Nucleophilic substitution reactions competition with 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. 

One would expect these nucleophilic substitution reactions to proceed with inversion of configuration (8 2), but occasionally, competitive reactions result in retention of configuration. Typically, the racemic product is observed the stereochemical results are discussed in more detail in Chapters 10, 11, and 28. In addition to these stereochemical problems, there are other potential drawbacks for the nucleophilic substitution reaction, owing to competing reactions such as MgX-LG exchange, elimination, and to a smaller extent, electron-transfer reactions. 

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. 

Acetoxylation of poly(vinyl chloride) can be carried out under homogeneous conditions. Crown ethers, like 18-crown-6, solubilize potassium acetate in mixtures of benzene, tetrahydrofuran, and methyl alcohol to generate unsolvated, strongly nucleophilic naked acetate anions. These react readily with the polymer under mild conditions. Substitutions of the chlorine atoms on the polymeric backbones by anionic species take place by a Sn2 mechanism. The reactions can also proceed by a Sivl mechanism. That, however, requires formations of cationic centers on the backbones in the rate-determining step and substitutions are in competition with elimination reactions. It is conceivable that anionic species may (depending upon basicity) also facilitate... 

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... 

A chemical reaction Is the result of competition It Is a race that Is won by the fastest runner. A collection of molecules tend to do, by and large, what Is easiest for them. An alkyl halide with p-hydrogen atoms when reacted with a base or a nucleophile has two competing routes substitution (Sj,jl and Sj,j2) and elimination. Which route will be taken up depends upon the nature of alkyl halide, strength and size of base/nucleophile and reaction conditions. Thus, a bulkier nucleophile will prefer to act as a base and abstracts a proton rather than approach a tetravalent carbon atom (steric reasons) and vice versa. 

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. 

An important feature of many elimination reactions is that they occur with the same combinations of reagents that cause nucleophilic substitution. In fact, elimination and substitution often are competitive reactions. Therefore it should be no surprise that substitution and elimination have closely related mechanisms. 

Solvolysis of the R,R and R,S isomers of 2-bromo-9-(l-X-ethyl)fluorenes, X = Cl, Br, I, or OBs, in 25% (v/v) acetonitrile in water has been studied with respect to rates of formation of elimination products and of substitution products (X = OH or NHCOMe).142 The parent 9-(l-X-ethyl)fluorenes and the 2,2/-dibromo-9-(l-X-ethyl)-fluorenes were also studied. Various effects of leaving group and of the presence of nucleophiles on the competition between the reactions were observed and the Bronsted equation was applied to the results for the elimination reactions. A related study of solvolysis of 9-(X-methyl)fluorenes, X = I, Br, or Bs, was also carried out, in which the Swain-Scott equation was applied to nucleophilic selectivities in the S 2 reactions.143... 

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. 

The competition between elimination and substitution channels when an alkyl halide is allowed to react with a nucleophile in the gas phase is a difficult problem to tackle, since in most gas-phase experiments only the ionic products of reaction are monitored (a few exceptions are reported below). Thus, for example, when w-propyl bromide is allowed to react with methoxide ion in the gas phase, the bromide ion produced can arise either by elimination (a) or by substitution (b) and the two pathways cannot be distinguished from the ions alone (Scheme 34). In this specific case it was possible to establish that the reaction follows exclusively the elimination channel through collection and analysis of the neutral products246. The experiments were performed on a FA apparatus configured with a novel cold finger trap coupled to a GC/MS system. Material collected by the trap was separated by capillary gas chromatography and the individual components identified by their retention times and El mass spectra246. 

Examples of the solvent-dependent competition between nucleophilic substitution and / -elimination reactions [i.e. SnI versus Ei and Sn2 versus E2) have already been given in Section 5.3.1 [cf. Table 5-7). A nice example of a dichotomic y9-elimination reaction, which can proceed via an Ei or E2 mechanism depending on the solvent used, is shown in Eq. (5-140a) cf. also Eqs. (5-20) and (5-21) in Section 5.3.1. The thermolysis of the potassium salt of racemic 2,3-dibromo-l-phenylpropanoic acid (A), prepared by bromine addition to ( )-cinnamic acid, yields, in polar solvents [e.g. water), apart from carbon dioxide and potassium bromide, the ( )-isomer of l-bromo-2-phenylethene, while in solvents with low or intermediate polarity e.g. butanone) it yields the (Z)-isomer [851]. 

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. 

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). ° ... 

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. 

Hubaut et has studied the liquid phase hydrogenation of polyunsaturated hydrocarbons and carbonyl compounds over mixed copper-chromium oxides. The selectivity of monohydrogenation was almost 100 % for conjugated dienes but much lower for a,p-unsaturated carbonyls. This was due to the adsorption competition between the unsaturated carbonyls and alcohols as primary products. It was suggested that the hydrogenation site was an octahed-rally coordinated Cu ion with two anionic vacancies, and an attached hydride ion. The Cr ion in the same environment was probably the active site for side reactions (hydrodehydroxylation, nucleophilic substitution, bimolecular elimination). 

Part Z The Mechanism of Substitution and Part 3 Elimination and Addition Pathways and Products are concerned with organic reaction mechanisms. Curly arrows are introduced and the key features of the two common mechanisms of nucleophilic substitution are reviewed. Including kinetic features, stereochemical outcome and reaction coordinate diagrams. This leads to a discussion of the features of El and E2 elimination reactions. The book finishes with a discussion of the factors that affect the competition between substitution and elimination reactions. Much of the teaching of substitution mechanisms Is carried out via interactive CD-ROM activities. 

For secondary halides in aqueous solvents, unimolecular and bimolecular processes compete, and the result is usually a mixture of products. With strong bases and protic solvents other than water, bimolecular elimination is usually faster than substitution, although this is only an assumption and accurate predictions can be difficult with secondary substrates. In polar aprotic solvents, bimolecular processes are usually faster. If a strong base is present and a protic solvent is used, bimolecular elimination is usually preferred to bimolecular substitution, but this is another assumption. If ethanol is used as a solvent and sodium ethoxide is a nucleophilic base. Table 2.9 shows the competition between bimolecular substitution (Sn2) and bimolecular elimination (E2) for a series of alkyl bromides. The preference for E2 reactions of secondary and tertiary halides in this protic solvent is clearly shown. 

Elimination reactions compete with substitution reactions. The competition occurs because the nucleophile is also a base. When it reacts as a base, it removes a proton from the carbon adjacent to the leaving group, resulting in the formation of the elimination product. 

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-... 

These two reactions, dehydration and the formation of an alkyl halide, also fiunish another example of the competition between nucleophilic substitution and elimination (see Section 6.18). Very often, in conversions of alcohols to alkyl halides, we find that the reaction is accompanied by the formation of some alkene (i.e., by elimination). The free energies of activation for these two reactions of carbocations are not very different from one another. Thus, not all of the carbocations become stable products by reacting with nucleophiles some lose a j8 proton to form an alkene. 

Table 13.1 shows the competition between bimolecular substitution (Sn2) and bimolecular elimination (E2) for a series of alkyl bromides that react with a nucleophile that is also a base. There is a clear preference for Sn2 over E2 with primary halides, and the preference for E2 over 8 2 for tertiary halides is also apparent. In this case, secondary halides give predominantly E2, but it will be seen that this preference is changed as the solvent as well as other reaction conditions is changed. 

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. 

Although in principle any base can be made to induce an E2 reaction under appropriate experimental conditions, chemists commonly employ particularly strong bases such as hydroxide, alkoxides, and amide anions (NR ). These bases have conjugate acids with above 11. When we use other bases whose conjugate acid p. s are near or below 11 (e.g., carboxylates, thiolates, and cyanide, the intention is to effect a substitution reaction via using these reactants as nucleophiles. Therefore, one simplifying aspect of the competition between substitution and elimination is to consider an E2 pathway only when hydroxide, alkoxides, acetylides, and amide anions are used. 

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