Organofluorine chemistry


Organofluorine chemistry describes the chemistry of organofluorine compounds, organic compounds that contain a carbon–fluorine bond. Organofluorine compounds find diverse applications ranging from oil and water repellents to pharmaceuticals, refrigerants, and reagents in catalysis. In fact, "about 40% of new pharmaceuticals... and 25% of all those on the market... contain fluorine".
In addition to these applications, some organofluorine compounds are pollutants because of their contributions to ozone depletion, global warming, bioaccumulation, and toxicity. The area of organofluorine chemistry often requires special techniques associated with the handling of fluorinating agents.

The carbon–fluorine bond

Fluorine has several distinctive differences from all other substituents encountered in organic molecules. As a result, the physical and chemical properties of organofluorines can be distinctive in comparison to other organohalogens.
  1. The carbon–fluorine bond is one of the strongest in organic chemistry. This is significantly stronger than the bonds of carbon with other halogens and is one of the reasons why fluoroorganic compounds have high thermal and chemical stability.
  2. The carbon–fluorine bond is relatively short.
  3. The Van der Waals radius of the fluorine substituent is only 1.47 Å, which is shorter than in any other substituent and is close to that of hydrogen. This, together with the short bond length, is the reason why there is no steric strain in polyfluorinated compounds. This is another reason for their high thermal stability. In addition, the fluorine substituents in polyfluorinated compounds efficiently shield the carbon skeleton from possible attacking reagents. This is another reason for the high chemical stability of polyfluorinated compounds.
  4. Fluorine has the highest electronegativity of all elements: 3.98. This causes the high dipole moment of C–F bond.
  5. Fluorine has the lowest polarizability of all atoms: 0.56 10−24 cm3. This causes very weak dispersion forces between polyfluorinated molecules and is the reason for the often-observed boiling point reduction on fluorination as well as for the simultaneous hydrophobicity and lipophobicity of polyfluorinated compounds whereas other perhalogenated compounds are more lipophilic.
In comparison to aryl chlorides and bromides, aryl fluorides form Grignard reagents only reluctantly. On the other hand, aryl fluorides, e.g. fluoroanilines and fluorophenols, often undergo nucleophilic substitution efficiently.

Types of organofluorine compounds

Fluorocarbons

Formally, fluorocarbons only contain carbon and fluorine. Sometimes they are called perfluorocarbons. They can be gases, liquids, waxes, or solids, depending upon their molecular weight. The simplest fluorocarbon is the gas tetrafluoromethane. Liquids include perfluorooctane and perfluorodecalin. While fluorocarbons with single bonds are stable, unsaturated fluorocarbons are more reactive, especially those with triple bonds. Fluorocarbons are more chemically and thermally stable than hydrocarbons, reflecting the relative inertness of the C–F bond. They are also relatively lipophobic. Because of the reduced intermolecular van der Waals interactions, fluorocarbon-based compounds are sometimes used as lubricants or are highly volatile. Fluorocarbon liquids have medical applications as oxygen carriers.
The structure of organofluorine compounds can be distinctive. As shown below, perfluorinated aliphatic compounds tend to segregate from hydrocarbons. This "like dissolves like effect" is related to the usefulness of fluorous phases and the use of PFOA in processing of fluoropolymers. In contrast to the aliphatic derivatives, perfluoroaromatic derivatives tend to form mixed phases with nonfluorinated aromatic compounds, resulting from donor-acceptor interactions between the pi-systems.
Image:Aliphatic Fluorocarbon.jpg|right|thumb|225px|Segregation of alkyl and perfluoroalkyl substituents.
Image:Aromatic Fluorocarbon.jpg|right|thumb|150px|Packing in a crystal pentafluorotolan, illustrating the donor-acceptor interactions between the fluorinated and nonfluorinated rings.

Fluoropolymers

Polymeric organofluorine compounds are numerous and commercially significant. They range from fully fluorinated species, e.g. PTFE to partially fluorinated, e.g. polyvinylidene fluoride and polychlorotrifluoroethylene. The fluoropolymer polytetrafluoroethylene is a solid.

Hydrofluorocarbons

Hydrofluorocarbons, organic compounds that contain fluorine and hydrogen atoms, are the most common type of organofluorine compounds. They are commonly used in air conditioning and as refrigerants in place of the older chlorofluorocarbons such as R-12 and hydrochlorofluorocarbons such as R-21. They do not harm the ozone layer as much as the compounds they replace; however, they do contribute to global warming. Their atmospheric concentrations and contribution to anthropogenic greenhouse gas emissions are rapidly increasing, causing international concern about their radiative forcing.
Fluorocarbons with few C–F bonds behave similarly to the parent hydrocarbons, but their reactivity can be altered significantly. For example, both uracil and 5-fluorouracil are colourless, high-melting crystalline solids, but the latter is a potent anti-cancer drug. The use of the C–F bond in pharmaceuticals is predicated on this altered reactivity. Several drugs and agrochemicals contain only one fluorine center or one trifluoromethyl group.
Unlike other greenhouse gases in the Paris Agreement, hydrofluorocarbons have other international negotiations.
In September 2016, the so-called New York Declaration urged a global reduction in the use of HFCs. On 15 October 2016, due to these chemicals contribution to climate change, negotiators from 197 nations meeting at the summit of the United Nations Environment Programme in Kigali, Rwanda reached a legally binding accord to phase out hydrofluorocarbons in an amendment to the Montreal Protocol.

Fluorocarbenes

As indicated throughout this article, fluorine-substituents lead to reactivity that differs strongly from classical organic chemistry. The premier example is difluorocarbene, CF2, which is a singlet whereas carbene has a triplet ground state. This difference is significant because difluorocarbene is a precursor to tetrafluoroethylene.

Perfluorinated compounds

Perfluorinated compounds are fluorocarbon derivatives, as they are closely structurally related to fluorocarbons. However, they also possess nitrogen, iodine, or oxygen. Perfluorinated carboxylic acids are examples.
Highly fluorinated substituents, e.g. perfluorohexyl confer distinctive solubility properties to molecules, which facilitates purification of products in organic synthesis. This area, described as "fluorous chemistry," exploits the concept of like-dissolves-like in the sense that fluorine-rich compounds dissolve preferentially in fluorine-rich solvents. Because of the relative inertness of the C–F bond, such fluorous phases are compatible with harsh reagents. This theme has spawned techniques of fluorous tagging and fluorous protection. Illustrative of fluorous technology is the use of fluoroalkyl-substituted tin hydrides for reductions, the products being easily separated from the spent tin reagent by extraction using fluorinated solvents.
Triphenylphosphine has been modified by attachment of perfluoroalkyl substituents that confer solubility in perfluorohexane as well as supercritical carbon dioxide. As a specific example, borate, are useful in Ziegler–Natta catalysis and related alkene polymerization methodologies. The fluorinated substituents render the anions weakly basic and enhance the solubility in weakly basic solvents, which are compatible with strong Lewis acids.

Methods for preparation of C–F bonds

Organofluorine compounds are prepared by numerous routes, depending on the degree and regiochemistry of fluorination sought and the nature of the precursors. The direct fluorination of hydrocarbons with F2, often diluted with N2, is useful for highly fluorinated compounds:
Such reactions however are often unselective and require care because hydrocarbons can uncontrollably "burn" in, analogous to the combustion of hydrocarbon in. For this reason, alternative fluorination methodologies have been developed. Generally, such methods are classified into two classes.

Electrophilic fluorination

Electrophilic fluorination rely on sources of "F+". Often such reagents feature N–F bonds, for example F-TEDA-BF4. Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from a prochiral substrate, rely on electrophilic fluorination reagents. Illustrative of this approach is the preparation of a precursor to anti-inflammatory agents:

Electrosynthetic methods

A specialized but important method of electrophilic fluorination involves electrosynthesis. The method is mainly used to perfluorinate, i.e. replace all C–H bonds by C–F bonds. The hydrocarbon is dissolved or suspended in liquid HF, and the mixture is electrolyzed at 5–6 V using Ni anodes. The method was first demonstrated with the preparation of perfluoropyridine from pyridine. Several variations of this technique have been described, including the use of molten potassium bifluoride or organic solvents.

Nucleophilic fluorination

The major alternative to electrophilic fluorination is nucleophilic fluorination using reagents that are sources of "F−," for Nucleophilic displacement typically of chloride and bromide. Metathesis reactions employing alkali metal fluorides are the simplest. For aliphatic compounds this is sometimes called the Finkelstein reaction, while for aromatic compounds it is known as the Halex process.
Alkyl monofluorides can be obtained from alcohols and Olah reagent or another fluoridating agents.
The decomposition of aryldiazonium tetrafluoroborates in the Sandmeyer or Schiemann reactions exploit fluoroborates as F− sources.
Although hydrogen fluoride may appear to be an unlikely nucleophile, it is the most common source of fluoride in the synthesis of organofluorine compounds. Such reactions are often catalysed by metal fluorides such as chromium trifluoride. 1,1,1,2-Tetrafluoroethane, a replacement for CFCs, is prepared industrially using this approach:
Notice that this transformation entails two reaction types, metathesis and hydrofluorination of an alkene.