Haloalkanes nucleophilic substitution

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). 

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... 

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 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. 

The catalyst is phosphoric acid. The laboratory synthesis of alcohols is by nucleophilic substitution of haloalkanes. 

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. 

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. 

When a haloalkane undergoes nucleophilic substitution, how can we tell whether it will proceed via an mechanism or an S 2 mechanism ... 

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. 

Similarly to what has been shown above96, that an aromatic cyano group in benzylic substrates facilitates nucleophilic substitution of the S l type, it has been demonstrated that an a-cyano group is also able to activate an haloalkane. Thus, the substitution of 2-bromo-2-cyanopropane with different nitronate anions by the S l mechanism has been described97. 

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... 

Haloalkanes are susceptible to nucleophilic substitution, in which a reactant that seeks out centers of positive charge in a molecule (a nucleophile) replaces a halogen atom. 

Substitutions involving haloalkanes involve a type of substition called Nucleophilic substitution, in which the substituent Y is a nucleophile. A nucleophile is an electron pair donor. The nucleophile replaces the halogen, an electrophile, which becomes a leaving group. The leaving group is an electron pair acceptor. Nuclephilic substition reactions are abbreviated as Sn reactions. 

Recall tlrat haloalkanes can be converted to alcohols through nucleophilic substitution. 

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. 

Imidazoles react with haloalkanes in the absence of strong bases because the pyridine-like N-atom effects a nucleophilic substitution of halogen. The quaternary salts that are formed initially usually undergo rapid deprotonation to 1-alkylimidazoles. These can react with a second mole of haloalkane to give 1,3-dialkylimidazolium salts ... 

Properties and Reactions of Haloalkanes Bimolecular Nucleophilic Substitution... 

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

---