Equilibrium constants aldol additions

As these freely reversible aldol additions often have less favorable equilibrium constants [30,34], synthetic reactions usually have to be driven by an excess of pyruvate to achieve satisfactory conversions. A few related enzymes have been identified that utilize phosphoenolpyruvate instead of pyruvate, which upon C—C bond formation releases inorganic phosphate, and thus renders the aldol addition essentially irreversible (Figure 10.4) [16]. Although attractive from a synthetic point ofview, the latter enzymes have been less studied as yet for preparative applications [35]. 

NeuA, has broad substrate specificity for aldoses while pyruvate was found to be irreplaceable. As a notable distinction, KdoA was also active on smaller acceptors such as glyceraldehyde. Preparative applications, for example, for the synthesis of KDO (enf-6) and its homologs or analogs (16)/(17), suffer from an unfavorable equilibrium constant of 13 in direction of synthesis [34]. The stereochemical course of aldol additions generally seems to adhere to a re-face attack on the aldehyde carbonyl, which is complementary to the stereoselectivity of NeuA. On the basis of the results published so far, it may be concluded that a (31 )-configuration is necessary (but not sufficient), and that stereochemical requirements at C-2 are less stringent [71]. 

Rate and equilibrium constants have been determined for the aldol condensation of a, a ,a -trifluoroacetophenone (34) and acetone, and the subsequent dehydration of the ketol (35) to the cis- and fraw -isomeric enones (36a) and (36b)." Hydration of the acetophenone, and the hydrate acting as an acid, were allowed for. Both steps of the aldol reaction had previously been subjected to Marcus analyses," and a prediction that the rate constant for the aldol addition step would be 10" times faster than that for acetophenone itself is borne out. The isomeric enones are found to equilibrate in base more rapidly than they hydrate back to the ketol, consistent with interconversion via the enolate of the ketol (37), which loses hydroxide faster than it can protonate at carbon. 

The equilibrium constant is favorable for the aldol addition of ethanal, as in fact it is for most aldehydes. For ketones, however, the reaction is much less favorable. With 2-propanone (acetone) only a few percent of the addition product diacetone alcohol, 11, is present at equilibrium ... 

In vivo, pyruvate lyases perform a catabolic function. The synthetically most interesting types are those involved in the degradation of sialic acids or the structurally related octulosonic acid KDO, which are higher sugars typically found in mammalian or bacterial glycoconjugates [62-64], respectively. Also, hexose or pentose catabolism may proceed via pyruvate cleavage from intermediate 2-keto-3-deoxy derivatives which result from dehydration of the corresponding aldonic acids. Since these aldol additions are freely reversible, the often unfavourable equilibrium constants require that reactions in the direction of synthesis have to be driven by an excess of one of the components, preferably pyruvate for economic reasons, in order to achieve a satisfactory conversion. 

Functionally and mechanistically reminiscent of the pyruvate lyases, the 2-deoxy-D-ribose 5-phosphate (121) aldolase (RibA EC 4.1.2.4) [363] is involved in the deoxynucleotide metabolism where it catalyzes the addition of acetaldehyde (122) to D-glyceraldehyde 3-phosphate (12) via the transient formation of a lysine Schiff base intermediate (class I). Hence, it is a unique aldolase in that it uses two aldehydic substrates both as the aldol donor and acceptor components. RibA enzymes from several microbial and animal sources have been purified [363-365], and those from Lactobacillus plantarum and E. coli could be induced to crystallization [365-367]. In addition, the E. coli RibA has been cloned [368] and overexpressed. It has a usefully high specific activity [369] of 58 Umg-1 and high affinity for acetaldehyde as the natural aldol donor component (Km = 1.7 mM) [370]. The equilibrium constant for the formation of 121 of 2 x 10M does not strongly favor synthesis. Interestingly, the enzyme s relaxed acceptor specificity allows for substitution of both cosubstrates propional-dehyde 111, acetone 123, or fluoroacetone 124 can replace 122 as the donor [370,371], and a number of aldehydes up to a chain length of 4 non-hydrogen atoms are tolerated as the acceptor moiety (Table 6). 

Rate and equilibrium constants have been measured for representative intramolecular aldol condensations of dicarbonyls.60a For the four substrates studied (32 n = 2, R = Me n = 3, R = H/Me/Ph), results have been obtained for both the aldol addition to give ketol (33), and the elimination to the enone (34). A rate-equilibrium mismatch for the overall process is examined in the context of Baldwin s rales. The data are also compared with Richard and co-workers study of 2-(2-oxopropyl)benzaldehyde (35), for which the enone condensation product tautomerizes to the dienol60b (i.e. /(-naphthol). In all cases, Marcus theory can be applied to these intramolecular aldol reactions, and it predicts essentially the same intrinsic barrier as for their intermolecular counterparts. 

The aldol reaction is catalyzed by base or by acid. Both base- and acid-catalyzed condensations are reversible in the 1,2-addition step. The equilibrium constant for the addition step is usually unfavorable for ketones. 

FDP aldolase catalyzes the reversible aldol addition reaction of DHAP and d-glyceraldehyde 3-phosphate (D-Gly 3-P) to form d-FDP (Fig. 14.1-1). The equilibrium constant for this reaction has a value of -104 m-1 in favor of FDP formation. The enzyme has been isolated from a variety of eukaryotic and prokaryotic sources, both in type I and type II forms[7 21). Generally, the type I FDP aldolases exist as tetramers (M.W. 160 KDa), while the type II enzymes are dimers (M. W. 80 KDa). For the... 

One of the most important characteristics of the aldol reaction is its easy reversibility under many conditions. Since this factor has such a generally profound effect, we briefly introduce the topic here. For an aldol addition reaction that is carried out under the influence of a catalytic amount of acid or base in protic medium A//° and AG° can be estimated from thermochemical data. Guthrie has estimated A// and AG for the aldol addition depicted in equation (3) to be -9.8 kcal mol and -2.4 kcal mol , respectively (1 cal = 4.18 J). ° The thermochemical values used in this estimation, and the derived values of A// and AG% refer to species at equilibrium with the covalently hydrated aldehydes. It is not expected that values for the free aldehydes would be greatly different. The equilibrium constant for equation (3) is 4(X) M- ... 

Table 1 Equilibrium Constants for Aldol Addition Equilibria ...

Aldol addition reactions of ketones are rarely successful, since they are usually endoergonic. For example, the base-mediated aldolization of acetone provides only a few percent of the aldol, diacetone alcohol (equation 26). However, the conversion may be accomplished in 75% yield by refluxing acetone under a Soxhlet extractor containing calcium or barium hydroxide. - On the other hand, di-methoxyacetone dimerizes under basic conditions to the aldol, with an equilibrium constant significantly greater than unity (K = 10 dm mol equation 27). The difference in equilibrium constants of equations (26) and (27) parallels the equilibrium constants for hydration of the two ketones, and results from the inductive effect of the methoxy groups. 

The equilibrium constant for the dehydration phase of aldol condensations is usually favorable, largely because a conjugated a,jS-unsaturated carbonyl system is formed. When the reaction conditions are sufficiently vigorous to cause dehydration, the overall reaction can go to completion even if the equilibrium constant for the addition phase is not favorable. 

Ketones also undergo the aldol condensation, although a successful reaction often requires "enhanced" conditions, since the addition involves an unfavorable equilibrium constant. This is the situation in the reaction in which 4-nitrochalcone is synthesized. With the odds against it, why is the reaction successful in this case ... 

There are several reasons that this crossed aldol is successful. First, the rate of addition of the enolate to the carbonyl group of benzaldehyde is much greater than that of addition to /erf-butyl methyl ketone because the carbonyl groups of aldehydes are more reactive than those of ketones. Second, the equilibrium constant for the addition to an aldehyde carbonyl is more favorable than that for addition to a... 

The extended nine-carbon backbone of sialic acids can be constructed from hexose building blocks by aldol addition of a pyruvate unit. Synthetic studies for sialic acid and its modifications have extensively used the catabolic enzyme NeuA, which catalyzes the reversible addition of pyruvate (5) to N-acetyl-D-mannosamine (ManNAc, 4) to form the parent siahc acid NeuSAc (1 Scheme 17.4) [16, 17, 19]. These freely reversible aldol additions have equilibrium constants in favor of cleavage direction [20], which requires that synthetic reactions have to be driven by an excess of one substrate to achieve satisfactory conversions for economic reasons, this usually is 5. In contrast, NeuS utilizes PEP (6) as a high-energy nucleophile, which upon C-C bond formation releases inorganic phosphate and thus renders the addition essentially irreversible [21]. Despite its considerable synthetic potential, NeuS still is an orphan catalyst which so far has been less studied for preparative applications [22]. 

Guthrie JP (1978) Equilibrium constants for a series of simple aldol condensations, and linear free energy relations with other carbonyl addition reactions. Can J Chem 56 962-973... 

In vivo, pyruvate-dependent lyases mostly serve a catabolic function in the degradation of sialic acids and KDO (2-keto-3-deoxy-manno-octosonate) and in that of 2-keto-3-deoxy aldonic acid intermediates from hexose or pentose catabolism. Because these freely reversible aldol additions often have less favorable equilibrium constants [29], synthetic reactions are usually driven by excess pyruvate to achieve a satisfactory conversion. 

The 2-deoxy-D-ribose 5-phosphate aldolase (RibA or DERA EC 4.1.2.4) is a class I enzyme that, in vivo, catalyzes the reversible addition of acetaldehyde to D-glyceraldehyde 3-phosphate (34 Figure 5.57) in the metabolic degradation of 127 from deoxyribonucleosides [269], ivith an equilibrium constant for synthesis of 2 x lO m [56]. It is, therefore, unique among the aldolases in that it uses an aldehyde rather than a ketone as the aldol donor. RibA has been isolated from eukaryotic and prokaryotic sources [270, 271],... 

The success of the directed aldol condensation via metalloenamines arises from several factors. Most importantly, imines show little tendency to self-condense. Under basic conditions a C=N bond is less electrophilic than a C=0 bond because nitrogen is less electronegative than oxygen. As mentioned earlier (Section 1.9), metalloenamines are more nucleophilic than enolate ions, so the addition phase of the process should be more favorable. It is also believed that the adduct of a metalloenamine and a carbonyl compound is strongly stabilized by chelation, increasing the equilibrium constant for the addition phase. 

What is the role of water under these conditions It has been suggested that water suppresses the formation of proHne-oxazoUdinone, which has been considered to be a parasitic species [11]. Then, the role of water is to prevent deactivation rather than to promote activity. Studies, carried out on the proUne-catalyzed reaction between acetone and 2-chlorobenzaldehyde allow one to hypothesize a conflicting role of water. Water increases the total catalyst concentration due to suppression of unproductive species and decreases the relative concentration of productive intermediates by shifting the iminium ion back to proline [12]. Addition of water suppresses formation of both on- and ofF-cyde iminium ions 1 and 2 by Le Chatelier s principle (Scheme 24.2a). The net effect of added water on the globally observed rate will depend on the relative concentrations of iminium ions 1 and 2, which may be different for different aldehydes and can be a function of substrate concentrations and rate and equilibrium constants. Seebach and Eschen-moser have raised doubts about the fact that oxazoUdinones are unproductive and parasitic species in proline-catalyzed aldol reactions [13]. The small excess of water will potentially facilitate proton-transfer in the transition state (Scheme 24.2b), which both lowers the LUMO of the incoming electrophile as well as directs the enantioselectivity of the newly formed stereocenters. 

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