Unfavourable equilibrium

A new development is the industrial production of L-phenylalanine by converting phenylpyruvic add with pyridoxalphosphate-dependent phenylalanine transaminase (see Figure A8.16). The biotransformation step is complicated by an unfavourable equilibrium and the need for an amino-donor (aspartic add). For a complete conversion of phenylpyruvic add, oxaloacetic add (deamination product of aspartic add) is decarboxylated enzymatically or chemically to pyruvic add. The use of immobilised . coli (covalent attachment and entrapment of whole cells with polyazetidine) is preferred in this process (Figure A8.17). 

By driving over an unfavourable equilibrium using the mass action effect. 

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. 

A de novo synthesis of GDP-Fuc (13), UDP-Gal (16) and UDP-GalNAc (19) by isolated enzymes of the salvage pathways (see Fig. 14) has not yet been described. A crude extract from porcine submaxillary glands gave a yield of 80% for the synthesis of p-L-fucose-1-phosphate (12), but the synthesis of 13 was less successful with a yield of 20% [312]. The main pathways for 16 and 19 involve 4-epimerases (Table 4 and Fig. 14) which are not suitable for preparative synthesis due to their unfavourable equilibrium constants [347, 348], An alternative is Gal-l-P uridyltransferase which is only specific for Gal-l-P and GalNH2-l-P (Table 4). 

The reactions by which (50) is converted into chasmanine were studied in model systems.38 An earlier scheme40 (cf. Vol. 7, p. 258) was found to be unsatisfactory due to the unfavourable equilibrium between (51) and (52). The next model... 

Among ions, the opening of a cyclopropyl anion is exemplified by the reactions of the trans and cis aziridines 6.55 and 6.58, which are isoelectronic with the cyclopropyl anion. They open in the conrotatory sense to give the W- and sickle-shaped ylids 6.56 and 6.59, respectively, which are isoelectronic with the corresponding allyl anions. This step is an unfavourable equilibrium, which can be detected by the 1,3-dipolar cycloaddition of the ylids to dimethyl acetylenedicarboxylate, which takes place suprafacially on both components to give the cis and trans dihydropyrroles 6.57 and 6.60. The conrotatory closing of a pentadienyl cation can be followed in the NMR spectra of the ions 6.61 and 6.62, and the disrotatory closing of a pentadienyl anion can be seen in what is probably the oldest known pericyclic reaction, the formation of amarine 6.64 from the anion 6.63. 

The energy expenditure of the mitochondrial ATP-driven transhydrogenase reaction has been estimated to one ATP per NADPH formed [29,30,46,53,60-62]. Since the equilibrium constant of the nonenergy-linked transhydrogenase reaction is 0.79 [2] and that of ATP hydrolysis is about 10 M [63], the equilibrium constant of the overall reaction is also of the order of 10 M. In spite of the very unfavourable equilibrium a reversibility of the energy-Unked transhydrogenase reaction has been demonstrated using ATP production [64] or uptake of lipophilic anions [65-67] as assay. 

Detailed kinetic studies on other monomers than styrene are not numerous. The data are assembled in Table 5. a-Methylstyrene has received the most extensive study with data available for several counter-ions and three solvents [20, 118, 136,142]. The kp values in the table are those extrapolated to 25°C, the actual temperature range studied was lower owing to the unfavourable equilibrium between monomer and polymer at room temperature. Some inaccuracy may result from this extrapolation. In dioxane [142] the activation energy decreases from 13 to 8 kcal mole between Na and Rb , evidently the characteristics of a contact-ion-pair. In tetrahydropyran [20] the kp value of the lithium compound is much higher than the others, presumably caused by a contribution from solvent-separated pairs. This is confirmed by the fact TABLE 5... 

Owing to the experimental difficulties of measuring accurate rate constants for reactions with unfavourable equilibrium constants, the forward and reverse rate constants are often measured with reagents with no overlap in the ranges of substituent. In these circumstances it is necessary to have confidence that the free energy relationships are linear over the extrapolated range (line A in Figure 1) and that curvature does not exist. 

With carboxylic acids, the condensation reaction is an unfavourable equilibrium, promoted by using non-aqueous solvent (if any) and a dehydrating agent such as sulphuric acid (which also catalyses the reaction). 

The clue to the new pathway was provided in 1958 by S. J. Wakil, in the U.S.A. Wakil sought a system whereby the cell could bypass the unfavourable equilibrium of reaction (6), and found that the trick was done, just as by UDPG in glycogen synthesis, by an activation of the reactants. Once again, activation is provided at the expense of ATP and a new coenzyme. What the cell does is to convert acetyl-CoA into another, more reactive substance, malonyf-CoA. Malonic add is produced by the addition of a molecule of carbon dioxide to acetic acid, (7) ... 

The less reactive ketones can be persuaded to react with other, usually non-enolisable, carbonyl compounds as in the reaction of cyclohexanone 5 with diethyl carbonate to give the P-keto-ester 7. This reaction is really under thermodynamic control as the favourable equilibrium between the product 7 and its stable enolate 8 more than compensates for the unfavourable equilibrium between 5 and its unstable enolate 6. This stable enolate 8 is a specific enolate. 

The tendency of a certain process to occur or not may be expressed in terms of the equilibrium constant. If we study the results of simple thermal measurements, thermodynamics will help us to calculate equilibrium constants of processes which have not been previously attempted, or which are difficult to study directly. It can answer the question how far but is quite unable to answer how fast A host of industrial processes, such as the cracking of light naphtha to form ethylene, or the synthesis of ethanol from ethylene and water vapour, depend initially on a very careful analysis of the equilibrium situation over a wide range of temperatures. Only when the feasibility of a new process has been demonstrated, by thermodynamic methods, is it necessary to build pilot plants and choose catalysts. Once a reaction strikes the rocks of an unfavourable equilibrium constant, no mere catalyst can salvage the wreck. 

A common bottleneck in these processes remains the undesired enzymatic hydrolysis of the activated side-chain molecule to the usually poorly soluble amino acid [57]. In combination with unfavourable equilibrium conditions in the coupling reaction, this still leads to a tedious and costly purification technology. 

Fluorobis(phenylsulfonyl)methane (139) has been successfully added to benzalde-hyde to give the a-fluorinated carbanion that - on protonation - gives a-fluoroalcohol (140). Previously, failure had been ascribed to unfavourable equilibrium. The new protocol uses a lithium base (LiHDMS) in DCM at -94 °C, followed by protonation with TFA at the same temperature. VT- F-NMR evidence indicates a key role for lithium coordination of the carbinolate and that an equilibrium shift to (PhS02)2CF Li+ and aldehyde readily occurs at, for example, -19°C." °... 

Cyclic Ketones.—Many examples exist of reversible reactions that are not pre-paratively useful because of unfavourable equilibrium constants, and numerous other reactions are preparatively poor through self-condensation of the substrate. Both of these problems occur in the cyclopentenone preparation shown [equation (13)]. However, a cunning solution has been found whereby both the acid- and base-catalysed steps may be carried out concurrently using a mixed-ion-exchange resin consisting of sulphonic acid beads and quaternary ammonium hydroxide beads, giving the cyclopentenone in 87% (crude) yield. ... 

---