Dual XH–π Interaction of Hexafluoroisopropanol with Arenes: A Comprehensive Review

Dual XH–π Interaction of Hexafluoroisopropanol with Arenes: A Comprehensive Review

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) exhibits a unique dual hydrogen-bond-donating ability, engaging both its O–H and C–H bonds in strong π interactions with aromatic surfaces. These dual XH–π interactions result in higher binding energies than traditional CH–π interactions, significantly lowering the molecular orbital energy levels of arenes and enhancing solvent effects in organic transformations.

Background

HFIP is widely used as a solvent and additive in organic synthesis due to its high acidity (pKa ≈ 9.3) and strong electron-withdrawing CF₃ groups. It can form both classical O–H–π and unconventional C–H–π hydrogen bonds, leading to micelle-like aggregation and unique solvation properties.

Computational Methods

Geometries of HFIP conformers and their benzene complexes were optimized at the M06-2X/6-311++G(2d,2p) level, with counterpoise corrections for basis-set superposition error. Post-Hartree–Fock interaction energies were computed via CCSD(T)/CBS extrapolation. Density of states (DOS), partial DOS (PDOS), and overlap population DOS (OPDOS) analyses were carried out with Multiwfn, and charge decomposition analysis (CDA) dissected orbital contributions.

Results and Discussion

Three HFIP/benzene conformers were identified. The synperiplanar conformer exhibited a dual XH–π interaction energy of –7.49 kcal mol⁻¹, surpassing comparable CHCl₃/benzene and isopropanol/benzene complexes by over 1.8 kcal mol⁻¹. Correlation energy contributions (~ –7.47 kcal mol⁻¹) underscore the dominance of dispersion forces in dual-binding.

Figure 1. Optimized HFIP/benzene conformers showing dual XH–π, CH–π, and OH–π interactions and their complexation energies.

DOS analysis reveals a significant lowering (~0.73 eV) of benzene HOMO levels upon complexation, indicating non-superpositional orbital mixing. PDOS and OPDOS profiles confirm constructive overlap in HOMO–1, LUMO, and higher unoccupied orbitals, while antibonding character appears in certain deeper MOs.

Figure 2. (a) DOS of isolated benzene, HFIP, and their complex; (b) PDOS of the HFIP/benzene complex; (c) OPDOS indicating bonding (positive) and antibonding (negative) interactions.

Across 24 aromatic substrates, HFIP forms complexes 1.48× stronger than isopropanol and 1.61× stronger than chloroform, except with electron-deficient arenes. Single-crystal X-ray diffraction of HFIP benzoate (CCDC 2083861) validates the C–H hydrogen-donating capability.

Conclusions

This review elucidates the mechanism and energetics of dual XH–π interactions between HFIP and arenes. The synergy of O–H and C–H binding explains HFIP’s remarkable solvent effects and informs its strategic application in organic synthesis and materials science.

References

1. Lu, L.; Hua, R. “Dual XH–π Interaction of Hexafluoroisopropanol with Arenes: A Comprehensive Review.” Molecules 2021, 26(15), 4558. doi.org/10.3390/molecules26154558
2. Zhao, Y.; Truhlar, D. G. “The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements.” Theor. Chem. Acc. 2008, 120, 215–241. doi.org/10.1007/s00214-007-0310-x
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4. Lu, T.; Chen, F. “Multiwfn: A multifunctional wavefunction analyzer.” J. Comput. Chem. 2012, 33, 580–592. sobereva.com/multiwfn/
5. Frisch, M. J.; et al. Gaussian 16 Revision C.01; Gaussian, Inc.: Wallingford, CT, 2016. gaussian.com/g16
6. Ostojić, B. D.; Stilinović, V.; Glumac, B.; et al. “Aromatic CH as a hydrogen-bond donor: crystallographic evidence.” Chem. Commun. 2008, 48, 6546–6548. doi.org/10.1039/B810699A
7. Rocher-Casterline, B. E.; Vázquez, J.; Zwier, T. S. “Determination of the (H₂O)₂ bond dissociation energy.” J. Chem. Phys. 2011, 134, 211101. doi.org/10.1063/1.3562767
8. Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T. J. “Hexafluoroisopropanol as a highly versatile solvent.” Nat. Rev. Chem. 2017, 1, 0088. doi.org/10.1038/s41570-017-0088
9. Nakagawa, K.; et al. “Characterizing dipole–quadrupole CH–π interactions.” Chem. Sci. 2011, 2, 1234–1240. doi.org/10.1039/C1SC00045B
10. Li, H.-Y.; Zhao, D.; Cui, H.-L.; Lai, T.-T.; Zhao, P. “Hexafluoroisopropanol in organic synthesis: mechanistic insights and applications.” Tetrahedron 2016, 72, 8593–8604. doi.org/10.1016/j.tet.2016.10.030

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

Monomer-Polymer-Monomer Method - From Monomers to High-Value Molecules

Introduction

Functionalization of the benzene ring of benzofuran is synthetically challenging because direct electrophilic aromatic substitution (S_EAr) is directed to the 2- and 3-positions of the furan ring. The Monomer-Polymer-Monomer (MPM) method overcomes this bias via a concise three-step cycle—cationic polymerization, S_EAr on the polymer, and thermal depolymerization—enabling regioselective access to 5-substituted benzofurans with high theoretical atom economy.

Concept of the MPM Strategy

In the MPM approach, benzofuran monomers are first “locked” into solvent-soluble, linear polybenzofuran (PBF) chains by cationic polymerization in hexafluoro-2-propanol (HFIP) using trifluoromethanesulfonic acid (TfOH) as the initiator. This polymeric intermediate uniformly activates the benzene ring for subsequent S_EAr reactions.

Graphical Abstract

Graphical Abstract from Hua & Lu, Asian Journal of Organic Chemistry 2021, 10(8), 2137–2142. Source: ScienceDirect

Polymerization in HFIP

Under optimized conditions (0.2 mol % TfOH in HFIP at 0 °C), benzofuran undergoes rapid cationic polymerization to yield soluble, linear PBF. Real-time UV–vis spectroscopy and TD-DFT studies reveal cationic π- and σ-complex intermediates, and ¹³C NMR shows two characteristic signals at 83.7 ppm and 49.0 ppm.

Regioselective S_EAr on PBF

The soluble PBF intermediate undergoes S_EAr with various electrophiles—acylation, halogenation, nitration, etc.—installing substituents para to the alkoxy linkage in each repeat unit with excellent regiocontrol and broad functional-group tolerance.

Thermal Depolymerization

Substituted PBF chains cleanly depolymerize at 320 °C under nitrogen to regenerate 5-substituted benzofuran monomers in high yield, completing the MPM cycle with minimal waste and high selectivity.

References

1. R. Hua & L. Lu, “A Monomer-Polymer-Monomer (MPM) Organic Synthesis Strategy: Synthesis and Application of Polybenzofuran for Functionalizing Benzene Ring of Benzofuran,” Asian Journal of Organic Chemistry 2021, 10(8), 2137–2142. https://www.sciencedirect.com/science/article/pii/S2193580722023868