Elimination-substitution reactions, stereochemistry

The stereochemistry of the PLP-dependent elimination/substitution reactions involving the /3- and -y-carbons of amino acid substrates generally conforms to the trends observed among the PLP-dependent transamination and decarboxylation reactions at the a-carbon [Eq. (44)]. All of the enzymes so far studied that catalyze nucleophilic replacement reactions at the j8-carbon (five examples e.g., tryptophan synthase) and/or a,j3-elimination reactions (seven examples e.g., tryptophanase) involve retention of configuration at the jS-carbon (231) (Eq. (54)] ... 

Secondary bromides and tosylates react with inversion of stereochemistry, as in the classical SN2 substitution reaction.24 Alkyl iodides, however, lead to racemized product. Aryl and alkenyl halides are reactive, even though the direct displacement mechanism is not feasible. For these halides, the overall mechanism probably consists of two steps an oxidative addition to the metal, after which the oxidation state of the copper is +3, followed by combination of two of the groups from the copper. This process, which is very common for transition metal intermediates, is called reductive elimination. The [R 2Cu] species is linear and the oxidative addition takes place perpendicular to this moiety, generating a T-shaped structure. The reductive elimination occurs between adjacent R and R groups, accounting for the absence of R — R coupling product. 

Every new class of reactions (additions, eliminations, substitutions, etc.) has its own terminology for stereochemistry. As you learn each of these classes of reactions, keep a watchful eye on what terminology is used to describe the stereochemistry. Then, look at the mechanism of each reaction within each class, and try to understand why the mechanism dictates the stereochemistry. 

After free existence of l-azetin-4-one had been demonstrated, it seems that the mechanism of the so-called nucleophilic substitution reactions of 4-substituted 2-azetidinone follows an elimination-addition pathway. The intermediacy of (1) in displacement reactions is fully consistent with the stereochemistry of the reaction (83CJC1899 91TL2265). 

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. 

Chapter 8 discussed the stereochemistry of substitution reactions—that is, what happened to the stereochemistry when the reaction occurred at a carbon chirality center. This section discusses the regiochemistry of the elimination reaction—that is, what happens when a reaction can produce two or more structural isomers. The structural isomers that can often be produced in elimination reactions have the double bond in different positions. As shown in Figure 9.5, elimination of hydrogen chloride from neomenthyl chloride produces two structural isomers but in unequal amounts. 

However primitive these treatments are, the conclusion has a certain appeal, for it implies that having two more electrons in the transition structure changes the stereochemistry, from inversion in the SN2 reaction to syn in the SN2 reaction. We saw the same change in substitution reactions, retention for SE2 to inversion for Sn2, and for elimination reactions, anti for E2 to syn for E2 [see (Section 5.1.2.2) page 157], but in neither of those cases, nor in the SN2 reaction, is it reliable. 

Treatment of a primary aliphatic amine with nitrous acid or its equivalent produces a diazonium Ion which results in the formation of a variety of products through solvent displacement, elimination and solvolysis with 1,2-shift and concurrent elimination of nitrogen. The stereochemistry of the deamination-substitution reaction of various secondary amines was investigated as early as 1950, when an Swl-type displacement was suggested. Thus, the process can hardly be utilized for the preparation of alcohols except in cases where additional factors controlling the reaction course exist. Deamination-substitution of a-amino acids can be utilized for the preparation of chiral alcohols. 

A third mechanism for substitution at C(sp3)-X bonds under basic conditions, elimination-addition, is occasionally seen. The stereochemical outcome of the substitution reaction shown in the figure tells us that a direct Sn2 substitution is not occurring. Two sequential Sn2 reactions would explain the retention of stereochemistry, but the problem with this explanation is that backside attack of MeO- on the extremely hindered top face of the bromide is simply not reasonable. The SrnI mechanism can also be ruled out, as the first-row, localized nucleophile MeO- and the 2° alkyl halide are unlikely substrates for such a mechanism. 

Obtaining both an isotope effect, k /k, and an element effect, k fk, are the experimental evidence that the C-H and C-X bonds are breaking in the transition structure. Since measurement of heavy atom isotope effects requires special instrumentation, the element effect has taken the place of heavy atom isotope effects in most investigations. The element effect was first proposed by Bunnett in a 1957 paper dealing with the nucleophilic substitution reactions of activated aromatic compounds [27], and later applied to dehydrohalogenation mechanisms by Bartsch and Burmett [28]. The lack of any incorporation of deuterium prior to elimination has also been used as experimental evidence favoring the concerted mechanism [29]. The stereochemistry should be a trans-elimination. 

The tau bond model is an intriguing, but evidently defective approach to understanding the stereochemistry of elimination reactions. The problem therefore remains—there is no simple and satisfying way to explain the stereochemistry beyond the simple /3-elimination. We shall return to the problem later, when we come to discuss how cr bonds adjacent to a re bond influence the stereochemistry of attack on the n bond, but first we must discuss the angle of attack on a re bond, and the stereochemistry of their addition and substitution reactions. 

The amino acid L-serine 60 and its derivatives, having a leaving group in the p position, are ideally situated for -substitution reactions via the elimination addition process outlined in Scheme 5,4c = 15i= l6. The stereochemistry of such processes can be ascertained if samples of serine stereospecifically labeled at C-3 are available. 

The reactions of organic compounds can be divided into three main types addition reactions, substitution reactions, and elimination reactions. The particular type of reaction a compound undergoes depends on the functional group in the compound. Part 2 discusses the reactions of compounds whose functional group is a carbon-carbon double bond or a carbon-carbon triple bond. We will see that these compounds undergo addition reactions, or, more precisely, electrophilic addition reactions. Part 2 also examines stereochemistry, thermodynamics and kinetics, and electron delocalization—topics that can be important when trying to determine the outcome of a reaction. 

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