Mandelic acid crystals

An example of tests for chirality is provided by studies of mandelic acid crystals (Figure 14.23). These crystals are polar and noncentrosymmetric, space group T 2i, but no hemihedral faees develop and therefore there are no external indications that allow one to distinguish the two ends of its polar axis b. Other techniques have to be used. In order to differentiate between the two ends of the hexagonally-shaped crystals (which were shown, by X-ray diffraction studies to have the c axis along the unique axis of the crystal). The directions of the a and b axes with respect to crystal habit were also established by X-ray diffraction studies. 

FIGURE 14.23. Determination of the sense of chirality of mandelic acid crystals (Ref. 99). (a) Molecular packing in a crystal. 

Mandelic acid crystallizes from water in rhombic crystals, which melt at 118°. The acid contains an asymmetric carbon atom the inactive synthetic variety can be converted into dextro- and levo-rotatory acids by crystallizing its cinchonine salt, or by the action of certain bacteria. 

A. Extraction with Benzene.—The mandelic acid is separated from the ammonium chloride by extraction with hot benzene. This is best done by dividing the solid mixture into ten approximately equal parts (Note 7). One of these portions is placed in flask with i 1. of boiling benzene. After a few minutes the hot benzene solution is decanted through a suction funnel (Note 8). The filtrate is cooled in an ice bath and the mandelic acid that crystallizes is filtered with suction. The benzene is returned to the extraction flask containing the residue from the first extraction, and a new portion of the ammonium chloride-mandelic acid mixture is added and extracted as before. The process is repeated until the mandelic acid is completely removed from the ammonium chloride (Note 9). 

The funnel should be previously heated and have fairly large holes so as not to be clogged by the mandelic acid that begins to crystallize as soon as the solution cools slightly. Only a slight suction should be applied during filtration. 

Usually two or three extractions of the ammonium chloride residues after the addition of the last portion of the crude mixture are necessary in order to obtain all of the mandelic acid. On concentrating the benzene used for the extraction, about 5 g. of impure mandelic acid may be obtained. To diminish mechanical losses it is recommended that the same container be used to collect and crystallize the several filtrates. 

A. Ethyl mandelale. To 152 g. (1.0 mole) of mandelic acid and 200 ml. of absolute ethanol in a 1-1. round-bottomed flask f< ui[)ped with a reflux condenser, there is added 100 ml. of abso-liile ethanol containing about 10 g. of anhydrous hydrogen chlo-lidc (Note 1). The solution is heated under reflux on a steam bath for 5 hours, then poured into 11. of ice water in a 3-1. beaker (Note 2). A saturated aqueous solution of sodium bicarbonate is added until the mixture is faintly alkaline (Note 3). It is I lien extracted with two 300-ml. portions of ether in a 2-1. separatory funnel. The ether extracts are washed with a 200-ml. por-lioii of water and dried over 50 g. of anhydrous sodium sulfate. The dried ether solution is concentrated by distillation from a 25()-ml. Claisen flask, and the residue is distilled at reduced pressure. I here is obtained 147-154 g. (82-86%) of ethyl mandel-iilc, l).p. 144-145°/16 mm. The ester may crystallize upon standing for a prolonged period. It melts at 30.5-31.5°. 

A solution of 76 g (S)-( + )-mandelic acid in 400 ml methanol and 5 ml acetic acid was reduced over 5% rhodium-on-alumina under 100 psig for 10 h. The catalyst was removed by filtration through Celite, and the methanol was removed in a rotary evaporator. The white, solid residue was dissolved in I 1 of hot diethyl ether and filtered while hot. After reduction of the volume to 400 ml, 250 ml cyclohexane was added. The remainder of the ether was removed, and the cyclohexane solution was stored for several hours in a refrigerator. The white crystals were filtered and dried in vacuo at 40 C the yield of (S)-( + )-hexahydromandelic acid was 71%. 

If the reaction mixture is cooled at this point, some of the mandelic acid may crystallize. If this happens, the precipitate should not be filtered, as it is contaminated with sodium chloride. 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

Hydrolysis of the Nitrile.—The nitrile, mixed in a porcelain basin with four times its volume of concentrated hydrochloric acid, is heated on the water bath until an abundant separation of crystals begins to take place on the surface of the liquid. The reaction mixture is then allowed to stand over night in a cool place, and the crystals which have been deposited, after being rubbed with a little water, are separated at the filter pump and washed with water (not too much). A further quantity of the acid is obtained from the filtrate by extraction with ether. The crude mandelic acid is pressed on a porous plate, dried, and purified by crystallisation from benzene. Melting point 118°. Yield about 10-15 g. 

After the ammonia has been removed to a point where a pulverulent mass remains, the product is treated with 475 cc. of hot absolute alcohol and the resulting solution is filtered through a hot funnel to remove insoluble impurities. The filtrate is cooled in an ice bath to give about 90 g. of glistening white crystals of mandelamide melting at 1320 (62 per cent of the theoretical amount based upon the mandelic acid) (Notes 3 and 4). 

A hot solution of 180 g (1.18 mol) of (S)-a-hydroxybenzeneacetic acid (mandelic acid) in 300 mL of acetone (distilled from calcium chloride) is added to a hot stirred solution of 180 g (1.15 mol) of rac-2- tcrt-buty 1 -3-methyl-4-imidazolidinone in 100 mL of acetone. After seeding and stirring, the solution is allowed to cool down very slowly to 4 °C by insulating the flask. The crystals formed are filtered off and suspended in 290 mL of acetone and stirred under reflux for 1 h. After cooling, filtering and redissolving in 170 mL of acetone as above, the crystals formed on cooling are collected to yield the (S)-imidazolidinone (S)-mande-late yield 108 g (30%) mp 115.5-116.5 °C [a]D +89 (c = 1, ethanol). 

The diamine (99) was prepared from (S)-proline90b) or (S)-glutamic acid I15) maintaining the asymmetric center. Racemic 2-(anilinomethyl)pyrrolidine, prepared from (RS)-5-oxopyrrolidine-2-carboxylic acid, was effectively resolved into a pair of enantiomers by fractional crystallization of its mandelic acid salt U6). Moreover, the preferential crystallization of its 4-hydrobenzoic acid salt was found to produce both enantiomers in high optical purities by alternate seeding116). 

In a 500-cc. Claisen distilling flask with a low side-tube connected to a condenser, are placed 105 g. of mandelic acid (m.p. xi8°) and 151 g. of acetyl chloride. A reaction sets in without the application of heat (Note 1). As soon as a clear solution results, the flask is warmed on a water bath and the excess acetyl chloride is distilled. The last trace of acetyl chloride may be removed by prolonged drying in a vacuum. The acetyl mandelic acid then crystallizes in large, round, white clusters after one or two days standing. The yield is I3° I33 g- (97 99 Per cent the theoretical amount) (Note 2). 

The melting points given in the literature range from 39 to 8o°. The acetyl mandelic acid is difficult to crystallize but may be purified from benzene or chloroform, preferably the former. The product thus obtained melts at about 79-80°. 

Mravik, A., Bocskei, Zs., Katona, Z., Markovits, I., Pokol, Gy., Menyhard, D.K., and Fogassy, E. A new optical resolution method coordinative resolution of mandelic acid esters. The crystal structure of calcium hydrogen (2R,3R)-0,0 -dibenzoyltartrate-(2i )-methyl mandelate, J. Chem. Soc. Chem. Commun. 1996, 1983. 

For example, in the optical resolution of diltiazem, a benzothiazepin derivative, with optically active mandelic acid, one of the diastereomeric salts with the same stereochemical sign (+) (+) or (-) (-) is crystallized from ethyl acetate whereas another with the opposite stereochemical sign (+) ( ) or (-) (+) is obtained from a mixed solvent of ethyl acetate and benzene (1 1).21 In the resolution of 1-phenyl-2-(p-tolyl)ethylamine with the same chiral acid, the same sign salt crystallizes from 50 % aqueous methanol and the opposite one from 2-propanol.22... 

To 21.6 kg (17.8 I) of 98% formic acid was added 1.14 kg (7.5 mols) of D-(-)-mandelic acid and the reaction mixture was heated for 4 hours at 70°C with stirring. The excess formic acid was evaporated off in vacuo and the residual syrup was dissolved in 6 I of benzene. The solution was washed twice with 6 I portions of water and was dried over magnesium sulfate. The drying agent was filtered and washed with 1.5 I of benzene, the washes being added to the filtrate. The dried filtrate was evaporated in vacuo to obtain the D-(-)-mandelic acid formate ether as a syrup. The product can be crystallized from cyclohexane to yield material melting at about 55°C to 58°C. 

Frankland and Price 17 were the first to attempt the resolution of alcohols (and acids) by fractional crystallization of their solid esters. The isomeric solid esters formed from Z-s-butylcarbinol and di-dibenzoyl-glyceric acid failed to separate on crystallization the corresponding di-alcohol-i-acid ester was liquid. Marckwald and McKenzie 18-19 effected partial resolutions of dl-mandelic acid and related acids with 1-menthol and d-bomeol, and of di-2-octanol with d-tartaric acid, but did not develop a satisfactory method for resolving alcohols. Later investigators, however, have employed the following resolving agents in several more or less successful resolutions of certain alcohols (a) i-menthyl isocyanate, (6) d-camphoric acid, (c) d- or i-mandelic acid, (d) d- or... 

The single crystal structure of racemic mandelic acid was originally reported by Cameron and Duffin [11], and then re-determined by Wei and Ward [12]. The compound crystallizes in the orthorhombic Pbca space group, with the unit cell parameters being ... 

Figure 3. Single crystal structures of (a) racemic mandelic acid and (b) (S)-mandelic acid. The figures were adapted from references [12] and [13], respectively.

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