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
. 2023 Mar 27;28(7):2968.
doi: 10.3390/molecules28072968.

An Efficient Continuous Flow Synthesis for the Preparation of N-Arylhydroxylamines: Via a DMAP-Mediated Hydrogenation Process

Jianli Chen  1   2 , Xinyu Lin  2 , Feng Xu  3 , Kejie Chai  2 , Minna Ren  2 , Zhiqun Yu  2 , Weike Su  2 , Fengfan Liu  2
Affiliations

An Efficient Continuous Flow Synthesis for the Preparation of N-Arylhydroxylamines: Via a DMAP-Mediated Hydrogenation Process

Jianli Chen et al. Molecules. .

Abstract

The selective hydrogenation of nitroarenes to N-arylhydroxylamines is an important synthetic process in the chemical industry. It is commonly accomplished by using heterogeneous catalytic systems that contain inhibitors, such as DMSO. Herein, DMAP has been identified as a unique additive for increasing hydrogenation activity and product selectivity (up to >99%) under mild conditions in the Pt/C-catalyzed process. Continuous-flow technology has been explored as an efficient approach toward achieving the selective hydrogenation of nitroarenes to N-arylhydroxylamines. The present flow protocol was applied for a vast substrate scope and was found to be compatible with a wide range of functional groups, such as electron-donating groups, carbonyl, and various halogens. Further studies were attempted to show that the improvement in the catalytic activity and selectivity benefited from the dual functions of DMAP; namely, the heterolytic H2 cleavage and competitive adsorption.

Keywords: 4-(dimethylamino) pyridine; N-arylhydroxylamine; catalytic activity; continuous flow; selectivity.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
General routine for the catalytic hydrogenation of nitroarene.
Figure 1
Figure 1
Reaction profile for 1a hydrogenation in batch at 60 °C (a) and 30 °C (b). Conditions: 6 mmol of 1a, 10 mg of 5 wt.% Pt/C, 20 mL of THF, 600 rpm, 10 bar H2. Samples were withdrawn from the reactor for HPLC analysis.
Figure 2
Figure 2
Pt/C-catalyzed hydrogenation of 1a in different solvents. Reaction condition: 0.1 M solution of 1a in solvents, 5 wt.% Pt/C (1 cartridge; Ø3.0 × 50 mm; 0.1 g), H2 pressure (6 bar), back pressure (4 bar), liquid flowrate (0.5 mL·min−1), temperature (25 °C). Samples were determined by HPLC.
Figure 3
Figure 3
The conversion and selectivity of hydrogenation in different equivalent of DMAP (a), temperature (b), and liquid flow rate (c). Conditions: 0.1 M solution of 1a in THF, 5 wt.% Pt/C (1 cartridge; Ø3.0 × 50 mm; 0.1 g), H2 pressure (6 bar), back pressure (4 bar).
Scheme 2
Scheme 2
Selective reduction of nitroarenes 1a–10a catalyzed by Pt/C combined with DMAP in flow. Conditions: 0.1 M solution of nitroarenes in THF, 5 wt.% Pt/C (1 cartridge; Ø3.0 × 50 mm; 0.1 g), H2 pressure (6 bar), back pressure (4 bar), liquid flowrate (0.5 mL·min−1), temperature (25 °C). Samples were determined by HPLC.
Figure 4
Figure 4
Reaction profile for 1a hydrogenation catalyzed by 5 wt.% Pt/C combined with DMAP in batch. Conditions: 6 mmol of 1a, 10 mg of 5 wt.% Pt/C, 0.6 mmol of DMAP, 20 mL of THF, 1200 rpm, 10 bar H2, 30 °C. Samples were withdrawn from the reactor for HPLC analysis.
Figure 5
Figure 5
Structures (A,B) and charge difference (C,D) of adsorbed DMAP models. White, blue, and grey spheres depict H, N, and C atoms, respectively. The blue areas denote electron accumulation and the yellow ones denote depletion.
Figure 6
Figure 6
Hypothetical formation mechanism of FLP: HED-1 (A), HED-2 (B), HED-3 (C), HED-4 (D), HED-5 (E).
Figure 7
Figure 7
Dissociative adsorption energy for H2 activation.
Figure 8
Figure 8
Proposed mechanism for Pt-catalyzed catalytic hydrogenation of nitroarene into N-AHA via a frustrated Lewis pair approach and competitive adsorption.
Figure 9
Figure 9
µPBR continuous-flow reactor setup of hydrogenation of nitroarenes.
Figure 10
Figure 10
The packing method of catalyst in µPBR.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Liu Y., Bai S., Du Y., Qi X., Gao H. Expeditious and efficient ortho-selective trifluoromethane-sulfonylation of arylhydroxylamines. Angew. Chem. Int. Ed. 2022;61:e202115611. doi: 10.1002/anie.202115611. - DOI - PubMed
    1. Yuan H., Guo L., Liu F., Miao Z., Feng L., Gao H. Copper-catalyzed tandem o-vinylation of arylhydroxylamines/[3,3]-rearrangement/cyclization: Synthesis of highly substituted indoles and benzoindoles. ACS Catal. 2019;9:3906–3912. doi: 10.1021/acscatal.9b00470. - DOI
    1. Dounay A.B., Anderson M., Bechle B.M., Campbell B.M., Claffey M.M., Evdokimov A., Evrard E., Fonseca K.R., Gan X., Ghosh S., et al. Discovery of brain-penetrant, irreversible kynurenine aminotransferase ii inhibitors for schizophrenia. ACS Med. Chem. Lett. 2012;3:187–192. doi: 10.1021/ml200204m. - DOI - PMC - PubMed
    1. Vyas P.M., Roychowdhury S., Woster P.M., Svensson C.K. Reactive oxygen species generation and its role in the differential cytotoxicity of the arylhydroxylamine metabolites of sulfamethoxazole and dapsone in normal human epidermal keratinocytes. Biochem. Pharmacol. 2005;70:275–286. doi: 10.1016/j.bcp.2005.04.023. - DOI - PubMed
    1. Yadav J.S., Reddy B.V.S., Sreedhar P. Three-component one-pot synthesis of α-hydroxylamino phosphonates using ionic liquids. Adv. Synth. Catal. 2003;345:564–567. doi: 10.1002/adsc.200202209. - DOI

LinkOut - more resources