Substitution, competition with elimination

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

Key point. Alkyl halides are composed of an alkyl group bonded to a halogen atom (X = F, Cl, Br, I). As halogen atoms are more electronegative than carbon, the C-X bond is polar and nucleophiles can attack the slightly positive carbon atom. This leads to the halogen atom being replaced by the nucleophile in a nucleophilic substitution reaction, and this can occur by either an SN1 (two-step) mechanism or an Sn2 (concerted or one-step) mechanism. In competition with substitution is elimination, which results in the loss of HX from alkyl halides to form alkenes. This can occur by either an El (two-step) mechanism or an E2 (concerted) mechanism. The mechanism of the substitution or elimination reaction depends on the alkyl halide, the solvent and the nucleophile/base. 

Reagents with basic properties (affinity for protons) often also possess nucleophilic character (affinity to form bonds to carbon). Consequently, bi-molecular elimination reactions occur frequently in competition with substitution reactions, viz-... 

Elimination becomes more competitive with substitution as the number of alkyl substituents on the substrate increases. Table 10.2 shows rate constants for Sn2 and E2 reactions of a series of alkyl bromides with sodium ethoxide in ethanol at 55°C. The rate constant for elimination increases along the series from ethyl bromide to propyl bromide to isobutyl bromide. The more substituted alkenes formed with propyl bromide and (to a greater extent) with isobutyl bromide are more stable than the alkene formed from ethyl bromide. Because the transition structures have some double bond... 

For a secondary halide in a reaction with a base, with water as the solvent, ionization is a competitive process. Most of the time, the 8 2 is faster than the Sf fl reaction because direct attack at the a-carbon is more facile than ionization, but the extent of direct substitution versus ionization and then trapping with a nucleophile depend on the strength and nature of the nucleophile. If the nucleophile is a weak base, the Sn2 reaction will dominate in an aprotic solvent. If the nucleophile is a strong base, elimination competes with substitution, and a mixture of Sn2 and E2 products is predicted. In water, it is not obvious whether ionization will lead to the major product, although it is assumed that in aqueous media the 8 1 reaction will dominate. 

Because eliminations are in competition with substitutions (see Sections 10.13.3 and 11.5.16), these two paths can be used to check for a common intermediate in the two different... 

We have seen (Section 7-7) that strong bases may give rise to elimination through the E2 pathway. Is there some straightforward way to predict how much elimination will occur in competition with substitution in any particular situation Yes, but other factors need to be considered. Let us examine the reactions of sodium ethoxide, a strong base, with several halides, measuring the relative amounts of ether and alkene produced in each case. 

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... 

Substitution and elimination reactions are almost always in competition with each other. In order to predict the products of a reaction, you must determine which mechanism(s) win the competition. In some cases, there is one clear winner. For example, consider a case in which a tertiary alkyl halide is treated with a strong base, such as hydroxide ... 

We mentioned earlier in this section that when a sulfonyl group possesses a hydrogen on the carbon adjacent to the S02 group, an elimination-addition mechanism (193)—(194) for substitution, involving a sulfene as an intermediate, can be in competition with the direct substitution pathway and may, in fact, be preferred. Let us now discuss what is known about the mechanistic details of substitutions going by such an elimination-addition (sulfene) pathway, and the factors determining how readily such a process will occur under different conditions. 

Reactions of (ii)-l-decenyl(phenyl)iodonium salt (6a) with halide ions have been examined under various conditions. The products are those of substitution and elimination, usually (Z)-l-halodec-l-ene (6b) and dec-l-yne (6c), as well as iodobenzene (6d), but F gives exclusively elimination. In kinetic studies of secondary kinetic isotope effects, leaving-group substituent effects, and pressure effects on the rate, the results are compatible with the in-plane vinylic mechanism for substitution with inversion. The reactions of four ( )-jS-alkylvinyl(phenyl)iodonium salts with CP in MeCN and other solvents at 25 °C have been examined. Substitution with inversion is usually in competition with elimination to form the alk-l-yne. 

Alkyl halides undergo not only nucleophilic substitution but also elimination, and both reactions are carried out in basic reagents. Often substitution and elimination reactions occur in competition with each other. In general, most nucleophiles can also act as bases, therefore the preference for elimination or substitution is determined by the reaction conditions and the alkyl halide used. 

Many secondary and tertiary halides undergo El elimination in competition with the SN1 reaction in neutral or acidic solutions. For example, when tert-butyl chloride solvolyzes in 80% aqueous ethanol at 25°, it gives 83% tert-butyl alcohol by substitution and 17% 2-methylpropene by elimination ... 

When ArNH2 is o-phenylenediamine (80), the reaction is poorly catalysed by the second amino group, but it is mainly catalysed by an external molecule of amine. As a consequence, internal catalysis by an intramolecular complex such as 81 is unlikely. In competition with the substitution (Scheme 34), when the nucleophile (or a base) attacks a hydrogen atom in a fi position with respect to the leaving group, an elimination reaction takes place. 

Predicting products can be challenging when you have to consider substitution and elimination reactions simultaneously. So far, we have seen substitution and elimination reactions separately. But now the truth comes out—substitution and elimination reactions are generally in competition with each other. To predict the products properly, you need to compare all factors for substitution and elimination reactions, and you then need to decide which of the four mechanisms predominates (S l or Sn2 or El or E2). 

This is the difficult step in the synthesis it requires a nucleophilic substitution of the SN2 type involving a secondary alkyl halide. Competition of elimination with substitution results in only a 37% observed yield of alkylated diethyl acetamidomalonate. 

Nakai, T. Tanaka, K. Ishikawa, N. The reaction of 2,2,2-trifluoroethyl iodide with sodium phenolate. A novel competition between substitution and elimination reactions. /. Fluorine Chem. 1977, 9, 89-93. 

A proton on a y-carbon may be eliminated in competition with a proton on the a-carbon, and subsequent addition of the nucleophile to the central carbon atom of the intermediate substituted allene (189) would result in an overall substitution (equation 18). In this j8,y-elimination-... 

Substitution in the 1-2 cluster leads to 4-fluoroaniline+ (HC1 elimination). This new channel is in competition with the HF elimination ... 

Russell and coworkers62,109,110 have shown that simple enolates undergo free radical-chain nucleophilic substitution reactions with a-chloronitroalkanes by an SRN2 rather than an S l mechanism, and competition with a chain dimerization process was also observed. Using two equivalents of the enolate anion in the reaction allows complete elimination of HN02 to yield a,/i-unsaturated ketones. The synthetic potential of these reactions has also been reported110. 

As we saw in Chapter 8, elimination reactions often compete with nucleophilic substitution reactions. Both reactions can be useful in synthesis if this competition can be controlled. This chapter discusses the two common mechanisms by which elimination reactions occur, the stereochemistry of the reactions, the direction of the elimination, and the factors that control the competition between elimination and substitution. Based on these factors, procedures are presented that can be used to minimize elimination if the substitution product is the desired one or to maximize elimination if the alkene is the desired product. 

Elimination reactions are a useful method for the preparation of alkenes, provided that certain limitations are recognized. One problem is the competition between substitution and elimination. The majority of eliminations are done under conditions that favor the E2 mechanism. In these cases, steric hindrance can be used to slow the competing SN2 pathway. Tertiary substrates and most secondary substrates give good yields of the elimination product when treated with strong bases. Sterically hindered bases can be employed with primary substrates to minimize substitution. 

Scheme 6.4 SN2 Substitution reactions can occur in competition with E2 elimination reactions.

Katritzky and coworkers have extensively developed the activation of amines by reaction with pyry-lium salts to provide (V-alkyl (or N-aryl) pyridinium compounds. When buttressing substituents were present to discourage attack on the pyridine ring, the N-alkyl substituent was subject to displacement and elimination processes. In general, primary alkyl substituents reacted with most nucleophiles in a normal 5n2 process as shown in Scheme 12, whereas competition between substitution and elimination took place with the secondary analogs, with elimination dominating the reactions starting from cycloalkyl-amines. 

El eliminations begin with the same unimolecular dissociation we saw in the S i reaction, but the dissociation is followed by loss of H from the intermediate carbocation rather than by substitution. In fact, the El and SnI reactions normally occur in competition whenever an alkyl halide is treated in a protic solvent with a nonbasic nucleophile. Thus, the best El substrates are also the best siibstrates, 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 (S[jl) and 2-methylpropene (El) results ... 

Elimination reactions are closely related mechanistically to substitution reactions, and are often in competition with them in the reaction mixture. 

The competitive elimination (ET) and substitution (iSn2) reactions of cyclohexyl tosylate with triphenylphosphine have been examined. Triphenylphosphine is considered to be representative of neutral weak bases which have good nucleophilic afiinity for carbon, but it is a poor reagent for elimination when compared with anionic weak bases that are also good carbon nucleophiles. The reaction of triphenylphosphine with cyclohexyl bromide occurs with almost complete substitution. Tertiary phosphines react with fluorosulphonyl isocyanate and with isothiocyanates to form the zwitterionic adducts (56) and (57). 

A few cases of nucleophilic additions to P-ketophosphonates have been reported. When the a-carbon atom to phosphorus is fully substituted, it appears unlikely that the reaction at phosphorus is competitive with the addition to carbonyl group. Thus, treatment of diethyl 1-fluoro-1-ethoxy-carbonyl-2-ethoxycarbonyl-2-oxoethylphosphonate with Grignard reagents at low temperature in THF gives an ( )/(/) mixture of a-fluoro-a,P-unsaturated diesters in 49-68% yields. The initial step is the nucleophilic attack of Grignard reagent at the carbonyl group, followed by intramolecular elimination of diethyl phosphate (Scheme 7.104). ° ... 

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