Sodium ammonium racemate

G. B. Kauffman, I. Bernal and H.-W. Schiitt, Overlooked opportunities in stereochemistry, Part IV. Eilhard Mitscherlich s near discovery of conglomerate crystallization on the sesquicentennial of Pasteur s resolution of sodium ammonium racemate , Enantiomer, 1999, 4, 33—45. 

Splitting Racemic Compounds.—The methods by which racemic compounds may be split into their optically active components are several. The three methods used were all originated by Pasteur. The first method has been referred to and consists of the mechanical separation of the two oppositely hemi-hedral forms in which the salts of a racemic compound crystallize. This method is especially applicable in the case of tartaric acid when the sodium-ammonium salt is used. The crystallization and separation must be carried out under definite conditions. If the racemic acid salt is crystallized below 28° the two forms of crystals are produced and a separation can be accomplished. If, however, the crystallization takes place above 28° the two forms of crystals are not produced but the sodium-ammonium racemate crystallizes in unseparable crystals of one form. That is, above 28° the sodium-ammonium racemate crystallizes as such, while, below 28° the racemate splits into its two isomeric components and equal amouts of the sodium-ammonium dextro tartrate and the sodium-ammonium levo tartrate are formed. The second method for the splitting of a racemic compound into its optically active components consists of the formation of the cinchonine, strychnine, or other similar alkaloid salts. When the cinchonine salt of racemic acid is formed it splits into the... 

German name, Trauben-saure, is derived from the word for grapes. It is probable that it does not exist in grapes as racemic acid but that it is formed from the dextro acid as this transformation can easily be effected by the action of acids or even by water alone. When tartaric acid is prepared synthetically from succinic acid, from glyoxal, or from malic, maleic or fumaric acids either racemic acid or meso-tartaric acid is always formed. That is, synthetic reactions result in the formation of an inactive form. The methods of splitting racemic acid into its optically active components has been fully discussed. The sodium-ammonium racemate is the only salt that is of importance. This has been spoken of in connection with the method of splitting racemic acid into its components.. Like the free acid this salt exists, in dilute solution, as equal molecular parts of the dextro and levo forms. Only in concentrated solution does it exist as the racemate itself. 

Similar relationships are met with in the case of sodium ammonium d- and Z-tartrate and sodium ammonium racemate but in this case the racemate is the stable form in contact with solution above the transition point (27 ). Below the transition point, therefore, the solubility curve of the mixed tartrates will lie below the solubility curve of the racemate. Below the transition point, therefore, sodium ammonium racemate will break up in contact with solution into a mixture of sodium ammonium d- and Z-tartrates. At a higher temperature, 35°, sodium ammonium racemate undergoes decomposition into sodium racemate and ammonium racemate. ... 

The behaviour of sodium ammonium racemate is of interest from the fact that it was the first racemic substance to be resolved into its optically active forms by a process of crystallisation. On neutralising a solution of racemic tartaric acid, half with soda and half with ammonia, and allowing the solution to evaporate, Pasteur obtained a mixture of sodium ammonium d- and Z-tartrates. Since Pasteur was unaware of the existence of a transition point, the success of his experiment was due to the happy chance that he allowed the solution to evaporate at a temperature below 27° for had he employed a temperature above this, separation of the racemate into the two enantiomorphous forms would not have occurred. For this reason the attempt of Staedel to perform the same resolution met only with failure/... 

For a full discussion of the solubility relations of sodium ammonium racemate, see van t Hoff, Bildung und Spaltungvon Bappelsalzen p. 81. 

It was shown later that if the crystals of sodium ammonium racemate are deposited from solution at a temperature above 28°, crystals of but one kind are obtained. These differ in form and content of water of crystallization from the crystals of the corresponding salts of d-tartaric and Z-tartaric acids, which are obtained when the temperature is below 28°. 

Pasteur s other main important discovery, among many others in this field, was the resolution of sodium ammonium racemate, an optically inactive compound, by crystallization (1848-1850). In describing his discovery, he remarks ... 

Crystals of sodium ammonium tartrate, obtained under conditions yielding the hemihedral facets distinctive of the (a) dextrorotatory and (b) levorotatory forms. Also shown is the (c) morphology associated with the holohedral modification of sodium ammonium racemate. (The figure was adapted from Ref 17.)... 

Holohedral crystal of sodium ammonium racemate (Scacchi). 

Bacterial attack was also shown by Pasteur to be effective in the resolution of racemic acid. Penicillium glaucum allowed to grow in a dilute solution of sodium ammonium racemate destroys the d form but, apart from being a rather wasteful process, the attack is not always completely selective. 

We now know that sodium ammonium racemate crystallises into the d and I tartrates only below 27° above this temperature the racemate crystallises as... 

A young Louis Pasteur observed that many salts of tartaric acid formed chiral crystals (which he knew was related to their ability to rotate the plane of polarization of plane-polarized light). He succeeded in solving the mystery of racemic acid when he found that the sodium ammonium salt of racemic acid could be crystallized to produce a crystal conglomerate. After physical separation of the macroscopic enantiomers with a dissecting needle, Pasteur... 

Crystals composed of the R and S enantiomers of the same racemic mixture must be related by mirror symmetry in terms of both their internal structure and external shape. Enantiomorphous crystals may be sorted visually only if the crystals develop recognizable hemihedral faces. [Opposite (hid) and (hkl) crystal faces are hemihedral if their surface structures are not related to each other by symmetry other than translation, in which case the crystal structure is polar along a vector joining the two faces. Under such circumstances the hemihedral (hkl) and (hkl) faces may not be morphologically equivalent.] It is well known that Pasteur s discovery of enantiomorphism through die asymmetric shape of die crystals of racemic sodium ammonium tartrate was due in part to a confluence of favorable circumstances. In the cold climate of Paris, Pasteur obtained crystals in the form of conglomerates. These crystals were large and exhibited easily seen hemihedral faces. In contrast, at temperatures above 27°C sodium ammonium tartrate forms a racemic compound. 

Mechanical Separation of Crystals. The first instance of resolution was by L. Pasteur who was able to resolve crystals of sodium ammonium tartrate (which recrystallizes in two distinct, nonsuperimposable forms below 2TC). Although this procedure is rarely used, one might be able to seed a racemic solution resulting in only one... 

Through luck, in 1848, Louis Pasteur was able to separate or resolve racemic tartaric acid into its (+) and (—) forms by crystallization. Two enantiomers of the sodium ammonium salt of tartaric acid give rise to two distinctly different types of chiral crystal that can then be separated easily. However, only a very few organic compounds crystallize into separate crystals (of two enantiomeric forms) that are visibly chiral as are the crystals of the sodium ammonium salt of tartaric acid. Therefore, Pasteur s method of separation of enantiomers is not generally applicable to the separation of enantiomers. 

Later, Pasteur 15) had arrived at the general stereochemical criterion for a chiral or dissymmetric molecular structure. Thus, the specific rotations of the two sets of sodium ammonium tartrate crystals in solution, isolated from the racemic mixture by hand-picking, were equal in magnitude and opposite in sign, from which Pasteur inferred that enantiomorphism of the dextro- and laevorotatory crystals is reproduced in the microscopic stereochemistry of the (+)- and (—)-tartaric acid molecules. The term dissymmetry or chirality is used when there is no superimposability between the two enantiomers, as seen in Sect. 2.1. 

The crystallization procedure employed by Pasteur for his classical resolution of ( )-tartaric acid (Section 5-1C) has been successful only in a very few cases. This procedure depends on the formation of individual crystals of each enantiomer. Thus if the crystallization of sodium ammonium tartrate is carried out below 27°, the usual racemate salt does not form a mixture of crystals of the (+) and (—) salts forms instead. The two different kinds of crystals, which are related as an object to its mirror image, can be separated manually with the aid of a microscope and subsequently may be converted to the tartaric acid enantiomers by strong acid. A variation on this method of resolution is the seeding of a saturated solution of a racemic mixture with crystals of one pure enantiomer in the hope of causing crystallization of just that one enantiomer, thereby leaving the other in solution. Unfortunately, very few practical resolutions have been achieved in this way. 

In 1848, the French scientist Louis Pasteur prepared the sodium ammonium salt of racemic tartaric acid and allowed it to crystallize in large crystals which are visually distinctive from hemihedral forms.4 By discriminating the asymmetric faces of the crystals, he picked out the two kinds of crystals mechanically with a pair of tweezers and a loupe. Finally he obtained two piles of crystals, one of (+) and one of (-)-sodium ammonium tartrate. This was the first separation of optically active compounds from their racemate. 

It was Pasteur, in the middle of the 19th century, who first recognized the breaking of chiral symmetry in life. By crystallizing optically inactive sodium anmonium racemates, he separated two enantiomers of sodium ammonium tartrates, with opposite optical activities, by means of their asymmetric crystalline shapes [2], Since the activity was observed even in solution, it was concluded that optical activity is due to the molecular asymmetry or chirality, not due to the crystalline symmetry. Because two enantiomers with different chiralities are identical in every chemical and physical property except for optical activity, in 1860 Pasteur stated that artificial products have no molecular asymmetry and continued that the molecular asymmetry of natural organic products establishes the only well-marked line of demarcation that can at present be drawn between the chemistry of dead matter and the chemistry... 

Louis Pasteur was the first scientist to study the effect of molecular chirality on the crystal structure of organic compoimds [23], finding that the resolved enantiomers of sodium ammonium tartrate could be obtained in a crystalline form that featured nonsuperimposable hemihedral facets (see Fig. 9.1). Pasteur was quite surprised to learn that when he conducted the crystallization of racemic sodium ammonium tartrate at temperatures below 28 °C, he also obtained crystals of that contained nonsuperimposable hemihedral facets. He was able to manually separate the left-handed crystals from the right-handed ones, and foimd that these separated forms were optically active upon dissolution. More surprising was the discovery that when the crystallization was conducted at temperatures exceeding 28 °C, he obtained crystals having different morphologies that did not contain the hemihedral crystal facets (also illustrated in Fig. 9.1). Later workers established that this was a case of crystal polymorphism. 

R. Kuroda, S.M. Mason, Crystal structures of dextrorotatory and racemic sodium ammonium tartrate, J. Chem. Soc., Dalton Trans. B50 (1994) 59-68. 

Kuroda s research interests have always centered on chirality. She likes to go back to the famous story about Pasteur and Scacchi. Pasteur observed the spontaneous resolution of sodium ammonium tartrate whereas Scacchi obtained racemic samples when he repeated Pasteur s experiment. The difference was due to a phase transition at 27°C. Scacchi was working in Italy, so his lab was much warmer than Pasteur s. 

On studying the sodium-ammonium salt of ordinary tartaric acid (dextro tartaric acid), to see if there was any indication of unsymmetrical crystalline form with which to connect the optical activity, according to the suggestion of Herschel, Pasteur observed that the crystals possessed hemi-hedral facets. These gave to the crystals an unsymmetrical form. He then turned his attention to the second known tartaric acid, viz., racemic acid, which is optically inactive. His expectation was that in this acid no such unsymmetrical form would exist as it did not possess optical activity. But to his surprise he found, in the crystals of the sodium-ammonium salt, the same hemi-hedral facets that he had just found in the salts of the active acid. On closer examination. 

Thus from a study of the crystalline sodium-ammonium salt of racemic acid and of dextro tartaric acid Pasteur showed, conclusively, the relationship of these two acids to each other and also discovered the existence of a third isomer optically active but of opposite direction to the ordinary tartaric acid already known. Racemic acid, therefore, is optically inactive because it consists of equal molecules of the ordinary dextro tartaric acid and the newly discovered levo tartaric acid. Also racemic acid can be resolved into its optically isomeric components by mechanically separating the two forms of crystals of the sodium-ammonium salt. The two active forms of tartaric acid, when mixed in equal molecular amounts, yield the inactive or racemic acid. Later, Pasteur prepared the fourth variety of tartaric acid, viz., meso-tartaric acid, by heating the cinchonine salt of dextro tartaric acid. This new acid proved to be inactive like racemic acid, but, unlike it, was unable to be resolved into optically active components. Its relation to the other three forms of tartaric acid was unexplained by Pasteur. 

Mechanical Separation This is the method by which Pasteur proved that racemic acid was actually a mixture of (+)- and (—(-tartaric acids.In the case of racemic sodium ammonium tartrate, the enantiomers crystallize... 

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