Alkyl halides elimination from substituted

I Primary alkyl halides S 2 substitution occurs if a good nucleophile is used, 2 elimination occurs if a strong base is used, and ElcB elimination occurs if the leaving group is two carbons away from a carbonyl group. 

When we want the product of a substitution reaction, elimination is a nuisance to be avoided. But when we want an alkene from an alkyl halide, elimination is what we are trying to bring about. To do this, we use a solvent of low polarity, and a high concentration of a strong base concentrated alcoholic potassium hydroxide. 

Alkyl halides undergo competitive substitution and elimination reactions. The ratio of products derived from substitution and elimination depends on the nature of the alkyl halide, the base/nucleophile, the solvent and the temperature. SN2 reactions are normally in competition with E2 reactions, while SN1 reactions are normally in competition with El reactions. 

It is not immediately obvious how to carry out this synthesis, so let s use retrosynthetic analysis to find a way. The only method you know for introducing a C=N group into a molecule is nucleophilic substitution. The alkyl halide for that substitution reaction can be obtained from die addition of HBr to an alkene in the presence of a peroxide. The alkene for that addition reaction can be obtained from an elimination reaction using an alkyl halide obtained by benzylic substitution. 

The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order m eliminations Iodine has the weakest bond to carbon and iodide is the best leaving group Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more reactive than alkyl chlorides Fluorine has the strongest bond to car bon and fluonde is the poorest leaving group Alkyl fluorides are rarely used as sub states m nucleophilic substitution because they are several thousand times less reactive than alkyl chlorides... 

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... 

FIGURE 8 11 When a Lewis base reacts with an alkyl halide either substitution or elimination can occur Sub stitution (Sn2) occurs when the Lewis base acts as a nu cleophile and attacks carbon to displace bromide Elimi nation (E2) occurs when the Lewis base abstracts a pro ton from the p carbon The alkyl halide shown is iso propyl bromide and elimi nation (E2) predominates over substitution with alkox ide bases... 

Secondary and tertiary alkyl halides are not suitable because they react with alkox ide bases by E2 elimination rather than by 8 2 substitution Whether the alkoxide base IS primary secondary or tertiary is much less important than the nature of the alkyl halide Thus benzyl isopropyl ether is prepared m high yield from benzyl chloride a pri mary chloride that is incapable of undergoing elimination and sodium isopropoxide... 

In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates. 

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. 

Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first qualernized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination. 

The preparation of mono- and di-tm-butylcyclopentadienes 1 and 2 starting from monomeric cyclopentadiene was reported first in 1963 [23]. It was noted that the nucleophilic attack of the cyclopentadienide anion on ferf-alkyl halide has to compete with elimination reaction giving isobutene. The yield of the di- and tri-fer/-butylcyclopentadienes 2 and 3 was therefore reported to be modest to low [23, 24], Recently an elegant improvement for this synthesis using phase transfer catalysis was presented (Eq. 1), but the availability of the tri-substituted derivative... 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

A stmple and general synthesis of 2,2,4,5-tetrasubstituted furan-3(2//)-ones from 4-hydroxyalk-2-ynones and alkyl halides via tandem CO, addition-elimination protocol is described <96S 1431>. Palladiuni-mediated intramolecular cyclization of substituted pentynoic adds offers a new route to y-arylidenebutyrolactones <96TL1429>. The first total synthesis of (-)-goniofupyrone 39 was reported. Constmction of the dioxabicyclo[4.3.0]nonenone skeleton was achieved by tosylation of an allylic hydroxy group, followed by exposure to TBAF-HF <96TL5389>. 

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

The El reaction involves the formation of a planar carbocation intermediate. Therefore, both syn and anti elimination can occur. If an elimination reaction removes two substituents from the same side of the C—C bond, the reaction is called a syn elimination. When the substituents are removed from opposite sides of the C—C bond, the reaction is called an anti elimination. Thus, depending on the substrates El reaction forms a mixture of cis (Z) and trans (E) products. For example, tert-hutyl bromide (3° alkyl halide) reacts with water to form 2-methylpropene, following an El mechanism. The reaction requires a good ionizing solvent and a weak base. When the carbocation is formed, SnI and El processes compete with each other, and often mixtures of elimination and substitution products occur. The reaction of t-butyl bromide and ethanol gives major product via El and minor product via SnI-... 

During an elimination reaction, a bond forms by the removal of two atoms or groups from the original molecule. In most instances, the bond that forms is a n bond. Elimination reactions compete with substitution reactions when alkyl halides react with a nucleophile. 

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