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Trifluoromethyl group covalently bonded to an R groupThe trifluoromethyl group is a functional group 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. Some common examples are trifluoromethane H&#;CF
3, 1,1,1-trifluoroethane H
3C&#;CF
3, and hexafluoroacetone F
3C&#;CO&#;CF
3. Compounds with this group are a subclass of the organofluorines.
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The trifluoromethyl group has a significant electronegativity that is often described as being intermediate between the electronegativities of fluorine and chlorine.[1] For this reason, trifluoromethyl-substituted compounds are often strong acids, such as trifluoromethanesulfonic acid and trifluoroacetic acid. Conversely, the trifluoromethyl group lowers the basicity of compounds like trifluoroethanol.
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The trifluoromethyl group occurs in certain pharmaceuticals, drugs, and abiotically synthesized natural fluorocarbon based compounds. The medicinal use of the trifloromethyl group dates from , although research became more intense in the mid-s.[2] 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 nonsteroidal anti-inflammatory drug.
Sulfoxaflor is used as a systemic insecticide. Trifluralin is a selective pre-emergent herbicide.
The trifluoromethyl group can also be added to change the solubility of molecules containing other groups of interest.
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Various methods exist to introduce this functionality. Carboxylic acids can be converted to trifluoromethyl groups by treatment with sulfur tetrafluoride 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 carbonyls can be prepared by reaction of aldehydes and esters with Ruppert's reagent.[3]
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Trifluoromethylpyridine (TFMP) and its intermediates are important ingredients for the development of agrochemical and pharmaceutical compounds. The presence of a fluorine atom and a carbon-containing pyridine are thought to bestow many of the distinctive physical&#;chemical properties observed with this class of compounds. Dr Masamitsu Tsukamoto and Mr Tadashi Nakamura, of Ishihara Sangyo Kaisha, Ltd, Japan, take a closer look at this class of compounds. They explore the different synthetic methods for introducing TFMP groups within other molecules, and investigate their wide-ranging potential applications.
With the global population rapidly expanding, agrochemicals are in increasing demand to maintain crop production. In addition, the agricultural research community faces the challenge of producing pesticides that not only prevent crop losses caused by parasites, but also protect human populations from the spread of diseases such as malaria, dengue fever, or the Zika virus, all of which are carried by mosquitoes. Trifluoromethylpyridine (TFMP) and its intermediates have gained a fundamental role as key structural ingredients for the development of many agrochemical and pharmaceutical compounds.
TFMP contains three fluorine atoms, a methyl group (a unit made of a hydrogen atom and three carbon atoms), and a ring-shaped carbon-containing structure known as pyridine. TFMP derivatives are characterised by the presence of a fluorine atom and a pyridine in their structure, which are thought to bestow many of the distinctive physical&#;chemical properties observed in this class of compounds. To develop compounds with unique biological properties, hydrogen is commonly replaced with fluorine. Dr Masamitsu Tsukamoto and Mr Tadashi Nakamura, of Ishihara Sangyo Kaisha (ISK) Ltd Central Research Institute, Japan, are interested in the properties and applications of pesticides. The researchers published a detailed literature review on the synthesis of TFMP intermediates.
The demand for TFMP derivatives has been increasing steadily in the last 30 years. In their review, Tsukamoto and Nakamura guide the readers through the different synthetic methods for introducing TFMP groups within the structures of other molecules. The researchers explain that this is generally achieved via two main methods: one involving an exchange between chlorine and fluorine atoms using trichloromethyl-pyridine. The second method relies on the assembly of pyridine from a trifluoromethyl-containing building block. Whether TFMP intermediates are manufactured using the direct fluorination method or the building-block method, depends largely on the identity of the desired target compound.
2,3-dichloro-5-(trifluoromethyl) pyridine (2,3,5-DCTF) is used in the production of several crop-protection products. Notably, of all the TFMP derivatives, it is in highest demand. It can be obtained by direct chlorination and fluorination of 3-picoline and followed by aromatic nuclear chlorination of the pyridine ring. Several cyclo-condensation reactions for the synthesis of TFMP derivatives from a trifluoromethyl building block have been reported. The process of cyclo-condensation involves the molecular assembly of a large, ring-shaped molecule (in this case a pyridine) from smaller, fluorinated building blocks &#; either ethyl 2,2,2-trifluoroacetate, 2,2,2-trifluoroacetyl chloride, ethyl 4,4,4-trifluoro-3-oxobutanoate, or (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one.
The first herbicide to incorporate a TFMP derivative is called fluazifop-butyl. Developed in , this compound proved to be an excellent growth inhibitor of perennial grass weeds. 2,5-CTF was used as a key fluorinated building block for its synthesis. Following the success of fluazifop-butyl, other herbicides were synthesised and commercialised that displayed a similar herbicidal spectrum to their predecessor, while exhibiting a longer residual soil activity.
In , Flazasulfuron was first reported by ISK. Flazasulfuron is a crop protector, and is selective for turf, sugarcane, and perennial crops such as citrus and grape. As with other herbicides, a fluorinated building block is used as an intermediate for the synthesis of flazasulfuron; in this case, 2,3-CTF is used as the key synthetic intermediate. Of course, the use of herbicides does not come without problems; as Tsukamoto and Nakamura point out, 2-methoxy-4-(trifluoromethyl)phenyl analogues were developed as very effective herbicides for the control of key weeds in cereal crops, such as wheat, but were found to cause significant damage to the crops. Pyridine analogues do not cause the same amount of damage to wheat crops, and for this reason, Dow AgroSciences LLC produced pyroxsulam. Incorporating pyridine in its structure, pyroxsulam retains the herbicidal properties of the 2-methoxy-4-(trifluoromethyl) parent compounds, while displaying more selective protection of wheat crops.
2,3,5-DCTF is the starting raw material for the synthesis of chlorfluazuron, a compound developed by ISK, which acts as an insect growth regulator (IGR). Chlorfluazuron inhibits the growth of the target insects at their larval stages. The screening of various TFMP derivatives revealed that some compounds containing nicotinamide were particularly effective against aphids. This led to the development of flonicamid by ISK. Flonicamid contains the 4-trifluoromethyl-pyridine structure, which is obtained by condensation in the presence of ammonia.
Sulfoxaflor, sold by Dow AgroSciences, is an insecticide that works by targeting pests that feed on sap.
Sulfoxaflor is based on the 6-(trifluoromethyl)pyridine. Its pyridine sulfide intermediate is prepared via a condensation reaction by with a trifluoromethyl-containing building block.
Pyridalyl, a TFMP derivative containing the 5-(trifluoromethyl)pyridine molecular structure, was discovered and reported by Sumitomo Chemical Co, Ltd. As observed with other TFMP derivatives, the presence of fluorine and pyridine structure result in its superior pest control properties when compared to traditional phenyl-containing insecticides. The synthesis of pyridalyl, as is the case for other TFMPs, encompasses a condensation step that includes the reaction between a trifluoromethyl pyridine building block and a larger chlorinated counterpart.
A large number of compounds containing the TFMP sub-structure are currently undergoing clinical trial.Fluazinam, discovered by ISK, is a potent fungicide, and interferes with the biochemistry of respiration. It was found that the trifluoromethyl-substituted pyridine derivative showed higher fungicidal activity than chlorine and other derivatives. 2,3,5-DCTF is utilised in the synthesis of fluazinam, as a building block for the condensation.
Tsukamoto and Nakamura estimate that about 40% of pharmaceutical compounds contain fluorine in their structure. Of these, almost 20% contain a trifluoromethyl structure. Even though only five TFMP compounds have so far been approved for use as pharmaceuticals (that is, antivirals or antitumour agents), a large number of compounds containing the TFMP sub-structure are currently undergoing clinical trial. Many are expected to be approved as new drugs in the near future.
One of the most successful TFMP-containing drugs is tipranavir, developed and commercialised by Boehringer. Tipranavir is a non-peptide anti-human immunodeficiency virus (HIV) drug and acts by binding to and inhibiting the HIV protease enzyme. The molecule is synthesised by condensation using a 2,5-CTF building block.
Tsukamoto and Nakamura have studied the chemistry of TFMP derivatives, which are used in the pharmaceutical industry and as chemical feedstock for pest control, fungicidal, and herbicidal agents. The researchers have published a detailed review of the physical and chemical properties and the synthetic routes of the fluorine-containing compounds via either a chlorine/fluorine substitution reaction or a condensation mechanism that employs a molecular building block containing fluorine and a pyridine in its structure.
Trifluoromethylpyridine: Its chemistry and applications
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