Nucleophilic substitution reactions, haloalkanes

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. 

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... 

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 is important to be able to look at a molecular structure and deduce the possible reactions it can undergo. Take an alkene, for example. It has a 7t bond that makes it electron-rich and able to attack electrophiles such as water, halogens and hydrogen halides in electrophilic addition reactions. Haloalkanes, on the other hand, contain polar carbon-halogen bonds because the halogen is more electronegative than carbon. This makes them susceptible to attack by nucleophiles, such as hydroxide, cyanide and alkoxide ions, in nucleophilic substitution reactions. 

C—Cl bond acquires a partial double bond character due to resonance. As a result, the bond cleavage in haloarene Is difficult than haloalkane and therefore, they are less reactive towards nucleophilic substitution reaction. 

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. 

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... 

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. 

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). 

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. 

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... 

Haloalkanes undergo nucleophilic substitution reactions and j3-elimination reactions. 

Nucleophilic substitution reactions can be used to transform haloalkanes into alcohols, ethers, thiols, sulfides, alkyl iodides, and alkyl ammonium ions, to name a few. 

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) ... 

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). 

Nucleophilic Substitution in Haloalkanes Mechanisms of Nucleophilic Aliphatic Substitution Experimental Evidence for S 1 and S 2 Mechanisms Analysis of Several Nucleophilic Substitution Reactions S-Elimination... 

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. 

Predictions about the mechanism for a particular nucleophilic substitution reaction must be based on considerations of the structure of the haloalkane, the nucleophile, the leaving group, and the solvent. Following are five nucleophilic substitution reactions and an analysis of the factors that favor an S l or Sj 2 mechanism for each and the products that result from the mechanism used. Note that in the following examples, we ignore competing elimination because it has not been discussed yet. 

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

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. 

Primary haloalkanes react in nucleophilic substitution reactions by an Sj 2 mechanism. 

Tertiary haloalkanes undergo substitution reactions only by an S l mechanism because there is too much steric hindrance for an Sj 2 reaction to occur. However, a tertiary haloalkane can undergo an elimination reaction by either an E2 or an El process. The mechanism depends on the basicity of the nucleophile and the polarity of the solvent. If the nucleophile is a weak base, S l and El processes compete, and the amounts of the two types of products depend only on the stability of the carbocation that forms as an intermediate. For example, 2-bromo-2-methylbutane reacts in ethanol to give about 64% of an ether product from an S l process. The ratio of S l to El products is about 2 1. 

As we will soon see, nucleophilic substitution of haloalkanes occurs via one of two mechanisms. Before examining the mechanisms, let s consider a few specific examples of nucleophilic substitution reactions. 

The haloalkane is a 2° haloalkane. Secondary haloalkanes undergo substitution reactions by either the Sisjl or Sisj2 depending on the nucleophile and solvent. (See Table 27.2.)... 

Nucleophilic substitution is one of a variety of mechanisms by which living systems detoxify halogenated organic compounds introduced into the environment Enzymes that catalyze these reactions are known as haloalkane dehalogenases The hydrolysis of 1 2 dichloroethane to 2 chloroethanol for example is a biological nude ophilic substitution catalyzed by a dehalogenase... 

The formation of C-O, C-S, C-N and C-C bonds by nucleophilic substitution is described in subsequent chapters. In this section the synthesis of haloalkanes by halogen-halogen exchange and related reactions are presented. 

---