Enediolate elimination reaction

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

FIGURE 9 Isomerization and elimination reactions (a) The conversion of glucose 6-phosphate to fructose 6-phosphate, a reaction of sugar metabolism catalyzed by phosphohexose isomerase. (b) This reaction proceeds through an enediol intermediate. The curved blue ar-... 

The enolisation is catalysed by (relatively unhindered) substituted quinucli-dine bases with a Bronsted (3 value of 0.45 and 0.48 for glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. The elimination reaction of the enediolate (Figure 6.3) gives a clock whereby the relative efficiency of reprotonation can be measured from slopes of the plot of the ratio of reprotonation to elimination product against buffer concentration. This leads to a Bronsted a value of 0.47 for reprotonation to dihydroxyacetone phosphate (reprotonation to glyceraldehyde phosphate could not be observed in the quinuclidinium-catalysed reaction, but in the water-catalysed reaction. 

In the proton-transfer mechanism, the alcohol is presumed to form a hemiacetal at the C(5) carbonyl group. Then an acid-base pair in the active site performs an elimination reaction, producing the aldehyde product and the reduced cofactor, PQQH2. The hydride-transfer mechanism envisions the approximation of the scis-sile C-H bond of the alcohol to C(5) of the cofactor, followed by an acid-base catalyzed delivery of hydride ion to C(5), resulting in formation of the aldehyde product and the ketol form of PQQH2, which can readily rearrange to the enediol form. 

Saccharinic acid formation has been studied for several years. The four-step reaction proceeds rapidly in alkaline solution because of basic catalysis, particularly in the last two steps. Initially formed is an enediol that can undergo j8-elimination of a functional group, usually a hydroxyl group. The final two steps involve tautomerization to an a,j8-dicarbonyl intermediate followed by a benzilic acid rearrangement. This sequence is shown in Scheme 6 for the formation of the a- and j8 -xylometasac-charinic acids (30) by way of 3-deoxy-D-g/ycero-pentos-2-ulose (29). 

The dehydration reactions initiated by eliminating a hydroxyl group from an enediol are discussed in the present article. The products (usually dicarbonyl compounds) of these eliminations are normally transient intermediates, and undergo further reaction. The final products formed are determined by the carbohydrate reacting, the conditions of reaction, and the character of the medium. Except for a Section on analytical methods (see p. 218), the subject matter is restricted to aqueous acids and bases. The presence of compounds other than the carbohydrate under study has only been considered where it has helped to elucidate the mechanism involved. The approach here is critical and interpretative, with emphasis on mechanism. An attempt has been made to demonstrate how similar reactions can logically lead to the various products from different carbohydrates a number of speculative mechanisms are proposed. It is hoped that this treatment will emphasize the broad functions of these reactions, an importance that is not fully recognized. No claim is made for a complete coverage of the literature instead, discussion of results in the articles that best illustrate the principles involved has been included. 

The acyclic, enolic compounds 7 and 9 may exist in either cis or trans forms. Methyl ethers of 7 have been isolated in the cis form,8 but it is not known whether the trans forms, which must be acyclic, exist. The relative proportion of isomers is controlled by the geometry of the parent sugar enediol. Although the acyclic forms are readily interconvertible tautomers, it appears that, in acidic medium, further reaction occurs much more rapidly than any equilibrating reactions. Compound 7 undergoes rapid elimination of a second hydroxyl group to give 11. This acyclic product, also, may exist as either a cis or a trans isomer, both forms of which have been isolated.8 The loss of a third molecule of water per molecule occurs after, or simultaneously with, the cyclization of 11 (see Section II, 3 p. 171), and results in formation of 5-(hydroxymethyl)-2-furaldehyde (5). 

The first two reactions of the sequence are similar to reactions that occur in acidic medium. The 1,2- and 2,3-enediols, and the unsaturated elimination-products derived from them, are present both in acidic and basic solutions. In general, however, reactions in basic solution are much faster than in acidic solution, because of the greater catalytic effect of the hydroxyl ion on the transformation reactions Mechanistic differences between the media become operative in steps c and d. In acid, further dehydration, if it is possible, occurs rapidly, before equilibrium of the deoxy-enediol with the dicarbonyl compound has been established,17 and the products are furans. In alkaline solution, the rapid formation of the tautomeric dicarbonyl compound permits the benzilic acid rearrangement42 to proceed. 

The rather toxic methylglyoxal is formed in many organisms and within human tissues.174 It arises in part as a side reaction of triose phosphate isomerase (Eq. 13-28) and also from oxidation of acetone (Eq. 17-7) or aminoacetone, a metabolite of threonine (Chapter 24).175 In addition, yeast and some bacteria, including E. coli, have a methylglyoxal synthase that converts dihydroxyacetone to methylglyoxal, apparently using a mechanism similar to that of triose phosphate isomerase. It presumably forms enediolate 2 of Eq. 13-26, which eliminates inorganic phosphate to yield methyl-... 

Stacey and Turton61 objected to Isbell s mechanism on two counts first, that he did not specify that a proton acceptor must be used to promote the reaction and second, that the orthoacetate intermediate would not be applicable in the conversion which they demonstrated (by absorption spectra data) to take place on treatment with dilute, aqueous sodium hydroxide. (The presence of the proton acceptor seems implicit in Isbell s general description of the process of enolization.) The mechanism of Stacey and Turton is shown in Formulas XXIV to XXVIII it calls for the donation of electrons by pyridine to the incipient, ionic proton at C2 and elimination of acetic acid between C2 and C3 with the formation of the partially acetylated enediol-pyridinium complex. The pyridinium ion is removed by acetic acid. Electronic readjustment results in the elimination of acetic acid from positions 4 and 5. The final step, conversion of XXVII to XXVIII, was not explained. Stacey and Turton considered that with sodium hydroxide the reaction proceeds after deacetylation by a similar mechanism except that hydroxyl groups take the place of acetyl groups. Neither mechanism requires a free hydroxyl group at Cl, a condition considered by Maurer to be essential to kojic acid formation. 

The so-called acyloin condensation consists of the reduction of esters—and the reduction of diesters in particular—with sodium in xylene. The reaction mechanism of this condensation is shown in rows 2-4 of Figure 14.51. Only the first of these intermediates, radical anion C, occurs as an intermediate in the Bouveault-Blanc reduction as well. In xylene, of course, the radical anion C cannot be protonated. As a consequence, it persists until the second ester also has taken up an electron while forming the bis(radical anion) F. The two radical centers of F combine in the next step to give the sodium glycolate G. Compound G, the dianion of a bis(hemiacetal), is converted into the 1,2-diketone J by elimination of two equivalents of sodium alkoxide. This diketone is converted by two successive electron transfer reactions into the enediolate I, which is stable in xylene until it is converted into the enediol H during acidic aqueous workup. This enediol tautomerizes subsequently to furnish the a-hydroxyketone—or... 

Fig. 2-33. Alkaline peeling reaction of cellulose (R = cellulose chain). 1 — 2, Isomerization 2 — 3, 2,3-enediol formation 3 — 4, j3-alkoxy elimination 4 —> 5, tautomerization 5 — 6, benzilic acid rearrangement leading to glucoisosaccharinic acid.

Fig. 2-34. Stopping reaction. 1 —>2, 1,2-Enediol formation 2 — 3, j3-hydroxy elimination 3 —> 4, tautomerization 4 —> 5, benzilic acid rearrangement leading to a glucometasaccharinic acid end group, (cf. Fig. 2-33.)...

Another potential side reaction of the enediol(ate) intermediate is formation of the dicarbonyl compound, l-deoxy-D-glycero-2,3-pentodiulose 5-phosphate, resulting from p-elimination of the Cl-phosphate due to improper stabilization and/or premature dissociation of enediol(ate) from the enzyme active site. This compound has been characterized by reduction with borohydride, oxidation with H2O2, complexation with o-phenylenediamine, and 13C-NMR (23, 34). The p-elimination product is not detected in reactions with wild-type R. rubrum Rubisco but is formed in substantial amounts with mutants in which the Cl-phosphate ligands are substituted, demonstrating the required role of these amino acid side chains in stabilizing the enediol(ate) intermediate (34-35). 

There are currently two proposed mechanisms for the acyloin ester condensation reaction. In mechanism A the sodium reacts with the ester in a single electron transfer (SET) process to give a radical anion species, which can dimerize to a dialkoxy dianion. Elimination of two alkoxide anions gives a diketone. Further reduction (electron transfer from the sodium metal to the diketone) leads to a new dianion, which upon acidic work-up yields an enediol that tautomerizes to an acyloin. In mechanism B an epoxide intermediate is proposed. ... 

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