Beginning in the 1950s, many studies exploring the physical properties of fluorinated alcohols laid the groundwork for understanding the complex interactions of these solvents. Prior to this, the idea that the introduction of fluorine would increase the acidity of alcohols can be traced back to Swarts, Henne and Pelley et al. who experimentally confirmed this in 1952.Swarts first described the preparation of trifluoroethanol (TFE) by catalytic reduction of trifluoroacetic anhydride over a platinum-black catalyst. In 1960, Knunyants et al. reported the first synthesis of hexafluoroisopropanol (HFIP) by reduction of hexafluoroacetone with sodium borohydride. Later, they isolated HFIP from the Grignard reaction of hexafluoroacetone with isopropylmagnesium bromide.
In 1964, Middleton and Lindsey et al. reported that HFIP had a significant hydrogen bonding capacity compared to several fluorinated sec- and tert-fluorinated alcohols, which stemmed from the cumulative inductive effect of the six fluorine atoms. Fluorinated alcohols with strong hydrogen bonding ability can form stable, distillable, or recrystallizable equimolar complexes with suitable hydrogen-bonded acceptor compounds; for example, the HFIP-THF complex boils at 100 °C.
Applied research
Throughout the 1960s and 1970s, researchers began to realize that hexafluoroisopropanol was a superior solvation medium and began to explore its utility in facilitating chemical reactions. Some of these reports focused on the physical chemistry of trifluoroethanol (TFE) in solvent decomposition chemistry, such as alkyl toluenesulfonate. Fluorinated alcohols were also reported to be excellent solvents for dissolving polymeric materials.
In the late 1970s, HFIP and TFE were demonstrated in the four-component condensation of Ugi, one of the earliest uses in organic synthesis.Sieber et al. also described the use of TFE (90% aqueous TFE) as a solvent for the mild, pH-controlled deprotection of N (α)-trityl ( N-trityl) in the presence of other acids under acidolytic conditions. This selective deprotection strategy is essential to accomplish the total synthesis of human insulin. Similarly, aniline protected with the very acid-unstable dicyclopropylmethoxycarbonyl group was deprotected by simple dilution in HFIP.Grell et al. subsequently showed that a 4:1 mixture of DCM and HFIP was used to cleave fully protected peptides from o-chlorotriphenylmethyl resins without significant racemization while preserving peptide utility in solution.
Kopple et al. further investigated the use of HFIP as a solvent for peptide coupling and determined that solvent decomposition of the active carboxyl component yielded HFIP esters that could be used as mild acylating agents for peptide coupling. Although HFIP is a suitable solvent for solubilizing peptides and cleaving acid-sensitive protecting groups, peptide coupling in HFIP is much slower than in dimethoxyethane (DME) or N , N-dimethylformamide (DMF).
Physicochemical properties
Of the fluorinated alcohols, hexafluoroisopropanol and TFE are the most widely used by organic chemists because of their low cost and better physical properties, including boiling point (bp) and melting point (mp), than other fluorinated alcohols (e.g., perfluoro-tertiary alcohols). Butanol (PFTB; boiling point 45 °C), 1-phenyl-2,2,2-trifluoroethanol (PhTFE) and perfluoropinacol (PFP; mp 26 °C). The presence of a strong electron-withdrawing trifluoromethyl group gives TFE and hexafluoroisopropanol their properties of high polarity, increased Bronsted acidity of hydroxyl protons (low pKa), high ionizability, low nucleophilicity, and a strong hydrogen-bond-donating (HBD) ability. Hydrogen bond acceptance is poor and the ability to solvate anions and stabilize cations is superior to similar non-fluorinated alcohols, ethanol and 2-propanol.
Legros et al. investigated the effect of polyfluorinated alcohols on Bronsted acidity and hydrogen bond donor capacity as well as their ability to act as solvent promoters. The authors observed that the hydrogen bond donor capacity was sensitive to the spatial site resistance around the hydroxyl group of the various fluorinated alcohols, while the Brønsted acidity was mainly influenced by the number of CF3 groups present in the molecule rather than the overall structure. The authors' tests of various polyfluoroalcohol solvents as promoters of the sulfoxide oxidation and iminium Diels-Alder reactions showed that the hydrogen bond donor capacity plays a major role in promoting these reactions, whereas the Brønsted acidity appeared to have little or no effect, and that hexafluoroisopropanol is preferred to the other fluorinated solvents in these reactions. On the other hand, it completely inhibited the epoxide ring-opening reaction with piperidine by forming an almost irreversible hydrogen-bonded adduct with the basic piperidine.
References.
[1] Hashim F. Motiwala, Ahlam M. Armaly, Jackson G. Cacioppo, Thomas C. Coombs, Kimberly R. K. Koehn, Verrill M. Norwood IV, and Jeffrey Aubé. Chemical Reviews 2022, 122(15), 12544-12747. DOI: 10.1021/acs.chemrev.1c00749