trifluoromethylation

The first to investigate trifluoromethyl groups in relationship to biological activity was F. Lehmann in 1927.Lehmann, F. "Chemical constitution and activity. Aromatic fluorine compounds." Arch. exp. Pathol. Pharmakol 130 (1928): 250-255. An early review appeared in 1958.{{Cite journal | doi = 10.1021/jm50003a001| pmid = 13665284| title = The Trifluoromethyl Group in Medical Chemistry| journal = Journal of Medicinal and Pharmaceutical Chemistry| volume = 1| issue = 2| pages = 121–133| year = 1959| last1 = Yale | first1 = H. L.}} An early synthetic method was developed by Frédéric Swarts in 1892,{{cite journal |last=Swarts|journal=Acad. Roy. Belg|volume=3|issue=24|page=474|year=1892}} based on antimony fluoride. In this reaction benzotrichloride was reacted with SbF₃ to form PhCF₂Cl and

PhCF₃. In the 1930s Kinetic Chemicals and IG Farben replaced SbF₃ with HF.

The McLoughlin-Thrower reaction (1968) is an early coupling reaction using iodofluoroalkanes, iodoaromatic compounds and copper.{{Cite journal | doi = 10.1016/S0040-4020(01)83100-8| title = A route to fluoroalkyl-substituted aromatic compounds involving fluoroalkylcopper intermediates| journal = Tetrahedron| volume = 25| issue = 24| pages = 5921–5940| year = 1969| last1 = McLoughlin | first1 = V. C. R. | last2 = Thrower | first2 = J.}} In 1969 Kobayashi & Kumadaki adapted their protocol for trifluoromethylations.{{Cite journal | doi = 10.1016/S0040-4039(01)88624-X| title = Trifluoromethylation of aromatic compounds| journal = Tetrahedron Letters| volume = 10| issue = 47| pages = 4095–4096| year = 1969| last1 = Kobayashi | first1 = Y. | last2 = Kumadaki | first2 = I.}}{{Cite journal | doi = 10.1016/S0040-4020(99)00951-5| title = Fluoroform: An Efficient Precursor for the Trifluoromethylation of Aldehydes| journal = Tetrahedron| volume = 56| issue = 2| pages = 275–283| year = 2000| last1 = Folléas | first1 = B. ̂T. | last2 = Marek | first2 = I. | last3 = Normant | first3 = J. F. | last4 = Saint-Jalmes | first4 = L.}}

Preparation of the trifluoromethyltrimethylsilane was reported by Ingo Ruppert in 1984.{{cite journal|last1=Ruppert|first1=Ingo|last2=Schlich|first2=Klaus|last3=Volbach|first3=Wolfgang|title=Die ersten CF3-substituierten organyl(chlor)silane|journal=Tetrahedron Letters|date=January 1984|volume=25|issue=21|pages=2195–2198|doi=10.1016/S0040-4039(01)80208-2}} In 1989, Prakash and Olah first reported activation of TMSCF₃ by fluoride to perform nucleophilic trifluoromethylation of carbonyl compounds.{{cite journal|last1=Prakash|first1=G. K. Surya|last2=Krishnamurti|first2=Ramesh|last3=Olah|first3=George A.|title=Synthetic methods and reactions. 141. Fluoride-induced trifluoromethylation of carbonyl compounds with trifluoromethyltrimethylsilane (TMS-CF3). A trifluoromethide equivalent|journal=Journal of the American Chemical Society|date=January 1989|volume=111|issue=1|pages=393–395|doi=10.1021/ja00183a073|bibcode=1989JAChS.111..393P }} In the same year, Stahly described similar reactions for the synthesis of trifluoromethylated phenols and anilines.{{cite journal|last1=Stahly|first1=G. Patrick|last2=Bell|first2=Donald R.|title=A new method for synthesis of trifluoromethyl-substituted phenols and anilines|journal=The Journal of Organic Chemistry|date=June 1989|volume=54|issue=12|pages=2873–2877|doi=10.1021/jo00273a020}} Since then TMSCF₃ has been widely used as a nucleophilic trifluoromethylating agent.{{cite journal | journal = Chemical Reviews | year = 1997 | volume = 97 | pages = 757–786 | doi = 10.1021/cr9408991 | title = Perfluoroalkylation with Organosilicon Reagents | author = G. K. Surya Prakash; Andrei K. Yudin | pmid=11848888 | issue = 3}}{{cite journal | journal = Chemical Reviews | year = 2015 | volume = 115 | pages = 683–730 | doi =10.1021/cr400473a | title = Trifluoromethyltrimethylsilane: Nucleophilic Trifluoromethylation and Beyond | author = Xiao Liu, Cong Xu, Mang Wang, and Qun Liu| pmid= 24754488| issue = 2}}

An example is the trifluoromethylation of cyclohexanone in THF using tetrabutylammonium fluoride.{{cite journal|last1=Ramaiah|first1=Pichika|last2=Krishnamurti|first2=Ramesh|last3=K. Surya Prakash|first3=G.|title=1-TRIFLUOROMETHYL-1-CYCLOHEXANOL|journal=Organic Syntheses|date=1995|issue=72|page=232|doi=10.15227/orgsyn.072.0232|volume=72}}

The substrates can be aryl halides.{{cite journal | last1 = Morimoto | first1 = H. | last2 = Tsubogo | first2 = T. | last3 = Litvinas | first3 = N. D. | last4 = Hartwig | first4 = J. F. | year = 2011 | title = A Broadly Applicable Copper Reagent for Trifluoromethylations and Perfluoroalkylations of Aryl Iodides and Bromides | journal = Angewandte Chemie | volume = 123 | issue = 16| pages = 3877–3882 | doi = 10.1002/ange.201100633 | pmid = 21442711 | pmc = 3159489 | bibcode = 2011AngCh.123.3877M }}{{cite journal | last1 = Oishi | first1 = Masahiro | last2 = Kondo | first2 = Hideaki | last3 = Amii | first3 =Hideki | year = 2009| title = Aromatic trifluoromethylation catalytic in copper | journal = Chemical Communications | volume = 2009 | issue = 14| pages = 1909–1911 | doi = 10.1039/B823249K| pmid = 19319442 }} Potassium (trifluoromethyl)trimethoxyborate for this purpose has been synthesised from B(OMe)₃, CF₃SiMe₃ and KF.{{cite journal | last1 = Knauber | first1 = T. | last2 = Arikan | first2 = F. | last3 = Röschenthaler | first3 = G.-V. | last4 = Gooßen | first4 = L. J. | year = 2011 | title = Copper-Catalyzed Trifluoromethylation of Aryl Iodides with Potassium (Trifluoromethyl)trimethoxyborate | journal = Chemistry: A European Journal | volume = 17 | issue = 9| pages = 2689–2697 | doi = 10.1002/chem.201002749 | pmid = 21274956}} Aryl functionalization by C-H activation has also been reported.{{cite journal | last1 = Ye | first1 = Yingda | last2 = Lee | first2 = Shin Hee | last3 = Sanford | first3 = Melanie S. | year = 2011 | title = Silver-Mediated Trifluoromethylation of Arenes Using TMSCF3 | journal = Organic Letters| volume = 13 | issue = 20| pages = 5464–5467 | doi = 10.1021/ol202174a | pmid = 21932827 | pmc = 3229100}}{{cite journal | last1 = Hafner | first1 = A. | last2 = Bräse | first2 = S. | year = 2012 | title = Ortho-Trifluoromethylation of Functionalized Aromatic Triazenes | journal = Angewandte Chemie International Edition | volume = 51 | issue = 15| pages = 3713–3715 | doi = 10.1002/anie.201107414| pmid = 22318969 }}

Sodium trifluoroacetate as a reagent for trifluoromethylations was introduced by Matsui in 1981. In the original scope the substrate was an aromatic halide and the metal salt copper(I)iodide.{{cite journal|last1=Matsui|first1=Kiyohide|last2=Tobita|first2=Etsuko|last3=Ando|first3=Midori|last4=Kondo|first4=Kiyosi|title=A convenient trifluoromethylation of aromatic halides with sodium trifluoroacetate.|journal=Chemistry Letters|volume=10|date=1981|issue=12|pages=1719–1720|doi=10.1246/cl.1981.1719|doi-access=free}}{{cite journal|last1=Langlois|first1=Bernard R.|last2=Roques|first2=Nicolas|title=Nucleophilic trifluoromethylation of aryl halides with methyl trifluoroacetate|journal=Journal of Fluorine Chemistry|date=October 2007|volume=128|issue=10|pages=1318–1325|doi=10.1016/j.jfluchem.2007.08.001|bibcode=2007JFluC.128.1318L }}

Fluoroform (CF₃H) has been employed as a trifluoromethylation reagent for aldehydes in combination with a strong base.{{cite journal|last1=Folléas|first1=Benoît|last2=Marek|first2=Ilan|last3=Normant|first3=Jean-F|last4=Jalmes|first4=Laurent Saint|title=Fluoroform: an efficient precursor for the trifluoromethylation of aldehydes|journal=Tetrahedron Letters|date=May 1998|volume=39|issue=19|pages=2973–2976|doi=10.1016/S0040-4039(98)00391-8}}

Trifluoroiodomethane is a reagent in aromatic coupling reactions. It has also been used with enones, for example with chalcone, a reaction catalysed by diethyl zinc and Wilkinson's catalyst:{{cite journal|last1=Sato|first1=Kazuyuki|last2=Omote|first2=Masaaki|last3=Ando|first3=Akira|last4=Kumadaki|first4=Itsumaro|title=TRIFLUOROMETHYLATION AT THE a-POSITION OF b,b-UNSATURATED KETONES: 4-PHENYL-3-(TRIFLUOROMETHYL)BUTAN-2-ONE|journal=Organic Syntheses|date=2006|issue=83|page=177|doi=10.15227/orgsyn.083.0177|volume=83|doi-access=free}}

Trifluoromethyl sulfone (PhSO₂CF₃) and trifluoromethyl sulfoxide (PhSOCF₃) can be used for trifluoromethylations of electrophiles{{cite journal|last1=Prakash|first1=G. K. Surya|last2=Hu|first2=Jinbo|last3=Olah|first3=George A.|title=Alkoxide- and Hydroxide-Induced Nucleophilic Trifluoromethylation Using Trifluoromethyl Sulfone or Sulfoxide|journal=Organic Letters|date=September 2003|volume=5|issue=18|pages=3253–3256|doi=10.1021/ol035045u|pmid=12943400}}

Trifluoromethanesulfonyl chloride (or triflyl chloride, CF3SO2Cl) can be used in a highly efficient method to introduce a trifluoromethyl group to aromatic and heteroaromatic systems, including known pharmaceuticals such as Lipitor. The chemistry is general and mild, and uses a photoredox catalyst and a light source at room temperature.{{cite journal|last1=Nagib|first1=David A.|last2=MacMillan|first2=David W. C.|title=Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis|journal=Nature|date=8 December 2011|volume=480|issue=7376|pages=224–228|doi=10.1038/nature10647|pmid=22158245|pmc=3310175|bibcode=2011Natur.480..224N}}

:File:Photoredox trifluoromethylation.png

Sodium trifluoromethanesulfinate (CF₃SO₂Na) as a trifluoromethylation reagent was introduced by Langlois in 1991.{{cite journal|last1=Langlois|first1=Bernard R.|last2=Laurent|first2=Eliane|last3=Roidot|first3=Nathalie|title=Trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions.|journal=Tetrahedron Letters|date=December 1991|volume=32|issue=51|pages=7525–7528|doi=10.1016/0040-4039(91)80524-A}} The reaction requires t-butyl hydroperoxide and generally a metal and proceeds through a radical mechanism. The reagent has been applied with heterocyclic substrates{{cite journal|last1=Ji|first1=Y.|last2=Brueckl|first2=T.|last3=Baxter|first3=R. D.|last4=Fujiwara|first4=Y.|last5=Seiple|first5=I. B.|last6=Su|first6=S.|last7=Blackmond|first7=D. G.|last8=Baran|first8=P. S.| author-link8 = Phil S. Baran | title=Innate C-H trifluoromethylation of heterocycles|journal=Proceedings of the National Academy of Sciences|date=15 August 2011|volume=108|issue=35|pages=14411–14415|doi=10.1073/pnas.1109059108|pmid=21844378|pmc=3167544|bibcode=2011PNAS..10814411J|doi-access=free}}

File:5-(Trifluoromethyl)dibenzothiophenium tetrafluoroborate.svg

Umemoto reagents are (trifluoromethyl)dibenzoheterocyclic salts, such as 5-(trifluoromethyl)dibenzothiophenium triflate and 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate.{{cite journal|last1=Zhang|first1=Cai|title=Recent advances in trifluoromethylation of organic compounds using Umemoto's reagents|journal=Organic & Biomolecular Chemistry|date=11 July 2014|volume=12|issue=34|pages=6580–9|doi=10.1039/C4OB00671B|pmid=25011917}}{{cite journal|last1=Li|first1=Huiqin|title=Umemoto's Reagent|journal=Synlett|date=3 September 2012|volume=23|issue=15|pages=2289–2290|doi=10.1055/s-0032-1317176|doi-access=free}}

Many CF₃-containing metal complexes have been prepared, and some are useful for trifluoromethylation. The most obvious reagent is CF₃Li, which can be generated by lithium-iodide exchange. This compound is however unstable even at low temperatures. It degrades to lithium fluoride and difluorocarbene. Trifluoromethyl copper(I) reagents are more useful. These reagents are generated in situ by reaction of CF₃I with copper powder in polar solvents.Donald J. Burton, Long Lu "Fluorinated Organometallic Compounds" Topics in Current Chemistry, 1997, Vol. 193, p. 45. Hg(CF₃)₂, prepared by decarboxylation of the trifluoroacetate, has proven useful for the trifluoromethylation of other metals,Reint Eujen "Bis(Trifluoromethyl)Mercury" 1986, volume 24, p. 52. {{doi|10.1002/9780470132555.ch16}} although for low-temperature reactions it may prove useful to transmetallate to bis(trifluoromethyl)cadmium.{{cite journal|doi=10.1021/ja00401a015|journal=Journal of the American Chemical Society|year=1981|issue=103|pages=2995–3001|title=Trifluoromethyl group 2B compounds: Bis(trifluoromethyl)cadmium·base: New, more powerful ligand-exchange reagents and low-temperature difluorocarbene sources}}

In coupling reactions between aromatic compounds and metal-trifluoromethyl complexes the metal is usually copper, Pd and Ni are less prominent. The reactions are stoichiometric or catalytic. In the McLoughlin-Thrower reaction (1962) iodobenzene reacts with trifluoroiodomethane (CF₃I) and copper powder in dimethylformamide at 150 °C to trifluoromethylbenzene. The intermediate in this reaction type is a perfluoromethyl-metal complex.

A palladium acetate catalysed reaction described in 1982 used zinc powder with the main intermediate believed to be CF₃ZnI with Pd(0) is the active catalyst.{{cite journal | last1 = Kitazume | first1 = Tomoya | title = Palladium-Catalyzed Cross-Coupling Reactions Between Allyl, Vinyl or Aryl Halide and Perfluoroalkyl Iodide with Zinc and Ultrasonic Irradiation | last2 = Ishikawa | first2 = Nobuo | year = 1982 | journal = Chemistry Letters | volume = 11 | issue = 1| pages = 137–140 | doi = 10.1246/cl.1982.137 }}{{cite journal | last1 = Kitazume | first1 = Tomoya | last2 = Ishikawa | first2 = Nobuo | year = 1985 | title = Ultrasound-promoted selective perfluoroalkylation on the desired position of organic molecules | journal = Journal of the American Chemical Society | volume = 107 | issue = 18| pages = 5186–5191 | doi = 10.1021/ja00304a026 | bibcode = 1985JAChS.107.5186K }} The first copper catalysed coupling was reported in 2009 and based on an iodoarene, a trifluoromethylsilane, copper iodide and 1,10-phenanthroline.{{cite journal | last1 = Oishi | first1 = M. | last2 = Kondo | first2 = H. | last3 = Amii | first3 = H. | year = 2009| title = Aromatic trifluoromethylation catalytic in copper | journal = Chem. Commun. | volume = 2009 | issue = 14| pages = 1909–1911 | doi = 10.1039/B823249K | pmid = 19319442 }} Variations include another CF₃ donor potassium (trifluoromethyl)trimethoxyborate,{{cite journal | last1 = Knauber | first1 = T. | last2 = Arikan | first2 = F. | last3 = Roschenthaler | first3 = G.-V. | last4 = Gooßen | first4 = L. J. | year = 2011 | title = Copper-catalyzed trifluoromethylation of aryl iodides with potassium (trifluoromethyl) trimethoxyborate | journal = Chem. Eur. J. | volume = 17 | issue = 9| pages = 2689–2697 | doi = 10.1002/chem.201002749 | pmid = 21274956}} the use of aryl boronic acids{{cite journal | last1 = Chu | first1 = L. | last2 = Qing | first2 = F.-L. | year = 2010 | title = Copper-mediated oxidative trifluoromethylation of boronic acids | journal = Org. Lett. | volume = 12 | issue = 21| pages = 5060–5063 | doi = 10.1021/ol1023135 | pmid = 20923196}}{{cite journal|last1=Senecal|first1=Todd D.|last2=Parsons|first2=Andrew T.|last3=Buchwald|first3=Stephen L.|title=Room Temperature Aryl Trifluoromethylation via Copper-Mediated Oxidative Cross-Coupling|journal=The Journal of Organic Chemistry|date=18 February 2011|volume=76|issue=4|pages=1174–1176|doi=10.1021/jo1023377|pmid=21235259|pmc=3093444}} or the use of a trifluoromethyl sulfonium salt{{cite journal | last1 = Cheng- | first1 = Cheng-Pan| last2 = Zhang | first2 = Pan | last3 = Wang | first3 = Ling | last4 = Prof | first4 = Chun-Tao| last5 = Chen | first5 = Yun | last6 = Zhang | first6 = Tao | last7 = Gu | first7 = Cheng | last8 = -Qing- | first8 = Chun Dr. Yu- | last9 = Ji-Chang | first9 = Xiao | year = 2011 | title = Copper-mediated trifluoromethylation of heteroaromatic compounds by trifluoromethyl sulfonium salts | journal = Angew. Chem. Int. Ed. | volume = 50 | issue = 8| pages = 1896–1900 | doi = 10.1002/anie.201006823 | pmid = 21328665| display-authors =3}} or the use of a trifluoromethylcopper(I) phenanthroline complex.{{cite journal | last1 = Morimoto | first1 = H. | last2 = Tsubogo | first2 = T. | last3 = Litvinas | first3 = N. D. | last4 = Hartwig | first4 = J. F. | year = 2011 | title = A broadly applicable copper reagent for trifluoromethylations and perfluoroalkylations of aryl iodides and bromides | journal = Angew. Chem. Int. Ed. | volume = 50 | issue = 16| pages = 3793–3798 | doi = 10.1002/anie.201100633 | pmid = 21442711 | pmc = 3159489 }} A catalytic palladium catalysed reaction was reported in 2010 using aryl halides, (trifluoromethyl)triethylsilane and allylpalladium chloride dimer{{cite journal|last1=Cho|first1=E. J.|last2=Senecal|first2=T. D.|last3=Kinzel|first3=T.|last4=Zhang|first4=Y.|last5=Watson|first5=D. A.|last6=Buchwald|first6=S. L.|title=The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides|journal=Science|date=24 June 2010|volume=328|issue=5986|pages=1679–1681|doi=10.1126/science.1190524|pmid=20576888|bibcode=2010Sci...328.1679C|pmc=3005208}}

In radical trifluoromethylation the active species is the trifluoromethyl free radical.{{cite journal|last1=Ma|first1=Jun-An|last2=Cahard|first2=Dominique|title=Strategies for nucleophilic, electrophilic, and radical trifluoromethylations|journal=Journal of Fluorine Chemistry|date=September 2007|volume=128|issue=9|pages=975–996|doi=10.1016/j.jfluchem.2007.04.026|bibcode=2007JFluC.128..975M }} Reagents such as bromotrifluoromethane and haloform have been used for this purpose{{cite journal|last1=Andrieux|first1=Claude P.|last2=Gelis|first2=Laurence|last3=Saveant|first3=Jean-Michel|title=Unusual reactions resulting from the addition on olefins of trifluoromethyl radicals obtained from dissociative electron transfer between electrochemically generated aromatic anion radicals and trifluoromethyl bromide|journal=Tetrahedron Letters|date=January 1989|volume=30|issue=37|pages=4961–4964|doi=10.1016/S0040-4039(01)80554-2}}{{cite journal|last1=Uneyama|first1=Kenji|last2=Kitagawa|first2=Kouichi|last3=Kitagawa|first3=Kouichi|title=Perfluoroalkyl-selenation of olefins|journal=Tetrahedron Letters|date=January 1991|volume=32|issue=3|pages=375–378|doi=10.1016/S0040-4039(00)92632-7}}{{cite journal|last1=Uneyama|first1=Kenji|last2=Kanai|first2=Masatomi|title=Generation of perfluoroalkyl radicals at low temperature by tellurolate mediated electron transfer|journal=Tetrahedron Letters|date=December 1991|volume=32|issue=50|pages=7425–7426|doi=10.1016/0040-4039(91)80124-O}} but in response to the Montreal Protocol alternatives such as trifluoroiodomethane have been developed as replacement.{{cite journal|last1=Rasmusson|first1=Gary H.|last2=Brown|first2=Ronald D.|last3=Arth|first3=Glen E.|title=Photocatalyzed reaction of trifluoromethyl iodide with steroidal dienones|journal=The Journal of Organic Chemistry|date=March 1975|volume=40|issue=6|pages=672–675|doi=10.1021/jo00894a002|pmid=1133630}}{{cite journal|last1=Lan-Hargest|first1=Hsuan-Yin|last2=Elliott|first2=John D.|last3=Eggleston|first3=Drake S.|last4=Metcalf|first4=Brian W.|title=The photochemical rearrangement of a steroidal dienol triflate|journal=Tetrahedron Letters|date=January 1987|volume=28|issue=52|pages=6557–6560|doi=10.1016/S0040-4039(00)96912-0}} One particular combination is CF₃I / triethylborane{{cite journal|last1=Miura|first1=Katsukiyo|last2=Takeyama|first2=Yoshihiro|last3=Oshima|first3=Koichiro|last4=Utimoto|first4=Kiitiro|title=Triethylborane Induced Perfluoroalkylation of Silyl Enol Ethers and Ketene Silyl Acetals with Perfluoroalkyl Iodides.|journal=Bulletin of the Chemical Society of Japan|date=1991|volume=64|issue=5|pages=1542–1553|doi=10.1246/bcsj.64.1542|doi-access=free}}{{cite journal|last1=Miura|first1=Katsukiyo|last2=Taniguchi|first2=Masahiko|last3=Nozaki|first3=Kyoko|last4=Oshima|first4=Koichiro|last5=Utimoto|first5=Kiitiro|title=Triethylborane induced perfluoroalkylation of silyl enol ethers or germyl enol ethers with perfluoroalkyl iodides|journal=Tetrahedron Letters|date=January 1990|volume=31|issue=44|pages=6391–6394|doi=10.1016/S0040-4039(00)97073-4}}

Other reagents that generate the CF₃ radical are sodium trifluoromethanesulfinate and bis(trifluoroacetyl) peroxide.

In the CF₃ radical the fluorine atom is an electron-withdrawing group via the inductive effect but also a weak pi donor through interaction of the fluorine lone pair with the radical center's SOMO. Compared to the methyl radical the CF₃ radical is pyramidal (angle 107.8 °C ) with a large inversion barrier, electrophilic and also more reactive. In reaction with styrene it is 440 times more reactive.{{cite journal|last1=Studer|first1=Armido|title=A "Renaissance" in Radical Trifluoromethylation|journal=Angewandte Chemie International Edition|date=3 September 2012|volume=51|issue=36|pages=8950–8958|doi=10.1002/anie.201202624|pmid=22890985}} An early report (1949) describes the photochemical reaction of iodotrifluoromethane with ethylene to 3-iodo-1,1,1-trifluoropropane.{{cite journal|last1=Haszeldine|first1=R. N.|title=603. The reactions of fluorocarbon radicals. Part I. The reaction of iodotrifluoromethane with ethylene and tetrafluoroethylene|journal=Journal of the Chemical Society (Resumed)|date=1949|pages=2856|doi=10.1039/JR9490002856}} Reagents that have been reported for the direct trifluoromethylation of arenes are CF₃I, CF₃Br (thermal or photochemical), silver trifluoroacetate/TiO₂ (photochemical) and sodium trifluoromethanesulfinate/Cu(OSO₂CF₃)₂/tBuOOH.

In nucleophilic trifluoromethylation the active species is the CF₃⁻ anion.{{cite journal|last1=Langlois|first1=Bernard R.|last2=Billard|first2=Thierry|last3=Roussel|first3=Solveig|title=Nucleophilic trifluoromethylation|journal=Journal of Fluorine Chemistry|date=February 2005|volume=126|issue=2|pages=173–179|doi=10.1016/j.jfluchem.2004.11.007}} It was, however, widely believed that the trifluoromethyl anion is a transient species and thus cannot be isolated or observed in the condensed phase. Contrary to the popular belief, the CF₃ anion, with [K(18-crown-6)]⁺ as a countercation, was produced and characterized by Prakash and coworkers.{{cite journal | journal = Angew. Chem. Int. Ed.| year = 2014 | volume = 53 | pages = 11575–11578 | doi = 10.1002/anie.201406505| title = Long-Lived Trifluoromethanide Anion: A Key Intermediate in Nucleophilic Trifluoromethylations | author = Prof. Dr. G. K. Surya Prakash, Dr. Fang Wang, Zhe Zhang, Prof. Dr. Ralf Haiges, Dr. Martin Rahm, Prof. Dr. Karl O. Christe, Dr. Thomas Mathew, Prof. Dr. George A. Olah| pmid= 25146595| issue = 43}} The challenges associated with observation of CF₃ anion are alluded to its strong basic nature and its tendency to form pentacoordinated silicon species, such as [Me₃Si(CF₃)₂]⁻ or [Me₃Si(F)(CF₃)]⁻.

The reactivity of fluoroform in combination with a strong base such as t-BuOK with carbonyl compounds in DMF is an example. Here CF₃⁻ and DMF form an hemiaminolate adduct ([Me₂NCH(O)CF₃]K).{{cite journal|last1=Shono|first1=Tatsuya|last2=Ishifune|first2=Manabu|last3=Okada|first3=Toshio|last4=Kashimura|first4=Shigenori|title=Electroorganic chemistry. 130. A novel trifluoromethylation of aldehydes and ketones promoted by an electrogenerated base|journal=The Journal of Organic Chemistry|date=January 1991|volume=56|issue=1|pages=2–4|doi=10.1021/jo00001a002}}{{cite journal|last1=Barhdadi|first1=Rachid|last2=Troupel|first2=Michel|last3=Périchon|first3=Jacques|title=Coupling of fluoroform with aldehydes using an electrogenerated base|journal=Chemical Communications|date=1998|issue=12|pages=1251–1252|doi=10.1039/A801406J}}{{cite journal|last1=Large|first1=Sylvie|last2=Roques|first2=Nicolas|last3=Langlois|first3=Bernard R.|title=Nucleophilic Trifluoromethylation of Carbonyl Compounds and Disulfides with Trifluoromethane and Silicon-Containing Bases|journal=The Journal of Organic Chemistry|date=December 2000|volume=65|issue=26|pages=8848–8856|doi=10.1021/jo000150s|pmid=11149825}}

In electrophilic trifluoromethylation the active trifluoromethyl donor group carries a positive charge.{{Cite journal | doi = 10.3762/bjoc.6.65| pmid = 20703379| title = Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective| journal = Beilstein Journal of Organic Chemistry| volume = 6| pages = 65| year = 2010| last1 = Shibata | first1 = N. | last2 = Matsnev | first2 = A. | last3 = Cahard | first3 = D.| pmc = 2919266}}{{Cite journal | doi = 10.1021/cr941149u| title = Electrophilic Perfluoroalkylating Agents| journal = Chemical Reviews| volume = 96| issue = 5| pages = 1757–1778| year = 1996| last1 = Umemoto | first1 = T.| pmid=11848810}} Production of an CF₃⁺ cation has been described as "extremely hard" {{Cite journal | doi = 10.1002/chem.201404005| pmid = 25335765| title = Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents| journal = Chemistry: A European Journal| volume = 20| issue = 51| pages = 16806–16829| year = 2014| last1 = Barata-Vallejo | first1 = S. N. | last2 = Lantaño | first2 = B. | last3 = Postigo | first3 = A.| hdl = 11336/30347| hdl-access = free}} The first relevant reagent, a diaryl(trifluoromethyl) sulfonium salt (Ar₂S⁺CF₃SbF₆⁻) was developed in 1984 by reaction of an aryltrifluoromethyl sulfoxide 1 with SF₃⁺SbF₆⁻ followed by reaction with an electron-rich arene.Yagupolskii, L. M.; Kondratenko, N. V.; Timofeeva, G. N. J. Org. Chem. USSR 1984, 20, 103–106. The reagent was used in trifluoromethylation of a thiophenolate.

S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate is a commercially available and known trifluoromethylation reagent based on the same principle first documented in 1990.{{Cite journal | doi = 10.1016/S0040-4039(00)94447-2| title = Power-variable trifluoromethylating agents, (trifluoromethyl)dibenzothio- and -selenophenium salt system| journal = Tetrahedron Letters| volume = 31| issue = 25| pages = 3579–3582| year = 1990| last1 = Teruo | first1 = U. | last2 = Sumi | first2 = I.}}{{Cite journal | doi = 10.1021/ja00059a009| title = Power-variable electrophilic trifluoromethylating agents. S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium salt system| journal = Journal of the American Chemical Society| volume = 115| issue = 6| pages = 2156–2164| year = 1993| last1 = Umemoto | first1 = T. | last2 = Ishihara | first2 = S.| bibcode = 1993JAChS.115.2156U}} In this type of compound sulfur has been replaced by oxygen, selenium and tellurium. Examples of substrates that have been investigated are pyridine, aniline, triphenylphosphine and the lithium salt of phenylacetylene.

Another group of trifluoromethyl donors are hypervalent iodine(III)Here, iodine is considered to be less electronegative (2.3) than carbon (2.5), per the IUPAC definition that de facto mandates that Allen electronegativity be used; the more commonly encountered Pauling electronegativity scale would imply that the molecule in question would be that of iodine(I), not iodine(III).–CF₃ reagents for example 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole.{{Cite journal | doi = 10.1002/chem.200501052| pmid = 16402401| title = Novel 10-I-3 Hypervalent Iodine-Based Compounds for Electrophilic Trifluoromethylation| journal = Chemistry: A European Journal| volume = 12| issue = 9| pages = 2579–2586| year = 2006| last1 = Eisenberger | first1 = P. | last2 = Gischig | first2 = S. | last3 = Togni | first3 = A.}}{{Cite journal | doi = 10.1002/anie.200603497| title = Mild Electrophilic Trifluoromethylation of Carbon- and Sulfur-Centered Nucleophiles by a Hypervalent Iodine(III)–CF3 Reagent| journal = Angewandte Chemie International Edition| volume = 46| issue = 5| pages = 754–757| year = 2007| last1 = Kieltsch | first1 = I. | last2 = Eisenberger | first2 = P. | last3 = Togni | first3 = A. | pmid=17154193}}{{Cite journal | doi = 10.1039/B801424H| pmid = 18354804| title = Mild electrophilic trifluoromethylation of secondary and primary aryl- and alkylphosphines using hypervalent iodine(iii)–CF3 reagents| journal = Chemical Communications| issue = 13| pages = 1575–7| year = 2008| last1 = Eisenberger | first1 = P. | last2 = Kieltsch | first2 = I. | last3 = Armanino | first3 = N. | last4 = Togni | first4 = A.| s2cid = 205709340}}{{Cite journal | doi = 10.1021/jo8014825| title = Reactivity of a 10-I-3 Hypervalent Iodine Trifluoromethylation Reagent with Phenols| journal = The Journal of Organic Chemistry| volume = 73| issue = 19| pages = 7678–7685| year = 2008| last1 = Stanek | first1 = K. | last2 = Koller | first2 = R. | last3 = Togni | first3 = A. | pmid=18771328}} Some of these are known as Togni reagents, such as Togni reagent II. Substrates are thiols, alcohols, phosphines, (hetero) arenes,{{Cite journal | year = 2011| title = Preparation of a Trifluoromethyl Transfer Agent: 1-Trifluoromethyl-1,3-Dihydro-3,3-Dimethyl-1,2-Benziodoxole| journal = Organic Syntheses| volume = 88| pages = 168| doi = 10.15227/orgsyn.088.0168 | doi-access = free}} unactivated olefins{{Cite journal | doi = 10.1002/anie.201104053| title = Copper-Catalyzed Trifluoromethylation of Unactivated Olefins| journal = Angewandte Chemie International Edition| volume = 50| issue = 39| pages = 9120–9123| year = 2011| last1 = Parsons | first1 = A. T. | last2 = Buchwald | first2 = S. L. | pmid=21919144 | pmc=3390945}} and unsaturated carboxylic acids.{{Cite journal | doi = 10.1002/anie.201200140| pmid = 22407851| title = Copper-Catalyzed Di- and Trifluoromethylation of α,β-Unsaturated Carboxylic Acids: A Protocol for Vinylic Fluoroalkylations| journal = Angewandte Chemie International Edition| volume = 51| issue = 16| pages = 3944–3947| year = 2012| last1 = He | first1 = Z. | last2 = Luo | first2 = T. | last3 = Hu | first3 = M. | last4 = Cao | first4 = Y. | last5 = Hu | first5 = J.}}

The reaction mechanism of electrophilic trifluoromethylations has been described as controversial with polar substitution or single electron transfer as likely candidates.

In asymmetric trifluoromethylation the trifluoromethyl group is added to the substrate in an enantioselective way.{{cite journal|last1=Ma|first1=Jun-An|last2=Cahard|first2=Dominique|title=Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions|journal=Chemical Reviews|date=December 2004|volume=104|issue=12|pages=6119–6146|doi=10.1021/cr030143e|pmid=15584697}}{{cite journal|last1=Lin|first1=Jin-Hong|last2=Xiao|first2=Ji-Chang|title=Recent advances in asymmetric fluorination and fluoroalkylation reactions via organocatalysis|journal=Tetrahedron Letters|date=November 2014|volume=55|issue=45|pages=6147–6155|doi=10.1016/j.tetlet.2014.09.031}} Ruppert's reagent has been used for this purpose in an asymmetric induction approach to functionalise chiral amino acid derivates,{{cite journal|last1=Skiles|first1=Jerry W.|last2=Fuchs|first2=Victor|last3=Miao|first3=Clara|last4=Sorcek|first4=Ronald|last5=Grozinger|first5=Karl G.|last6=Mauldin|first6=Scott C.|last7=Vitous|first7=Jana|last8=Mui|first8=Philip W.|last9=Jacober|first9=Stephen|title=Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones|journal=Journal of Medicinal Chemistry|date=February 1992|volume=35|issue=4|pages=641–662|doi=10.1021/jm00082a005|pmid=1542092}} saccharides,{{cite journal|last1=Bansal|first1=Romesh C.|last2=Dean|first2=Barbara|author-link3=Sen-itiroh Hakomori|last3=Hakomori|first3=Sen-itiroh|last4=Toyokuni|first4=Tatsushi|title=Synthesis of trifluoromethyl analogue of L-fucose and 6-deoxy-D-altrose|journal=Journal of the Chemical Society, Chemical Communications|date=1991|issue=12|pages=796|doi=10.1039/C39910000796}} and steroids.

Because Ruppert's reagent requires a tetraalkylammonium fluoride, chiral ammonium fluorides have been employed in asymmetric catalysis.{{cite journal|last1=Iseki|first1=Katsuhiko|last2=Nagai|first2=Takabumi|last3=Kobayashi|first3=Yoshiro|title=Asymmetric trifluoromethylation of aldehydes and ketones with trifluoromethyltrimethylsilane catalyzed by chiral quaternary ammonium fluorides|journal=Tetrahedron Letters|date=May 1994|volume=35|issue=19|pages=3137–3138|doi=10.1016/S0040-4039(00)76850-X}}{{cite journal|last1=Caron|first1=Stéphane|last2=Do|first2=Nga|last3=Arpin|first3=Patrice|last4=Larivée|first4=Alexandre|title=Enantioselective Addition of a Trifluoromethyl Anion to Aryl Ketones and Aldehydes|journal=Synthesis|date=August 2003|volume=2003|issue=11|pages=1693–1698|doi=10.1055/s-2003-40889}}

In the field of electrophilic trifluoromethylation an early contribution involved reaction of a metal enolate with a trifluoromethyl chalcogen salt in presence of a chiral boron catalyst.{{cite journal|last1=Umemoto|first1=Teruo|last2=Adachi|first2=Kenji|title=New Method for Trifluoromethylation of Enolate Anions and Applications to Regio-, Diastereo- and Enantioselective Trifluoromethylation|journal=The Journal of Organic Chemistry|date=September 1994|volume=59|issue=19|pages=5692–5699|doi=10.1021/jo00098a030}}

More recent examples of highly enantioselective methods for the α-trifluoromethylation of carbonyls are available through enamine catalysis of aldehydes (photoredox{{cite journal|last=Nagib|first=David A.|author2=Scott, Mark E. |author3=MacMillan, David W. C. |title=Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis|journal=Journal of the American Chemical Society|year=2009|volume=131|issue=31|pages=10875–10877|doi=10.1021/ja9053338|pmid=19722670|pmc=3310169|bibcode=2009JAChS.13110875N }} or iodonium{{cite journal|last=Allen|first=Anna E.|author2=MacMillan, David W. C. |title=The Productive Merger of Iodonium Salts and Organocatalysis: A Non-photolytic Approach to the Enantioselective α-Trifluoromethylation of Aldehydes|journal=Journal of the American Chemical Society|year=2010|volume=132|issue=14|pages=4986–4987|doi=10.1021/ja100748y|pmid=20297822|pmc=2880471|bibcode=2010JAChS.132.4986A }}), copper catalysis of β-ketoesters,{{cite journal|last=Deng|first=Qing-Hai|author2=Wadepohl, Hubert |author3=Gade, Lutz H. |title=Highly Enantioselective Copper-Catalyzed Electrophilic Trifluoromethylation of β-Ketoesters|journal=Journal of the American Chemical Society|year=2012|volume=134|issue=26|pages=10769–10772|doi=10.1021/ja3039773|pmid=22693950|bibcode=2012JAChS.13410769D }} and radical addition to zirconium enolates.{{cite journal|last=Herrmann|first=Aaron T.|author2=Smith, Lindsay L. |author3=Zakarian, Armen |title=A Simple Method for Asymmetric Trifluoromethylation of-Acyl Oxazolidinones via Ru-Catalyzed Radical Addition to Zirconium Enolates|journal=Journal of the American Chemical Society|year=2012|volume=134|issue=16|pages=6976–6979|doi=10.1021/ja302552e|pmid=22486383|pmc=3375393|bibcode=2012JAChS.134.6976H }}

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Category:Organic reactions