Alkyl halides with typical nucleophiles

The interaction of alkyl halide with mercaptans or alkali mercaptides produces thioalkyl derivatives. This is a typical nucleophilic substitution reaction, and one cannot tell by the nature of products whether or not it proceeds through the ion radical stage. However, the version of the reaction between 5-bromo-5-nitro-l,3-dioxan and sodium ethylmercaptide may be explained only by an intermediate stage involving electron transfer. As has been found (Zorin et al. 1983), this reaction in dimethylsulfoxide leads to diethyldisulfide (yield 95%), sodium bromide (quantitative yield), and 5,5 -bis(5-nitro-l,3-dioxanyl) (yield 90%). 

How can we predict whether substitution or elimination will be the principal reaction observed with a particular combination of reactants The two most important factors 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 isopropyl bromide reacts with a typical nucleophile such as sodium ethoxide mainly by elimination ... 

Substitution and Addition Reactions. All types of reactions between inorganic anions and organic partners can be executed under the PTC conditions. Nucleophilic aliphatic substitution in alkyl halides with cyanide anions to form nitriles was presented in the Introduction as a typical example of PTC on which the basic principles and characteristic features of this catalysis were discussed. 

Acidic ether cleavages are typical nucleophilic substitution reactions, either SN1 or Sn2 depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S 2 mechanism, in which or Br attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

The reaction of phosphines and alkyl halides presents an alternative way to generate phosphonium electrophiles (Scheme 3.8). In particular, the combination of a phosphine and carbon tetrabromide (the Appel reaction) allows for in situ formation of a phosphonium dibromide salt (48, X = Br). Treatment of a hemiacetal donor 1 with the phosphonium halide 48 initially provides the oxophosphonium intermediate 38 (X = Br). However, the oxophosphonium intermediate 38 can react with bromide ion to form the anomeric bromide intermediate 49 (X = Br) with concomitant generation of phosphine oxide. With the aid of bromide ion catalysis (i.e. reversible, catalytic formation of the more reactive P-anomeric bromide 50) [98], the nucleophile displaces the anomeric bromide to form the desired glycoside product 3. The hydrobromic add by-product is typically buffered by the presence of tetramethyl urea (TMU). 

Carbanion-enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical S 2 reactions, Carbanion-enolates are best formed using lithium diisopropylamide (lda), (r-Pr)2N Li, in tetrahydrofuran. This base is very strong and converts all the substrate to the anion. Furthermore, it is too sterically hindered to react with RX. 

The typical reactions of carbocation intermediates were discussed in Chapter 7. The solvolysis of alkyl halides is an example of the involvement of carbocations in the SnI mechanism, in other words, where the final outcome is a nucleophilic substitution. The first step is a heterolytic cleavage of the C—X bond. Properties of X which favor heterolytic cleavage, namely electronegativity difference with carbon (the larger, the better) and the degree of overlap of the X orbital with the spn orbital of carbon (the smaller the better), have already been elucidated (Chapter 4). The transition state has partial... 

Some typical nucleophiles are the hydroxy group (OH), the alkoxy group (RO), and the cyanide ion ( C=N). Reaction of these nucleophiles with an alkyl halide (R—X) gives the following reactions and products ... 

The kinetics of the reaction between Irons- Ml N2Me)Br(dppe)21 and methyl iodide in tetrahydrofuran exhibit a first-order dependence in the concentration of complex and first-order in the concentration of methyl iodide. When M = W, the reaction with methyl iodide is 38 times faster than the reaction with ethyl iodide, which is typical ofSN2 reactions. Therefore, it is concluded that the secondary alkylation is a bimolecular nucleophilic substitution (Scheme 10) in which nucleophilic attack of the diazenido ligand on the carbon atom of the alkyl halide is the rate-limiting step (93). 

The synthesis of the cation is typically performed by alkylation of an amine, phosphine or sulfide, most commonly using an alkyl halide [ ]. In most cases the reaction is carried out with chloro-, bromo- and iodoalkanes as readily available alkylating reagents, with the reaction conditions becoming more gentle changing from chloride to bromide to iodide, as can be expected for nucleophilic substitution... 

Typical bases such as sodium hydroxide or an alkoxide ion cannot be used to form enolates for alkylation because at equilibrium a large quantity of the hydroxide or alkoxide base is still present. These strongly nucleophilic bases give side reactions with the alkyl halide or tosylate. Problem 22-4 shows an example of these side reactions. Lithium diisopropylamide (LDA) avoids these side reactions. Because it is a much stronger base, LDA converts the ketone entirely to its enolate. All the LDA is consumed in forming the enolate, leaving the enolate to react without interference from the LDA. Also, LDA is a very bulky base and thus a poor nucleophile, so it generally does not react with the alkyl halide or tosylate. 

Neutral a-alkyliron complexes are obtained upon reaction of Na[Cp(CO)2pe] (5) with alkyl halides (9) (Scheme 6), and as with Collman s reagent this occurs in an Sn2 fashion with inversion of coirfiguration at the carbon atom. Epoxides also participate in this reaction, but tertiary alkyl halides are poor substrates. Alternatively, complexes (9) may be prepared by reaction of an appropriate metal alkyl with Cp(CO)2PeX (6). Typically complexes of this type are prepared in order to gain access to the synthetically nseful cationic rf--alkene iron complexes (Section 4.1.2). Also, nucleophilic addition of (5) to heteroatom-snbstituted alkyl halides (snch as methoxymethylchloride or chloromethyl methyl snllide) affords complexes of type (9) that can be converted to cationic... 

Aromatic amines are less basic than their aliphatic counterparts. The lone pair on the nitrogen atom is delocalized over the 7t-system of the aromatic ring. Furthermore, the basicity is influenced by substituents on the aromatic ring. Thus 4-nitroaniline (4.5) is less basic than aniline. However, the aromatic amines behave as typical nucleophiles. Alkylation of the nitrogen by alkyl halides leads to the mono- and dialkylanilines. Reaction with acetic anhydride or acetyl chloride affords acetanilides. 

The chemistry takes place via an initial reduction of vitamin B12 or a similar cobalt(III) species 202, in a process that sees the conversion of cobalt from the -f3 to the -fl oxidation state, and the opening of two sites of unsaturation, to afford 203 [47]. This very reactive, highly nucleophilic intermediate reacts rapidly with the alkyl halide to form the octahedral complex 204, and reestablish a -f3 oxidation state on cobalt. A catalytic cycle is secured when this material undergoes reaction with a typical Michael acceptor leading to the formation of product, 205 (Scheme 18). 

It is typical of aryl halides that they undergo nucleophilic substitution only with extreme difficulty. Except for certain industrial processes where very severe conditions are feasible, one does not ordinarily prepare phenols (ArOH). ethers (ArOR), amines (ArNH2), or nitriles (ArCN) by nucleophilic attack on aryl halides. We cannot use aryl halides as we use alkyl halides in the Friedel-Crafts reaction. 

Sulfur is one of the most frequently employed elements in organic synthesis. Typical functionalities containing sulfur atoms are illustrated below (la-ld) they all stabUize the adjacent caibanion, which serves as a nucleophile. The carbanion reacts with alkyl halides or adds to CmmX rr-bonds (X = C, O, N, etc.) to form a C— bond, which is an essential process in organic synthesis. 

Hence the larger the n value, the stronger the nucleophile, and the smaller the [nucl]50o/o. As already pointed out earlier, the [nucl]50o/o values given in Table 2 show that in uncontaminated freshwaters, hydrolysis is by far the most important nucleophilic substitution reaction. Furthermore, since the hydrolysis of a carbon-halogen bond is generally not catalyzed by acids, one can assume that the hydrolysis rate of aliphatic halides will be independent of pH at typical ambient conditions (i.e., pH < 10). In this context it is also important to note that no catalysis of the hydrolysis of alkyl halides by solid surfaces has been observed (El-Amamy and Mill, 1984 Haag and Mill, 1988). In salty or contaminated waters, reactions of organic chemicals with nucleophiles other than water or j hydroxide ion may be important. Zafiriou (1975), for example, has demonstrated j that in seawater ([Cl ] 0.5 M), a major sink for naturally produced methyl j iodide is transformation to methyl chloride j... 

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