Reactions and Applications of Fluorinated Alkynes in Organic Synthesis and Industrial Chemistry

Fluorinated alkynes Fluorinated alkynes, a new and fascinating chemical class with diverse functionalities in organic synthesis, have become much-discussed in recent years. They are much more reactive than non-fluorinated alkynes because of their electronegativity and inductive property (driven primarily by fluorine atoms) and thus enable a variety of reactions impossible with non-fluorinated alkynes. In this article, we consider the main reactions of fluorinated alkynes, various applications in functional-molecule synthesis, and industrial relevance.

Nucleophilic Addition Reactions

Fluorinated alkynes, especially fluoralkyl-replaced ethynyl and propargyl esters, are more responsive to nucleophilic addition reactions. In contrast to conventional alkynes, which must be activated for nucleophilic attack, fluorinated alkynes readily bind to nucleophiles when conditions are low. Fluoralkyl ethynyl and fluoralkyl propargyl esters, for instance, are nucleophilically added to THF to form alkenes (mainly E-isomers). This is most clearly shown by the response of 1,1,1-trifluoro-6-methyl-2,4-heptadiyne, which reacts only at the fluorinated alkyne moiety to nucleophiles, indicating the selective nature of fluorinated alkyne reactivity.

Fig.1 Fluoroalkyl acetylene or ethyl fluoroalkyl propargylate are formed into the corresponding olefins by a very large stream in a tetrahydrofuran solvent. The former is a cis-addition and the latter a trans-addition^[1].

Electrophilic Addition Reactions

Electrophilic addition reactions of fluorinated alkynes also take place very efficiently. One example is reaction of trifluoromethyl substituted alkynyl alcohol products with metal hydrides, which hydrogenate the alkyne selectively to its alkene. The reaction is very sensitive to solvent and alkyne structure: the typical trans-products from lithium aluminum hydride and cis-products from copper or boron hydrides of reduction. Such reactions provide an uncontrolled means of obtaining specialised stereoisomers of alkynyl alcohols that is fundamental to fine chemical synthesis.

Radical Reactions

Fluorinated alkynes also take part in radical reactions (caused by ionizing radiation or peroxide-based initiators). In gamma radiation, for instance, perfluorobutyne reacts with acetaldehyde to create an ultra-stereoselective addition, giving us a single trans-addition product. When the reaction is first run with benzoyl peroxide at 75°C, the same reaction gives a combination of mono- and di-addition products. Being able to tune the stereoselectivity of these reactions is highly useful in the construction of large organic molecules.

Fig.2 (a) Highly stereoselective reaction of perfluorobutyne and acetaldehyde under γ-irradiation. (b) Diels-Alder reaction carried out by perfluorobutyne.

Diels-Alder Reactions

Fluorinated alkynes, in particular perfluorophenylacetylene, are particularly reactive in Diels-Alder reactions because the electron-withdrawing nature of the fluorine atoms makes the alkyne more electrophilic and able to join in more readily with cycloaddition reactions. Since perfluorophenylacetylene is so reactive in these reactions, a perfluorophenyl group can be added to the product and fluorine-modified polycyclic molecules are generated. This is what makes fluorinated alkynes good starting materials for constructing high-order fluorinated heterocyclic structures.

1,3-Dipolar Cycloaddition Reactions

Fluorinated alkynes also function as good dipolarophiles in 1,3-dipolar cycloaddition reactions. The triple bond, polarised by the fluorine atom, renders these compounds more reactive and makes them very active against 1,3-dipoles like azides. For instance, fluoralkyl-substituted alkynes are regioselectively cycloadditioned to diazoalkanes to produce fluoralkyl-substituted pyrazoles. This reactivity is advantageous for the preparation of biologically active heterocyclics, including pyrazoles, isoxazoles and triazoles, useful as pharmaceuticals and agrochemicals.

Rearrangement Reactions

Even fluorinated alkynes can engage in rearrangement reactions, especially under basic conditions. Fluorinated alkynes, like fluorinated alkynyl esters and alkynyl phosphates, may be rearranged in such a way that the migratory particle transfers to the β-carbon attached to the fluorine atom. In sodium hydroxide solutions, for instance, fluorinated alkynyl esters undergo a highly stereoselective "alkyne-ester-ene" recombination, where the Z-isomer dominates in more than 90% of the cases. In a similar manner, perfluorobutyl-modified propargyl alcohol is rearranged to yield yield-expanding intermediates, including propargyl phosphates, when combined with dichlorodiethylphosphine.

Fig.3 Fluorinated alkynes can undergo rearrangement reactions, especially under alkaline conditions.

Reactions with Organometallic Compounds

Fluorinated alkynes react with transition metal complexes that lead to a range of organic transformations. These metal reactions take advantage of fluorine atoms stabilising the reactive intermediates, thereby increasing the efficiency of the conversion. New work has been looking at the interactions of fluorinated alkynes with transition metal complexes to trigger cross-coupling, cyclisation and C-H activation reactions that are crucial for new synthetic strategies.

Applications of Fluorinated Alkynes in Synthesis

Fluorinated alkynes are very versatile intermediates in organic synthesis, particularly when building highly complex fluorine molecules. They find use in medicine, material science and agricultural chemistry.

Fig.4 (a) In the presence of polyphosphonic acid, fluorinated alkynyl esters and aniline and its derivatives are condensed, and the intermediate enamine and imine are cyclized to form 2-fluoroalkyl-4-hydroxyquinoline. (b) Fluorinated benzoyl ureas can be used as insecticides. (c) Synthesis of prostaglandin precursors. (d) Synthesis of antiandrogens.^[2][3][4]

• Synthesis of Bioactive Compounds

Fluorinated alkynes are the important intermediates of bioactive compounds. With polyphosphoric acid, for example, fluorinated alkynyl esters bond to aniline derivatives to form 2-fluoroalkyl-4-hydroxyquinolines, which could be used as antitumour agents. So too with fluorinated acetylenic ketones, catalytic hydrogenation and chlorination produce intermediates which together with 1,2,4-triazoles give us fungicides.

• Pesticide and Herbicide Development

Fluorinated alkynes are also used in agrochemicals. Combinations of fluorinated alkynes and aromatics, like phenyl isocyanates, give fluorinated benzoyl ureas, which are effective insecticides. Fluorine atoms are added to the molecular matrix and make the compound stable and biologically active.

• Polymer Synthesis

Because fluorine's electron-donating properties are unusual, fluorinated alkynes were employed to create new polymers. Fluorinated alkynes, for instance, polymerise in controlled atmospheres to produce polyfluoroalkynes, which are very well-conductive and heat-stable. These materials are also promising for advanced electronics such as flexible electronics and super-hard coatings.

• Prostanoid Synthesis

Fluorinated alkynes were also used to create prostanoid precursors, the building blocks of inflammation and vascular biology. Fluorinated alkynes are also flexible scaffolds for selective fluorination of carbon atoms in prostanoid analogs, and thus to their pharmacological action.

Conclusion

Fluorinated alkynes are a rare class of organics found in contemporary synthetic chemistry. Because of their special reactivity, due to fluorine's strong electron-extraction activity, they are good intermediates for a variety of reactions such as nucleophilic and electrophilic additions, radical processes and cycloaddition reactions. Fluorinated alkynes have a wide array of applications including bioactive molecules, agricultural chemicals, polymers and prostanoid derivatives. As work progresses in this area, there will be even more applications and synthetic pathways for fluorinated alkynes, with enormous potential for innovation in academia and industry.

References

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2. Pétillon F.Y., et al. (1985). "Reaction of Dinuclear Thiolato-bridged Cobalt compounds with Activated alkynes. Formation and X-ray Structure of an Unusual Trinuclear Cobalt Complex, [Co3(η5-C5H5)3(SMe)2(CF3C=CCF3)2]." Journal of Organometallic Chemistry., 281(2-3), 305-315.
3. Elbe H.L., et al. (1986). "Substituted Hydroxyalkylazole Fungicidal Agents Their Preparation and Their Use Us Patent 4584308. April 22 1986." Official Gazette of the United States Patent and Trademark Office Patents., 1065(4), 1911.
4. Yasuda A., et al. PCT Int AppJ. WO 8404917 (1984). C. A., 1986, 104, 129612.