Fluoroalkane

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 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.
# The carbon–fluorine bond is one of the strongest in organic chemistry (an average bond energy around 480 kJ/mol). This is significantly stronger than the bonds of carbon with other halogens (an average bond energy of e.g. C–Cl bond is around 320 kJ/mol) and is one of the reasons why fluoroorganic compounds have high thermal and chemical stability.
# The carbon–fluorine bond is relatively short (around 1.4 Å).
# 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 (1.2 Å). 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.
# Fluorine has the highest electronegativity of all elements: 3.98. This causes the high dipole moment of C–F bond (1.41 D).
# Fluorine has the lowest polarizability of all atoms: 0.56 $\times$ 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 (CF₄). 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.

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 ( H₂CF₂sub>n) and polychlorotrifluoroethylene ( FClCF₂sub>n). The fluoropolymer polytetrafluoroethylene (PTFE/Teflon) is a solid.

Hydrofluorocarbons

Hydrofluorocarbons (HFCs), 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 (HFCs) 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 (CH₂) 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 new atoms such as nitrogen, iodine, or ionic groups, such as perfluorinated carboxylic 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.

: + → + (M = Na, K, Cs)

Alkyl monofluorides can be obtained from alcohols and Olah reagent (pyridinium fluoride) 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:
: Cl₂C=CClH + 4 HF → F₃CCFH₂ + 3 HCl
Notice that this transformation entails two reaction types, metathesis (replacement of Cl⁻ by F⁻) and hydrofluorination of an alkene.

Deoxofluorination

Deoxofluorination convert a variety of oxygen-containing groups into fluorides. The usual reagent is sulfur tetrafluoride:
:RCO₂H + SF₄ → RCF₃ + SO₂ + HF
A more convenient alternative to SF₄ is the diethylaminosulfur trifluoride, which is a liquid whereas SF₄ is a corrosive gas:
:

Apart from DAST, a wide variety of similar reagents exist, including, but not limited to, 2-pyridinesulfonyl fluoride (PyFluor) and ''N''-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor). Many of these display improved properties such as better safety profile, higher thermodynamic stability, ease of handling, high enantioselectivity, and selectivity over elimination side-reactions.

From fluorinated building blocks

Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF₃Si(CH₃)₃, is used as a source of the trifluoromethyl group, for example. Among the available fluorinated building blocks are CF₃X (X = Br, I), C₆F₅Br, and C₃F₇I. These species form Grignard reagents that then can be treated with a variety of electrophiles. The development of fluorous technologies (see below, under solvents) is leading to the development of reagents for the introduction of "fluorous tails".

A special but significant application of the fluorinated building block approach is the synthesis of tetrafluoroethylene, which is produced on a large-scale industrially via the intermediacy of difluorocarbene. The process begins with the thermal (600–800 °C) dehydrochlorination of chlorodifluoromethane:
:CHClF₂ → CF₂ + HCl
:2 CF₂ → C₂F₄
Sodium fluorodichloroacetate (CAS# 2837-90-3) is used to generate chlorofluorocarbene, for cyclopropanations.

¹⁸F-Delivery methods

The usefulness of fluorine-containing radiopharmaceuticals in ¹⁸F-positron emission tomography has motivated the development of new methods for forming C–F bonds. Because of the short half-life of ¹⁸F, these syntheses must be highly efficient, rapid, and easy. Illustrative of the methods is the preparation of fluoride-modified glucose by displacement of a triflate by a labeled fluoride nucleophile:
:

Biological role

Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals.Murphy CD, Schaffrath C, O'Hagan D.
"Fluorinated natural products: the biosynthesis of fluoroacetate and 4-fluorothreonine in ''Streptomyces cattleya''"
Chemosphere. 2003 Jul;52(2):455-61. The most common example is fluoroacetate, which occurs as a plant defence against herbivores in at least 40 plants in Australia, Brazil and Africa. Other biologically synthesized organofluorines include ω-fluoro fatty acids, fluoroacetone, and 2-fluorocitrate which are all believed to be biosynthesized in biochemical pathways from the intermediate fluoroacetaldehyde. Adenosyl-fluoride synthase is an enzyme capable of biologically synthesizing the carbon–fluorine bond.

Applications

Organofluorine chemistry impacts many areas of everyday life and technology. The C–F bond is found in pharmaceuticals, agrochemicals, fluoropolymers, refrigerants, surfactants, anesthetics, oil-repellents, catalysts, and water-repellents, among others.

Pharmaceuticals and agrochemicals

The carbon-fluorine bond is commonly found in pharmaceuticals and agrochemicals. An estimated 1/5 of pharmaceuticals contain fluorine, including several of the top drugs. Examples include 5-fluorouracil, flunitrazepam (Rohypnol), fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole. Introducing the carbon–fluorine bond to organic compounds is the major challenge for medicinal chemists using organofluorine chemistry, as the carbon–fluorine bond increases the probability of having a successful drug by about a factor of ten. Over half of agricultural chemicals contain C–F bonds. A common example is trifluralin. The effectiveness of organofluorine compounds is attributed to their metabolically stability, i.e. they are not degraded rapidly so remain active. Also, fluorine acts as a bioisostere of the hydrogen atom.

Inhaler propellant

Fluorocarbons are also used as a propellant for metered-dose inhalers used to administer some asthma medications. The current generation of propellant consists of hydrofluoroalkanes (HFA), which have replaced CFC-propellant-based inhalers. CFC inhalers were banned as part of the Montreal Protocol because of environmental concerns with the ozone layer. HFA propellant inhalers like FloVent and ProAir (Salbutamol) have no generic versions available as of October 2014.

Fluorosurfactants

Fluorosurfactants, which have a polyfluorinated "tail" and a hydrophilic "head", serve as surfactants because they concentrate at the liquid-air interface due to their lipophobicity. Fluorosurfactants have low surface energies and dramatically lower surface tension. The fluorosurfactants perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two of the most studied because of their ubiquity, proposed toxicity, and long residence times in humans and wildlife.

Triphenylphosphine has been modified by attachment of perfluoroalkyl substituents that confer solubility in perfluorohexane as well as supercritical carbon dioxide. As a specific example, [(C₈F₁₇C₃H₆-4-C₆H₄)₃P.

Solvents

Fluorinated compounds often display distinct solubility properties. Dichlorodifluoromethane and chlorodifluoromethane were at one time widely used refrigerants. CFCs have potent ozone depletion potential due to the homolytic cleavage of the carbon-chlorine bonds; their use is largely prohibited by the Montreal Protocol. Hydrofluorocarbons (HFCs), such as tetrafluoroethane