Proton exchange, racemization

Fig. 6.4 Reversible interconversion of amino acid and keto acid. Conjugation of the imine bond in the aldimine with the electron sink of the pyridine ring plus protonation of the pyridine nitrogen as well as the metal ion - all this results in weakening of the C-H bond of the amino acid residue. Thus, also catalyzed is a-proton exchange, racemization of a chiral center at the a-carbon atom and decarboxylation of the appropriate amino acid. ...

For all systems studied so far it is found that the rates of racemization R and proton exchange E (measured either by DjO exchange (Sec. 3.9.5) or by nmr line coalescence methods (Sec. 3.9.6)) are both first-order in [OH ]. 

Studies on catalytic asymmetric aza-Baylis-Hillman reaction has shown that the reaction involves rate-limiting proton transfer in the absence of added protic species, but exhibits no autocatalysis.41 Brpnsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. Furthermore, it has been found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the aza-Baylis-Hillman product by proton exchange at the stereogenic centre. 

Because of the basicity of the hydroxide counter-anion, diazonium ions formed in deamination can be expected to be particularly susceptible to anion exchange by the proton-transfer mechanism described above. White has shown that the deamination of optically active 2-phenyl-2-butylamine in acetic acid yields alcohol with 74% retention of configuration and acetate with 61% retention, together with a small amount of nitrite. He points out that the formation of acetate and nitrite are readily explained by proton exchange between the hydroxide ion and molecules of acetic and nitrous acid. As is expected, the product of collapse with the original counter anion shows the least amount of racemization (White and Stuber, 1963). Similar results have been obtained by Huisgen and Ruchardt (1956b) for the deamination of optically active -phenethylamine. 

Leitner and coworkers [27] found that triphenylphosphine either alone or in combination with protonic additives could cause racemization of the aza MBH product by proton exchange at the stereogenic center, but the chiral catalyst 19a developed by Shi s group did not induce any racemization on a similar time scale. 

The enzyme exists in two different protonation states of the active site cysteines, each binding a different enantiomer. Conversion between enantiomers can be through the racemization path (upper manifold of Fig. 7.16) or through direct proton exchange with water (lower manifold of Fig. 7.16). Knowles and coworkers found that interconversion of enzyme protonation states was kinetically significant [82]. This was determined by measuring rates of tritiated proline washout as a function of the proline concentration. It was found that higher concentrations of proline promote slower washout of the Ca proton. Additional support for the rela-... 

Knowles and coworkers also performed competitive deuterium washouts (i.e., an equilibrium perturbation-type washout experiments), using deuterated substrates in H2O solutions, which yielded the (V/K) values for both directions [85]. Further confirmation of these KIE values was validated by a double competitive deuterium washout experiment, in which both substrates are Ca deuterated, which yielded a ratio of the two (V/K) values. The authors were also able to perform competitive deuterium washout experiments where direct proton exchange between free enzyme forms is rate-limiting (i.e., at high substrate concentration the lower manifold of Fig. 7.16 is dominant). This experiment indicated that interconversion of free enzyme forms is very similar to the racemization manifold, in that loss of proton from one form yields the other free enzyme form, with water acting as the catalyst. Fig. 7.16. 

Along with steric aspects, the kinetics of the enantioselective protonation plays a crucial role. Here it is important that proton exchange reactions between electronegative atoms are usuaUy very fasL since there is a threat that the reactions become diffusion-controUed. Thermodynamic control then leads to the racemic product. 

The enols and enolates are capable of undergoing many reactions at the a position, among them exchange, racemization, halogenation, alkylation, addition to ketones or aldehydes, and addition to esters. The aldol condensation involves reaction of the enolate, a strong nucleophile, with the electrophilic carbonyl compound, or of the less strongly nucleophilic enol with the powerful electrophile, the protonated carbonyl. 

Considering that the a-proton-exchange of racemic azlactones occurred rapidly in the presence of a tertiary amine base. Song and coworkers demonstrated enan-tioselective synthesis of a-deuterated a-amino acids via dynamic kinetic resolution (DKR) of azlactones with EtOD using cinchona-derived dimeric squaramide catalyst 33 (Scheme 10.34) [112]. The authors noted that by increasing the amount of EtOD, the level of deuterium incorporation increased, whereas the enantioselectivity decreased. By using 50 equivalents of EtOD, the products were obtained with... 

Solvent for Base-Catalyzed Reactions. The abihty of hydroxide or alkoxide ions to remove protons is enhanced by DMSO instead of water or alcohols (91). The equiUbrium change is also accompanied by a rate increase of 10 or more (92). Thus, reactions in which proton removal is rate-determining are favorably accompHshed in DMSO. These include olefin isomerizations, elimination reactions to produce olefins, racemizations, and H—D exchange reactions. 

The stereochemistry of hydrogen-deuterium exchange at the chiral carbon in 2-phenylbutane shows a similar trend. When potassium t-butoxide is used as the base, the exchange occurs with retention of configuration in r-butanol, but racemization occurs in DMSO. The retention of configuration is visualized as occurring through an ion pair in which a solvent molecule coordinated to the metal ion acts as the proton donor... 

Mandelate racemase, another pertinent example, catalyzes the kinetically and thermodynamically unfavorable a-carbon proton abstraction. Bearne and Wolfenden measured deuterium incorporation rates into the a-posi-tion of mandelate and the rate of (i )-mandelate racemi-zation upon incubation at elevated temperatures. From an Arrhenius plot, they obtained a for racemization and deuterium exchange rate was estimated to be around 35 kcal/mol at 25°C under neutral conditions. The magnitude of the latter indicated mandelate racemase achieves the remarkable rate enhancement of 1.7 X 10, and a level of transition state affinity (K x = 2 X 10 M). These investigators also estimated the effective concentrations of the catalytic side chains in the native protein for Lys-166, the effective concentration was 622 M for His-297, they obtained a value 3 X 10 M and for Glu-317, the value was 3 X 10 M. The authors state that their observations are consistent with the idea that general acid-general base catalysis is efficient mode of catalysis when enzyme s structure is optimally complementary with their substrates in the transition-state. See Reference Reaction Catalytic Enhancement... 

Attempts to achieve an asymmetric 1,3-proton shift reaction of (/ )-33, obtained from ethyl 3,3,3-trifhioro-2-oxopropanoate and (f )-l-phenylethanamine in 81 % yield, resulted in conversion into 34 in 89% yield, but without any reliably delectable enantiomeric excess.26 Even at 10% conversion, the Shiff base 34 formed is completely racemic. Imine 34 undergoes isotopic exchange in triethylamine/methanoI-r/4 at a rate 10 times slower than the isomerization of 33 to 34. The authors reason that if a 1.3-proton shift mechanism is operating, some enantiomeric excess would have to be observable in product 34 at low conversion. Since this is not the ease, a 1,5-proton shift to the carbonyl oxygen, via stabilized anion 37, to form achiral intermediate enol 38, was proposed.26... 

Many base catalysed isotope exchange or racemization processes involve either rate-determining proton abstraction or rapid preequilibrium formation of the anion (19) followed by ratedetermining reaction with solvent (20) (L is an isotope of hydrogen). 

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