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- Odd Hassel
A useful property of alkyl halides is the ease with which they may be converted to other classes of compounds. The three most important reactions of alkyl halides are nucleophilic substitution, elimination, and conversion to organomagnesium compounds.
Nucleophilic substitution
Nucleophilic substitution, which can be represented by the following general equation, permits the halogen to be replaced by oxygen, sulfur, nitrogen, or another carbon.
The source of the negatively charged nucleophile Y− is normally an ionic sodium or a potassium salt (Na+Y−or K+Y−). A specific example of a nucleophilic substitution is the reaction of sodium hydroxide and benzyl chloride:
The relative order of alkyl halide reactivity is governed by the carbon-halogen bond strength. Alkyl iodides have the weakest carbon-halogen bond and react at the fastest rate. Alkyl fluorides have the strongest carbon-halogen bond and react so slowly as to rarely undergo nucleophilic substitutions.
Various families of organic compounds can be prepared by the appropriate choice of nucleophile. These include ethers (ROR′), esters (RCOOR′), nitriles (RCN), and sulfides (RSR′):
Alkyl fluorides are normally prepared by fluoride acting as a nucleophile toward an alkyl chloride, bromide, or iodide—e.g., NaF + RX → RF + NaX. While the reaction is reversible in principle, the greater strength of the carbon-fluorine bond causes the alkyl fluoride to predominate over the alkyl chloride, bromide, or iodide. Alkyl iodides can be prepared from alkyl chlorides and alkyl bromides by reaction with a solution of sodium iodide (NaI) in acetone (CH3COCH3). In this case the reaction proceeds in the direction shown because neither sodium chloride (NaCl) nor sodium bromide (NaBr) is soluble in acetone; precipitation of sodium chloride or sodium bromide from the reaction mixture causes the position of equilibrium to shift to the right.
Chemists generally agree that the reactions of alkyl halides described to this point take place through a mechanism in which the nucleophile approaches the alkyl halide from the side opposite the bond to the leaving group. Substitution occurs in a single step by way of a transition state (a high-energy, unstable, nonisolable structure) in which the carbon being attacked is partially bonded to both the nucleophile and the leaving group. Any one-step process involving two species is defined as bimolecular, and this reaction mechanism is termed SN2 (substitution-nucleophilic-bimolecular).
The rate of bimolecular nucleophilic substitution strongly depends on the structure of the alkyl halide and is believed to be governed by the degree of crowding at the carbon undergoing nucleophilic attack. Methyl halides (CH3X) react at the fastest rate. Primary alkyl halides (RCH2X) react faster than secondary alkyl halides (RR′CHX), which in turn react faster than tertiary alkyl halides (RR′R″CX). When the substituents R, R′, and R″ are small—e.g., R = R′ = R″ = H in CH3X—the transition state is not very crowded, and the nucleophile displaces the leaving group from carbon rapidly. Successive replacement of R, R′, and R″ by alkyl groups increasingly hinders the approach of the nucleophile to carbon, makes the transition state more crowded, and slows the rate. The blocking of access to a reactive site by nearby groups is referred to as steric hindrance.
Tertiary alkyl halides are so sterically hindered that, when they undergo nucleophilic substitution, they do so by a mechanism other than SN2. A two-step mechanism is believed to be followed, the first step of which is slower than the second and determines the overall rate of the reaction.
Because the rate-determining (slow) step involves only one molecule, the mechanism is described as unimolecular, and the term SN1 (substitution-nucleophilic-unimolecular) is applied. The species formed in the slow step contains a positively charged, electron-deficient carbon and is called a carbocation. Carbocations are unstable and react rapidly with substances such as nucleophiles that have unshared electrons available for bond formation.
Elimination
When the attacking species is a strong base such as hydroxide (−OH) or alkoxide (−OR), nucleophilic substitutions carried out for synthetic objectives are practical only when the alkyl halide is primary. The principal reaction observed when a strong base reacts with a secondary or tertiary alkyl halide is elimination, as in the attack of sodium methoxide on 2-chloro-2-methylpropane.
Elimination competes with substitution because the negatively charged ion, in this case methoxide (−OCH3), can either attack carbon (act as a nucleophile) or remove a proton (act as a base). The bonding changes that accompany elimination are often represented using curved-arrow notation to track the movement of electron pairs.
Elimination of alkyl halides in the manner described is believed to occur in a single step and is given the mechanistic symbol E2, which stands for elimination-bimolecular. Elimination always accompanies nucleophilic substitution and is the chief limitation on efficient synthetic applications of nucleophilic substitution. By using a sufficiently strong base, it is usually possible to cause elimination to predominate over substitution, and dehydrohalogenation of alkyl halides by the E2 mechanism is one of the main methods by which alkenes are prepared (see hydrocarbon).
Preparation of Grignard reagents
Many metals, especially those of Groups 1 and 2, reduce alkyl halides, converting the carbon-halogen bond to a carbon-metal bond. (Substances that contain a carbon-metal bond are referred to as organometallic compounds.) The most generally useful organometallic compounds are those of magnesium (Mg), formulated as alkylmagnesium halides, RMgX.
Organomagnesium compounds, called Grignard reagents, are versatile in synthetic organic chemistry. These highly reactive substances are normally prepared and stored in inert solvents, especially diethyl ether (CH3CH2OCH2CH3), until used. The preparation of Grignard reagents is of broad scope. The organohalogen compound may be an alkyl, alkenyl, or aryl halide; if it is an alkyl halide, it may be primary, secondary, or tertiary. It may be an iodide (most reactive toward reduction by magnesium), bromide, or chloride. Even alkyl fluorides, which normally do not react with magnesium, can be converted to Grignard reagents by using a specially prepared highly reactive form of the metal.
The most useful reaction of Grignard reagents is their reaction with aldehydes and ketones to form alcohols. Grignard reagents react with formaldehyde to give primary alcohols having one more carbon atom than the alkyl halide from which the Grignard reagent was derived. Aldehydes give secondary alcohols, while ketones yield tertiary alcohols. Alcohols can also be prepared by the reaction of Grignard reagents with epoxides or esters (for more information about these reactions, see alcohol and phenol).
Vinylic halides
Natural occurrence
Vinylic chlorides and bromides constitute a diverse class of marine natural products. For example, the following compounds have all been isolated from the volatile oil of Chondrococcus hornemanni, a red seaweed found in the Pacific Ocean. (In line formulas such as the following, a carbon atom is assumed to be at every intersection of two lines and at the end of each line, unless otherwise labeled, with hydrogen atoms attached as necessary to each carbon.)
Preparation
The two major methods for preparing vinylic halides are dehydrohalogenation of a dihalide and addition of a hydrogen halide to an alkyne.
Dehydrohalogenation of a dihalide
Treatment of a geminal dihalide (both halogens on the same carbon) or a vicinal dihalide (halogens on adjacent carbons) with a base such as sodium ethoxide (NaOCH2CH3) yields a vinylic halide.
The vinylic halide prepared in greatest amount as an industrial chemical is vinyl chloride (CH2=CHCl). It is prepared from 1,2-dichloroethane (ClCH2CH2Cl).
Addition of a hydrogen halide to an alkyne
When a hydrogen halide adds to the carbon-carbon triple bond of an alkyne, addition of the first molecule is faster than the second, and a vinylic halide can be isolated.
Chloroprene, the monomer used in the formation of the elastomer neoprene, is prepared from vinylacetylene by this reaction.
Certain vinylic halides are prepared by methods that are not applicable in general but are unique to the individual substance. Tetrafluoroethylene (CF2=CF2), for example, is prepared by heating chlorodifluoromethane (ClCHF2) at temperatures of 600–750 °C (1,100–1,400 °F). Tetrafluoroethylene is the monomer from which the polymer polytetrafluoroethylene (PTFE; familiarly known by its trade name, Teflon) is prepared.
Reactions
Vinylic halides differ from alkyl halides in being essentially unreactive toward nucleophilic substitution. They do undergo elimination reactions similar to alkyl halides, although at slower rates, and they normally require very strong bases such as sodium amide (NaNH2).
Vinylic halides may be converted to Grignard reagents by reaction with magnesium, and these reagents undergo the same types of reaction as those derived from alkyl halides.
Vinylic halides resemble alkenes in that they undergo addition to their double bond. An example is the addition of hydrogen chloride to vinyl chloride to yield 1,1-dichloroethane. The product is a geminal dihalide (both halogens are bonded to the same carbon).
Polymerization of certain vinylic halides yields materials of economic value. Among synthetic polymers, the annual production of polyvinyl chloride, or PVC, is second only to that of polyethylene.
Polyvinyl chloride is used in siding for houses, shingles, gutters and downspouts, floor tiles, and pipes and fittings. The copolymer of vinyl chloride and vinylidene chloride (CH2=CCl2), called saran, has properties that make it a useful self-clinging transparent wrapping material.
Polymerization of tetrafluoroethylene gives a carbon chain that bears only fluorine substituents. Its strong carbon-fluorine bonds make polytetrafluoroethylene relatively inert toward both thermal and chemical degradation. The weakness of the attractive forces between fluorocarbon chains and other molecules causes the polymer to have a low coefficient of friction, making it well suited for nonstick coatings.
Aryl halides
Natural occurrence
Many organohalogen compounds in which the halogen is directly attached to a benzenoid ring occur naturally. Unlike alkyl and vinylic halides, for which marine origins are the most common, aryl halides are found in a variety of sources. l-Thyroxine, for example, is an iodine-containing amino acid secreted by the thyroid gland that acts as a regulator of metabolism. At one time, natural l-thyroxine extracted from the thyroids of animals was used to treat patients with thyroxine deficiencies, but today almost all of the l-thyroxine used to treat thyroid disorders is synthetic.
The sex pheromone of the lone star tick, Amblyomma americanum, is 2,6-dichlorophenol, and 2,6-dibromophenol has been isolated from the acorn worm, Balanoglossus biminiensis.
Several halogen-containing aromatic compounds, while not natural products in the customary sense of the word, have become widely dispersed in the environment. The most familiar example is 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, or DDT.![Chemical Compounds. Organothalogen compounds. Aryl Halides. Natural occurrence. [Chemical structure of DDT.]](https://cdn.britannica.com/22/16622-004-505283B1/structure-DDT.jpg)
DDT was introduced in the early 1940s and soon became both the agricultural insecticide of choice and the principal means of combating disease-bearing insects. One of the advantages of DDT is that it is a persistent insecticide, meaning that it is only slowly degraded by natural processes and survives for a long time after its initial application. DDT proved so effective in increasing crop yields and controlling insect-borne diseases such as malaria that Paul Müller, the Swiss chemist who developed the insecticide, was awarded the Nobel Prize for Physiology or Medicine in 1948. Studies in the 1960s, however, revealed that DDT accumulated in the fatty tissue of fishes, birds, and other animals and that the DDT levels increased in moving up the food chain. High DDT levels in birds were associated with fragile eggshells and reproductive abnormalities. Potential harm to wildlife and humans, along with the fact that many insects had become resistant to DDT, prompted the U.S. Environmental Protection Agency (EPA) to impose in 1972 an almost complete ban on its use.
A second chlorine-containing aromatic compound that is widespread in the environment is 2,3,7,8-tetrachlorodibenzo-p-dioxin (known simply as dioxin).
Dioxin is formed in small amounts as a by-product in the synthesis of the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), in chlorine-based bleaching processes during paper production, and whenever organic material burns in the presence of a source of chloride ion Cl−, as in forest fires, for example. It is a very stable compound and gradually accumulates in the environment. Because dioxin is exceedingly toxic, carcinogenic, and teratogenic to test animals, regulations designed to limit further environmental contamination have been implemented.
A group of aryl halides called polychlorinated biphenyls (PCBs) were formerly prepared on a large scale for use as heat-transfer mediums and insulating materials in transformers and other electrical equipment. Many of the problems associated with DDT and dioxin as environmental pollutants apply to PCBs as well, and PCB production was banned by the EPA in 1979.
