Introduction

In recent years, pentafluorophenol (PFP; Figure 1) has emerged as a versatile and efficient catalyst in organic synthesis, owing to its strong electron-withdrawing nature, unique reactivity, and low pKa (~5.5), which make it highly acidic and effective in protonation and activation of electrophiles. Its ability to facilitate cyclizations, condensations, and C-C bond-forming reactions under mild, metal-free conditions has been well established. Applications of pentafluorophenol include use as a reagent in chemical synthesis and use in research concerning pollutant?soil organic matter interactions. Pentafluorophenol is not expected to be present in the atmosphere at detectable levels; however, pentafluorophenol can serve as a model aromatic compound to help improve our understanding of the Cl- and OH-initiated reactions of aromatic compounds. Despite its utility in organic synthesis, pentafluorophenol has not been explored in the synthesis of carbazole derivatives.[1-2]

1. Pentafluorophenol-Catalyzed Metal-Free Fischer Indole Synthesis

Recognizing this gap, Diksha and his coworkers have developed a novel pentafluorophenol-catalyzed approach, leveraging its strong acidity and activation properties to achieve high efficiency and selectivity. Notably, they have previously demonstrated the utility of pentafluorophenol in the synthesis of spirobenzazepinoindole, further highlighting its versatility as an effective catalyst in complex heterocyclic frameworks.The strong electron-withdrawing properties and low pKa of PFP facilitate the effective activation of electrophiles, leading to improved yields and selectivity. A comprehensive exploration of substrate diversity has been conducted, resulting in the synthesis and thorough characterization of various carbazole derivatives using ¹H NMR, ¹³C NMR, DEPT-135, IR, and mass spectrometry. A scale-up synthesis was also executed to validate the method’s scalability. Additionally, a natural carbazole alkaloid was synthesized, followed by post-synthetic modifications to enhance the diversity of the compound library. This approach provides a valuable alternative to traditional acid-catalysed methods, thereby broadening the synthetic avenues for carbazoles and their derivatives.[1]

2. Atmospheric Chemistry of Pentafluorophenol (C₆F₅OH)

The kinetic data obtained in this study can be used to estimate the atmospheric lifetime of pentafluorophenol. Removal of pentafluorophenol from the atmosphere proceeds through a reaction with OH radicals, Cl atoms, O₃, and NO₃ radicals and by wet and dry deposition. Pentafluorophenol is not expected to be removed effectively by either wet or dry deposition. Degradation initiated by O₃ and NO₃ radicals is typically negligible as the reactions are slow. The global mean concentration of Cl atoms in the atmosphere is around 3 orders of magnitude lower than the global mean average of OH radicals, [OH] = 1×10⁶ molecule cm^?3 versus [Cl] = 1×10³ molecule cm^?3. This, as well as the rate constant ratio k(C₆F₅OH+Cl)/k(C₆F₅OH+OH)≈4, shows that Cl-initiated degradation will not compete with OH-initiated degradation. The lifetime of C₆F₅OH with regard to OH is estimated by combining the global average OH concentration ([OH] = 1×10⁶ molecule cm^?3) and the value of k₇ determined in this study, resulting in a lifetime of approximately 40 days. The same is done for the loss of pentafluorophenol by Cl atoms using [Cl] = 1×10³ molecule cm^?3 and the determined value for k₁₁, yielding a lifetime of approximately 1 year. The photolysis rate of pentafluorophenol relative to CH₃CHO at 254 nm determined in this study suggests a relatively short photolysis lifetime with respect to 254 nm irradiation. However,since the flux of solar radiation below 300 nm is insignificant in the Earth’s troposphere, photolysis of pentafluorophenol would likely be of no importance as an atmospheric sink. Thus, loss of pentafluorophenol is effectively determined by a reaction with OH radicals and its global average atmospheric lifetime is approximately 40 days.[2]

3. Pentafluorophenol (C₆F₅OH) Catalyzed Pictet-Spengler Reaction

Herein, Mahato and his coworkers have disclosed pentafluorophenol as an operative catalyst for synthesizing (spirocyclic) tetrahydro-β-carbolines via the Pictet-Spengler reaction. This straightforward catalytic protocol works under mild conditions resulting indole alkaloids in excellent yield with remarkable functional group tolerance, including late-stage modifications. This transformation demonstrates a practical and adaptable approach to produce a highly effective gram-scale synthesis of the natural alkaloid Komavine and enables the synthesis of the commercial drug Tadalafil.[3]

References

[1]Bansal D, Sivaganesan P, Elanchezhian C, Nataraj G, Das MK, Chaudhuri S. Pentafluorophenol-Catalyzed Metal-Free Fischer Indole Synthesis: A Novel Approach to Carbazole Derivatives and Desbromoarborescidine A. Chem Asian J. Published online February 20, 2025. doi:10.1002/asia.202500246

[2]Hasager F, Andersen ST, Hass SA, Sulbaek Andersen MP, Nielsen OJ. Atmospheric Chemistry of Pentafluorophenol: Kinetics and Mechanism of the Reactions of Cl Atoms and OH Radicals. J Phys Chem A. 2019;123(47):10315-10322. doi:10.1021/acs.jpca.9b07781

[3]Mahato R, Hazra CK. Pentafluorophenol (C6 F5 OH) Catalyzed Pictet-Spengler Reaction: A Facile and Metal-Free Approach Towards Tetrahydro-β-Carbolines. Chemistry. 2023;29(27):e202203924. doi:10.1002/chem.202203924