Preparation of Alkyl Halides

Most syntheses of alkyl halides exploit the chemistiy of functional groups we have not yet covered. For now, we review free-radical halogenation and only summarize other, often more usefuJ, syntheses of alkyl halides. The other syntheses are discussed in subsequent chapters. 

Although we discussed its mechanism at length in Section 4-3, free-radical halogenation is rarely an effective method for the synthesis of alkyl halides. It usually produces mixtures of products because there are different kinds of hydrogen atoms that can be abstracted. Also, more than one halogen atom may react, giving multiple substitutions. For example, the chlorination of propane can give a messy mixture of products. 

We have seen (Section 4-13C) that bromination is highly selective, with only the most stable radical being formed. If there is an allylic position, the allylic radical is usually the most stable of the radicals that might be formed. For example, consider the free-radical bromination of cyclohexene. Under the right conditions, free-radical bromination of cyclohexene can give a good yield of 3-bromocyclohexene, where bromine has substituted for an allylic hydrogen on the carbon atom next to the double bond. 

The mechanism is similar to other free-radical halogenations. A bromine radical abstracts an allylic hydrogen atom to give a resonance-stabilized allylic radical. This radical reacts with Br2, regenerating a bromine radical that continues the chain reaction. 

The general mechanism for allylic bromination shows that either end of the resonance-stabilized allylic radical can react with bromine to give products. In one of the products the bromine atom appears in the same position where the hydrogen atom was abstracted. The other product results from reaction at the carbon atom that bears the radical in the second resonance fonn of the allylic radical. This second compound is said tobe the product of an allylic shift. 

The preparation of alkyl halides by substitution reactions usually starts from alcohols because alcohols are widely available. Hydroxide ion is a poor leaving group, so the OH must first be converted into a better leaving group, either by protonation in acid or by conversion to a sulfonate or similar ester (see Section 8.9), as illustrated in the following equations  

Protonation of the alcohol can be accomplished by using the halogen acids, HC1, HBr, and HI, which also provide the nucleophile for the reaction. These reaction conditions favor the SN1 mechanism, although primary alcohols still follow the SN2 path unless a resonance-stabilized carbocation can be formed. The acids HBr and HI work with most alcohols, but HC1, a weaker acid, requires the presence of ZnCl2 (a Lewis acid) as a catalyst when the alcohol is primary or secondary. Examples are shown in the following equations  

Show all the steps in the mechanism for the reaction of 1-butanol with HBr in water. Solution 

The reactant is a primary alcohol, so the mechanism must be SN2. First the hydroxy group is protonated. Then bromide ion acts as a nucleophile. 

We ve already seen several methods for preparing alkyl halides, including the reactions of HX and X2 with alkenes in electrophilic addition reactions (Sections 6.8 and 7.2). The hydrogen halides HCl, HBr, and HI react with alkenes by a polar mechanism to give the product of Markovnikov addition. Bromine and chlorine yield trans 3,2 dihalogenated addition products. 

Recall from Section 5.3 that radical substitution reactions require three kinds of steps initiation, propagation, and termination. Once an initiation step has started the process by producing radicals, the reaction continues in a self-sustaining cycle. The cycle requires two repeating propagation steps in which a radical, the halogen, and the alkane yield alkyl halide product plus more radical to carry on the chain. The chain is occasionally terminated by the combination of two radicals. 

Though interesting from a mechanistic point of view, alkane halogena-tion is a poor synthetic method for preparing different haloalkanes. Let s see why. 

Mechanism of the radical chlorination of methane. Three kinds of steps are required initiation, propagation, and termination. The propagation steps are a repeating cycle, with Cl a reactant in step 1 and a product in step 2, and with CH3 a product in step 1 and a reactant in step 2. (The symbol hv shown in the initiation step is the standard way of indicating irradiation with iight.) 

Ketones can be a-brominated on solid phase by treatment with synthetic equivalents of bromine, such as pyridinium tribromide (Entry 2, Table 6.1) or phenyltri-methylammonium tribromide (DCM, 20 °C, 3 h [10]). Resin-bound organometallic compounds, such as vinylstannanes [11] or organozinc derivatives [12], react cleanly with iodine to yield the corresponding vinyl or alkyl iodides (see also Section 3.13). Additions of halogens or their synthetic equivalents to C=C double bonds on cross- 

Nucleophilic substitutions offer a more versatile means of access to alkyl halides than oxidative halogenations. The most common starting materials for this purpose are resin-bound alcohols, which can be converted into halides either directly or via the intermediate formation of sulfonates [23]. Polystyrene-bound halides can also be 

Polystyrene-bound allylic or benzylic alcohols react smoothly with hydrogen chloride or hydrogen bromide to yield the corresponding halides. The more stable the intermediate carbocation, the more easily the solvolysis will proceed. Alternatively, thionyl chloride can be used to convert benzyl alcohols into chlorides [7,25,26]. A milder alternative for preparing bromides or iodides, which is also suitable for non-benzylic alcohols, is the treatment of alcohols with phosphines and halogens or the preformed adducts thereof (Table 6.2, Experimental Procedure 6.1 [27-31]). Benzhy-dryl and trityl alcohols bound to cross-linked or non-cross-linked polystyrene are particularly prone to solvolysis, and can be converted into the corresponding chlorides by treatment with acetyl chloride in toluene or similar solvents (Table 6.2 [32-35]). 

Experimental Procedure 6.1 ( omersion of Wang resin into /7-ben/yloxybenzyl bromide resin [49] 

Aliphatic alcohols do not undergo solvolysis as readily as benzylic alcohols, and are generally converted into halides under basic reaction conditions via an intermediate sulfonate. Because of the hydrophobicity of polystyrene, however, nucleophilic substitutions with halides on this support do not always proceed as readily as in solution (Table 6.3). Alternatively, phosphorus-based reagents can also be used to convert aliphatic alcohols into halides. 

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION 

SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON 

CHAPTER 3 substitution processes have been the use of the crown ethers as complexing 

FUNCTIONAL GROUP agents and the use of phase transfer catalysts. The crown ethers are a family of B NUCLEom cyclic polyethers, three examples of which are shown below  

The replacement of a halide or tosylate by cyanide ion, extending the carbon chain by one atom and providing an entry into the family of carboxylic acid derivatives, has been a reaction of synthetic importance since the earliest days of organic chemistry. 

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Preparation of Alkyl Halides from Alcohols and Hydrogen Halides... 

PREPARATION OF ALKYL HALIDES FROM ALCOHOLS AND HYDROGEN HALIDES... 

The procedures to be described m the remainder of this chapter use either an alkane or an alcohol as the starting material for preparing an alkyl halide By knowing how to prepare alkyl halides we can better appreciate the material m later chapters where alkyl halides figure prominently m key chemical transformations The preparation of alkyl halides also serves as a focal point to develop the principles of reaction mechanisms... 

We 11 begin with the preparation of alkyl halides from alcohols by reaction with hydro gen halides... 

Chemical reactivity and functional group transformations involving the preparation of alkyl halides from alcohols and from alkanes are the mam themes of this chapter Although the conversions of an alcohol or an alkane to an alkyl halide are both classi tied as substitutions they proceed by very different mechanisms... 

Darzen s procedure org chem Preparation of alkyl halides by refluxing a molecule of an alcohol with a molecule of thionyl chloride in the presence of a molecule of pyridine. dar-zonz pr3,se- 3r ... 

Other methods for the preparation of alkyl halides are electrophilic addition of hydrogen halides (HX) to alkenes (see Section 5.3.1) and free radical halogenation of alkanes (see Section 5.2). 

Addition of hydrogen halides to alkenes preparation of alkyl halides... 

In addition to being the most valuable starting material for the 1,3,5-triazines, cyanuric chloride has been used for the preparation of alkyl halides, acid chlorides, peptides, dicarbodiimides and macrocyclic lactones (see Section 2.20.3.12.2). 

Silver(I) carboxylates have been obtained by the addition of equivalent amounts of freshly prepared silver oxide to aqueous solutions of the appropriate acid.247 Their degradation by halogens provides a convenient method for the preparation of alkyl halides (Hunsdiecker reaction) or esters (Simonini reaction).248 Equations (14)-(18) have been proposed to account for the products obtained and were the result of extensive studies. 

Although a substantial number of reactions are described in the text, they belong to a relatively modest number of mechanistic types. The preparation of alkyl halides from alcohols and HX, the cleavage of ethers, and the preparation of amines from alkyl halides and ammonia (and many other reactions) all, for example, occur by a nucleophilic substitution mechanism. The following is a brief review of the main mechanistic pathways discussed in the text. 

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