Reactivity - Lesson 4 - Eliminations - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part II. Introduction

Chapter 17. Eliminations

17.D. Reactivity

In this section, we examine the effects of changes in the substrate, base, leaving group, and medium on (1) overall reactivity, (2) E1 versus E2 versus E1cB,107 and (3) elimination versus substitution.

17.D.i. Effect of Substrate Structure

1. Effect on Reactivity. The carbon containing the nucleofuge (X) is referred to as the α carbon and the carbon that loses the positive species (usually a proton) as the β carbon. Groups attached to the α or β carbons can exert at least four kinds of influence:

a. They can stabilize or destabilize the incipient double bond (both α and β groups).

b. They can stabilize or destabilize an incipient negative charge, affecting the acidity of the proton (β groups only).

c. They can stabilize or destabilize an incipient positive charge (α groups only).

d. They can exert steric effects (e.g., eclipsing effects) (both α and β groups).

Effects a and d can apply in all three mechanisms, although steric effects are greatest for the E2 mechanism. Effect b does not apply in the E1 mechanism, and effect c does not apply in the E1cB mechanism. Groups such as Ar and C=C increase the rate by any mechanism, except perhaps when formation of the C=C bond is not the rate-determining step, whether they are α or β (effect a). Electron-withdrawing groups increase the acidity when in the β position, but have little effect in the a position unless they also conjugate with the double bond. Thus Br, Cl, CN, Ts, NO2, CN, and SR in the β position all increase the rate of E2 eliminations.

2. Effect on E1 versus E2 versus E1cB. The α alkyl and α aryl groups stabilize the carbocation character of the transition state, shifting the spectrum toward the E1 end. β Alkyl groups also shift the mechanism toward E1, since they decrease the acidity of the hydrogen. However, β aryl groups shift the mechanism the other way (toward E1cB) by stabilizing the carbanion. Indeed, as seen in Section 17.A.iii, all electron-withdrawing groups in the β position shift the mechanism toward E1cB.108 α alkyl groups also increase the extent of elimination with weak bases (E2C reactions).

3. Effect on Elimination versus Substitution. Under second-order conditions, increased branching increases elimination, to the point where tertiary substrates undergo few SN2 reactions, as seen in Chapter 10. 109110For example, Table 17.2 shows results on some simple alkyl bromides. Similar results were obtained with SMe2+ as the leaving group.111 Two reasons can be presented for this trend. One is statistical: As α branching increases, there are usually more hydrogen atoms for the base to attack. The other is that α branching presents steric hindrance to attack of the base at the carbon. Under first-order conditions, increased α branching also increases the amount of elimination (E1 vs SN1), although not so much, and usually the substitution product predominates. For example, solvolysis of tert-butyl bromide gave only 19% elimination112 (cf. with Table 17.2). β Branching also increases the amount of E2 elimination with respect to SN2 substitution (Table 17.2), not because elimination is faster, but because the SN2 mechanism is so greatly slowed (Sec. 10.G.i). Under first-order conditions too, β branching favors elimination over substitution, probably for steric reasons.113 However, E2 eliminations from compounds with charged leaving groups are slowed by β branching. This is related to Hofmann's rule (Sec. 17.B, category 4). Electron-withdrawing groups in the β position not only increase the rate of E2 eliminations and shift the mechanisms toward the E1cB end of the spectrum, but also increase the extent of elimination as opposed to substitution.

Another method that compares E2 and SN2 reactions is called the activation-strain model. In this model, the activation energy = activation strain + transition state interaction, and corresponds directly to the strength of the Lewis acid or base. A more basic nucleophile or base, with a higher energy HOMO, and a more acidic substrate, with a lower energy LUMO, interact more strongly.114 Activation strain is connected with the strength of the bonds broken: A strong C-leaving group bond has a higher activation strain and a higher barrier. Using this model, the E2 reaction has a higher activation strain than SN2 because two bonds are broken, and with weak bases, SN2 dominates E2 because SN2 has less activation strain.115 With strong bases, a favorable interaction of the more acidic transition state for the E2 reaction leads to a preference for E2.

Table 17.2 The Effect of α and β Branching on the Rate of E2 Elimination and the Amount of Alkene Formeda

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aThe reactions were between the alkyl bromide and img. The rate for isopropyl bromide was actually greater than that for ethyl bromide, if the temperature difference is considered. Neopentyl bromide, the next compound in the β-branching series, cannot be compared because it has no β hydrogen and cannot give an elimination product without rearrangement.

17.D.ii. Effect of the Attacking Base

1. Effect on E1 versus E2 versus E1cB. In the E1 mechanism, an external base is generally not required: The solvent acts as the base. Hence, when external bases are added, the mechanism is shifted toward E2. Stronger bases and higher base concentrations cause the mechanism to move toward the E1cB end of the E1–E2–E1cB spectrum.116 However, weak bases in polar aprotic solvents can also be effective in elimination reactions with certain substrates (the E2C reaction). Normal E2 elimination has been accomplished with the following bases:117 H2O, NR3, OH, OAc, OR, OAr, NH2, CO32−, LiAlH4, I, CN, and organic bases. However, the only bases of preparative importance in the normal E2 reaction are OH, OR, and NH2, usually in the conjugate acid as solvent, and certain amines. Weak bases effective in the E2C reaction are Cl, Br F, OAc, and RS. These bases are often used in the form of their R4N+ salts.

2. Effect on Elimination versus Substitution. Strong bases not only benefit E2 as against E1, but also benefit elimination as against substitution. With a high concentration of strong base in a nonionizing solvent, bimolecular mechanisms are favored and E2 predominates over SN2. At low-base concentrations, or in the absence of base altogether, in ionizing solvents, unimolecular mechanisms are favored, and the SN1 mechanism predominates over the E1. Chapter 10 pointed out that some species are strong nucleophiles but weak bases (Sec. 10.G.ii). The use of these obviously favors substitution, except that, as seen, elimination can predominate if polar aprotic solvents are used. It has been shown for the base cyanide that in polar aprotic solvents, the less the base is encumbered by its counterion in an ion pair (i.e., the freer the base), the more substitution is favored at the expense of elimination.118

17.D.iii. Effect of the Leaving Group

1. Effect on Reactivity. The leaving groups in elimination reactions are similar to those in nucleophilic substitution. The E2 eliminations have been performed with the following groups: +NR3, +PR3, +SR2, +OHR, SO2R, OSO2R, OCOR, OOH, OOR, NO2,119 F, Cl, Br, I, and CN (not+ OH2). The E1 eliminations have been carried out with: +NR3, +SR2, +OH2, +OHR, OSO2R, OCOR, Cl, Br, I, and +N2.120 However, the major leaving groups for preparative purposes are +OH2 (always by E1) and Cl, Br, I, and +NR3 (usually by E2).

2. Effect on E1 versus E2 versus E1cB. Better leaving groups shift the mechanism toward the E1 end of the spectrum, since they make ionization easier. This effect has been studied in various ways. One way already mentioned was a study of ρ values (Sec. 17.A.iv). Poor leaving groups and positively charged leaving groups shift the mechanism toward the E1cB end of the spectrum because the strong electron-withdrawing field effects increase the acidity of the β hydrogen.121 The E2C reaction is favored by good leaving groups.

3. Effect on Elimination versus Substitution. As seen previously (Sec. 17.A.ii), for first-order reactions the leaving group has nothing to do with the competition between elimination and substitution, since it is gone before the decision is made as to which path to take. However, where ion pairs are involved, this is not true, and results have been found where the nature of the leaving group does affect the product.122 In second-order reactions, the elimination/substitution ratio is not greatly dependent on a halide leaving group, although there is a slight increase in elimination in the order I > Br > Cl. When OTs is the leaving group, there is usually much more substitution. For example, n-C18H37Br treated with t-BuOK gave 85% elimination, while n-C18H37OTs gave, under the same conditions, 99% substitution.123 On the other hand, positively charged leaving groups increase the amount of elimination.

17.D.iv. Effect of the Medium

1. Effect of Solvent on E1 versus E2 versus E1cB. With any reaction a more polar environment enhances the rate of mechanisms that involve ionic intermediates. For neutral leaving groups, it is expected that E1 and E1cB mechanisms will be aided by increasing the polarity of the solvent and by increasing the ionic strength. With certain substrates, polar aprotic solvents promote elimination with weak bases (the E2C reaction).

2. Effect of Solvent on Elimination versus Substitution. Increasing polarity of solvent favors SN2 reactions at the expense of E2. In the classical example, alcoholic KOH is used to effect elimination, while the more polar aq KOH is used for substitution. Charge-dispersal discussions, similar to those in Section 10.G.iv,124 only partially explain this. In most solvents, SN1 reactions are favored over E1. The E1 reactions compete best in polar solvents that are poor nucleophiles, especially dipolar aprotic solvents125 A study made in the gas phase, where there is no solvent, has shown that when 1-bromopropane reacts with MeO only elimination takes place (no substitution) even with this primary substrate.126

3. Effect of Temperature. Elimination is favored over substitution by increasing temperature, whether the mechanism is first or second order.127 The reason is that the activation energies of eliminations are higher than those of substitutions (because eliminations have greater changes in bonding).