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  • Perspective
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A green chemistry perspective on catalytic amide bond formation

Abstract

The synthesis of amides is of widespread importance, and there has been considerable recent interest in the development of catalytic methods to access these molecules. In this Perspective, we provide an overview of the current state of the art in amide synthesis, and assess new catalytic amide formation methods in the context of efficiency and sustainability. The advantages and disadvantages of catalytic approaches are highlighted and areas for future research are identified.

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Fig. 1: Methods for amide synthesis.
Fig. 2: Analysis of methods currently used for the preparation of amides.
Fig. 3: Catalytic direct amidation reactions.
Fig. 4: Alternative catalytic amidation approaches.

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Data availability

All data analysed in this article are included in the Supplementary Information (SI) file.

References

  1. Valeur, E. & Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 38, 606–631 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Dunetz, J. R., Magano, J. & Weisenburger, G. A. Large-scale applications of amide coupling reagents for the synthesis of pharmaceuticals. Org. Process Res. Dev. 20, 140–177 (2016).

    Article  CAS  Google Scholar 

  3. Anastas, P. T. & Warner, J. C. Green Chemistry: Theory and Practice (Oxford University Press, New York, 1998).

    Google Scholar 

  4. Jimenez-Gonzalez, C. et al. Using the right green yardstick: Why process mass intensity is used in the pharmaceutical industry to drive more sustainable processes. Org. Process Res. Dev. 15, 912–917 (2011).

    Article  CAS  Google Scholar 

  5. Constable, D. J. C. et al. Key green chemistry research areas — a perspective from pharmaceutical manufacturers. Green Chem. 9, 411–420 (2007).

    Article  CAS  Google Scholar 

  6. Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Sherwood, J., Farmer, T. J. & Clark, J. H. Catalyst: possible consequences of the N-methyl pyrrolidone REACH restriction. Chem. 4, 2010–2012 (2018).

    Article  CAS  Google Scholar 

  8. Sherwood, J. European restrictions on 1,2-dichloroethane: C-H activation research and development should be liberated and not limited. Angew. Chem. Int. Ed. 57, 14286–14290 (2018).

    Article  CAS  Google Scholar 

  9. Prat, D. et al. CHEM21 selection guide of classical- and less classical-solvents. Green Chem. 18, 288–296 (2016).

    Article  Google Scholar 

  10. Li, C.-J. & Trost, B. M. Green chemistry for chemical synthesis. Proc. Natl Acad. Sci. USA 105, 13197–13202 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Ishihara, K., Ohara, S. & Yamamoto, H. 3,4,5-Trifluorobenzeneboronic acid as an extremely active amidation catalyst. J. Org. Chem. 61, 4196–4197 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. MacMillan, D. S. et al. Evaluation of alternative solvents in common amide coupling reactions: replacement of dichloromethane and N,N-dimethylformamide. Green Chem. 15, 596–600 (2013).

    Article  CAS  Google Scholar 

  13. Ho, G.-J. et al. Carbodiimide-mediated amide formation in a two-phase system. A high-yield and low-racemization procedure for peptide synthesis.J. Org. Chem. 60, 3569–3570 (1995).

    Article  CAS  Google Scholar 

  14. Carey, J. S. et al. Analysis of the reactions used for the preparation of drug candidate molecules. Org. Biomol. Chem. 4, 2337–2347 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Braddock, D. C. et al. Tetramethyl orthosilicate (TMOS) as a reagent for direct amidation of carboxylic acids. Org. Lett. 20, 950–953 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Gabriel, C. M. et al. Amide and peptide bond formation in water at room temperature. Org. Lett. 17, 3968–3971 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Wehrstedt, K. D., Wandrey, P. A. & Heitkamp, D. Explosive properties of 1-hydroxybenzotriazoles. J. Hazard. Mater. 126, 1–7 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Allen, C. L., Chhatwal, A. R. & Williams, J. M. J. Direct amide formation from unactivated carboxylic acids and amines. Chem. Commun. 48, 666–668 (2012).

    Article  CAS  Google Scholar 

  19. Lundberg, H., Tinnis, F. & Adolfsson, H. Direct amide coupling of non-activated carboxylic acids and amines catalysed by zirconium(IV) chloride. Chem. Eur. J. 18, 3822–3826 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Lundberg, H., Tinnis, F. & Adolfsson, H. Titanium(IV) isopropoxide as an efficient catalyst for direct amidation of nonactivated carboxylic acids. Synlett 23, 2201–2204 (2012).

    Article  CAS  Google Scholar 

  21. Lundberg, H. & Adolfsson, H. Hafnium-catalyzed direct amide formation at room temperature. ACS Catal. 5, 3271–3277 (2015).

    Article  CAS  Google Scholar 

  22. Tang, P. Boric acid catalyzed amide formation from carboxylic acids and amines: N-benzyl-4-phenylbutyramide. Org. Synth. 81, 262–272 (2005).

    Article  CAS  Google Scholar 

  23. Sabatini, M. T., Boulton, L. T. & Sheppard, T. D. Borate esters: simple catalysts for the sustainable synthesis of complex amides. Sci Adv. 3, e1701028 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Sabatini, M. T. et al. Protecting-group-free amidation of amino acids using Lewis Acid catalysts. Chem. Eur. J. 24, 7033–7043 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Arnold, K. et al. Synthesis, evaluation and application of novel bifunctional N,N-diisopropylbenzylamineboronic acid catalysts for direct amide formation between carboxylic acids and amines. Green Chem. 10, 124–134 (2008).

    Article  CAS  Google Scholar 

  26. Fatemi, S., Gernignon, N. & Hall, D. G. A multigram-scale lower E-factor procedure for MIBA-catalyzed direct amidation and its application to the coupling of alpha and beta aminoacids. Green Chem. 17, 4016–4028 (2015).

    Article  CAS  Google Scholar 

  27. Wang, K., Lu, Y. & Ishihara, K. The ortho-substituent on 2,4-bis(trifluoromethyl)phenylboronic acid catalyzed dehydrative condensation between carboxylic acids and amines. Chem. Commun. 54, 5410–5413 (2018).

    Article  CAS  Google Scholar 

  28. Maki, T., Ishihara, K. & Yamamoto, H. 4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol as an effective catalyst for the amide condensation of sterically demanding carboxylic acids. Org. Lett. 8, 1431–1434 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Noda, H. et al. Unique physicochemical and catalytic properties dictated by the B3NO2 ring system. Nat. Chem. 9, 571–577 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. British Geological Survey http://www.go.nature.com/2PT10DY (2015).

  31. Moore, J. A. et al. An assessment of boric acid and borax using the IEHR evaluative process for assessing human developmental and reproductive toxicity of agents. Reproductive Toxicol. 11, 123–160 (1997).

    Article  CAS  Google Scholar 

  32. Bannister, R. B. et al. A scaleable route to the pure enantiomers of verapamil. Org. Process Res. Dev. 4, 467–472 (2000).

    Article  CAS  Google Scholar 

  33. Mylavarapu, R. K. et al. Boric acid catalyzed amidation in the synthesis of active pharmaceutical ingredients. Org. Process Res. Dev. 11, 1065–1068 (2007).

    Article  CAS  Google Scholar 

  34. Limanto, J. et al. A highly efficient asymmetric synthesis of vernakalant. Org. Lett. 16, 2716–2719 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Lee, D. S. et al. Investigating scale-up and further applications of DABAL-Me3 promoted amide synthesis. Org. Process Res. Dev. 19, 831–840 (2015).

    Article  CAS  Google Scholar 

  36. Sabot, C. et al. A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent-free conditions. Tetrahedron Lett. 48, 3863–3866 (2007).

    Article  CAS  Google Scholar 

  37. Weiberth, F. J. et al. Demonstration on pilot-plant scale of the utility of 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst in the efficient amidation of an unactivated methyl ester. Org. Process Res. Dev. 16, 1967–1969 (2012).

    Article  CAS  Google Scholar 

  38. Yang, X. & Birman, V. B. Acyl transfer catalysis with 1,2,4-triazole anion. Org. Lett. 11, 1499–1502 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McPharson, C. G. et al. Amidation of unactivated ester derivatives mediated by trifluoroethanol. Org. Biomol. Chem. 15, 3507–3518 (2017).

    Article  Google Scholar 

  40. Lenstra, D. C., Nguyen, D. T. & Mecinović, J. Zirconium-catalyzed direct amide bond formation between carboxylic esters and amines. Tetrahedron Lett. 71, 5547–5553 (2015).

    Article  CAS  Google Scholar 

  41. Nguyen, D. T., Lenstra, D. C. & Mecinović, J. Chemoselective calcium-catalysed direct amidation of carboxylic esters. RSC Adv. 5, 77658–77661 (2015).

    Article  CAS  Google Scholar 

  42. Morimoto, H. et al. Lanthanum(III) triflate catalyzed direct amidation of esters. Org. Lett. 16, 2018–2021 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Sanz Sharley, D. D. & Williams, J. M. J. Acetic acid as a catalyst for the N-acylation of amines using esters as the acyl source. Chem. Commun. 53, 2020–2023 (2017).

    Article  CAS  Google Scholar 

  44. Tillack, A., Rudloff, I. & Beller, M. Catalytic amination of aldehydes to amides. Eur. J. Org. Chem. 2001, 523–.

  45. Gunanathan, C., Ben-David, Y. & Milstein, D. Direct synthesis of amides from alcohols and amines with liberation of H2. Science 317, 790–792 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Fang, W. et al. Highly efficient aminocarbonylation of iodoarenes at atmospheric pressure catalyzed by a robust acenaphthoimidazolyidene allylic palladium complex. Org. Lett. 15, 3678–3681 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Dorr, B. M. & Fuerst, D. E. Enzymatic amidation for industrial applications. Curr. Opin. Chem. Bio. 43, 127–133 (2018).

    Article  CAS  Google Scholar 

  48. Comerford, J. W. et al. Clean, reusable and low cost heterogeneous catalyst for amide synthesis. Chem. Commun. 0, 2562–2564 (2009).

    Article  CAS  Google Scholar 

  49. Petchey, T. H. M. et al. Optimization of amidation reactions using predictive tools for the replacement of regulated solvents with safer biobased alternatives. ACS Sus. Chem. Eng. 6, 1550–1554 (2018).

    Article  CAS  Google Scholar 

  50. Nadin, A., Hattotuwagama, C. & Churcher, I. Lead‐oriented synthesis: a new opportunity for synthetic chemistry. Angew. Chem. Int. Ed. 51, 1114–1122 (2012).

    Article  CAS  Google Scholar 

  51. Alder, C. M. et al. Updating and further expanding GSK’s solvent sustainability guide.Green Chem. 18, 3879–3890 (2016).

    Article  CAS  Google Scholar 

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Acknowledgements

M.T.S. would like to acknowledge financial support for a postdoctoral position from UCL via the EPSRC Impact Acceleration Account (EP/R511638/1), and for a PhD studentship from UCL and GSK. L.T.B and H.F.S would like to thank K. Wheelhouse (GSK) for initial work on GSK portfolio reaction classification.

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M.T.S. and T.D.S wrote the manuscript and collected and analysed the Reaxys dataset, L.T.B and H.F.S. collected and analysed the large-scale amidation dataset and contributed to the writing of the manuscript.

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Correspondence to Tom D. Sheppard.

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Supplementary Data 1

Data supporting Figures 2 and 3

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Sabatini, M.T., Boulton, L.T., Sneddon, H.F. et al. A green chemistry perspective on catalytic amide bond formation. Nat Catal 2, 10–17 (2019). https://doi.org/10.1038/s41929-018-0211-5

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