NUCLEOPHILIC SUBSTITUTION REACTIONS OF HALOALKANES

A typical example of a nucleophilic substitution reaction is the substitution of bromide ion for iodide ion in a haloalkane such as iodomethane. 

A similar reaction occurs when the hydroxide ion replaces the halide ion to produce an alcohol. When the oxygen-containing nucleophile is an alkoxide ion (RO ), the product is an ether. 

Haloalkanes also undergo nucleophilic substitution reactions with sulfur-containing nucleophiles such as hydrogen sulfide ion (HS ) and thiolate ions (RS ). These reactions yield sulfur analogs of alcohols and ethers namely, thiols and thioethers. 

Haloalkanes also react with carbon nucleophiles. These reactions increase the length of the carbon chain. One example of a carbon-containing nucleophile is cyanide ion (CN), which reacts with haloalkanes to give nitriles with the formula R—CN. We will see later that nitriles can be transformed into carboxylic acids and amines. Carbon-containing nucleophiles derived from aUtynes are called alkynide ions. These nucleophiles, the conjugate bases of alkynes, react to form alkynes containing the carbon atoms of both the haloalkane and the alkynide. 

Using compounds containing no more than three carbon atoms, propose two ways to prepare CH CH—S—CH CH CH, 

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Secondary haloalkanes may react by either an Sfjl or an 8 2 mechanism, depending on the nucleophile and solvent. The competition between electronic and steric factors and their effects on relative rates of nucleophilic substitution reactions of haloalkanes are summarized in Figure 7.3. 

Why do tertiary alcohols react with HX by formation of carbocation intermediates, whereas primary alcohols react by direct displacement of —OH (more accurately, by displacement of —OHg ) The answer is a combination of the same two factors involved in nucleophilic substitution reactions of haloalkanes (Section 7.5B) ... 

Tertiary haloalkanes react by an S l mechanism because 3° carbocation intermediates are relatively stable and tertiary haloalkanes are protected against backside attack. In fact, 3° haloalkanes are never observed to react by an mechanism. In contrast, halomethanes and primary haloalkanes are never observed to react by an mechanism. They have little crowding around the reaction site and react ty an Sj 2 mechanism because methyl and primary carbocations are unstable. Secondary haloalkanes may react by either 8, 1 or 8, 2 mechanisms, depending on the nucleophile and solvent. The competition between electronic and steric factors and their effects on relative rates of nucleophilic substitution reactions of haloalkanes are summarized in Figure 9.3. 

In contrast with the reactions involving sulphide or hydrogen sulphide anions, aryl alkyl thioethers and unsymmetrical dialkyl thioethers (Table 4.3) are obtained conveniently by the analogous nucleophilic substitution reactions between haloalkanes and aryl or alkylthiols under mildly basic conditions in the presence of a quaternary ammonium salt [9-15] or polymer-supported quaternary ammonium salt [16]. Dimethyl carbonate is a very effective agent in the formation of methyl thioethers (4.1.4.B) [17]. 

As an alternative to the oxidation of sulphides and sulphoxides (see Chapter 10), sulphones can be prepared by the nucleophilic substitution reaction of the sulphinite anion on haloalkanes. In the absence of a phase-transfer catalyst, the reaction times are generally long and the yields are low, and undesirable O-alkylation of the sulphinite anion competes with S-alkylation. The stoichiometric reaction of the preformed tetra-n-butylammonium salt of 4-toluenesulphinic acid with haloalkanes produces 4-tolyl sulphones in high yield [1], but it has been demonstrated that equally good... 

Devi-Kesavan, L.S. and Gao, J. (2003). Combined QM/MM study of the mechanism and kinetic isotope effect of the nucleophilic substitution reaction in haloalkane de-halogenase. J. Am. Chem. Soc. 125 (6), 1532-1540... 

In Chapter 7, we learned that amines are moderate nucleophiles (Table 7.2) due to the presence of a lone pair of electrons on the nitrogen atom. Therefore, they should undergo nucleophilic substitution reactions with haloalkanes and other compounds containing a good leaving group (Section 7.5). 

The net result is a substitution reaction in which the stoichiometry resembles that of an Sj 2 substitution reaction of haloalkanes. However, an Sj 2 reaction occurs in a single step in which the nucleophile bonds to the carbon atom as the leaving group leaves. Nucleophilic acyl substitution occurs in two steps, and the rate-determining step is usually nucleophilic attack at the carbonyl carbon atom to form a tetrahedral intermediate. The loss of the leaving group occurs in a second, faster step. 

The alkylation process possesses the advantages that (a) a wide range of cheap haloalkanes are available, and (b) the substitution reactions generally occur smoothly at reasonable temperatures. Furthermore, the halide salts formed can easily be converted into salts with other anions. Although this section will concentrate on the reactions between simple haloalkanes and the amine, more complex side chains may be added, as discussed later in this chapter. The quaternization of amines and phosphines with haloalkanes has been loiown for many years, but the development of ionic liquids has resulted in several recent developments in the experimental techniques used for the reaction. In general, the reaction may be carried out with chloroalkanes, bromoalkanes, and iodoalkanes, with the reaction conditions required becoming steadily more gentle in the order Cl Br I, as expected for nucleophilic substitution reactions. Fluoride salts cannot be formed in this manner. 

As indicated in Chapter 8, the production of alkanes, as by-products, frequently accompanies the two-phase metal carbonyl promoted carbonylation of haloalkanes. In the case of the cobalt carbonyl mediated reactions, it has been assumed that both the reductive dehalogenation reactions and the carbonylation reactions proceed via a common initial nucleophilic substitution reaction and that a base-catalysed anionic (or radical) cleavage of the metal-alkyl bond is in competition with the carbonylation step [l]. Although such a mechanism is not entirely satisfactory, there is no evidence for any other intermediate metal carbonyl species. 

It should be mentioned that a solvent change affects not only the reaction rate, but also the reaction mechanism (see Section 5.5.7). The reaction mechanism for some haloalkanes changes from SnI to Sn2 when the solvent is changed from aqueous ethanol to acetone. On the other hand, reactions of halomethanes, which proceed in aqueous ethanol by an Sn2 mechanism, can become Sn 1 in more strongly ionizing solvents such as formic acid. For a comparison of solvent effects on nucleophilic substitution reactions at primary, secondary, and tertiary carbon atoms, see references [72, 784]. 

A fundamental route for the preparation of simple tetraalkylphosphonium salts is the reaction of a tertiary phosphine with a haloalkane or other substrate upon which a simple nucleophilic substitution reaction can occur. (In comparing phosphorus nucleophiles with the corresponding nitrogen-centered nucleophiles, it must be remembered that the phosphorus is significantly more nucleophilic than is the nitrogen. For example, while triphenylamine is devoid of nucleophilic character in reaction with ordinary haloalkanes, triphenylphosphine exhibits high reactivity.) Reactivity of the phosphorus in such nucleophilic substitution reactions, as with other types of nucleophiles, decreases with increasing substitution about the electrophilic site of the substrate. 

The quaternization of amines and phosphines with haloalkanes has been known for many years. In general, the reaction may be carried out using chloroalkanes, bromoaUcanes, and iodoalkanes, with the milder reaction conditions in the order Cl Br I, as is expected for nucleophilic substitution reactions. Fluoride salts cannot be formed in this manner. 

Properties and Reactions of Haloalkanes Bimolecular Nucleophilic Substitution... 

Chapter 6 PROPERTIES AND REACTIONS OF HALOALKANES BIMOLECUIAR NUCLEOPHILIC SUBSTITUTION... 

Even though most of the supported ionic liquid catalysts prepared thus far have been based on silica or other oxide supports, a few catalysts have been reported where other support materials have been employed. One example involves a polymer-supported ionic liquid catalyst system prepared by covalent anchoring of an imidazolium compound via a linker chain to a polystyrene support [79]. Using a multi-step synthetic strategy the polymeric support (e.g. Merrifield resin among others) was modified with l-hexyl-3-methylimidazolium cations (Scheme 5.6-4) and investigated for nucleophilic substitution reactions including fluorina-tions with alkali-metal fluorides of haloalkanes and sulfonylalkanes (e.g. mesylates, tosylates and triflates). 

In this chapter, we study two characteristic reactions of haloalkanes nucleophilic substitution and /3-elimination. Haloalkanes are useful molecules because they can be converted to alcohols, ethers, thiols, amines, and alkenes and are thus versatile molecules. Indeed, haloalkanes are often used as starting materials for the synthesis of many useful compounds encountered in medicine, food chemistry, and agriculture (to name a few). 

Nucleophilic substitution is one of the most important reactions of haloalkanes and can... 

Predictions about the mechanism for a particular nucleophilic substitution reaction must be based on considerations of the structure of the haloalkane, the nucleophile, and the solvent. Following are analyses of three such reactions ... 

Thus far, we have considered two types of reactions of haloalkanes nucleophilic substitution and 8-elimination. Many of the nucleophiles we have examined—for example, hydroxide ion and alkoxide ions—are also strong bases. Accordingly, nucleophilic... 

It is considerably easier to predict the ratio of substitution to elimination products for reactions of haloalkanes with reagents that act as both nucleophiles and bases. The guiding principles are as follows ... 

Secondary halides are borderline, and substitution or elimination may be favored, depending on the particular base/nucleophile, solvent, and temperature at which the reaction is carried out. Elimination is favored with strong bases/good nucleophiles—for example, hydroxide ion and ethoxide ion. Substitution is favored with weak bases/poor nucleophiles—for example, acetate ion. Table 7.7 summarizes these generalizations about substitution versus elimination reactions of haloalkanes. 

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