Secondary alkyl halides reactions

Substitution can take place by the S l or the 8 2 mechanism elimination by El or E2 How can we predict whether substitution or elimination will be the principal reac tion observed with a particular combination of reactants The two most important fac tors are the structure of the alkyl halide and the basicity of the anion It is useful to approach the question from the premise that the characteristic reaction of alkyl halides with Lewis bases is elimination and that substitution predominates only under certain special circumstances In a typical reaction a typical secondary alkyl halide such as iso propyl bromide reacts with a typical Lewis base such as sodium ethoxide mainly by elimination... 

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

Recall from Section 8 13 that the major pathway for reaction of alkoxide ions with secondary alkyl halides IS E2 not Sn2... 

Alkanethiolate ions (RS ) are weaker bases than alkoxide ions (RO ) and undergo synthetically useful 8 2 reactions even with secondary alkyl halides... 

The reaction is of the 8 2 type and works best with primary and secondary alkyl halides Elimination is the only reaction observed with tertiary alkyl halides Aryl and vinyl halides do not react Dimethyl sulfoxide is the preferred solvent for this reaction but alcohols and water-alcohol mixtures have also been used... 

Because fhe new carbon-carbon bond is formed by an 8 2 lype reaction fhe alkyl halide musl nol be slerically hindered Melhyl and primary alkyl halides work besl secondary alkyl halides give lower yields Tertiary alkyl halides fail reacting only by elimination nol subslilulion... 

Nucleophilic substitution by azide ion on an alkyl halide (Sections 8 1 8 13) Azide ion IS a very good nucleophile and reacts with primary and secondary alkyl halides to give alkyl azides Phase transfer cata lysts accelerate the rate of reaction... 

Sulfides, compounds of the type RSR, are prepared by nucleophilic substitution reactions. Treatment of a primary or secondary alkyl halide with an alkanethiolate ion (RS ) gives a sulfide ... 

Nucleophilic substitution by cyanide ion (Sections 8.1, 8.13) Cyanide ion is a good nucleophile and reacts with alkyl halides to give nitriles. The reaction is of the S m2 type and is limited to primary and secondary alkyl halides. Tertiary alkyl halides undergo elimination aryl and vinyl halides do not react. 

The alkyl halide must be one that reacts readily by an Sn2 mechanism. Thus, methyl and primary alkyl halides are the most effective alkylating agents. Elimination competes with substitution when secondary alkyl halides are used and is the only reaction observed with tertiary alkyl halides. 

It is a reaction of wide scope both the phosphite 1 and the alkyl halide 2 can be varied. Most often used are primary alkyl halides iodides react better than chlorides or bromides. With secondary alkyl halides side reactions such as elimination of HX can be observed. Aryl halides are unreactive. 

The reaction works well with primary alkyl halides, especially with allylic and benzylic halides, as well as other alkyl derivatives with good leaving groups. Secondary alkyl halides give poor yields. Tertiary alkyl halides react under the usual reaction conditions by elimination of HX only. Nitriles from tertiary alkyl halides can however be obtained by reaction with trimethylsilyl cyanide 4 ... 

From this and nearly a dozen other series of similar reactions, workers concluded that the nucleophilic substitution reaction of a primary or secondary alkyl halide or tosylate always proceeds with inversion of configuration. (Tertiary alkyl halides and tosylates, as we ll see shortly, give different stereochemical results and react by a different mechanism.)... 

Secondary alkyl halides Sjvj2 substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent, E2 elimination predominates if a strong base is used, and ElcB elimination takes place if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzyiic alkyl halides can also undergo S l and El reactions if a weakly basic nucleophile is used in a pro tic solvent. 

Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate ion (RS-), which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an Sn2 mechanism, analogous to the Williamson synthesis of ethers (Section 18.2). Thiolate anions are among... 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

The simplest method of nitrile preparation is the Sj 2 reaction of CN with a primary or secondary alkyl halide, as discussed in Section 20.5. Another method for preparing nitriles is by dehydration of a primary amide, RCONH2. Thionyl chloride is often used for the reaction, although other dehydrating agents such as POCI3 also work. 

A better method for preparing primary amines is to use the azide synthesis, in which azjde ion, N3, is used for SN2 reaction with a primary or secondary alkyl halide to give an alkyl azide, RN3. Because alkyl azides are not nucleophilic, overalkylation can t occur. Subsequent reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlK4. then leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

Recently, it has been reported that methyl 2-pyridyl sulphoxides (10) and related pyridyl derivatives (11) (see Schepie 25) are good phase transfer catalysts for SN2 reactions of various primary or secondary alkyl halides in a two-phase reaction system and for the alkylation of phenylacetonitrile or phenylacetone with alkyl halides in liquid-liquid two-... 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

Figure 6.13 Functional group interconversions of methyl, primary, and secondary alkyl halides using Sn2 reactions.

The mechanism of the reaction of secondary alkyl halides with low-valent transition metal complexes is considerably more complex, and radical processes have been clearly identified in some cases (13, 14). 

We looked briefly at reaction profiles in Section 8.2. Before we look at the reaction profile for the concurrent reactions of hydrolysing a secondary alkyl halide, we will look briefly at the simpler reaction of a primary alkyl halide, which proceeds via a single reaction path. And for additional simplicity, we also assume that the reaction goes to completion. We will look not only at the rate of change of the reactants concentration but also at the rate at which product forms. 

Now, to return to the hydrolysis of the secondary alkyl halides, we will call the reactions (1) and (2), where the 1 relates to the SnI reaction and the 2 relates to the Sn2 reactions. (And we write the numbers with brackets to avoid any confusion, i.e. to prevent us from thinking that the T and 2 indicate first- and second-order reactions respectively.) We next say that the rate constants of the two concurrent reactions are k(p and k(2) respectively. As the two reactions proceed with the same 1 1... 

Figure 8.19 Concentration profiles for a concurrent reaction, e.g. of a secondary alkyl halide + OH- -> alcohol reaction (2) is twice as fast as reaction (1) in this example...

The use of dimethyl sulphoxide as a dipolar aprotic solvent is well known,7 and the present method can be regarded as a model procedure and has been applied to the preparation of a number of N-w-alkyl-pyrroles and N-w-alkyl indoles.8 The yield of N-benzylindole is considerably higher than in previously reported preparations and is as good as that reported for the preparation of N-methylindole in liquid ammonia.4 The present method is, however, less laborious and quicker to carry out. Very high yields are obtained in reactions using w-alkyl halides and moderately good yields with secondary alkyl halides. The reactions should be compared with those recently reported for pyrryl-thallium.9... 

Nucleophilic substitution reactions of halide anions in aprotic solvents are often accompanied by elimination reactions. For instance, reactions of secondary alkyl halides with potassium fluoride solubilized in acetonitrile with the aid of 18-crown-6 [3] give olefins as the main reaction product (Liotta and Harris, 1974). Similarly, the dicyclohexyl-18-crown-6 complex of potassium iodide acted exclusively as a base in its reaction with 2-bromo-octane in DMF (Sam and Simmons, 1974). The strongly basic character of weakly solvated fluoride has been exploited in peptide synthesis (Klausner and Chorev, 1977 Chorev and Klausner, 1976). It was shown that potassium fluoride solubilized... 

Substitution reactions of cyanide with secondary alkyl halides are often accompanied by the formation of elimination products in variable amounts (Cook et al., 1974). The same holds for reactions of metal acetate complexes of crown ethers (Liotta et al., 1974). 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

The process has also been adapted using resin supported catalysts [e.g. 23-28]. Generally, the reactivity of the alkyl halides follows the normal pattern of I>Br>Cl, but secondary alkyl halides are less reactive and require high reaction temperatures and tertiary alkyl halides fail to react. 

Primary alkyl iodides and bromides are excellent substrates for the Victor Meyer reaction, providing a route to both substituted and unsubstituted nitroalkanes (Table i. i).63,65,70,7i formation of the corresponding nitrite ester is a side-reaction and so the nitroalkane is usually isolated by distillation when possible. The reaction of primary alkyl chlorides with silver nitrite is too slow to be synthetically useful. Secondary alkyl halides and substrates with branching on... 

Reaction between acetonitrile and the radical-cations of secondary alkyl halides is almost entirely S l in character. Both direct substitution and 1,2-hydride shift reactions occur and the products from a chiral alkyl halide such as 2-iodooctane, are almost totally racemised [25]. 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Alkylation of hydroxylamines with secondary alkyl halides and alkyl sulfonates like 10 (equation 7) is one of the most frequently used synthetic approaches, especially to enantiomerically pure hydroxylamines such as 11 (equation 7). The reaction proceeds with inversion of configuration and does not produce appreciable amounts of diaUcyla-tion products. Both hydroxylamine as well as N- and O-alkylhydroxylamines have been successfully used. Alkyl trillates are probably the most useful substrates for these transformations since they can be prepared from a large pool of commercially available enantiomerically pure chiral secondary alcohols. 

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