Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Mar 2;13(13):3894-3901.
doi: 10.1039/d1sc07102e. eCollection 2022 Mar 30.

Acceptorless dehydrogenative synthesis of primary amides from alcohols and ammonia

Jie Luo  1 , Quan-Quan Zhou  1 , Michael Montag  1 , Yehoshoa Ben-David  1 , David Milstein  1
Affiliations

Acceptorless dehydrogenative synthesis of primary amides from alcohols and ammonia

Jie Luo et al. Chem Sci. .

Abstract

The highly desirable synthesis of the widely-used primary amides directly from alcohols and ammonia via acceptorless dehydrogenative coupling represents a clean, atom-economical, sustainable process. Nevertheless, such a reaction has not been previously reported, and the existing catalytic systems instead generate other N-containing products, e.g., amines, imines and nitriles. Herein, we demonstrate an efficient and selective ruthenium-catalyzed synthesis of primary amides from alcohols and ammonia gas, accompanied by H2 liberation. Various aliphatic and aromatic primary amides were synthesized in high yields, with no observable N-containing byproducts. The selectivity of this system toward primary amide formation is rationalized through density functional theory (DFT) calculations, which show that dehydrogenation of the hemiaminal intermediate into primary amide is energetically favored over its dehydration into imine.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Direct dehydrogenative coupling of alcohols and ammonia for the synthesis of primary amides.
Fig. 1
Fig. 1. Amidation reaction progress.
Scheme 2
Scheme 2. Control experiments.
Fig. 2
Fig. 2. Ammonia concentrations in the catalytically-relevant solvents at room temperature, after initial introduction of 10 bar of NH3. A, toluene/tAmOH, 4 : 2; B, toluene/1,4-dioxane, 4 : 2 (volumetric ratios, mL/mL).
Scheme 3
Scheme 3. Mechanistic studies and proposed catalytic cycle.
Fig. 3
Fig. 3. Computed energy profile for primary amide formation by the current catalytic system. Ethanol (R = CH3) was used as a minimal alcohol model, and toluene as an implicit solvent. Mass balance is ensured throughout.
See this image and copyright information in PMC

References

    1. Roundhill D. M. Chem. Rev. 1992;92:1–27. doi: 10.1021/cr00009a001. - DOI
    2. McCullough K. J., in Encyclopedia of Reagents for Organic Synthesis, ed. L. A. Paquette, Wiley: Chichester, U.K., 2001, ch. Ammonia
    3. Klinkenberg J. L. Hartwig J. F. Angew. Chem., Int. Ed. 2011;50:86–95. doi: 10.1002/anie.201002354. - DOI - PMC - PubMed
    4. Kim i. Kim H. J. Chang S. Eur. J. Org. Chem. 2013:3201–3213. doi: 10.1002/ejoc.201300164. - DOI
    1. Gunanathan C. Milstein D. Angew. Chem., Int. Ed. 2008;47:8661–8664. doi: 10.1002/anie.200803229. - DOI - PubMed
    2. Pingen D. Müller C. Vogt D. Angew. Chem., Int. Ed. 2010;49:8130–8133. doi: 10.1002/anie.201002583. - DOI - PubMed
    3. Ye X. Plessow P. N. Brinks M. K. Schelwies M. Schaub T. Rominger F. Paciello R. Limbach M. Hofmann P. J. Am. Chem. Soc. 2014;136:5923–5929. doi: 10.1021/ja409368a. - DOI - PubMed
    4. Balaraman E. Srimani D. Diskin-Posner Y. Milstein D. Catal. Lett. 2015;145:139–144. doi: 10.1007/s10562-014-1422-2. - DOI
    5. Fujita K.-i. Furukawa S. Morishima N. Shimizu M. Yamaguchi R. ChemCatChem. 2018;10:1993–1997. doi: 10.1002/cctc.201702037. - DOI
    6. Daw P. Ben-David Y. Milstein D. J. Am. Chem. Soc. 2018;140:11931–11934. doi: 10.1021/jacs.8b08385. - DOI - PMC - PubMed
    7. Daw P. Kumar A. Espinosa-Jalapa N. A. Ben-David Y. Milstein D. J. Am. Chem. Soc. 2019;141:12202–12206. doi: 10.1021/jacs.9b05261. - DOI - PubMed
    8. Wang Y. Furukawa S. Zhang Z. Torrente-Murciano L. Khan S. A. Yan N. Catal. Sci. Technol. 2019;9:86–96. doi: 10.1039/C8CY01799A. - DOI
    9. Wang Y. Furukawa S. Yan N. ACS Catal. 2019;9:6681–6691.
    1. Zhang J. Leitus G. Ben-David Y. Milstein D. J. Am. Chem. Soc. 2005;127:10840–10841. doi: 10.1021/ja052862b. - DOI - PubMed
    2. Gunanathan C. Ben-David Y. Milstein D. Science. 2007;317:790–792. doi: 10.1126/science.1145295. - DOI - PubMed
    3. Gnanaprakasam B. Zhang J. Milstein D. Angew. Chem., Int. Ed. 2010;49:1468–1471. doi: 10.1002/anie.200907018. - DOI - PubMed
    4. Balaraman E. Khaskin E. Leitus G. Milstein D. Nat. Chem. 2013;5:122–125. doi: 10.1038/nchem.1536. - DOI - PubMed
    5. Crabtree R. H. Chem. Rev. 2017;117:9228–9246. doi: 10.1021/acs.chemrev.6b00556. - DOI - PubMed
    6. Espinosa-Jalapa N. A. Kumar A. Leitus G. Diskin-Posner Y. Milstein D. J. Am. Chem. Soc. 2017;139:11722–11725. doi: 10.1021/jacs.7b08341. - DOI - PubMed
    7. Luo J. Rauch M. Avram L. Diskin-Posner Y. Shmul G. Ben-David Y. Milstein D. Nat. Catal. 2020;3:887–892. doi: 10.1038/s41929-020-00514-9. - DOI
    1. Zeng H. Guan Z. J. Am. Chem. Soc. 2011;133:1159–1161. doi: 10.1021/ja106958s. - DOI - PMC - PubMed
    2. Prechtl M. H. G. Wobser K. Theyssen N. Ben-David Y. Milstein D. Leitner W. Catal. Sci. Technol. 2012;2:2039–2042. doi: 10.1039/C2CY20429K. - DOI
    3. Srimani D. Balaraman E. Hu P. Ben-David Y. Milstein D. Adv. Synth. Catal. 2013;355:2525–2530. doi: 10.1002/adsc.201300620. - DOI
    4. Spasyuk D. Vicent C. Gusev D. G. J. Am. Chem. Soc. 2015;137:3743–3746. doi: 10.1021/ja512389y. - DOI - PubMed
    5. Zou Y.-Q. Zhou Q.-Q. Diskin-Posner Y. Ben-David Y. Milstein D. Chem. Sci. 2020;11:7188–7193. doi: 10.1039/D0SC02065F. - DOI - PMC - PubMed
    6. Kar S. Xie Y. Zhou Q.-Q. Diskin-Posner Y. Ben-David Y. Milstein D. ACS Catal. 2021;11:7383–7393. doi: 10.1021/acscatal.1c00728. - DOI - PMC - PubMed
    1. The Amide Linkage: Structural Significance in Chemistry, Biochemistry and Material Science, ed. A. Greenberg, C. M. Breneman and J. F. Liebman, Wiley, New York, 2000
    2. Humphrey J. M. Chamberlin A. R. Chem. Rev. 1997;97:2243–2266. doi: 10.1021/cr950005s. - DOI - PubMed
    3. Bray B. L. Nat. Rev. Drug Discovery. 2003;2:587–593. doi: 10.1038/nrd1133. - DOI - PubMed
    4. Dineen T. A. Zajac M. A. Myers A. G. J. Am. Chem. Soc. 2006;128:16406–16409. doi: 10.1021/ja066728i. - DOI - PubMed
    5. Pattabiraman V. R. Bode J. W. Nature. 2011;480:471–479. doi: 10.1038/nature10702. - DOI - PubMed
    6. Szostak M. Spain M. Eberhart A. J. Procter D. J. J. Am. Chem. Soc. 2014;136:2268–2271. doi: 10.1021/ja412578t. - DOI - PMC - PubMed
    7. Ganesan M. Nagaraaj P. Org. Chem. Front. 2020;7:3792–3814. doi: 10.1039/D0QO00843E. - DOI
    8. Thakur R. Jaiswal Y. Kumar A. Tetrahedron. 2021;93:132313. doi: 10.1016/j.tet.2021.132313. - DOI