**3.1.2.3 Kinetic control**

The above mentioned examples (**FoPA** and **AcPG**) demonstrated both the conglomerate and racemate behaviour during fractionated precipitation of enantiomeric mixtures under thermodynamic control. However a new type of crystallization order was observed when the propionyl derivatives of phenylalanine and phenylgylcine (**PPA** and **PPG,** respectively) were examined. This type of compounds presented different behaviour during the enantiomeric enrichment processes than expected on the basis of their binary (melting point/composition) phase diagrams. Binary phase diagram of *N*-propionyl-phenylglycine (**PPG**) indicated conglomerate type behavior, while that of *N*-propionyl-phenylalanine (**PPA**) was a racemate type with *ee*eu 59%. The results of selective precipitations contradicted the anticipations based on these findings. In these case the results of selective precipitations were rather similar to a conglomerate like behaviour. This can be explained with a faster crystallization of enantiomeric excess than the expected racemic proportion.35

Separation of the Mixtures of Chiral Compounds by Crystallization 19

between 34-95%, (on the average 60%), while the average of the six greatest difference was 70%. This means that the purification of enantiomers by crystallization is a wery fruitful route (independently from the method applied (from melt to using a solvent) to enantiopure

Another approach is the resolution of an enantiomeric mixture with a structurally similar resolving agent. It is the situation when one of the enantiomers of the racemic compound is transformed (with a minimal chemical transformation) into a reagent able to form diastereoisomeric salt with the initial racemic compound. It can be done if the aminoacid is *N*-acylated and one of the pure enantiomers is esterified, or if its carboxylic group is

For example, the racemic *N*-acetyl-phenylglycine (**AcPG**) can be reacted with methyl (*S)* phenylglycinate (**MePG**). The resolution can be treated as a recrystallization of a quasi enantiomeric mixture with *ee0=*50% from water when the less soluble diastereoisomeric salt (namely, the heterochiral quasi-racemic mixture) crystallized containing (*R)*-**AcPG** in good

water

If the substituents of the compounds would be removed (Ac from **AcPG** → R and S and Me

1R + 3S ≡ RS + SS Namely, the starting mixture would be an "enantiomeric mixture with ee= 50%". Therefore

The situation was almost the same when the *N*-acetyl-phenylalanine (**AcPA**) was reacted with methyl (*S)*-phenylalaninate (**MePA**) according to the preceding resolution. The obtained crystalline diastereoisomeric salt also will be a quasi-racemate, but its enantiomeric

It was also observed, that the average *ee* and F values of diastereoisomeric salts obtained at the resolutions (in number 28 resolutions) of racemic *N*-acetyl-phenylalanine and phenylglycine (**AcPA** and **AcPG**) with structurally similar bases (resolving agents) correspond to the eutectic composition (*eeE* value) of the adequate racemate (in these cases the enantiomers of the racemic compounds form racemates). Consequently, if the resolution of a racemic compound is accomplished with structurally similar resolving agents (in water) the purity of the enantiomer obtained from the crystalline diastereoisomeric salt corresponds to the biner phase diagram of the enatiomeric mixture or converge to the

(*R*)-**AcPG.**(*S*)-**MePG** (*S*)-**AcPG.**(*S*)-**MePG** crystalline solid in solution +

ee: 79%

transformed into an amide, or changed with methyl group, respectively.

COOCH3

NH2

(*S*)-**MePG**

the above shown crystalline diastereoisomeric salt is a quasi-racemate.

from **MePG** → S), the composition of the mixture would be

excess (ee: 93%) was even higher than that of the former case.

materials.

enantiomeric excess (*ee*: 79%).

+ 2

COOH NHCOCH3

(*R*)-**AcPG**

(*S*)-**AcPG**

COOH NHCOCH3

Selective precipitation of (*R>S*)-*N*-propionyl-phenylalanine (**PPA**) was effectuated starting from the aqueous solution of its sodium salt. Addition of less than equimolar amount of hydrochloric acid resulted in the crystallization of the excess of (*R*)-**PPA** to such an extent, that in certain cases the usually remaining racemic composition become unbalanced, too (therefore the (S) enantiomer is enriched in the filtrate)


Essentially the same phenomenon was observed at the fractionated precipitation of the enantiomeric mixture of (*R>S*)-*N*-propionyl-phenylglycine (**PPG**).


In light of these experimental data it should be mentioned, that during the purification of enantiomeric mixtures of *N*-acyl-aminoacids not only the suitable methods but also the subtituent on the molecule skeleton (acyl group) may determine the productivity of enrichment.
