Mechanochemically Driven Radical Nitration of Electron-Rich ortho and para Di- and Trialkoxyarenes Using Iron(III) Nitrate

Samuel Andrejčák; Peter Dudáš; Michal Májek

doi:10.1055/a-2547-8910

Synlett, Table of Contents

Synlett
DOI: 10.1055/a-2547-8910

letter

14th EuCheMS Organic Division Young Investigator Workshop

Mechanochemically Driven Radical Nitration of Electron-Rich ortho and para Di- and Trialkoxyarenes Using Iron(III) Nitrate

Samuel Andrejčák‡

,

Peter Dudáš‡

,

Michal Májek ∗

Abstract

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Abstract

This study introduces a sustainable mechanochemical approach for the nitration of electron-rich ortho and para di- and trialkoxyarenes using iron(III) nitrate nonahydrate (Fe(NO₃)₃·9H₂O) as a source of nitro radicals. Conventional nitration methods require harsh conditions and hazardous reagents, limiting their application. Herein, mechanochemical activation offers a rapid and efficient alternative with minimal solvent and a reduced reaction time. Screening identified Fe(NO₃)₃ as the most effective nitrating agent, with successful application with a variety of ortho and para di- and trialkoxyarenes while maintaining high regioselectivity. The scalability and environmental benefits of the method underscore its potential in organic synthesis, advancing a practical, green protocol for radical aromatic nitration.

Key words

radicals - mechanochemistry - nitration - arenes - nitryl radical - iron(III) nitrate - liquid-assisted grinding

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References

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48 General Procedure A 1.5 mL stainless-steel milling jar was charged with the aromatic compound 1 (1.0 equiv), Fe(NO₃)₃·9H₂O (1.1 equiv) and MeCN (0.3 μL/mg of solid reagents) as a liquid-assisted grinding agent, along with a 6 mm stainless-steel ball. In some cases, the addition of MeCN was unnecessary. The jar was sealed and subjected to ball milling in a shaker mill at a frequency of 30 Hz for 25 min (unless otherwise specified). After milling, the crude reaction mixture was transferred from the jar using dichloromethane, dried over MgSO₄, and then filtered. The mixture was further filtered through a short pad of Celite and concentrated under reduced pressure. The product 2 was either isolated at this stage or further purified by silica gel column chromatography using a gradient of hexane and ethyl acetate as the eluent.
49 1,4-Dimethoxy-2-nitrobenzene (2a) Yield: 92 mg (quant.); yellow solid; mp 70–72 °C. IR (ATR): 3081, 3033, 2984, 2953, 2851, 1629, 1577, 1524, 1496, 1466, 1353, 1272, 1220, 1190, 1159, 1081, 1038, 1015, 912, 875, 811, 764, 737 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 3.0 Hz, 1 H), 7.11 (dd, J = 9.1, 3.1 Hz, 1 H), 7.03 (d, J = 9.1 Hz, 1 H), 3.92 (s, 3 H), 3.82 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 152.8, 147.3, 139.5, 120.8, 115.1, 110.0, 57.0, 56.0. MS (EI): m/z = 183.0 [M⁺], 138.0, 107.0, 79.1, 77.1. The characterization data matched those reported in the literature (see Refs. 26 and 50).
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