Elimination reactions stereoelectronics

A straightforward explanation for the unexpected stability of / -lactone enolate 2 has been put forward, a stereoelectronic reason in the rigid system 2 the essential orbitals are held orthogonal to each other as in 2 thus, an elimination reaction has a much higher activation energy than in an open system49. 

Suggest an explanation based on orbital interactions for the observed stereochemistry for E2 elimination reactions, that is, the strong stereoelectronic preference that the C—H and C—X bonds be anti-coplanar. 

The use of cyclic sulfates in synthetic applications has been limited in the past because, although cyclic sulfites are easily prepared from diols, a convenient method for oxidation of the cyclic sulfites to cyclic sulfates had not been developed. The experiments of Denmark [70] and of Lowe and co-workers [71 ] with stoichiometric ruthenium tetroxide oxidations and of Brandes and Katzenellenbogen [72a] and Gao and Sharpless [68] with catalytic ruthenium tetroxide and sodium periodate as cooxidant have led to an efficient method for this oxidation step. Examples of the conversion of several diols (67) to cyclic sulfites (68) followed by oxidation to cyclic sulfates (69) are listed in Table 6D.7. The cyclic sulfite/cyclic sulfate sequence has been applied to 1,2-, 1,3-, and 1,4-diols with equal success. Cyclic sulfates, like epoxides, are excellent electrophiles and, as a consequence of their stereoelectronic makeup, are less susceptible to the elimination reactions that usually accompany attack by nucleophiles at a secondary carbon. With the development of convenient methods for their syntheses, the reactions of cyclic sulfates have been explored, Most of the reactions have been nucleophilic displacements with opening of the cyclic sulfate ring. The variety of nucleophiles used in this way is already extensive and includes H [68], [68,73-76], F" [68,72,74], PhCOCT [68,73,74], NOJ [68], SCN [68],... 

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. 

Nucleophilic ring opening of epoxy sugars is a valuable method for the synthesis of many modified sugar derivatives. The reaction is accompanied by Walden inversion, and a wide range of nucleophiles can be used. The cyclic nature of epoxides renders the competing elimination process stereoelectronically unfavourable. For asymmetric epoxides, in principle, two regio-isomeric products can be formed however, in... 

The elimination reactions discussed above for diethyl ether are suggested to proceed via a transition state with a periplanar geometry. This hypothesis has been tested by studying the stereoelectronic control in the base-induced elimination reactions of cis- and /ra s-4-t-butylmethoxycyclohexane (de Koning and Nibbering, 1987). Both compounds give free and water-solvated methoxide by reaction with OTP, as summarized in (39a) and (39b). 

Although this is the only chapter in which stereoelectronics appears in the title, you will soon recognize the similarity between the ideas we cover here and concepts like the stereospecificity of E2 elimination reactions (Chapter 19), the Karplus relationship (Chapter 32), the Felkin-Anh transition state (Chapter 33), and the conformational requirements for rearrangement (Chapter 37) and fragmentation (Chapter 38) reactions. 

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). 

Fumarate hydratase. The most studied enzyme of this group is probably the porcine mitochondrial fumarate hydratase (fumarase see also Chapter 9), a tetramer of 48.5-kDa subunits with a turnover number of 2 x 10 s T It accelerates the hydration reaction more than lO -fold. A similar enzyme, the 467-residue fumarase C whose three-dimensional structure is known, is foxmd in cells of E. coli when grown aerobically. The product of the fumarate hydratase reaction is L-malate (S-malate). The stereospecificity is extremely high. If the reaction is carried out in HjO an atom of H is incorporated into the pro-R position, i.e., the proton is added strictly from the re face of the trigonal carbon (Eq. 13-12). To obtain L-malate the hydroxyl must have been added from the opposite side of the double bond. Such anti (trans) addition is much more common in both nonenzymatic and enzymatic reactions than is addition of both H and OH (or -Y) from the same side (syn, cis, or adjacent addition). For concerted addition it is a natural result of stereoelectronic control. Almost all enzymatic addition and elimination reactions involving free carboxylic acids are anti with the proton entering from the re face. 

Many examples of stereoelectronic effects have been proposed in numerous areas of organic chemistry. The textbook example is perhaps the requirement for the anti conformation of the electrons of the scissile C—H bond with the leaving group in the E2 elimination reaction. However, over the past decade, the term stereoelectronic effect has become synonymous with an effect otherwise termed the kinetic anomeric effect or the antiperiplanar lone-pair hypothesis. While it is quite erroneous to label this hypothesis as the stereoelectronic effect , the fact that this situation has come about does serve to emphasize the ascendency of this hypothesis in the minds of many organic chemists. 

But why This goes against all of what we said in Chapter 16 about axial substituents being more hindered, making conformations carrying axial substituents disfavoured. The key again is stereoelectronics, and we can now link up with the message we left you with at the end of the last section elimination reactions are possible only when the orbitals involved are parallel. 

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