The physical properties and chemical reactivities of organic molecules can be dramatically affected by fluorination. Today’s diverse commercial applications of organo-fluorine materials clearly manifest the possible beneficial effects of fluorination, and the numerous ways in which industry has taken practical advantage of these effects are the subjects of the following chapters in this book. This chapter focuses on the characteristic substituent effects that underlie the physicochemical properties of organofluorine compounds, especially those important to the design of commercial products. Fortunately, advances in both experimental and theoretical physical organofluorine chemistry over the past two decades have made the “unusual” behavior of fluorinated compounds much more understandable and predictable. General principles that govern the characteristic effects of fluorination will be presented, but important exceptions also will be noted. Misleading generalizations like “fluorination increases lipophilicity” and myths about fluorine steric effects will be dispelled, for example.

Characteristics of C-F Systems

Publisher Summary This chapter deals with the chemistry of five-membered ring fluorinated heterocycles. Fluorine and perfluoroalkyl groups positioned strategically in target molecules can considerably modify the chemical properties, biological activity, and selectivity. Fluoro-containing compounds play a significant role in medicinal and agricultural chemistry, as well as in material science. A number of fluoro and perfluoroalkyl-substituted pharmaceuticals, agrochemicals, dyes, and polymers are largely commercialized. Important differences in chemical reactivity of fluorinated compounds are based on the difference in: (1) carbon–fluorine, (2) carbon–hydrogen bond energy, and (3) electronegativity between fluorine and hydrogen. It is observed that fluorine introduced into biologically active molecules can block metabolism. There are two fundamentally different strategies, by which fluorine and perfluoroalkyl groups can be introduced into target molecules: (1) direct introduction that occurs by direct substitution of hydrogen by fluorine and perfluoroalkyl groups in a late step of the reaction sequence, and (2) introduction of fluorine and perfluoroalkyl groups by the application of fluorine-containing building blocks, derived from the readily available starting materials.

Fluoro Heterocycles with Five-Membered Rings

A photo-redox-catalyzed procedure for the one-step formation of sultones from α,ω-alkenols and trifluoromethylsulfonyl chloride is described. Using [Cu(dap)2]Cl (1 mol %), a wide range of substrates can be cleanly converted to the target compounds, while commonly employed photoelectron transfer catalysts such as [Ru(bpy)3]Cl2 or fac-Ir(ppy)3 fail in this transformation. The obtained fluorinated sultones are attractive as potential electrolyte additives or as structural motifs in drug synthesis, with the latter being demonstrated with the synthesis of a trifluoroethyl-substituted analogue of a benzoxathiin that has high anti-arrhythmic activity.

Synthesis of Trifluoromethylated Sultones from Alkenols Using a Copper Photoredox Catalyst.

A summary of the investigation and applications of the inverse electron demand Diels-Alder reaction is provided that have been conducted in our laboratory over a period that now spans more than 35 years. The work, which continues to provide solutions to complex synthetic challenges, is presented in the context of more than 70 natural product total syntheses in which the reactions served as a key strategic step in the approach. The studies include the development and use of the cycloaddition reactions of heterocyclic azadienes (1,2,4,5-tetrazines; 1,2,4-, 1,3,5-, and 1,2,3-triazines; 1,2-diazines; and 1,3,4-oxadiazoles), 1-aza-1,3-butadienes, α-pyrones, and cyclopropenone ketals. Their applications illustrate the power of the methodology, often provided concise and nonobvious total syntheses of the targeted natural products, typically were extended to the synthesis of analogues that contain deep-seated structural changes in more comprehensive studies to explore or optimize their biological properties, and highlight a wealth of opportunities not yet tapped.

Inverse Electron Demand Diels-Alder Reactions of Heterocyclic Azadienes, 1-Aza-1,3-Butadienes, Cyclopropenone Ketals, and Related Systems. A Retrospective.

New synthetic approach to α-fluoro-β-arylvinyl sulfones and their application in Diels–Alder reactions

Fluorinated β-sultones

Terminal and internal fluoroolefins and polyfluoro-1-alkenylsulfonyl fluorides as well as perfluoro-3-aza-2-pentene react with furan to give [2+4]-cycloadducts. Perfluoroazapropene and 1-cyanotetrafluoro-2-azopropene do not undergo this cycloaddition reaction.

[2+4]-Cycloaddition of fluoroolefins and fluoroazomethines with furan

1.

Terminal fluoroolefins and internal fluoroolefins and fluoroazomethines react with 1,3-cyclohexadiene at 220–270°C to give [2+4]-cycloadducts.




2.

Methoxycarbonyltetrafluorocrotononitrile and 1-polyfluoroalkene-1-sulfonyl fluorides react with 1,3-dicyclohexadiene at 50–80°C.

G. A. Sokol'skii

Papers

Fluorinated β-sultones

[2+4]-Cycloaddition of fluoroolefins and fluoroazomethines with furan

[2+4]-Cycloaddition of fluoroolefins and fluoroazomethines with 1,3-cyclohexadiene

Fluorine-containing ?-sultones: Communication 45. 2-hydropentafluoropropane-2-?-sultone

Fluorine-containing?-sultones: Communication 40. Sulfotrioxidation of octafluoroisobutylene