Orientation Effects in Elimination Reactions

In the El mechanism, the leaving group has completely ionized before C-H bond-breaking occurs. The direction of the elimination will then depend on the structure of the carbonium ion and on the identity of the base involved in the rapid proton removal that follows C-X heterolysis. It should be recognized that quite weak bases can suffice to effect proton removal. The solvent may often serve this function the role may also be played by the counter-ion formed in the ionization step. The 

In the Elcb mechanism, the direction of elimination is governed by the kinetic acidity of the available protons, which, in turn, is determined by the inductive and resonance effects of nearby substituents and by the degree of steric hindrance to approach of base to the proton. Alkyl substituents will tend to retard proton abstraction both electronically and sterically. Preferential proton abstraction from unhindered positions leads to the formation of less-substituted alkenes. 

Comp irison of the data for methoxide with t-butoxide in Table 6.3 illustrates the second general trend Stronger bases favor formation of the less-substituted 

The direction of elimination is also affected by steric effects. Highly hindered bases shift the orientation in dehydrohalogenations toward more Hofmann rule elimination. This effect can be reasonably attributed to the fact that the internal hydrogen that must be removed for Saytzeff rule elimination becomes inaccessible to very bulky bases, and abstraction of less-hindered protons is favored  

The data recorded in Table 6.4 for the 2-hexyl system illustrate two general trends that have been recognized in other systems as well. First, poorer leaving groups favor elimination according to the Hofmann rule, as shown, for example. 

Comparison of the data for methoxide with those for t-butoxide in Table 6.4 illustrates the second general trend Stronger bases favor formation of the less substituted alkene. A stronger base leads to an increase in the carbanion character at the transition state and thus shifts it in the Elcb direction. A linear correlation between the strength of the base and the difference in for the formation of 1-butene versus 2-butene has been established. Some of the data are given in Table 6.5. 

The direction of elimination is also affected by steric effects, and if both the base and the reactant are highly branched, steric factors will lead to preferential removal of the less hindered hydrogen. Thus, when 4-methyl-2-pentyl iodide reacts with very hindered bases such as potassium tricyclohexylmethoxide, there is preferential formation of the terminal alkene. In this case, potassium t-butoxide favors the internal alkene, although by a smaller ratio than for less branched alkoxides. 

Base (potassium salt) pK % 1-Butene from 2-iodobutane % 1-butene from 2-butyl tosylate  

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Brown, H. C. Wheeler, O. H. Steric Effects in Elimination Reactions. IX. The Effect of the Steric Requirements of the Leaving Group on the Direction of Bimolecular Elimination in 2-Pentyl Derivatives J. Am. Chem. Soc. 1956, 78, 2199-2202. Also see Bartsch, R. A. Bunnett, J. F. Orientation of Olefin-Forming Elimination in Reactions of 2-Substituted Hexanes with Potassium frrf-Butoxide-fiprf-Butyl Alcohol and Sodium Methoxide-Methanol /. Aw. Chem. Soc. 1969, 91, 1376-1382. Provide the products expected from the following olefin-forming reactions. (CJH-7)... 

TABLE 5.6. Leaving Group Effects on Orientation in Elimination Reactions ... 

Analysis of the butene fraction obtained in reactions between 2-halogeno-butanes and the alkoxides CHa-CHj ONa and CFs-CHg-ONa at 25 C in dipolar aprotic solvents (DMF and DMSO, to minimize solvation effects) has revealed that in each case change from ethoxide to 2,2,2-trifluoroethoxide results in a decrease in the tendency for but-l-ene to be formed. This demonstrates that base strength and not size is of prime importance in determining orientation in elimination reactions between 2-halogenoalkanes and alkoxides of modest proportions. ... 

Dimethyl sulfoxide (DMSO) has been used to effect the elimination of sulfonates at elevated temperatures (see, for example, ref. 237). Benzene-sulfonates are recommended. The elimination of a variety of sulfonates proceeds readily in this medium in the presence of potassium /-butoxide. A -Compounds have been formed at 100°, but heating is not necessary. The effects of temperature change, orientation of the hydroxy group and changes in the sulfonate employed have been examined. The principal side reaction appears to be formation of the original alcohol (uninverted), particularly with equatorial mesylates at low temperatures it is minimized with axial tosylates. 

The scope of heteroaryne or elimination-addition type of substitution in aromatic azines seems likely to be limited by its requirement for a relatively unactivated leaving group, for an adjacent ionizable substituent or hydrogen atom, and for a very strong base. However, reaction via the heteroaryne mechanism may occur more frequently than is presently appreciated. For example, it has been recently shown that in the reaction of 4-chloropyridine with lithium piperidide, at least a small amount of aryne substitution accompanies direct displacement. The ratio of 4- to 3-substitution was 996 4 and, therefore, there was 0.8% or more pyridyne participation. Heteroarynes are undoubtedly subject to orientation and steric effects which frequently lead to the overwhelming predominance of... 

In the intramolecular reactions studied by Bruice and Koshland and their co-workers, proximity effects (reduction in kinetic order and elimination of unfavourable ground state conformations) and orientation effects might give rate accelerations of 10 -10 . Hence, these effects can by themselves account for the enhancements seen in most intramolecular reactions. However, a factor of 10 -10 is less than the rate acceleration calculated for many enzyme reactions and certain intramolecular reactions, for example, hydrolysis of benzalde-hyde disalicyl acetal (3 X 10 ) (Anderson and Fife, 1973) and the lactonization reaction of[l] (10 ) where a trimethyl lock has been built into the system. If hydrolysis of tetramethylsuccinanilic acid (Higuchi et al., 1966) represents a steric compression effect (10 rate acceleration), then proximity, orientation, and steric compression... 

In the previous subsection, it was shown that the Ferrier reaction offers an opportunity to convert glycal derivatives into unsaturated sugar derivatives, which have an isolated double bond between C(2) and C(3). The Tipson-Cohcn reaction is another important reaction for the introduction of isolated double bonds.29 In this procedure, a cis or tram diols are converted into disulfonates (mesylates or tosylates) which are reductively eliminated with sodium iodide and zinc in refluxing DMF (Scheme 3.6a). In this reaction, the C(3) sulfonate is substituted by an iodide, which then is reductively removed by zinc with concomitant elimination of the second sulfonate moiety, introducing a double bond. Stereoelectronic effects make nucleophilic substitutions at C(3) more favourable than similar reactions at C(2) (see Section 3.2.3). Probably, the elimination proceeds through a boat conformation. In this case, the iodide and tosylate are in a syn relation. In most cases, E2 elimination proceeds via a transition state involving an anti orientation. Nevertheless, syn elimination becomes the dominant mode of reaction when structural features prohibit an anti orientation. 

Molecular orbital calculations of the w-electron distribution in pyridine predict that more 4- than 2-aminopyridine should be formed in the Tschitschibabin reaction.4 The fact that no 4-aminopyridine can be detected when the two positions are allowed to compete for a deficiency of sodamide (see, e.g., Abramovitch et al 268) has led to the suggestion that the observed orientation in this reaction depends on the relative ease of elimination of a hydride ion from C-2 and C-4 and not upon the initial mode of addition (which, by implication, must take place predominantly at C-4 as predicted by the molecular orbital calculations).4 This hypothesis necessitates that the addition step be rapidly reversible and that the second stage, the elimination of hydride ion, be the rate-determining one (Scheme VII). Although it seems reasonable to assume that the hydride ion eliminations are the slow steps in this reaction, the fact that no deuterium isotope effect was observed in the reaction of 3-picoline-2d and of pyridine-2d with sodamide implies that the first stage must be virtually irreversible,268 as was found also in the case of the addition of phenyllithium to pyridine.229 The addition stage must, therefore, be the product-... 

The ring nitrogen of pyridoxal phosphate exerts a strong electron withdrawing effect on the aldimine, and this leads to weakening of all three bonds about the a-carbon of the substrate. In nonenzymic reactions, all the possible pyridoxal-catalyzed reactions are observed - a-decarboxylation, aminotrans-fer, racemization and side-chain elimination, and replacement reactions. By contrast, enzymes show specificity for the reaction pathway followed which bond is cleaved will depend on the orientation of the Schiff base relative to reactive groups of the catalytic site. As discussed in Section 9.3.1.5, reaction specificity is not complete, and a number of decarboxylases also undergo transamination. 

In this chapter size effects in encounter and reaction dynamics are evaluated using a stochastic approach. In Section IIA a Hamiltonian formulation of the Fokker-Planck equation (FPE) is develojjed, the form of which is invariant to coordinate transformations. Theories of encounter dynamics have historically concentrated on the case of hard spheres. However, the treatment presented in this chapter is for the more realistic case in which the particles interact via a central potential K(/ ), and it will be shown that for sufficiently strong attractive forces, this actually leads to a simplification of the encounter problem and many useful formulas can be derived. These reduce to those for hard spheres, such as Eqs. (1.1) and (1.2), when appropriate limits are taken. A procedure is presented in Section IIB by which coordinates such as the center of mass and the orientational degrees of freedom, which are often characterized by thermal distributions, can be eliminated. In the case of two particles the problem is reduced to relative motion on the one-dimensional coordinate R, but with an effective potential (1 ) given by K(l ) — 2fcTln R. For sufficiently attractive K(/ ), a transition state appears in (/ X this feature that is exploited throughout the work presented. The steady-state encounter rate, defined by the flux of particles across this transition state, is evaluated in Section IIC. 

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