Elimination reactions: anti-process

We have previously seen (Scheme 2.9, enby 6), that the dehydrohalogenation of alkyl halides is a stereospecific reaction involving an anti orientation of the proton and the halide leaving group in the transition state. The elimination reaction is also moderately stereoselective (Scheme 2.10, enby 1) in the sense that the more stable of the two alkene isomers is formed preferentially. Both isomers are formed by anti elimination processes, but these processes involve stereochemically distinct hydrogens. Base-catalyzed elimination of 2-iodobutane affords three times as much -2-butene as Z-2-butene. 

The El reaction involves the formation of a planar carbocation intermediate. Therefore, both syn and anti elimination can occur. If an elimination reaction removes two substituents from the same side of the C—C bond, the reaction is called a syn elimination. When the substituents are removed from opposite sides of the C—C bond, the reaction is called an anti elimination. Thus, depending on the substrates El reaction forms a mixture of cis (Z) and trans (E) products. For example, tert-hutyl bromide (3° alkyl halide) reacts with water to form 2-methylpropene, following an El mechanism. The reaction requires a good ionizing solvent and a weak base. When the carbocation is formed, SnI and El processes compete with each other, and often mixtures of elimination and substitution products occur. The reaction of t-butyl bromide and ethanol gives major product via El and minor product via SnI-... 

Fig. 26 The elimination of HF from the 0-fluoroketone [68] is catalysed by antibody 1D4, elicited to hapten [70], to form the disfavoured (Z)-olefin [71]. This contrasts with the spontaneous process in which an anti-elimination reaction yields the ( )-<, 0-unsaturated ketone [69], The syn-eclipsed conformation of [70] is shaded.

It would appear safe to conclude that where stereoelectronic effects alone are operating, the anti elimination process is favored over the syru There are however several other parameters which are also important, such as the effects of the nucleophile, the solvent, the alkyl structure of the substrate and the nature of the leaving groups. Any of these variables is capable of completely reversing the stereochemical course of a concerted elimination reaction (83). 

The term stereoselective is often confused with the term stereospecific, and the literature abounds with views as to the most satisfactory definition. To offer some clarification, it is perhaps timely to recall a frequently used term, introduced a decade or so ago, namely the stereoelectronic requirements of a reaction. All concerted reactions (i.e. those taking place in a synchronised process of bond breaking and bond forming) are considered to have precise spatial requirements with regard to the orientation of the reactant and reagent. Common examples are SN2 displacement reactions (e.g. Section 5.10.4, p. 659), E2 anti) elimination reactions of alkyl halides (e.g. Section 5.2.1, p.488), syn (pyrolytic) elimination reactions (Section 5.2.1, p.489), trans and cis additions to alkenes (e.g. Section 5.4.5, p. 547), and many rearrangement reactions. In the case of chiral or geometric reactants, the stereoisomeric nature of the product is entirely dependent on the unique stereoelectronic requirement of the reaction such reactions are stereospecific. 

Elimination reactions often compete with substitution. They involve elimination of the halogen and a hydrogen from adjacent carbons to form an alkene. Like substitution, they occur by two main mechanisms. The E2 mechanism is a one-step process. The nucleophile acts as a base to remove the adjacent proton. The preferred form of the transition state is planar, with the hydrogen and the leaving group in an anti conformation. The E1 mechanism has the same first step as the SN1 mechanism. The resulting carbocation then loses a proton from a carbon atom adjacent to the positive carbon to form the alkene. 

The gas-phase base-induced elimination reaction of halonium ions was thoroughly investigated in radiolytic experiments22. Radiolytically generated acids C/JH5+ (n = 1,2) were allowed to react at 760 Torr with selected 2,3-dihalobutanes to form the halonium intermediates which, in the presence of trimethylamine, undergo base-induced bimolecu-lar elimination as shown in Scheme 6. This elimination reaction occurs in competition with unimolecular nucleophilic displacement to the cyclic halonium ion and subsequent rearrangement. Isolation and identification of the neutral haloalkenes formed and kinetic treatment of the experimental results indicated that 3-halo-1 -butene is formed preferentially with respect to the isomeric 2-halo-2-butenes and that the bimolecular elimination process occurs predominantly via a transition state with an anti configuration22. 

Probe orientation. Does the reaction have a preferred regiochemistry, like following Markovnikov s rule Is stereochemistry lost or retained in the reaction Is the process stereospecific Does addition or elimination occur anti or syn Is the chirality at the reacting center preserved, inverted, or lost ... 

Elimination reactions. Enzyme-catalyzed elimination reactions )8 to the carbonyl functions of ketones or thioesters, or those involving enamine intermediates, generally proceed by syn processes. anti-Eliminations are generally observed in the remaining cases. As with the carbon-carbon lyases, there appears to be a relationship between reaction stereochemistry and the stability of reaction intermediates. 

This process is synthetically important because a sacrificial alkene such as 1-decene or 1-hexadecene can be added to bias the overall reaction toward a specific target alkene. Mechanistically, thermal isomerization apparently involves a series of reversible elimination reactions of borane followed by re-addition in an anti-Markovnikov manner.2 If the sacrificial alkene has a significantly higher boiling point, then the desired alkene can he distilled from the reaction medium.22a xhe sacrificial alkene must not boil < 160°C, however, which is the temperature required for borane isomerization. This process makes it possible to isomerize the double bond of an alkene to a less substituted isomer, a process that Brown termed contrathermodynamic isomerization.29,30 methylenecyclohexane (41) was prepared from 1-methylcyclohexene by... 

As we have just seen in the formation of 53 or 54, regioselectivity is important is the formation of double bonds in elimination reactions. In Chapter 2 both E2 (anti) elimination (sec. 2.9.A) and syn elimination (sec. 2.9.C) processes were discussed. Regiocontrol in the elimination was achieved by binding the base to the... 

A knowledge of the stereochemistry of an elimination reaction is of major importance not only to a more complete understanding of the mechanism but also in connection with the use of beta-eliminations in synthetic processes. A variation in the dihedral angle between the bonds undergoing fragmentation not only influences the rate but can also modify the yield of olefin and influence the direction of elimination in secondary and tertiary structures. The terms anti-clinal and "syn-clinal" are used to describe the stereochemistry of the transition state when the dihedral angle between the parts being eliminated is 180°, 0°, 120° and 60°, respectively (761. The stereochemistry of beta-eliminations, the subject of numerous papers, has been extensively reviewed . ... 

The syn p-addition/elimination of water proved not to be superior to an anti process in chemical efficiency. The reason why the reaction catalyzed by enoyl-CoA hydratases follows the syn stereochemical course is because the two catalytic residues of the hydratase are located on the same side of the substrate (see Fig. 2). The reaction mechanism of D-3-hydroxyacyl-CoA dehydratase catalysis is not known. If it follows the anti stereochemical course, the D-specific dehydratases of the peroxisomal multifunctional... 

We have used some terms in classifying stereochemical courses of reactions that should now be explained in more detail. Addition and elimination reactions are classified as syn or anti, depending on whether the covalent bonds made or broken are on the same or opposite faces of the plane of the double bond. The terms syn and anti used in this context have replaced cis and trans when referring to processes, so as to avoid confusion with descriptions of alkene stereoisomerism. 

The unique feature of the Horner-Wittig reaction is that the addition intermediate can be isolated and purified, which provides a means for control of the reaction s stereochemistry. It is possible to separate the two diastereomeric adducts in order to prepare the pure alkenes. The elimination process is syn, so the stereochemistry of the alkene that is formed depends on the stereochemistry of the adduct. Usually the anti adduct is the major product, so it is the Z-alkene that is favored. The syn adduct is most easily obtained by reduction of (3-ketophosphine oxides.269... 

Enol lactones are assumed to form from iV-methylisoquinolinium salts as a result of a Hofmann-type degradation process. This P elimination is a highly stereospecific reaction in which Z isomers are produced from precursors of erythro configuration and isomers from threo diastereomers(5,97). This fact seems to suggest that syn rather than the more usual anti elimination takes place. Examination of models indicates, however, that there is a preferred conformation in which the C-8 hydrogen is in the syn and coplanar position to the quaternary nitrogen. This hypothesis was proved correct in experiments carried out in vitro (5,14,15,91-94). 

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