Haloalkane

Tetrafluoroethane (a haloalkane) is a colorless liquid that boils well below room temperature (as seen here) and can be extracted from common canned air canisters by simply inverting them during use.

The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of chemical compounds, derived from alkanes containing one or more halogens. They are a subset of the general class of halocarbons although the distinction is not often made. Haloalkanes are widely used commercially and consequently are known under many chemical and commercial names. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant.

Haloalkanes have been known for centuries. Ethyl chloride was produced synthetically in the 15th century. The systematic synthesis of such compounds developed in the 19th century in step with the development of organic chemistry and the understanding of the structure of alkanes. Methods were developed for the selective formation of C-halogen bonds. Especially versatile methods included the addition of halogens to alkenes, hydrohalogenation of alkenes, and the conversion of alcohols to alkyl halides. These methods are so reliable and so easily implemented that haloalkanes became cheaply available for use in industrial chemistry because the halide could be further replaced by other functional groups.

Classes of haloalkanes

From the structural perspective, haloalkanes can be classified according to the connectivity of the carbon atom to which the halogen is attached. In primary (1°) haloalkanes, the carbon that carries the halogen atom is only attached to one other alkyl group. An example is 1-chloroethane (CH₃CH₂Cl). In secondary (2°) haloalkanes, the carbon that carries the halogen atom has two C-C bonds. In tertiary (3°) haloalkanes, the carbon that carries the halogen atom has three C-C bonds.

Haloalkanes can also be classified according to the type of halogen. Haloalkanes containing carbon bonded to fluorine, chlorine, bromine, and iodine results in organofluorine, organochlorine, organobromine and organoiodine compounds, respectively. Compounds containing more than one kind of halogen are also possible, the best-known examples being the chlorofluorocarbons (CFCs).

Properties

Haloalkanes generally resemble the parent alkanes in being colorless, relatively odorless, and hydrophobic. Their boiling points are higher than the corresponding alkanes and scale with the atomic weight and number of halides. This is due to the increased strength of the intermolecular forces—from London dispersion to dipole-dipole interaction because of the increased polarity. Thus CI₄ is a solid whereas CF₄ is a gas. As they contain fewer C-H bonds, halocarbons are less flammable than alkanes, and some are used in fire extinguishers. Haloalkanes are better solvents than the corresponding alkanes because of their increased polarity. Haloalkanes are uniformly more reactive than the parent alkanes - it is this reactivity that is the basis of most controversies. Many are alkylating agents. The ozone-depleting abilities of the CFC's arises from the photolability of the C-Cl bond.

Occurrence

Haloalkanes are of wide interest because they are widespread and have diverse beneficial and detrimental impacts. The oceans are estimated to release 1-2 million tons of bromomethane annually.^[1]

A large number of pharmaceuticals contain halogens, especially fluorine. An estimated one fifth of pharmaceuticals contain fluorine, including several of the top drugs.^[2] Examples include 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole. The beneficial effects arise because the C-F bond is relatively unreactive. Fluorine-substituted ethers are volatile anesthetics, including the commercial products methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane. Perfluorinated alkanes are used as blood substitutes.

Teflon structure

Chlorinated or fluorinated alkenes undergo polymerization. Important halogenated polymers include polyvinyl chloride (PVC), and polytetrafluoroethene (PTFE, or Teflon). The production of these materials releases substantial amounts of wastes.

Nomenclature

IUPAC

The formal naming of haloalkanes should follow IUPAC nomenclature, which put the halogen as a prefix to the alkane. For example, ethane with bromine becomes bromoethane, methane with four chlorine groups becomes tetrachloromethane. However, many of these compounds have already an established trivial name, which is endorsed by the IUPAC nomenclature, for example chloroform (trichloromethane) and methylene chloride (dichloromethane). For unambiguity, this article follows the systematic naming scheme throughout.

Production

Haloalkanes can be produced from virtually all organic precursors. From the perspective of industry, the most important ones are alkanes and alkenes.

From alkanes

Alkanes react with halogens by free radical halogenation. In this reaction a hydrogen atom is removed from the alkane, then replaced by a halogen atom by reaction with a diatomic halogen molecule. The reactive intermediate in this reaction is a free radical and the reaction is called a radical chain reaction.

Free radical halogenation typically produces a mixture of compounds mono- or multihalogenated at various positions. It is possible to predict the results of a halogenation reaction based on bond dissociation energies and the relative stabilities of the radical intermediates. Another factor to consider is the probability of reaction at each carbon atom, from a statistical point of view.

Due to the different dipole moments of the product mixture, it may be possible to separate them by distillation.

From alkenes and alkynes

In hydrohalogenation, an alkene reacts with a dry hydrogen halide (HX) like hydrogen chloride (HCl) or hydrogen bromide (HBr) to form a mono-haloalkane. The double bond of the alkene is replaced by two new bonds, one with the halogen and one with the hydrogen atom of the hydrohalic acid. Markovnikov's rule states that in this reaction, the halogen is more likely to become attached to the more substituted carbon. This is a electrophilic addition reaction. Water must be absent otherwise there will be a side product of a cyanohydrin. The reaction is necessarily to be carried out in a dry inert solvent such as CCl₄ or directly in the gaseous phase. The reaction of alkynes are similar, with the product being a geminal dihalide; once again, Markovnikov's rule is followed.

Alkenes also react with halogens (X₂) to form haloalkanes with two neighboring halogen atoms in a halogen addition reaction. Alkynes react similarly, forming the tetrahalo compounds. This is sometimes known as "decolorizing" the halogen, since the reagent X₂ is colored and the product is usually colorless.

From alcohols

Tertiary alkanol reacts with hydrochloric acid directly to produce tertiary chloroalkane, but if primary or secondary alkanol is used, an activator such as zinc chloride is needed. This reaction is exploited in the Lucas test.

The most popular conversion is effected by reacting the alcohol with thionyl chloride in the "Darzen's process," which is one of the most convenient laboratory methods because the byproducts are gaseous. Both phosphorus pentachloride (PCl₅) and phosphorus trichloride (PCl₃) also convert the hydroxyl group to the chloride.

Alcohol may likewise be converted to bromoalkane using hydrobromic acid or phosphorus tribromide (PBr₃). A catalytic amount of PBr₃ may be used for the transformation using phosphorus and bromine; PBr₃ is formed in situ. Iodoalkanes may similarly be prepared using using red phosphorus and iodine (equivalent to phosphorus triiodide). The Appel reaction is also useful for preparing alkyl halides. The reagent is tetrahalomethane and triphenylphosphine; the co-products are haloform and triphenylphosphine oxide.

From carboxylic acids

Two methods for the synthesis of alkyl halides from carboxylic acids are the Hunsdiecker reaction and the Kochi reaction.

Biosynthesis

Many chloro and bromolkanes are formed naturally. The principal pathways involve the enzymes chloroperoxidase and bromoperoxidase.

Reactions

Haloalkanes are reactive towards nucleophiles. They are polar molecules: the carbon to which the halogen is attached is slightly electropositive where the halogen is slightly electronegative. This results in an electron deficient (electrophilic) carbon which, inevitably, attracts nucleophiles.

Substitution

Substitution reactions involve the replacement of the halogen with another molecule - thus leaving saturated hydrocarbons, as well as the halogenated product. Alkyl halides behave as the R⁺ synthon, and readily react with nucleophiles.

Hydrolysis - a reaction in which water breaks a bond - is a good example of the nucleophilic nature of halogenoalkanes. The polar bond attracts a hydroxide ion, OH^-. (NaOH_(aq) being a common source of this ion). This OH^- is a nucleophile with a clearly negative charge, as it has excess electrons it donates them to the carbon, which results in a covalent bond between the two. Thus C-X is broken by heterolytic fission resulting in a halide ion, X^-. As can be seen, the OH is now attached to the alkyl group, creating an alcohol. (Hydrolysis of bromoethane, for example, yields ethanol). Reaction with ammonia give primary amines.

Alkyl chlorides and bromides are readily substituted by iodide in the Finkelstein reaction. The alkyl iodides produced easily undergo further reaction. Sodium iodide is used thus as a catalyst. Alkyl halides react with ionic nucleophiles (e.g. cyanide, thiocyanate, azide); the halogen is replaced by the respective group. This is of great synthetic utility: alkyl chlorides are often inexpensively available. For example, after undergoing substitution reactions, alkyl cyanides may be hydrolyzed to carboxylic acids, or reduced to primary amines using lithium aluminium hydride. Alkyl azides may be reduced to primary alkyl amines by the Staudinger reduction or lithium aluminium hydride. Amines may also be prepared from alkyl halides in amine alkylation, the Gabriel synthesis and Delepine reaction, by undergoing nucleophilic substitution with potassium phthalimide or hexamine respectively, followed by hydrolysis.

In the presence of a base, alky halides alkylate alcohols, amines, and thiols to obtain ethers, N-substituted amines, and thioethers respectively. They are substituted by Grignard reagents to give magnesium salts and an extended alkyl compound.

Mechanism

Where the rate-determining step of a nucleophilic substitution reaction is unimolecular, it is known as an S_N1 reaction. In this case, the slowest (thus rate-determining step) is the heterolysis of a carbon-halogen bond to give a carbocation and the halide anion. The nucleophile attacks the carbocation to give the product.

S_N1 reactions are associated with the racemization of the compound, as the trigonal planar carbocation may be attacked from either face. They are favored mechanism for tertiary alkyl halides, due to the stabilization of the positive charge on the carbocation by three electron-donating alkyl groups. They are also preferred where the substituents are sterically bulky, hindering the S_N2 mechanism.

Elimination

Rather than creating a molecule with the halogen substituted with something else, one can completely eliminate both the halogen and a nearby hydrogen, thus forming an alkene. For example, with bromoethane and NaOH in ethanol, the hydroxide ion OH^- attracts a hydrogen atom - thus removing a hydrogen and bromine from bromoethane. This results in C₂H₄ (ethene), H₂O and Br^-. Thus, haloalkanes are able to give alkenes; dihaloalkanes give alkynes by dehydrohalogenation.

1,2-Dibromocompounds are debrominated by zinc dust to give alkenes. Geminal dihalides (where both halogen atoms are on the same carbon) react with strong bases to give carbenes as well.

Other

Alkyl halides undergo free-radical reactions with elemental magnesium to give alkylmagnesium compounds: Grignard reagents. Alkyl halides also react with lithium metal to give organolithium compounds. Both Grignard reagents and organolithium compounds behave as the R^- synthon. Alkali metals such as sodium and lithium are able to cause alkyl halides to couple in the Wurtz reaction, giving symmetrical alkanes. Alkyl halides, especially iodides, also undergo oxidative addition reactions to give organometallic compounds.

Applications

Haloalkanes are widely used as synthon equivalents to alkyl cation (R+) in organic synthesis. They can also participate in a wide variety of other organic reactions.

Short chain haloalkanes such as dichloromethane, trichloromethane (chloroform) and tetrachloromethane are commonly used as hydrophobic solvents in chemistry.

Chlorofluorocarbons have also been widely used as refrigerants, propellants and solvents due to their low toxicity and high heat capacity.

See also

• Halogenation
• Halomethane
• Halogenoarene

References