Haloalkanes reaction mechanisms with nucleophiles

In addition to Sn2, SnI, and El reactions, there is a fourth pathway by which haloalkanes may react with nucleophiles that are also strong bases elimination by a bimolecular mechanism. This method is the one employed when aUcene formation is the desired outcome. 

What is so special about tertiary haloalkanes that they undergo conversion by the SnI pathway, whereas primary systems follow Sn2 How do secondary haloalkanes fit into this scheme Somehow, the degree of substitution at the reacting carbon must control the pathway followed in the reaction of haloalkanes (and related derivatives) with nucleophiles. We shall see that only secondary and tertiary systems can form carbocations. For this reason, tertiary halides, whose steric bulk inhibits them from undergoing Sf/2 reactions, substitute almost exclusively by the SnI mechanism, primary haloalkanes only by Sn2, and secondary haloalkanes by either route, depending on conditions. 

The nucleophilidties and basicities of a series of structurally and chemically related nucleophiles—such as halide ions, oxygen-containing anions, and sulfur-containing anions—are not always related in a simple way. However, we can often find trends based on periodic properties of the elements, as we shall see below. Table 10.1 lists the relative rates of reaction of various nucleophiles with iodomethane. The reference nucleophile for the substitution reaction is methanol, a poor nucleophile, which is assigned a relative rale, k =. Since iodomethane is a primary haloalkane, we know that these reactions all occur by an mechanism. 

If the nucleophile is a strong base that is nM sterically hindered, primary haloalkanes react by either an or an E2 mechanism, with the reaction predominating by a wide margin. 

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. 

This means that it is first order with respect to the haloalkane and zero order with respect to the hydroxide ions. This implies that the rate-determining step (the slow step) of the mechanism only involves the haloalkane. Hence S l means that the reaction involves Substitution by a Nucleophile and that it follows first-order kinetics, i.e. only one species is involved in the rate-determining step. 

Recent studies on simple haloalkanes, especially iodoalkanes. suggest that the initial process is always homolytic carbon-halogen bond cleavage, but that iodo-systerns are especially susceptible to subsequent electron transfer from the alky) radical to the fairly unreactive iodine atom. This gives the alkyl carbonium ion that reacts with, for example, a nucleophilic solvent. The operation of this mechanism provides for the generation and reaction of vinyl carbonium ions from vinyl iodides fS.66), and this offers one of the lew ways of generating such intermediates. 

Two types of mechanisms have been proposed for the reactions of carbanions with per-haloalkanes, one ionic and the other a single electron transfer (SET). The ionic mechanism, also termed X-philic 630 or positive halogen substitution (S X)631, is a direct attack of the nucleophile on a positive halogen (equation 80) ... 

One of the oldest techniques for overcoming these problems is the use of biphasic water/organic solvent systems using phase-transfer methods. In 1951, Jarrouse found that the reaction of water-soluble sodium cyanide with water-insoluble, but organic solvent-soluble 1-chlorooctane is dramatically enhanced by adding a catalytic amount of tetra-n-butylammonium chloride [878], This technique was further developed by Makosza et al. [879], Starks et al. [880], and others, and has become known as liquid-liquid phase-transfer catalysis (PTC) for reviews, see references [656-658, 879-882], The mechanism of this method is shown in Fig. 5-18 for the nucleophilic displacement reaction of a haloalkane with sodium cyanide in the presence of a quaternary ammonium chloride as FT catalyst. 

In this chapter, we examined S 2, S l, E2, and El mechanisms and learned how they compete with each other depending upon the allleaving group, the solvent, and the nucleophile. We also examined solvent effects upon nucleophilicity. Nature does not always have clear-cut rules, but here we summarize guidelines that chemists use to predict the outcome of reactions between haloalkanes and various nucleophiles and bases. 

In Summary The reaction of chloromethane with hydroxide to give methanol and chloride, as well as the related transformations of a variety of nucleophiles with haloalkanes, are examples of the bimolecular process known as the 8 2 reaction. Two single-step mechanisms— frontside attack and backside attack—may be envisioned for the reaction. Both are concerted processes, consistent with the second-order kinetics obtained experimentally. Can we distinguish between the two To answer this question, we return to a topic that we have considered in detail stereochemistry. 

The kinetics of the reaction of nucleophiles with primary (and most secondary) haloalkanes are second order, indicative of a bimolecular mechanism. This process is called bimolecular nucleophilic substitution (Sn2 reaction). It is a concerted reaction, one in which bonds are simultaneously broken and formed. Curved arrows are typically used to depict the flow of electrons as the reaction proceeds. 

In Summary We have seen further evidence supporting the SnI mechanism for the reaction of tertiary (and secondary) haloalkanes with certain nucleophiles. The stereochemistry of the process, the effects of the solvent and the leaving-group ability on the rate, and the absence of such effects when the strength of the nucleophile is varied, are consistent with the unimolecular route. 

Give the mechanism and major product for the reaction of a secondary haloalkane in a polar aprotic solvent with the following nucleophiles. The p T value of the conjugate acid of the nucleophile is given in parentheses. 

The transfonnation is called nucleophilic aromatic substitution. The key to its success is the presence of one or more strongly electron-withdrawing groups on the benzene ring located ortho or para to the leaving group. Such substituents stabilize an intermediate anion by resonance. In contrast with the Sn2 reaction of haloalkanes, substitution in these reactions takes place by a two-step mechanism, an addition-elimination sequence similar to the mechanism of substitution of carboxylic acid derivatives (Sections 19-7 and 20-2). 

Secondary haloalkanes can react by Sj 2, E2, S l, and El mechanisms, and it is sometimes difficult to predict which of these processes will occur in a given reaction. However, secondary haloalkanes tend to react with strong nucleophiles that are weak bases, such as thiolates or cyanide ion, by an process. 

Methanol is the nucleophile and the haloalkane is the electrophile. Because the nucleophile is uncharged, its nucleophilicity is determined primarily by the polarizability of the nucleophilic atom (O). The O atom is relatively small and not very polarizable thus, CH3OH is a weak nucleophile. A weak nucleophile disfavors an Sisj2 reaction. Also, the solvent is polar protic and will help to stabilize a carbocation. With a weak nucleophile and a polar protic solvent, we expect the substitution reaction to occur by an S l mechanism. The carbocation that is formed reacts with a solvent molecule CH3OH (a solvolysis reaction) to form a protonated ether. The final product is an ether, which is obtained when a proton is transferred from the protonated ether to a CH3OH molecule from the solvent. We will obtain two products, the R and S stereoisomers, because CH3OH can attack the carbocation from either side. The steps are as follows ... 

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