Emerging unconventional organic solvents for C–H bond and related functionalization reactions

Abstract

Recognizing and classifying the recently appeared reactivity enabling unconventional solvents is the main objective of this tutorial review, for applications in the field of C–H bond functionalization reactions.

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C–H activation

“…While there are plenty of solvents known for their extraordinary assistance in various synthetic transformations, there are a few hidden gems often tagged as “unconventional solvents”. 2 1,1,1,3,3,3-Hexafluoro-2-propanol or HFIP is one of them. It could be the corrosive nature (highly burning sensation upon inhalation or skin contact) or inflammability of HFIP that mandates extra care while handling and storage or being expensive (US$130 per kg) 3 that holds back researchers across the globe to use the solvent immensely.…”

Access to the Syn diastereomers of cryptophane cages using HFIP

“…Quite recently, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) has become a popular solvent in chemistry. 14,15 It exhibits specific features due to the presence of the trifluoromethyl groups and the formation of dimers and trimers of HFIP. Compared to isopropanol, its ionizing power, Brønsted acidity and H-bond acidity are enhanced.…”

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

“…This transformation was also used to prepare an analog of bexarotene, an antineoplastic agent (42, 62%). When less electron-deficient styrene oxides were employed, such as 4-fluorostyrene oxide, styrene oxide, 2-(naphthalen-2-yl)oxirane, and 4-tert-butylstyrene oxide, the catalyst loading was decreased to 0.1 mol % to provide the target compounds in yields ranging from 52%-92% (50)(51)(52)(53)(54)(55)(56)(57)(58). These more reactive styrene oxides were not compatible with weak arene nucleophiles, such as benzene, due to the oligomerization of the former.…”

“…Herein, we describe the expansion of the Friedel-Crafts reaction to include most classes of terminal epoxides (ring-opening arylation), primary aliphatic alcohols (dehydroarylation), and a sequential dehydrodiarylation process stemming from their combination. The key to the reactivity is the use of the solvent hexafluoroisopropanol (HFIP) [50][51][52][53][54] with triflic acid (TfOH) as a catalyst. Indeed, the association of Lewis or Brønsted acid catalysts with HFIP is known to trigger transformations with rather unreactive alcohols, alkenes, and cyclopropanes through the formation of highly reactive hydrogen-bond networks.…”