Enantiomers and Racemic Compounds

FIGURE 56.18. Ternary solubility phase diagrams of racemic compound-forming systems (a) racemic compound forms solvate, (b) enantiomers form solvate, and (c) both enantiomers and racemic compound form solvates. 

Analytical Properties Resolution of enantiomers such as trans- 1,3-cyclohexene dibenzoate, 3,5-pentylene dibenzoate, 3,5-dichlorobenzoate, triacetylacetonates, and racemic compounds having phosphorus as a chiral center this phase will also resolve achiral compounds Reference 45, 46... 

Racemic compounds, or true racemates, exhibit two eutectic points each between the pure enantiomer and the racemic compound. The shape of the DSC diagrams can vary, depending on the relative positions of temperatures of eutectics and racemic compound and on the composition of the eutectics (Figs. 16B and C). In the case of Fig. 16C it is difficult to distinguish by DSC a racemic compound from a conglomerate. Other methods as IR or X-ray are suitable for proper interpretation. For example, propanol hydrochloride has been described as conglomerate or as racemate compound. ... 

Early studies on monolayers of chiral molecules like 2-hydroxyalkanes, amphiphilic amino acids, 2-methylhexacosanoic acid esters, and hydroxy-hexadecanoic acid and its esters have been reviewed. The interesting question about monolayers of chiral molecules is whether the parameters which can be determined and the phase transitions are different for pure enantiomers and racemates. For components of biomembranes like phosphatidylcholines 10 this appears not to be the case," but for synthetic compounds like iV-(a-methylbenzyl-stearamide) 11 specific interactions between the molecules of the enantiomers are observed (Chart 2). ° In recent years, advanced techniques have been developed to probe the order in monolayers at the air-water interface, including surface X-ray diffraction, and microscopic techniques, viz. fluorescence microscopy, and Brewster angle microscopy (BAM). The X-ray diffraction technique has been used to identify homochiral and heterochiral two-dimensional domains in mono-layers of racemic amphiphilic amino acids on subphases containing glycine. Fluorescence microscopy requires the introduction in the monolayer of a small... 

Resolution of compounds made as diastereoisomeric mixtures The synthesis of Jacobsen s Mn(III) epoxidation catalyst by resolution Resolution with half an equivalent of resolving agent Physical Separation of Enantiomers Chromatography on chiral columns Resolution of triazole fungicides by HPLC A commercial drug separation by chiral HPLC Differential Crystallisation or Entrainment of Racemates Conglomerates and racemic compounds Typical procedure for differential crystallisation (entrainment) Conventional resolution ofL-methyl DOPA Resolution ofL-methyl DOPA by differential crystallisation Finding a differential crystallisation approach to fenfluramine Resolution with Racemisation... 

We prepared the enantiomers and racemates of these compounds both as hydrochlorides and methiodides and so, effectively, we studied the enantiomers and race-mate of 4 compounds (Fig. 2). 

RESULTS OF TESTING THE ENANTIOMERS AND RACEMATES OF COMPOUNDS I AND II FOR ANTICHOLINERGIC... 

Table 1 lists theoretically possible polymorphs of chiral drugs and practical examples [13,21,28 35]. The most common are polymorphic enantiomers, polymorphic racemic compounds, and the existence of both a racemic conglomerate and a racemic compound of a chiral drug. Polymorphs may be discovered by crystallization from supersaturated solutions in various solvents, by solvent-mediated polymorphic transformation, by crystallization of amorphous solids under different conditions. 

Vapor Pressure. Differences in vapor pressure (i.e., in the heat of sublimation [Ai/subiim]) have been observed for enantiomers and racemates. It has been suggested that heterochiral interactions between solid enantiomers (as in a racemic compound) can be either stronger or weaker than the homochiral interactions, i.e., between the crystals of the 1 1 mechanical mixture [32]. These interactions have not been widely investigated in pharmaceutical formulations containing racemates or enantiomers. The difference in A/fsubiim can also be used to separate enantiomers from a mixture, and it is thought to be a better method of separation, at least in some cases, than recrystallization. 

Another recent study [57] focused on skin uptake of chiral terpenes. Stereoisomers of menthol have a 9°C lower melting point than racemic compound, while neomenthol enantiomers are present in the liquid state at room temperature, and its racemate melts at 51°C [50]. Changing the solvent composition had no significant effect on the racemate/enantiomers solubility ratio of both terpenes. In further experiments no differences in skin uptake of (+)- or (—)-menthol were examined, but the difference in the melting temperature and solubility of enantiomers vs. racemic compound was reflected in a clear enhancement of racemate skin uptake when compared to pure stereoisomers. In the case of neomenthol, a more than 26° C difference in the melting point resulted in enantiomeric/ racemic uptake ratios of between 2.5 and 8 (depending on the solvent composition). 

Figure 8.9. Simultaneous measurement of electric susceptibility (relative dielectric constants of the chiral enantiomer and racemate, top) and tilt susceptibility xe (labeled as 6/E, middle) and ratio k = x Xo) /x (bottom) in the smectic- phase of the chiral compound A7 (from [61]).

Phase transition is a fundamental defining characteristic of this approach to pure substances. Hence substances that exist in one phase only, easily decompose, only occur in solution, etc. can only be included by analogy. Timmermans [1928, 23-53] lists the following potentially difficult cases for the molar approach of substance definition as summarised in this section azeotropic mixtures, dissociative compounds in equilibrium, enantiomers and racemates ( 18), certain types of mixed crystals or other polymorphic compounds, polymers ( 16), many biochemical compounds, and systems that are not in thermodynamic equilibrium. 

FIGURE 4.4 Chromatograms showing chiral resolution of racemic compounds on (a) Microcrystalline cellulose frw(3,5-dimethylphenyl)carbamate of cellulose in the 1 1 (w/w) ratio as stationary phase. Eluent n-hexane/propan-2-ol (80 20, v/v). Visualization anisaldehyde reagent. Migration distance = 6 cm at room temperature. Enantiomers and racemic propranolol [36]. (b) Microcrystalline cellulose tris(2,3-dimethylphenyl)carbamate of cellulose in the 1 1 (w/w) ratio as stationary phase. Eluent n-hexane/propan-2-ol (90 10, w/w). Enantiomers and racemic bupranolol [36]. (c) Amino-propyl sUanized sihca gel (3 g) coated with rnj(cyclohexyl)carbamates of amylose (0.75 g) as stationary phase. Eluent n-hexane/propan-2-ol (90 10, v/v). Racemates (a) 2,2,2-trifluoro-(9-antryl)ethanol, (b) Troger s base, and (c) benzoin ethyl ether. Visualization UV (254 nm). Migration distance = 6.2 cm at room temperature [37]. 

The same kind of spontaneous racemization oc curs for any as 1 2 disubstituted cyclohexane in which both substituents are the same Because such compounds are chiral it is incorrect to speak of them as meso compounds which are achiral by definition Rapid chair-chair interconversion however converts them to a 1 1 mixture of enantiomers and this mix ture IS optically inactive... 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

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