Skip to main content

Thank you for visiting 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.

Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics


Primary aliphatic amines are important building blocks in organic synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Experimental and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermolecular HAT by an electrostatically accelerated interaction between the in situ-generated negatively charged carbamate and the positively charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissociation energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Strategies for α-functionalization of aliphatic amines.
Fig. 2: Reaction development.
Fig. 3: Exploration of substrate scope.
Fig. 4: Mechanistic and computational studies.


  1. 1.

    He, J., Wasa, M., Chan, K. S. L., Shao, Q. & Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 117, 8754–8786 (2017).

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–35 (1999).

    CAS  Article  Google Scholar 

  3. 3.

    Qvortrup, K., Rankic, D. A. & MacMillan, D. W. C. A general strategy for organocatalytic activation of C−H bonds via photoredox catalysis: direct arylation of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014).

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Jeffrey, J. L., Terrett, J. A. & MacMillan, D. W. C. O–H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols. Science 349, 1532–1536 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Shaw, M. H., Shurtleff, V. W., Terrett, J. A., Cuthbertson, J. D. & MacMillan, D. W. C. Native functionality in triple catalytic cross-coupling: sp 3 C–H bonds as latent nucleophiles. Science 352, 1304–1308 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Le, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W. C. Selective sp 3 C–H alkylation via polarity-match based cross-coupling. Nature 547, 79–83 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Beatty, J. W. & Stephenson, C. R. J. Amine functionalization via oxidative photoredox catalysis: methodology development and complex molecule synthesis. Acc. Chem. Res. 48, 1474–1484 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Nakajima, K., Miyake, Y. & Nishibayashi, Y. Synthetic utilization of α-aminoalkyl radicals and related species in visible light photoredox catalysis. Acc. Chem. Res. 49, 1946–1956 (2016).

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Kubiak, R., Prochnow, I. & Doye, S. Titanium-catalyzed hydroaminoalkylation of alkenes by C–H bond activation at sp 3 centers in the α-position to a nitrogen atom. Angew. Chem. Int. Ed. 48, 1153–1156 (2009).

    CAS  Article  Google Scholar 

  12. 12.

    Bexrud, J. A., Eisenberger, P., Leitch, D. C., Payne, P. R. & Schafer, L. L. Selective C–H activation α to primary amines. Bridging metallaaziridines for catalytic, intramolecular α-alkylation. J. Am. Chem. Soc. 131, 2116–2118 (2009).

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Das, S., Kumar, J. S. D., Thomas, K. G., Shivaramayya, K. & George, M. V. Photocatalyzed multiple additions of amines to α,β-unsaturated esters and nitriles. J. Org. Chem. 59, 628–634 (1994).

    CAS  Article  Google Scholar 

  14. 14.

    Adenier, A., Chehimi, M. M., Gallardo, I., Pinson, J. & Vilà, N. Electrochemical oxidation of aliphatic amines and their attachment to carbon and metal surfaces. Langmuir 20, 8243–8253 (2004).

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Largeron, M. Protocols for the catalytic oxidation of primary amines to imines. Eur. J. Org. Chem. 5225–5235 (2013).

    CAS  Article  Google Scholar 

  16. 16.

    Calleja, J. et al. A steric tethering approach enables palladium-catalysed C–H activation of primary amino alcohols. Nat. Chem. 7, 1009–1016 (2015).

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Willcox, D. et al. A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams. Science 354, 851–857 (2016).

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Dell’Amico, D. B., Calderazzo, F., Labella, L., Marchetti, F. & Pampaloni, G. Converting carbon dioxide into carbamato derivatives. Chem. Rev. 103, 3857–3897 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Chu, J. C. & Rovis, T. Amide-directed photoredox-catalysed C–C bond formation at unactivated sp 3 C–H bonds. Nature 539, 272–275 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Choi, G. J., Zhu, Q., Miller, D. C., Gu, C. J. & Knowles, R. R. Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer. Nature 539, 268–271 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Peeters, A., Ameloot, R. & De Vos, D. E. Carbon dioxide as a reversible amine-protecting agent in selective Michael additions and acylations. Green Chem. 15, 1550–1557 (2013).

    CAS  Article  Google Scholar 

  22. 22.

    Huang, Z., Wang, C. & Dong, G. Catalytic C(sp 3)–H arylation of free primary amines with an exo directing group generated in situ. Angew. Chem. Int. Ed. 55, 5299–5303 (2016).

    CAS  Article  Google Scholar 

  23. 23.

    Liu, Y. & Ge, H. Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nat. Chem. 9, 26–32 (2017).

    Google Scholar 

  24. 24.

    Wu, Y., Chen, Y.-Q., Liu, T., Eastgate, M. D. & Yu, J.-Q. Pd-catalyzed γ-C(sp 3)−H arylation of free amines using a transient directing group. J. Am. Chem. Soc. 138, 14554–14557 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lee, M. & Sanford, M. S. Platinum-catalyzed, terminal-selective C(sp 3)−H oxidation of aliphatic amines. J. Am. Chem. Soc. 137, 12796–12799 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C. Remote oxidation of aliphatic C−H bonds in nitrogen-containing molecules. J. Am. Chem. Soc. 137, 14590–14593 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Davis, H. J. & Phipps, R. J. Harnessing non-covalent interactions to exert control over regioselectivity and site-selectivity in catalytic reactions. Chem. Sci. 8, 864–877 (2017).

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Lowry, M. S. et al. Single-layer electroluminescent devices and photoinduced hydrogen production from an ionic iridium(iii) complex. Chem. Mater. 17, 5712–5719 (2005).

    CAS  Article  Google Scholar 

  29. 29.

    Liu, W.-Z. & Bordwell, F. G. Gas-phase and solution-phase homolytic bond dissociation energies of H−N+ bonds in the conjugate acids of nitrogen bases. J. Org. Chem. 61, 4778–4783 (1996).

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Caruano, J., Muccioli, G. G. & Robiette, R. Biologically active γ-lactams: synthesis and natural sources. Org. Biomol. Chem. 14, 10134–10156 (2016).

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Masuda, K., Ito, Y., Horiguchi, M. & Fujita, H. Studies on the solvent dependence of the carbamic acid formation from ω-(1-naphthyl)alkylamines and carbon dioxide. Tetrahedron 61, 213–229 (2005).

    CAS  Article  Google Scholar 

  32. 32.

    Finn, M., Friedline, R., Suleman, N. K., Wohl, C. J. & Tanko, J. M. Chemistry of the t-butoxyl radical: evidence that most hydrogen abstractions from carbon are entropy-controlled. J. Am. Chem. Soc. 126, 7578–7584 (2004).

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Barham, J. P., John, M. P. & Murphy, J. A. Contra-thermodynamic hydrogen atom abstraction in the selective C–H functionalization of trialkylamine N–CH3 groups. J. Am. Chem. Soc. 138, 15482–15487 (2016).

    CAS  Article  PubMed  Google Scholar 

Download references


The authors acknowledge financial support from NIGMS (T.R., GM125206), as well as partial support from the Catalysis Collaboratory for Light-activated Earth Abundant Reagents (C-CLEAR), which is supported by the National Science Foundation and the Environmental Protection Agency through the Network for Sustainable Molecular Design and Synthesis programme (NSFCHE-1339674, T.R.). Calculations were performed with computing resources granted by JARA-HPC from RWTH Aachen University under project ‘jara0091’. The authors thank J. Owen (Columbia University) for the use of his fluorometer.

Author information




T.R. and J.Y. conceived the concept. T.R. directed the investigation. J.Y. performed the experiments and analysed the data. I.K. and F.S. carried out computational studies. J.Y., T.R., I.K. and F.S. collated the data, discussed the implications and prepared the manuscript.

Corresponding authors

Correspondence to Franziska Schoenebeck or Tomislav Rovis.

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

Materials and methods, synthesis and characterization of products, Supplementary Figures 1–13, Supplementary Tables 1–6, NMR Spectra and computational details

Computational data

All computed structures that are included in the main Supplementary information file

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ye, J., Kalvet, I., Schoenebeck, F. et al. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nature Chem 10, 1037–1041 (2018).

Download citation

Further reading


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