

    Article  Google Scholar 

  42. Enders, D. & Henseler, A. A direct intermolecular cross-benzoin type reaction: N-heterocyclic carbene-catalyzed coupling of aromatic aldehydes with trifluoromethyl ketones. Adv. Synth. Catal. 351, 1749–1752 (2009).

    Article  CAS  Google Scholar 

  43. Enders, D. N-heterocyclic carbene catalysed asymmetric cross-benzoin reactions of heteroaromatic aldehydes with trifluoromethyl ketones. Chem. Commun. 46, 6282–6284 (2010).

    Article  CAS  Google Scholar 

  44. Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 107, 5606–5655 (2007).

    Article  CAS  Google Scholar 

  45. Renny, J. S., Tomasevich, L. L., Tallmadge, E. H. & Collum, D. B. Method of continuous variations: applications of Job plots to the study of molecular associations in organometallic chemistry. Angew. Chem. Int. Ed. 52, 11998–12013 (2013).

    Article  CAS  Google Scholar 

  46. Thordarson, P. Determining association constants from titration experiments in supramolecular chemistry. Chem. Soc. Rev. 40, 1305–1323 (2011).

    Article  CAS  Google Scholar 

  47. Neel, A. J., Milo, A., Sigman, M. S. & Toste, F. D. Enantiodivergent fluorination of allylic alcohols: data set design reveals structural interplay between achiral directing group and chiral anion. J. Am. Chem. Soc. 138, 3863–3875 (2016).

    Article  CAS  Google Scholar 

  48. Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials 1–133 (Wiley, Weinheim, 2011).

  49. Martínez-Aguirre, M. A. & Yatsimirsky, A. K. Brønsted versus Lewis acid type anion recognition by arylboronic acids. J. Org. Chem. 80, 4985–4993 (2015).

    Article  Google Scholar 

  50. Collett, C. J. et al. Rate and equilibrium constants for the addition of N-heterocyclic carbenes into benzaldehydes: a remarkable 2-substituent effect. Angew. Chem. Int. Ed. 127, 6991–6996 (2015).

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the Israel Science Foundation (Grant no. 1193/17). We thank M. Sigman, D. Toste, A. Neel and D. Pappo for fruitful discussions. D.V. acknowledges the PBC for a postdoctoral fellowship. S.C.G. acknowledges the Kreitman Graduate School for a postdoctoral fellowship. Z.A. acknowledges the Kreitman Graduate School for the chemo-tech scholarship. Mass spectra measurements were performed with the help of M. Shema-Mizrachi and M. M. Karpasas.

Author information

Authors and Affiliations

Authors

Contributions

All the authors designed and performed the experiments and analysed the data. The Supplementary Information was compiled by S.C.G. and D.V., the product distribution by HPLC was performed by Z.A. and mathematical modelling was performed by A.M.

Corresponding author

Correspondence to Anat Milo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information

Supplementary experimental details and compound characterization data.

Supplementary data

Excel spreadsheet listing parameters used in combination with MATLAB scripts for model development.

MATLAB scripts

A compressed directory of all the scripts used for model development.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dhayalan, V., Gadekar, S.C., Alassad, Z. et al. Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere. Nat. Chem. 11, 543–551 (2019). https://doi.org/10.1038/s41557-019-0258-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-019-0258-1

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing