Trifluoromethyl
Encyclopedia
Trifluoromethyl is a functional group
in organofluorine
s that has the formula
-CF3. The naming of is group is derived from the methyl group (which has the formula -CH3), by replacing each hydrogen
atom by a fluorine
atom. The trifluomethyl group has a significant electronegativity
that is often described as being intermediate between the electronegativities of fluorine and chlorine. For this reason, trifluoromethyl-substituted compounds are often strong acids, such as trifluoromethanesulfonic acid
and trifluoroacetic acid
. In other cases, the trifluoromethyl group is employed to lower the basicity of organic compounds or to confer distinctive solvation properties (e.g. trifluoroethanol).
The trifluoromethyl group occurs in certain pharmaceuticals, drugs, and abiotically synthesized natural fluorocarbon
based compounds. The medicinal use of the trifloromethyl group dates from 1928, although research became more intense in the mid-1940s. The trifluoromethyl group is often used as a bioisostere
to create derivatives by replacing a chloride or a methyl group. This can be used to adjust the steric and electronic properties of a lead compound
, or to protect a reactive methyl group from metabolic oxidation. Some notable drugs containing trifluoromethyl groups include efavirenz
(Sustiva), an HIV reverse transcriptase inhibitor; fluoxetine
(Prozac), an antidepressant; and celecoxib
(Celebrex), a non-steroidal anti-inflammatory.
and trihalomethyl compounds, particularly trifluoromethyl ethers and trifluoromethyl aromatics, are converted into trifluoromethyl compounds by treatment with antimony trifluoride
/antimony pentachloride
(the Swarts reaction). Another route to trifluoromethyl aromatics is the reaction of aryl iodides with trifluoromethyl copper. Finally, trifluoromethyl carbinols and ketones can be prepared by reaction of aldehydes and esters with Ruppert's reagent.
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
in organofluorine
Organofluorine
Organofluorine compounds are organic chemical compounds that contain carbon and fluorine bonded in the polarized and remarkably strong carbon–fluorine bond. Organofluorine compounds are diverse, they can be fluorocarbons, perfluorinated, or biologically synthesized mono-fluorinated compounds, among...
s that has the formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
-CF3. The naming of is group is derived from the methyl group (which has the formula -CH3), by replacing each hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atom by a fluorine
Fluorine
Fluorine is the chemical element with atomic number 9, represented by the symbol F. It is the lightest element of the halogen column of the periodic table and has a single stable isotope, fluorine-19. At standard pressure and temperature, fluorine is a pale yellow gas composed of diatomic...
atom. The trifluomethyl group has a significant electronegativity
Electronegativity
Electronegativity, symbol χ , is a chemical property that describes the tendency of an atom or a functional group to attract electrons towards itself. An atom's electronegativity is affected by both its atomic number and the distance that its valence electrons reside from the charged nucleus...
that is often described as being intermediate between the electronegativities of fluorine and chlorine. For this reason, trifluoromethyl-substituted compounds are often strong acids, such as trifluoromethanesulfonic acid
Trifluoromethanesulfonic acid
Trifluoromethanesulfonic acid, also known as triflic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the strongest acids. Triflic acid is mainly used in research as a catalyst for esterification.-Properties:Triflic acid is a hygroscopic, colorless...
and trifluoroacetic acid
Trifluoroacetic acid
Trifluoroacetic acid is the simplest stable perfluorinated carboxylic acid chemical compound, with the formula CF3CO2H. It is a strong carboxylic acid due to the influence of the electronegative trifluoromethyl group. TFA is almost 100,000-fold more acidic than acetic acid...
. In other cases, the trifluoromethyl group is employed to lower the basicity of organic compounds or to confer distinctive solvation properties (e.g. trifluoroethanol).
The trifluoromethyl group occurs in certain pharmaceuticals, drugs, and abiotically synthesized natural fluorocarbon
Fluorocarbon
Fluorocarbons, sometimes referred to as perfluorocarbons or PFCs, are organofluorine compounds that contain only carbon and fluorine bonded together in strong carbon–fluorine bonds. Fluoroalkanes that contain only single bonds are more chemically and thermally stable than alkanes...
based compounds. The medicinal use of the trifloromethyl group dates from 1928, although research became more intense in the mid-1940s. The trifluoromethyl group is often used as a bioisostere
Bioisostere
In medicinal chemistry, bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or...
to create derivatives by replacing a chloride or a methyl group. This can be used to adjust the steric and electronic properties of a lead compound
Lead compound
A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.Lead compounds are often found in...
, or to protect a reactive methyl group from metabolic oxidation. Some notable drugs containing trifluoromethyl groups include efavirenz
Efavirenz
Efavirenz is a non-nucleoside reverse transcriptase inhibitor and is used as part of highly active antiretroviral therapy for the treatment of a human immunodeficiency virus type 1....
(Sustiva), an HIV reverse transcriptase inhibitor; fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac), an antidepressant; and celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial...
(Celebrex), a non-steroidal anti-inflammatory.
Synthesis
Various methods exist to introduce this functionality. Carboxylic acids can be converted to trifluoromethyl groups by treatment with sulfur tetrafluorideSulfur tetrafluoride
Sulfur tetrafluoride is the chemical compound with the formula SF4. This species exists as a gas at standard conditions. It is a corrosive species that releases dangerous HF upon exposure to water or moisture...
and trihalomethyl compounds, particularly trifluoromethyl ethers and trifluoromethyl aromatics, are converted into trifluoromethyl compounds by treatment with antimony trifluoride
Antimony trifluoride
Antimony trifluoride is the inorganic compound with the formula SbF3. Sometimes called Swart's reagent, is one of two principal fluorides of antimony, the other being SbF5. It appears as a white solid...
/antimony pentachloride
Antimony pentachloride
Antimony pentachloride is a the chemical compound with the formula SbCl5. It is a colourless oil, but typical samples are yellowish due to impurities...
(the Swarts reaction). Another route to trifluoromethyl aromatics is the reaction of aryl iodides with trifluoromethyl copper. Finally, trifluoromethyl carbinols and ketones can be prepared by reaction of aldehydes and esters with Ruppert's reagent.