Stereochemistry of 1,2-Elimination Reactions

Elimination reactions, like displacement reactions, usually involve elements which are truns to each other. Thus cis 2-phcnyl-l-cyclo-hexanol (XXV) on dehydration with phosphoric acid gives principally 1-phenylcyclohexone (XXVI), but the corresponding trans alcohol (XXVII) gives mostly 3-phenylcyclohexene (XXVIIT).16 Similarly chlorofumaric acid (XXIX) is dehydrohalogenated to acetylenedicar- 

Another interesting example of the striking tendency towards trans elimination can be illustrated by the reaction of vincinal dibromides XXXI with iodide ion.18 The reaction may be generalized  

It was found that raeso-2,3-dibromobutane gave a butene which was 96 per cent trans and dI-2,3-dibromobutane gave a butene which was 91 per cent cis. These facts, together with second-order kinetics,19 suggest 

20 Young, Abstracts of Papers, Eighth National Organic Chemistry Symposium of the American Chemical Society, St. Louis, Mo., Dec. 1939, pp. 92-95. 

Acid-Induced Enolization. The acid-induced enolization of ketones may be considered an elimination reaction  

TABLE 10.2 Structurai Effects on Rate Constants of E2 and Sn2 Reactions with Sodium Ethoxide in Ethanoi Soiution at 55°C  

See the discussion of coplanar and periplanar by Kane, S. Hersh, W. H. ]. Chem. Educ. 2000, 77,1366. 

Orbital model for anti-coplanar (left) and syn-coplanar (right) elimination. 

Experimental data indicate that the anti pathway for E2 reactions is favored over the syn pathway. In one of the earliest studies of the stereochemistry of the E2 reaction, Cristol found the rate constant for the dehydrochlorination of the )3 isomer of benzene hexachloride (1,2,3,4,5,6-hexachlorocyclohexane, 6), in which each chlorine is cis to the hydrogen atoms on either side of it, to be only 10 times those of the other benzene hexachloride isomers. Since each of the other isomers has at least one hydrogen atom trans to a chlorine atom on an adjacent carbon atom, the low reactivity of 6 suggested that the E2 reaction occurs preferentially when there is a trans relationship for the hydrogen atom and chlorine atom on cyclohexane.  

A similar preference for an anti-periplanar relationship in acyclic compounds was reported by Cram and co-workers. f/ireo-l,2-Diphenyl-l-propyl chloride was found to undergo E2 elimination to give exclusively (E)-l,2-diphenyl-propene (equation 10.24), while the erythro diastereomer produced only the (Z)-l,2-diphenylpropene (equation 10.25).  

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The stereochemistry of -elimination reactions catalysed by D-galactonate dehydratase (GalD) and D-glucarate dehydratase (GlucD) enzymes is apparently not dictated by the pKas of the 7-protons of the carboxylate anion substrates.74 It had been observed previously that enzyme-catalysed dehydration initiated by abstraction of the 7-proton (p/y, > 29) from a carboxylate anion substrate usually proceeds via anti elimination, whereas syn elimination occurs when the proton is a- to an aldehyde, ketone, or thioester and correspondingly more acidic (pKa < 25). 

Now let s turn our attention to the stereochemistry of elimination reactions. El reactions go through an intermediate carbocation, so you lose stereospecificity. This means that if there are two possible stereoisomeric double bonds, you will get both of them ... 

These effects are minimized for n-o fragmentations, especially those where the intramolecular electron transfer takes place between spatially adjacent orbitals. Somewhat related stereoelectronic considerations apply to nucleophile or base assisted fragmentations where certain three-dimensional dispositions of existing bonds may favor the assistance, in a way related to, for example, the anti stereochemistry of elimination reactions (Sect. 5.2). 

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. 

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. 

When Cram S wished to study the stereochemistry of elimination reactions, he wanted a strong optically active base which would not substitute. Bases derived from hindered secondary amines (4) are often used for elimination reactions and Cram selected amine (5) for his purpose. 

The olefin distribution varied slightly with reaction conditions but the results show the competitive nature of syn- relative to a/i/i-elimination in these systems. Only in the cyclohexyl system is a/iri-elimination clearly predominant. Isotope-labelling studies obviously afford a more accurate method of estimating stereochemistry of elimination reactions than do rate profile approaches. Subsequent work questioned the validity of using dimethyl-substituted compounds as models for the parent alicyclic substrates as the substituents can influence the stereochemical outcome of the reaction, viz. 

A final piece of evidence involves the stereochemistry of elimination. (Jnlike the E2 reaction, where anti periplanar geometry is required, there is no geometric requirement on the El reaction because the halide and the hydrogen are lost in separate steps. We might therefore expect to obtain the more stable (Zaitsev s rule) product from El reaction, which is just what w e find. To return to a familiar example, menthyl chloride loses HC1 under El conditions in a polar solvent to give a mixture of alkenes in w hich the Zaitsev product, 3-menthene, predominates (Figure 11.22). 

AJkynes can be made by dehydrohalogenation of vinylic halides in a reaction that is essentially an E2 process. In studying the stereochemistry of this elimination, it was found that (Z)-2-chloro-2-butenedioic acid reacts 50 times as fast as the corresponding isomer. What conclusion can you draw about the stereochemistry of eliminations in vinylic halides How does this result compare with eliminations of alkyl halides ... 

The conversion of long-chain alkanoate CoA esters into the alkenoate CoA esters by acyl-CoA oxidase involves an anti elimination reaction. The stereochemistry of the reaction in Candida lipolytica was established using stearoyl-CoA-labeled with H at the 2 R)-, 3(R)-, and 3(5)-positions (Kawaguchi et al. 1980). 

The improvements in MNi so far achieved were mostly due to our efforts to eliminate the N site from MNi by changing preparation variables of the catalyst, while the other important factor i has not been satisfactorily considered. In the present study, hydrogenation of various prochiral ketones with TA-MNi almost freed from the N site were carried out in order to gain insight into the mode of stereo control on MNi, which was expected to determine the stereochemistry of the reaction and to take part in the origin of the factor i. 

Another important family of elimination reactions has as its common mechanistic feature cyclic TSs in which an intramolecular hydrogen transfer accompanies elimination to form a new carbon-carbon double bond. Scheme 6.20 depicts examples of these reaction types. These are thermally activated unimolecular reactions that normally do not involve acidic or basic catalysts. There is, however, a wide variation in the temperature at which elimination proceeds at a convenient rate. The cyclic TS dictates that elimination occurs with syn stereochemistry. At least in a formal sense, all the reactions can proceed by a concerted mechanism. The reactions, as a group, are often referred to as thermal syn eliminations. 

Finally, crown ethers have also been shown to produce marked changes in the stereochemistry of ElcB-reactions of methoxyacenaphthenes [189] promoted by KOt-Bu/t-BuOH (Hunter and Shearing, 1971). Addition of dicyclohexyl-18-crown-6 increases the ratio of the rates of exchange and elimination from 1.3 to 3.2, while for both exchange and elimination the cis/trans ratio decreases. 

The unique feature of the Horner-Wittig reaction is that the addition intermediate can be isolated and purified. This provides a means for control of the stereochemistry of the reaction. It is possible to separate the two diastereomeric adducts in order to prepare the pure alkenes. The elimination process is syn so that the stereochemistry of the alkene depends on the stereochemistry of the adduct. Usually, the anti adduct is the major product, so it is the Z-alkene which is favored. The syn adduct is most easily obtained by reduction of /i-keto phosphine oxides.160... 

The hydroxyl in (42-6) is then acylated with p-toluenesulfonyl chloride exposure of this to a base leads to elimination to form the 9,11 olehn (43-1). It should be noted that the hydroxyl group in the hrst-obtained fermentation product is equatorial and would eliminate only with great difficulty as it lacks a transoid proton at the adjacent position. Reaction of (43-1) with A -bromosuccinimide in an aqueous base leads to the addition of the elements of hypobromous acid. The stereochemistry of the reaction... 

We have mentioned many times that you need to think about the regiochemistry and stereochemistry of every reaction. We will now consider those issues for elimination reactions, beginning with regiochemistry. 

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. 

It is not always easy to distinguish an elimination reaction that is following the Elcb mechanism from one that follows the E2 pathway because the Elcb reaction usually exhibits second-order kinetics also. However, because the Elcb reaction is not concerted, there are no strict requirements concerning the stereochemistry of the reaction. In contrast to the preferred anti elimination that occurs in the E2 mechanism, Elcb reactions often produce a mixture of stereoisomers, as illustrated in the following equation ... 

For eliminations, form the carbon-carbon double bond according to Zaitsev s rule (except the Hofmann elimination) and use anti elimination to determine the stereochemistry of E2 reactions. 

Next, let s consider the stereochemistry of these reactions. Overall, addition reactions are the reverse of the elimination reactions we saw in Chapter 9. As was the case with the eliminations, there are two possible stereochemistries for the addition—syn and anti ... 

The third method is a concerted stereospecific removal of two adjacent hydrogen atoms from the chain of a fatty acid after synthesis. This is an aerobic route as oxidation is required and is used by mammals such as ourselves. The stereochemistry of the reaction is known from labelling studies to be cis elimination. 

Among the available methods for introducing an unsaturated carbon-carbon bond into organic molecules, selenoxide elimination reaction has been shown to be quite useful because of its simple procedure and its characteristic regioselec-tivity. Jones et al., who discovered the first selenoxide elimination, proposed an intramolecular mechanism entailing a five-membered ring structure to explain its syn nature [11]. This proposition was shown to be correct by Sharpless et al. who applied the method that was utilized by Cram to determine the stereochemistry of elimination in amine oxides [12]. Thus, the oxidation of erythro-selenide afforded only Z-olefin and that of f/zreo-selenide gave only -olefin (Scheme 4). 

Some interesting results have recently been obtained in studies on elimination reactions of esters of hydroxy acids. The mechanism is not fully established, but probably is of the bimolecular type. An especially interesting observation is that sodium iodide promotes the removal of two vicinal sul-fonyloxy groups by a process of cfs-elimination a series of elimination reactions of this type is known in carbohydrate chemistry, but apparently does not yet include an example from which the stereochemistry of the reaction could be deduced. 

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