Resolving agents, optical resolution

Optical resolution is another method of producing (—)-mentho1 from racemic materials. (A)-Menthol is treated with optically active resolving agents to separate the (—)-mentho1 from the (+)-menthol, which is further processed by racemization over a nickel catalyst and recycled (156). 

Eor an extensive list of reagents that have been used for this purpose and of compounds resolved, see Wilen, S.H. Tables of Resolving Agents and Optical Resolutions University of Notre Dame Press Notre Dame, IN, 1972. 

Exercise 19-3 The specific rotation of optically pure 2-methylbutanoic acid is [a]D 19.34° (neat) (f = 21°). Assume that you resolved the racemic acid with (+)-1-phenylethanamine and obtained a rotation for the product of +10.1° (neat) (f= 21°) calculate the enantiomeric purity (in percent) of the resolved acid. What resuits would you anticipate if you used the (—)-amine in place of the (+)-amine What effect on your resolution would there be if the resolving agent contained 90% of the (+)-amine and 10% of the (—)-amine ... 

Reactive crystallization/precipitation plays a role in a number of industrially relevant processes, such as liquid-phase oxidation of para-xylene to produce technical-grade terephthalic acid, the acidic hydrolysis of sodium salicylate to salicylic acid, and the absorption of ammonia in aqueous sulfuric acid to form ammonium sulfate (135). Reactive crystalhzation/precipitation is also widely applied in the pharmaceutical industry, to facilitate the resolution of the enantiomers (diastereomeric crystallization). Here, the racemate is reacted with a specific optically active material (resolving agent) to produce two diastereomeric derivatives (usually salts) that are easily separated by crystallization ... 

Optically active 19a was previously obtained by inclusion complexation with N -benzylcinchon idi um chloride 21 [36], Compound 21 was also a very efficient resolving agent for rac-17 [37], Crystal structure analysis of a (1 1) complex of 21 and selectively included (+)-17 showed that the molecular aggregate was associated by formation of a Cl HO hydrogen bond. Racemic compound 20 could be efficiently resolved only by complexation with (R,R)-(—)-trans-2,3-bis(hydroxydiphenylmethyl)-l,4-dioxaspiro[4.4]nonane 3b. A crude inclusion complex of 1 1 stoichiometry of 3b was formed selectively with (+)-20 in a 2 1 mixture of dibutyl ether/hexane. One recrystallization from the above combination of solvents gave a 34 % yield of the pure complex. Optically active (+)-20 was obtained by dissolving the complex in 10% NaOH, followed by acidification with HC1 and then recrystallization. The optical purity determined by HPLC (Chiralpack As) was >99.9 %. As far as we know, this is the only report of the resolution of 4,4 -dihydroxybiphenyl derivatives. Conversely, an inclusion... 

Optical Resolution with Application of Mixtures of Resolving Agents... 

Optical resolution did not provide pure enantiomers of 28 in any cases (Table 8) but repeated resolution of the complex forming enantiomeric mixture yielded (IR,2S,5R)-2H in 92-94 % ee. Treatment of the (1S,2R,5>S)-28 containing enantiomeric mixture with the same resolving agent (//.//-isomer of DBTA) did not affect dramatic change of the enantomeric ratio. Pure (lS,2R,5S)-28 could be prepared by the use of the mirror image isomer of DBTA during a repeated resolution (Table 9). 

Resolving agent Solvent Yield [%] Optical purity [%ee] Resolution efficiency E... 

By using this method, both substance (A) and resolving agent (B) can be resolved using a resolving agent composed of optically active and racemic form with a b ratio. Experimental results of the resolution of ( )-phenylglycine (PG) with 10-camphorsulfonic acid (CSA) (a b = 2 1) are shown below (Table 8). 

After the preparation of diastereoisomers by introduction of an optically active resolving agent, the next problem in an optical resolution is to separate the diastereoisomers. It should be recalled that the components of a pair of diastereoisomers necessarily have very similar properties. They contain exactly the same ligands and differ only in their arrangement around the metal atom. Several separation techniques have been used, based either on the fact that diastereoisomers differ in solubility, or in retention time during chromatography. 

The most useful and general of all methods of resolution is that which involves combination of a racemic substance with an optically active reagent (a so-called resolving agent) to give two diastereoisomeric derivatives, one derived from each of the two active components. These diastereoisomers often may be separated by conventional fractional crystallization. Each isomer then is treated to regenerate the pure active component. 

The C2S-dinitrobis(ethylenediamine)cobalt(III) ion was first resolved by Werner1,213 through the d-camphorsulfo-nate. However, that method, though it ultimately gives good yields of both optical antipodes, is laborious, and the resolving agent is comparatively expensive. Resolution is readily accomplished by the use of potassium cZ-antimony tartrate, and yields of each antipode of the order of 40 to 50% are obtained. 

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