Elimination with basic nucleophile

El eliminations begin with the same uni molecular dissociation we saw in the Sfsjl reaction, but the dissociation is followed by loss of H+ from the adjacent carbon rather than by substitution. In fact, the El and SN1 reactions normally occur together whenever an alkyl halide is treated in a protic solvent with a non-basic nucleophile. Thus, the best El substrates are also the best SN1 substrates, and mixtures of substitution and elimination products are usually obtained. For example, when 2-chloro-2-methylpropane is warmed to 65 °C in 80% aqueous ethanol, a 64 36 mixture of 2-methyl-2-propanol (Sjql) and 2-methylpropene (El) results. 

Secondary alkyl halides may undergo substitution or elimination under basic conditions, but with the strong hindered base and lousy nucleophile LDA, elimination is certain to occur. The product is CH3CH=CH2. 

A similar type of intramolecular reaction was achieved with basic carbamates of4-hydroxyanisole (8.134, X = MeO, n = 2 or 3, Fig. 8.10) [171]. The drug itself is a clinically effective melanocytotoxic agent. Intramolecular nucleophilic attack again resulted in cyclization-elimination, the pro-moiety being recovered as an imidazolidinone (Fig. 8.10, n = 2). In the series examined, the compounds were stable at pH 4, and became more reactive at higher pH values. At pH 7.4 and 37°, chain length and substitution at the two N-atoms had a marked influence on the f1/2 values for hydrolysis (Table 8.10). First, it is clear that a shorter chain (Fig. 8.10, n = 2) favors intramolecular attack, but a decrease in tm values for hydrolysis for three compared... 

Fluorine in 4-fluorophenyl ketones, as well as in 2,4-difluorophenyl ketones and in 2,4-difluoro-benzaldehydc, can readily be eliminated by sulfur nucleophiles under strongly basic conditions in polar solvents. With different substituents bonded to the carbonyl group a variety of products 4 can be obtained. 

Correlation of nucleophilic rate data for phenyldimethylsulfonium ions with common nucleophiles, with pX e values shows that the slopes of the lines, jS[ e, correlate qualitatively with the Edwards hardness parameter for the nucleophile and not with the Swain-Scott n parameter.144 cw,cw-2,4,6-Trimethyl-l,3,5-triaminocyclohexane is weakly basic in aqueous solution, because of steric inhibition to solvation of the conjugate acid.145 The three NH2 groups are axial and the steric effect also results in reduced reactivity as a nucleophile in, S n2 reactions. Highly stereoselective syntheses of N-. and O-glycosides have been carried out by addition of anionic nucleophiles to glycosyl iodides.146 5 n2 reactions are involved, but some substrates are susceptible to E2 elimination when treated with highly basic anions. 

Nucleophiles that undergo vinylic SN2 reaction involve sulfides, selenides [178], carboxylic acids [179], amides [180],thioamides [181],andphosphorose-lenoates [Eq. (102)] [182]. All of these reactions proceed with exclusive inversion of configuration. These nucleophiles are only weakly basic or non-basic. More basic nucleophiles would result in a facile a-elimination of vinyl-A3-iodanes generating alkylidene carbenes instead of the vinylic SN2 reaction. 

However, as a nucleophile s base strength and steric hindrance increase, its basicity tends to be accentuated. If there are abstractable protons at the p-position of the electrophile, an elimination pathway can compete with the nucleophilic substitution. 

A tertiary alkyl halide when treated with sodium methoxide forms an ether or an alkene (Above fig.). A protic solvent is used here and this favours both the SN1 and El mechanisms. However, a strong base is also being used and this favours the E2 mechanism. Therefore, the alkene would be expected to be the major product with only a very small amount of substitution product arising from the SN2 reaction. Heating the same alkyl halide in methanol alone means that the reaction is being done in a protic solvent with a non-basic nucleophile (MeOH). These conditions would yield a mixture of substitution and elimination products arising from the SN1 and El mechanism. The substitution product would be favoured over the elimination product. 

The enolate ions of esters or ketones can also be alkylated with alkyl halides to create larger carbon skeletons [Following fig.(b)]. The most successful nucleophilic substitutions are with primary alkyl halides. With secondary and tertiary alkyl halides, the elimination reaction may compete, particularly when the nucleophile is a strong base. The substitution of tertiary alkyl halides is best done in a protic solvent with weakly basic nucleophiles. However, yields may be poor. 

The target is now cyclopentanol. Alcohols can be prepared from alkyl halides by reaction with hydroxide ion as the nucleophile. Again, however, the combination of a strongly basic nucleophile and a secondary alkyl halide will result in an unacceptable amount of elimination. A better plan is to treat bromocyclopentane with acetate ion in an aprotic solvent such as DM SO. followed by cleavage of the ester to cyclopentanol ... 

In (i), the secondary substrate reacts with the good, but weakly basic, nucleophile to yield substitution product. In (ii), NaOH is a poorer nucleophile but a stronger base, and both substitution and elimination product are formed. 

Reaction of a secondary haloalkane with a basic nucleophile yields both substitution and elimination products. This is a less satisfactory method of ether preparation. 

Carbenium ions react with neutral nucleophiles to produce onium ions. A favorable equilibrium between active carbenium ions and temporarily inactive onium ions can be used to produce well-defined polymers (Chapter 4). However, rather than reacting directly with carbenium ions, nucleophiles may also react with Lewis acids to form strong complexes, thereby reducing their activity and ability to ionize covalent compounds. A third reaction that basic nucleophiles may be involved in is /3-proton elimination this transfer reaction may subsequently result in termination if it involves a strong base [Eq. (131)]. 

In controlled/living systems reactions B and C can be avoided or converted into reversible ones, if ligands such as fluorides are not used, if the concentration of moisture is very low in comparison with initiator and if weakly basic/nucleophilic components (additives, counteranions) are used. Contribution of reaction A is reduced at low temperatures but can not be eliminated completely. 

The familiar substitution reactions of derivatives of carboxylic acids with basic reagents illustrate nucleophihc substitution at aliphatic sp carbons. (Substitution reactions of carboxylic acids, and their derivatives, with acidic reagents are covered in Chapter 4.) The mechanisms of these reactions involve two steps (1) addition of the nucleophile to the carbonyl group and (2) elimination of some other group attached to that carbon. Common examples include the basic hydrolysis and aminolysis of acid chlorides, anhydrides, esters, and amides. 

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