HNO3/HFIP Nitration System: Unveiling the Arene–Nitronium π-Complex

HNO₃/HFIP Nitration System

Introduction

In 2018, Le Lu, Liu H., and Hua R. reported a mild, metal-free nitration of arenes using equimolar HNO₃ in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at room temperature, with direct UV–vis observation of the arene–nitronium π-complex.¹

The protocol avoids harsh mixed-acid conditions, employs only stoichiometric HNO₃, and delivers yields up to 98 % with high para-selectivity across both electron-rich and electron-poor arenes.¹

Background & Significance

Traditional “mixed-acid” nitration (conc. HNO₃/H₂SO₄) generates the nitronium ion at elevated temperatures but produces large acidic waste and often poor selectivity on deactivated substrates.²

Electrophilic aromatic substitution (S_EAr) encompasses nitration, halogenation, sulfonation, and Friedel–Crafts reactions, proceeding via σ-complex intermediates whose stability dictates regioselectivity.³

Role of HFIP

HFIP ((CF₃)₂CHOH) is a highly polar, strongly hydrogen-bond-donating solvent that stabilizes cationic intermediates.³

With a dielectric constant ε ≈ 16.7 and strong H-bond donor ability, HFIP creates a unique solvation shell that promotes arene–[NO₂]⁺ complexation at ambient temperature.³

The Nitronium Ion

The nitronium ion [NO₂]⁺, a linear cation isoelectronic with CO₂, serves as the active electrophile.⁴

In HFIP, [NO₂]⁺ is further stabilized by hydrogen-bond networks, enhancing its electrophilicity toward arenes.⁴

Experimental Methodology

Arenes and equimolar HNO₃ are stirred in HFIP at 20–25 °C under air. Reactions complete in 1–4 h, and nitroarenes are isolated by extraction and silica chromatography in yields up to 98 %.¹

Mechanistic & Computational Insights

In situ UV–vis spectra display absorptions at ≈327, 408, and 525 nm, characteristic of the arene–[NO₂]⁺ π- and σ-complexes.¹

DFT and TD-DFT studies (Gaussian 09; M06-2X/6-311G* for geometry optimizations, CCSD(T)/aug-cc-pVDZ benchmarking, and TD-DFT M06-2X/6-311+G(2d,2p) with explicit HFIP molecules + PCM ε = 16.7) reproduced these UV–vis bands and assigned them to specific electronic transitions within the π-complex.⁵

Substrate Scope & Selectivity

Electron-rich arenes (e.g., anisole → p-nitroanisole) and deactivated substrates (e.g., chlorobenzene) undergo clean mononitration with para-selectivity > 90 % and yields up to 98 %.¹

Sustainability & Practical Implications

Only stoichiometric HNO₃ is required, reducing acidic waste compared to mixed-acid protocols, and HFIP can be recovered by distillation for reuse, enhancing green metrics.⁶

References

1. Le Lu, H. Liu, R. Hua. “HNO₃/HFIP: A Nitrating System for Arenes with Direct Observation of π-Complex Intermediates.” Org. Lett. 2018, 20(11), 3197–3201. doi.org/10.1021/acs.orglett.8b01028
2. “Nitration.” Wikipedia. en.wikipedia.org/wiki/Nitration
3. “Hexafluoro-2-propanol.” Wikipedia. en.wikipedia.org/wiki/Hexafluoro-2-propanol
4. “Nitronium ion.” Wikipedia. en.wikipedia.org/wiki/Nitronium_ion
5. Gaussian 09 Users Guide; M06-2X/6-311G* optimizations; TD-DFT M06-2X/6-311+G(2d,2p) with explicit HFIP + PCM. (See Supporting Information of Lu et al.)
6. Green Chemistry principle applied: HFIP recovery by distillation reduces solvent waste. Green Chem. DOI: 10.1039/d5gc02232k