Organofluorine Chemistry

Fluorine—the superhdlogen—is by no means a rare element: found only in the form of its mononuclidic % MathType!MTEF!2!1!+- % feaagCart1ev2aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn % hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr % 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9 % vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x % fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaWaa0raaSqaai % aaiMdaaeaacaaIXaGaaGyoaaaaieaakiaa-zeadaahaaWcbeqaaGGa % aiab+jHiTaaaaaa!3A59!$${}_9^{19}{F^ - }$$ ion, it lies 13th in order of abundance of the elements in Earth’s crust, and therefore outranks chlorine and the other members of the “salt-forming” family (Cl, 20th; Br, 46th; I, 60th; Ar, the rarest element).1, 2a It is the most electronegative of all the chemical elements (Pauling values: F, 4.0; O, 3.4; Cl, 3.2; C, 2.6: H, 2.2) and easily the most reactive—a fact superbly underscored in the early 1960s by the direct synthesis of the noble-gas fluorides XeF _x (x = 2, 4, 6), 1 the difluoride being obtainable simply by exposing a mixture of xenon and fluorine to sunlight.2b

Fluoroorganic chemistry is virtually a man-made subject. Indeed, perfluorocarbon chemistry—which straddles organic and inorganic chemistry—is sometimes facetiously referred to as unnatural product chemistry. Fluorometabolites do occur in nature, but they are few in number and only monofluorides have been detected so far.1 The best known is the plant metabolite CH₂FCO₂H (see Chapter 1); the other nine include the related compounds CH₂FCOCH₃, 2-fluorocitric acid, F(CH₂) _n CO₂H (n = 9, 13, 15), and F(CH₂)₈CH=CH(CH₂)₇CO₂H. The most intriguing by far is nucleo-cidin (1), an antibiotic fluoro-sugar derivative produced by the microorganisms Streptomyces calvus.

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.

This chapter deals almost exclusively with the production, properties, and applications of saturated compounds containing only carbon and fluorine, i. e., saturated perfluorocarbons* It updates a previous account1 of a group of commercial perfluorocarbon (PFC) liquids known as Flutec™ Fluids with boiling points lying in the range 29–160°C.1 This range has now been extended to 260°C. Information on gaseous perfluorocarbons has also been included.

The Simons and CAVE (or Phillips) electrochemical fluorination (ECF) processes are surveyed in this chapter, together with commercial applications of perfluorinated fluids produced by the Simons methods. Applications of ECF-derived reactive materials are covered in Chapter 14.

The completely halogenated chlorofluorocarbons (CFCs) have easily been the most important organic fluorine chemicals produced in the world during the past 60 years. Selected for development by Midgley and his co-workers in the late 1920s, CFC-12* (CF₂CI₂) was considered to be the ideal refrigerant to replace sulfur dioxide and ammonia.1, 2 The low toxicity, nonflammability, and stability of CFC-12 quickly led to the search for other CFCs. Kinetic Chemicals, a joint venture between Du Pont and General Motors, was formed to manufacture the new materials, and later it became part of the Freon Division of Du Pont. As the list of available compounds grew, new application areas emerged such as aerosol propellants, foam blowing agents, and solvents. By the early 1970s, when they were first linked to the destruction of the ozone layer, CFCs were being produced in many countries around the world. Some major producers and their trade names are listed in Table 1.

Volatile chlorofluorocarbons (CFCs), man-made fully halogenated compounds having remarkably long atmospheric lifetimes, are implicated in the destruction of Earth’s protective stratospheric ozone layer (see Chapter 1). Studies by Lovelock in the early 1970s showed that there was a measurable concentration of trichlo-rofluoromethane (CFC-11)* in the atmosphere, suggesting that it can have a long atmospheric lifetime.1 This was followed in 1974 by the publication of a paper by Molina and Rowland, 2 in which they suggested that the chlorofluoromethanes CFCl₃ and CF₂Cl₂ (CFC-11 and -12, respectively) might survive transport to the stratosphere, where they could be broken down photochemically releasing chlorine atoms, which would then catalyze the destruction of ozone. Bromine-containing molecules (Halons), such as CF₃Br, were suspected to be even more harmful to the ozone layer. However, in the mid-70s to mid-80s, stratospheric science had not advanced enough to confirm these postulates. Because of their long atmospheric lifetimes, CFCs were also cited as possible contributors to global warming.3

Nowadays, perfluoroalkyl halides* of the bromo and iodo classes (R_FBR, R_FI) play an important part in organofluorine chemistry. The short-chain bromides are manufactured as fire-extinguishing agents.1 They can be used also, as can their iodo analogs, for the introduction of fluorinated groups into organic molecules.2, 3 The compounds so formed attract interest in pharmaceutical and agrochemicals circles, owing to the lipophilic properties of aromatic and heterocyclic rings substituted by small fluorinated groups.4, 5 Long-chain iodides are important intermediates for the preparation of tensioactive agents, owing to the low free surface energy associated with such fluorocarbon groups.6

This chapter concerns compounds in which fluorine is bonded to carbon forming part of an aromatic ring (ring-fluorinated aromatics, the simplest being fluorobenzene C₆H₅F) as distinct from those carrying fluorine at side chain positions (e. g., benzotri-fluoride, C₆H₅CF₃; see Chapter 10). Naturally, both types of C—F bond can occur in the same molecule, and all three types of compound are referred to as fluoroaromatics. Only placement of fluorine at the ring sites is considered here, and only methods developed for doing so on an industrial scale are discussed.

The market for benzotrifluoride [(trifluoromethyl) benzene] derivatives is much larger than that associated with fluorobenzenes, i. e., compounds with fluorine at ring sites (see Chapter 9), and three compounds are of major importance: 4-chlorobenzotrifluoride (1), which is the starting material for trifluralin-like herbicides [in 1986 trifluralin itself (2) was manufactured on a 50, 000 tonne-per-year world scale, with 12, 000 tonnes originating from the American industry; see Chapter 11];3, 4-dichlorobenzotrifluoride (3), on which a large family of agrochemicals of the diphenyl ether type is based (see Chapter 11);3-aminobenzotrifluoride (4), from which a wide range of products are manufactured for pharmaceutical and agrochemical purposes.

The past 15 years has been a very exciting time for research into agrochemicals, with many significant advances being achieved. Highly active and effective new series of compounds have been discovered in each of the agrochemical disciplines (herbicides, insecticides, fungicides, and plant growth regulators), and compounds have been introduced to the market which are often an order of magnitude more active than earlier products. This has all been achieved against a background of change in the agrochemicals industry. Finney has presented figures to show that while there has been a progressive decline in the profitability of the industry, expenditure on research and development has increased very substantially.1 This reflects the substantial increase in development costs required to satisfy increasing regulatory demands. Graham-Bryce has argued that these demands need to be considered in their proper perspective.2 Fluorine as a substituent has played a significant and increasingly important part in the development of new agrochemicals and is likely to continue to do so in the future.

The liquid crystalline state, located between the crystalline and the isotropic liquid states of matter, can be observed in certain types of organic compound, including polymers. A liquid crystal can flow like an ordinary liquid; however, other properties, such as birefringence, are remains of the crystalline phase. Through their anisotropy, liquid crystals are very sensitive to external changes such as electric field. Thus liquid crystals have been used as a practical means for monitoring, imaging, and other purposes.

The economic importance of reactive dyes for cotton, and in particular of fluorine-containing reactive dyes, has increased over the last twenty years.1–10 In 1990 an estimated 50, 000 tonnes of reactive dyes were used for dyeing and printing cellulosic fibers. This represents 15–20% of total consumption of dyes for cotton. Only sulfur and direct dyes achieve higher tonnages. In industrialized countries, such as the USA, Japan, and the Western Europe group, reactive dyes already account for about 30–40% of the market for cotton dyes. World sales of fluorine-containing reactive dyes in 1990 is estimated at 10, 000 tonnes.2, 9–13

From the industrial standpoint, the reason for the synthesis of fluorine-containing dyestuffs is the continuing search for improved properties for certain applications. Emphasis has been placed on the incorporation of the CF₃ group into azo dyes, though examples of all classes of organic dyes with fluorine-containing substituents are known. Whether the practical utilization of these dyes leads to commercial success, depends mainly on the synthesis costs, i. e., the price-performance ratio.

Fluorochemicals carrying perfluoroalkyl groups (R_F) are widely used to modify the surfaces of textiles and carpets, and hence impart resistance to water, oils, soils, and staining. In fact, fluorinated materials have essentially replaced silicones and hydrocarbon-based finishes as textile repellents, and function by imparting a condition of limited wettability to the treated substrate. The efficiency of the surface modification depends on the intrinsic repellency of the active fluorochemical, the extent of coverage of the textile by the fluorochemical, the orientation of the perfluoroalkyl segments, and the amount and location of the fluorochemical on the textile. Typically, 0.05 to 0.50 percent of the fluorochemical by weight of the textile is used to deliver durable repellency. The repellents are applied to textiles and carpets in mills as aqueous dispersions, and in some after-market applications, as solutions in halogenated solvents.

Fluorinated polymers have achieved commercial importance as thermoplastics, elastomers, membranes, and coatings due to their unique combination of properties. The highly fluorinated plastics, in particular, have high thermal stability, low dielectric constant, low moisture absorption, excellent weatherability, low flammability, low surface energy, and outstanding resistance to most chemicals. The presence of only strong1 C—F and C—C bonds in perfluoropolymers imparts a high degree of oxidative and hydrolytic stability which extends to a remarkable degree to less highly fluorinated analogs.

Although discovered more than 50 years ago, fluoropolymers are still growing in terms of production volume and of introduction of new compositions to meet industrial needs. Also, they still represent an active field of research holding great promise for new discoveries in the form of macromolecules with unusual properties. As a class fluoroelastomers account for less than ten percent of total fluoropolymer production, which is dominated by PTFE (mainly) and related crystalline fluoroplastics (see Chapter 15).

Fluoropolymers are distinguished particularly by their extremely high thermal and chemical resistance, high electrical resistivity, low surface energy, and low refractive index. Accordingly, various kinds of fluoropolymers have been widely used in industrial applications where these characteristics are required.1

The term fluorinated membranes generally refers to ion-exchange membranes composed of perfluorinated polymeric backbones. An overview of both the fundamental properties and the technological aspects of perfluorinated membranes is available.1 The first perfluorinated membranes, Nafion® membranes, were developed and commercialized by Du Pont in the early 1970s. They were made of the perfluorinated sulfonic acid ionomer called XR resin.2 Nafion® was first employed as a separator in fuel cells that were used in space exploration, and then as ion-exchange membranes that opened the way to the innovative electrolytic process for chlor-alkali production.3

It has been known for some years that the incorporation of trifluoromethyl groups, particularly in the form of the 1, 1, 1, 3, 3, 3-hexafluoroisopropylidene function, (CF₃)₂C (HFIP), into suitable monomers confers a rather unique property profile on the corresponding polymers.1, 2 Among the main advantages are enhanced solubility and processability, higher thermo-oxidative stability, and superior electrical properties. This has led to the synthesis of a large variety of such monomers and polymers, as disclosed in recent reviews.3, 4 The aim of this chapter is to focus on the synthesis of basic intermediates and important monomers, and to highlight important polymer classes containing the 1, 1, 1, 3, 3, 3-hexafluoroisopropylidene moiety.

The development of perfluoropolyethers (PFPEs) represents a major contribution of organofluorine chemistry to advanced technology. These water-white mellifluous fluids, benign toxicologically and environmentally, exhibit an impressive range of physicochemical properties that are already legendary in certain application areas. The aim of this chapter is to substantiate the above statements by dissection and analysis of PFPEs from the viewpoints of their intriguing synthetic chemistry, properties, derivatives, and applications.

Until the 1980s, perfluoropolyether (PFPE) oils had only limited, specialized uses, but since then their applications have expanded very rapidly. Major applications now include working fluids for vacuum pumps designed for semiconductor manufacturing and base oils for high-temperature lubricating greases.

This chapter describes the existing commercial applications of direct fluorination of polymer surfaces and briefly discusses some emerging applications that have not yet been commercialized. To those familiar with the highly oxidizing and toxic nature of gaseous elemental fluorine, its acceptance by industries that have traditionally avoided the use of potentially hazardous substances may be surprising. This acceptance in industries such as blow-molding is a tribute to the engineers, materials scientists, and chemists who have worked to develop safe and reliable methods for the production, storage, transport, and application of this powerful fluorinating agent.

Fluorinated carbon or graphite fluoride (CAS# 51311-16-2) is a nonstoichiometric solid made by the reaction of carbon with fluorine.* Its empirical formula is CF _x , where x can vary between almost 0 and about 1.3 and depends on the crystallinity of the starting carbon, reaction temperature, and time. Materials having x-values less than about 0.3 are composed of fluorinated and virgin carbon.1

This account of uses of fluorine in chemotherapy is the sometimes idiosyncratic view of a practicing medicinal chemist who has no special expertise or commitment to organofluorine chemistry, but who, like many or perhaps most medicinal chemists, has become increasingly keen to investigate fluorine-containing compounds in the search for improved drugs. Previous approaches to this subject have been based on the selection of compounds from particular biochemical or therapeutic areas mainly because they happen to contain fluorine.1–5 In this author’s opinion, such an approach inevitably tends to produce a very unbalanced view of the selected areas from a medicinal chemist’s standpoint; and clearly the one-time considerable value of such a compilation to fluorine chemists is increasingly limited as computer-based retrieval of complete structures and accompanying abstracts—based on part structures (e. g., C—F!) and keyword searches—becomes a routine matter. Additionally, a recent publication which is fully computer searchable provides a compilation of over 5500 compounds that have been used or studied as medicinal agents in man.6, 7 The output includes full structures, references, and, if available, therapeutic classification and some physical data. Another recent book provides information on the physical and chemical properties, structures, and pharmacological actions of all the most significant drugs in use today.8

No class of chemical compounds has contributed more toward the elimination of hospital trauma than anesthetics. These drugs have changed the operating room from a chamber of horrors to a place where medical care is provided in a tranquil atmosphere to some 50 million patients every year. When inhaled, anesthetics enter the brain and induce profound sleep (hypnosis), sedation (a passive state), muscle relaxation (flaccidity) and analgesia (the absence of pain) to the level required to perform surgery. Inhalation anesthetics leave the brain and the body chemically unchanged because they are exhaled and need not be metabolized to be eliminated. In addition, the newer inhalants are not metabolized to any great extent.

During the past 20 years, much attention has focused on the potential applications of emulsified perfluorochemicals (PFCs) in medicine and biology. Of particular interest has been their use as vehicles for respiratory gas transport, primarily as O₂-carrying resuscitation fluids designed to supplement conventional blood transfusion. For this reason, PFC emulsions have been frequently, but somewhat inaccurately, referred to as “blood substitutes”. However, important clinical applications for PFCs and their emulsions also exist in areas as diverse as hemodilution and microcirculatory management, cancer therapy, diagnostic tissue imaging, and ophthalmologic surgery. Moreover, PFCs appear to be valuable in both basic and applied research for perfusing isolated organs and for regulating the growth of cell cultures.

Hydrogen fluoride (HF) is the largest volume synthetic fluorine compound manufactured in America, and virtually all of the myriad fluorine products that surround us have their origins in HF. In 1991, U.S. domestic sales of fluorochemicals approached $3 billion. Annual production of HF throughout the world is close to one million tons, and it is manufactured almost exclusively by interaction of refined, or acid grade, fluorspar (CaF₂) with sulfuric acid. Attempts to manufacture HF from “phosphate rock” [fluorapatite, 3Ca₃(PO₄)₂*CaF₂] have largely been shelved as uneconomic. Fortunately, in view of the increasing demand for fluorine-containing products, known reserves of fluorspar are increasing.

The objective of this chapter is to provide a broad picture of the organofluorine chemicals industry in Western Europe as seen at the beginning of the 1990s. Commercialization worldwide of organofluorine chemistry has been driven by the demand for “speciality” and “effect” chemicals, and continues to be so. Although a surprisingly high proportion of the global effort devoted to the development of organofluorine chemistry has been expended in Western Europe, the U.S. and Japan feature more strongly in the commercial exploitation of the area. For convenience here, organofluorine products have been divided into three categories, namely, fluoroaliphatics, fluoroaromatics, and fluoropolymers.

The introduction of the chlorofluorocarbon (CFC) fluids in the early thirties marked the inception of the organofluorocarbon industry. Both in terms of tonnage produced and product value, they have dominated the industry and provided feedstocks for the development of other products, such as fluoropolymers (see Chapter 6).