PERSPECTIVES
CHEMISTRY
Fluoroform (CHF3), a waste product that has
been destroyed, can now be used to synthesize
a wide variety of fluorinated compounds.
Putting a Greenhouse Gas to Work
Günter Haufe
n 2011, 3 of the 10 best-selling pharma-
ceuticals and 7 of the 35 newly approved
such as KF or HF (12), from carboxylic acids
by treatment with SF4 in HF, or by oxidative
desulfurization-fluorination by treatment of
dithiocarboxylic acid esters (13) or even aryl
thioethers (14) with electrophiles in the pres-
ence of fluoride sources.
All these pathways do serve perfectly for
particular applications but lack general appli-
cability, are based on potentially dangerous
and expensive reagents, or suffer from both
drawbacks. In contrast, the method devel-
oped by Prakash et al., in which the use of
potassium hexamethyldisilazide (KHMDS)
as the base in common organic solvents
such as THF or toluene was carefully opti-
mized, provides smooth access to reagents
such as trifluoromethyl trialkylsilanes or tri-
fluoromethyl trialkylborates. The latter can
be transformed to the increasingly important
Pharmaceuticals
Agrochemicals
I
active ingredients were compounds bear-
ing organofluorine groups such as trifluo-
romethyl (CF3) (1). Similar statistics hold
for agrochemicals. Organofluorine groups
confer useful properties such as high lipo-
philicity (and membrane permeability) and
enhanced metabolic stability. The vast major-
ity of methods for the introduction of CF3
groups are based on CBrF3 (either directly
or as a starting material) and similar ozone-
depleting substances that have their atmo-
spheric emission strictly regulated by the
Montreal protocol. Thus, new trifluorometh-
ylating reagents are highly desirable. On page
1324 of this issue, Prakash et al. (2) report on
direct nucleophilic trifluoromethylation reac-
tions of a variety of silicon, boron, sulfur, and,
Materials
Waste treatment
CHF
3
Repurposing fluoroform. A major by-product of
the industrial synthesis of fluoropolymers and refrig-
erants, CHF3 is a powerful greenhouse gas that must
be destroyed as a waste. Its use as a common fluori-
nated building block, as developed by Prakash et al.,
should allow its use in synthesis of pharmaceuticals,
agrochemicals, and materials.
most interestingly, carbon electrophiles using tion by a strong base. CHF3 is a weak carbon trifluoromethyl trifluoroborate anion. Fur-
only stoichiometric amounts of CHF3 (fluoro- acid with an acidity constant or pKa of 25 to thermore, aromatic nonenolizable ketones,
form) facilitated by optimizing the base and 28 in water, intermediate between esters and aldehydes, chalcones, formate esters, benzyl
solvent used in the reaction. This compound amine. The development of bases to activate bromide, and methylbenzoate were success-
is actually an unwanted greenhouse-gas by- dates back more than 20 years, although the fully trifluoromethylated in moderate to good
product from the production of fluoropoly- methods have had limited scope. The elec- yields. Thus, this method is a welcome exten-
mers and refrigerants (see the figure).
trochemically generated anion of pyrrol- sion of the toolbox for trifluoromethylation
The synthesis of a particular organofluo- idone deprotonates CHF3, and the CF3 anion of various silicon, boron, sulfur, and car-
rine molecule is still challenging because an formed can add to carbonyl groups efficiently bon compounds. In the future, additional—
organic reaction that normally would pro- in dimethylformamide (DMF) in the pres- preferably atom-economic and environmen-
ceed smoothly might not work as well once ence of hexamethyldisilazane (6). Further- tally benign—methods will be desired.
parts of the molecule are fluorinated. The more, treatment of CHF3 with strong organic
References
extent of fluorination desired is often not bases in the presence of DMF provided a
1. A. Studer, Angew. Chem. Int. Ed. 51, 8950 (2012).
high; most pharmaceuticals contain either a form of the CF3 anion stabilized as a hemi-
2. G. K. S. Prakash, P. V. Jog, P. T. D. Batamack, G. A. Olah,
single aliphatic or aromatic fluorine atom or aminolate species, which reacted with car-
a CF3 group attached to aliphatic, aromatic, bonyl compounds (7). Recent studies demon-
or heteroaromatic positions (3, 4). A most strated the direct transition-metal–mediated
promising source for a fluorinating agent substitutive trifluoromethylations of aromatic
is CHF3 (trifluoromethane, also known as and heteroaromatic halides, including those
fluoroform, Freon 23, HFC 23, and R-23) applying fluoroform as starting material, as
because it is available at a rate of thousands highlighted recently (8).
Science 338, 1324 (2012).
3. S. Swallow, in Fluorine in Pharmaceutical and Medicinal
Chemistry. From Biophysical Aspects to Clinical Applica-
tions, V. Gouverneur, K. Müller Eds. (Imperial College
Press, London, 2012), pp. 141–174.
4. E. P. Cormier, M. Das, I. Ojima, in Fluorine in Medicinal
Chemistry and Chemical Biology, I. Ojima, Ed. (Wiley-
Blackwell, Chichester, 2009), pp. 525–603.
5. W. Han, Y. Li, H. Tang, H. Liu, J. Fluor. Chem. 140, 7
(2012).
6. T. Shono, M. Ishifune, T. Okada, S. Kashimura, J. Org.
Chem. 56, 2 (1991).
7. B. R. Langlois, T. Billard, ACS Symp. Ser. 911, 57 (2005).
8. O. A. Tomashenko, V. V. Grushin, Chem. Rev. 111, 4475
(2011).
9. J.-A. Ma, D. Cahard, J. Fluor. Chem. 128, 975 (2007).
10. J.-A. Ma, D. Cahard, Chem. Rev. 108, PR1 (2008).
11. N. Shibata, A. Matsnev, D. Cahard, Beilstein J. Org. Chem.
6, 65 (2010).
12. M. A. McClinton, D. A. M. McClinton, Tetrahedron 48,
6555 (1992).
13. M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 44, 214
(2005).
14. V. Hugenberg, G. Haufe, J. Fluor. Chem. 143, 238
(2012).
of tons per year. Its global warming poten-
In general, CF3 groups can be transferred
tial is up to 15,000 times that of carbon diox- to organic substrates by C-C bond formation
ide, and it has an atmospheric lifetime of 264 using three different strategies. In addition to
years (5), but there has been no major use for nucleophilic, radical and electrophilic triflu-
CHF3. Instead, it is decomposed at great costs oromethylations also were extensively used
by thermal oxidation, catalytic hydrolysis, (9), and asymmetric variations to trifluoro-
plasma destruction, or conversion to environ- methylate carbonyl compounds were devel-
mentally benign compounds (5). oped (10). Recently, both electrophilic (11)
The problem with using CHF3 versus and radical trifluoromethylations (1) have
CBrF3 is that the C-H bond is much stronger undergone a renaissance.
than the C-Br bond, and it requires activa-
Alternatively to the C-C bond-forming
methods, the CF3 group can also be prepared
from the corresponding CCl3 unit by treat-
ment with different inorganic fluoride sources
Organisch-Chemisches Institut, Universität Münster, D-48149
Münster, Germany. E-mail: haufe@uni-muenster.de
10.1126/science.1231092
Published by AAAS
1298
Surya Prakash
