The history of fluorinated heterocycles can be traced back to the seminal work of Chichibabin who carried out the synthesis of 2-fluoropyridine over 90 years ago. However, real progress in this field did not gain momentum until about four decades later, in the 1950s, with the development of new synthetic methods and more readily-handled fluorinating agents. It was in this period that 5-fluorouracil can be prepared by a rational approach to new anti-cancer agents. The effectiveness of this drug heralds the development of many related anti-cancer agents that still have important clinical applications 50 years after the original discovery. Another major success story followed shortly thereafter with the discovery of the fluoroquinolone family of antibiotics in the early 1970s. A particularly important member of this group, ciprofloxacine , was approved for human use in the US in late 1980s. There continues to be extensive work being done in the development of new fluoroquinolones.
Applications
Medical chemistry: Heterocyclic chemistry is a major component of the field of medicinal chemistry. This is due in part to the prevalence of heterocyclic rings in naturally occurring biologically important molecules—DNA and RNA bases, carbohydrates, alkaloids, etc. Since heterocyclic rings are particularly susceptible to the special properties of fluorine, selective fluorine substitution can be used to further tweak the physic-chemical properties of potential drugs, often with dramatic impact on biological properties. The role of flouorinated heterocylces is particularly notable, so both rational and empirical approaches have been taken to exploit fluorine in drug design. The aforementioned 5-flourouricil and fluoroquionlones are well known examples of successful applications of fluorinated heterocyclic rings. The growing impact of fluorine in drug design (it has been estimated that up to 20% of new drugs contain fluorine) and the prevalence of heterocyclic rings in medicinal chemistry readily explain the important role of fluorinated heterocycles in rational drug design and development. Some of the notable examples of fluorinated heterocyclic compounds as commercial drugs and include (on the drug side) the popular hypolipidemic drug Lipitor-Atorvastatin; anti-cancer compounds such as Xeloda-Capecitabine, Iressa-Gefitinib and Gemzar-Gemcitabine; the amyotrophic lateral sclerosis drug Rilutek-Riluzole; the anti-inflammatory COX-2 inhibitor Celebrex-Celecoxib; and the anti-depressant CelexaCitalopram.
Agriculture: A very similar trend has been observed in the area of agricultural chemistry where the relative share of new fluorinated products is even higher. The notable examples of agrochemicals include the acaricide Fluazuron; fungicides Thifluzamide, Flutriafol and Fluquinconazole; herbicides Flufenacet and Prosulfuron; insecticides Fipronil and Hydramethylnon. The last of these is an active ingredient of the popular Combat pest control systems.
Others: The uses of fluoronated heterocycles in other fields are becoming increasingly important. Ionic liquids, liquid crystals, energetic materials, fluorescent probes, electrophilic fluorinating agents, and peptide coupling reaction activators are some noteworthy applications.
