Racemic mixture

A racemate [ rat͡sema ː t] (also racemate; Latin: acidum racemicum = racemic acid, with the first successful racemate separation) is according to IUPAC Rule E -4.5, an equimolar mixture of the two enantiomers of a chiral compound. All racemates thus have an enantiomeric ratio of 1:1. A racemic mixture does not rotate the polarization plane of polarized light and is optically inactive, the value of α is therefore 0 °.

For identification of racemic mixtures in the substance name different descriptors are used, for example, rac-, (RS) -, DL- or ( ±) -.

5.1 Separation as enantiomers
5.2 Separation of diastereomers by
5.3 Fermentative resolution
5.4 Kinetic Resolution

Explanation

Molecules that contain at least one asymmetric center and, like image and mirror image behave the same and differ as two related finger gloves, each of which are in the same way, only different in terms of left and right, space for a thumb and four fingers. The 1:1 mixture of left and right " Gloves " is an example of a racemate. Resolution is the separation of a racemate into its enantiomers, in this example, the Order of the gloves after left and right gloves.

Properties

Discriminating whether a compound is present as a racemate or as a pure enantiomer, is important, as enantiomers, although having the same amount according to the physical, but often quite different physiological properties. So smells D-( )- carvone caraway, while L -(-) -carvone smells of mint. D-( -)- leucine taste sweet, whereas L-( )- leucine tastes bitter. Important are the properties in pharmacology, for example, the (S ) -configured β - blockers ( beta-blockers ) may be 100 times stronger than the (R ) enantiomer act. An enantiomer of thalidomide, the active ingredient of the sleeping pill thalidomide is a teratogen ( embryotoxic effect, see thalidomide scandal ). Here is a separation of the enantiomers is useless, since each of the enantiomers when taken orally in vivo in a mixture of ( S) - converts and (R) -enantiomer. One reason for the pharmacologically different effects of enantiomers of a racemic drug in organisms, is that enzymes and receptors are themselves chiral and are thus specialized for the key - lock principle to a particular enantiomer. Racemates of medicinally or nutritionally active substances, they are usually produced by a chemical synthesis, therefore, are undesirable because they are often not as specific as effective as pure enantiomers. Biotechnological processes, the use of enantiomerically pure starting materials or enantioselective syntheses usually lead directly to enantiomerically pure drugs. Alternatively, enantiomerically pure drugs are made by resolution. Older drugs are to date still often used as racemates, although now different, the pharmacological effect of the enantiomers is generally known. More recently, some of enantiomeric drugs were developed to replace as eutomer high turnover racemates (see also: enantiomerically pure drug synthesis ).

The full or pro-rata reduction of an existing enantiomeric excess is called racemization. The separation of a racemate into the individual enantiomers is done by resolution.

The melting point of the racemate is usually differs from the melting point of the pure enantiomers. Here, the melting point of the racemate may be lower or higher than that of the pure enantiomers. This unexpected at first sight phenomenon can be explained: If the racemate ( conglomerate ) crystallizes as a racemic mixture, are the crystals of ( ) - and (- )-form separately alongside one another, ie, the ( )-enantiomer has a higher affinity for ( ) molecules, and the (- ) enantiomer has a higher affinity for (-) molecules. Therefore, this results in the crystallization adjacent pure ( ) - and (-) crystals. The melting point of the racemic mixture is well below the melting point of the pure enantiomers. For example, both the pure ( ) - and ( -)-enantiomer of the drug glutethimide melt at 102-103 ° C. On the other hand has (±)- glutethimide, that the racemic mixture has a melting point of 84 ° C.

The situation is different when the ( )- enantiomers during crystallization preferentially with the - enantiomers crystallize together (). Then each crystal contains an equal number of molecules of both enantiomers. One calls this case a racemic compound. The racemic compound differs in physical properties of the pure enantiomers. The melting point is higher, the same or be lower than that of the pure enantiomers. For example, the pure enantiomers of the drug ibuprofen has a melting point of 50-52 ° C, racemic ibuprofen has a melting point of 75 to 77.5 ° C. So Racemic Ibuprofen crystallizes as a racemic compound.

History

Louis Pasteur was in 1848, at the age of 26 years, crystallize an aqueous solution of the sodium ammonium salt of racemic acid and separated from single crystals due to their asymmetric shape ( " hemihedrale surfaces "). A solution of the crystals showed a variety of optical activity into the one and the other in the opposite direction - the racemate was separated into enantiomers. They doubted Pasteur work on, and he had it under the supervision of Jean -Baptiste Biot repeat what succeeded. Pasteur was lucky: Had it been warmer in the laboratory, the experiment would be a failure. When sodium ammonium tartrate spontaneous racemate cleavage occurs (crystallization as a conglomerate ) only below 28 ° C, above would be only one type of crystals emerged - the racemic compound.

The research activities of the Dutch physical chemist Hendrik Willem Bakhuis Roozeboom (1854-1907) extended significantly to the field of thermodynamics and the study of multiphase systems. He has contributed to the understanding of the thermodynamics of enantiomer mixtures before Pasteur.

Crystallization

There are three different ways in which a racemate can crystallize. This has particular implications for resolution of racemates by crystallization. HWB has Roozeboom 1899 clearly defines how to distinguish between these types.

Racemic compound

A crystalline racemate which forms a single phase in which the two enantiomers appear well-ordered in a 1:1 ratio in the unit cell is called a racemic compound. The majority of the chiral compounds is crystallized in this manner.

Conglomerate

A conglomerate (racemic mixture ) is a crystalline racemic mixture, consisting of a 1:1 mixture of separate crystals of the pure enantiomers. The elementary cells of each crystal thus consist entirely of either the ( ) -enantiomer or the (-)- enantiomer. This crystal type is less common than the racemic compound.

Pseudoracemate

This is a crystalline racemic mixture in which the two enantiomers form the mixed crystals, the enantiomers are thus randomly distributed in the crystal lattice. Unequal amounts of the two enantiomers can co-crystallize in any ratio. Very few chiral compounds crystallize in this way.

Resolution

A resolution method for the separation of racemates into their enantiomers are referred to. The Auftrennungsprinzipien are:

Separation of enantiomers

Manual sorting of separately grown crystals. The classical method by Louis Pasteur, which is, however, practically insignificant, is the manual sorting of crystals under the microscope. A prerequisite is that the racemate forms of crystals from which only one of the enantiomers contain (spontaneous fission). Such crystals also differ macroscopically as image and mirror image.

Separation of racemates by seeding a supersaturated racemic solution with a small amount of one enantiomer of the same racemate and subsequent fractional crystallization .. requirement for this separation method: Crystallization as a conglomerate. Meanwhile, however, a process for separating connection bildener systems is explored.

Complex formation with ( enantioselective ) receptors

After separation of diastereomers

Chromatography with an enantioselective phase

Formation of diastereomeric salts by the addition of an enantiomerically pure auxiliary and subsequent separation by fractional crystallization taking advantage of their different physical properties

The usual in the organic chemistry laboratory method is to put you in touch with chiral materials. Chromatography choose to either mobile ( eluent ) or the stationary phase optically active. Which leads to the retention of two different enantiomers. Even a thin layer chromatographic separation of enantiomers using an enantioselective stationary phase is known.

Fermentative resolution

This method was first demonstrated also by Pasteur in 1858, which made the mold Penicillium glaucum with racemic tartaric acid grow as a nutrient. While one enantiomer was metabolized by the fungus, the other enantiomer was left in the solution.

Kinetic Resolution

Another method is the kinetic resolution. In this case a racemic substance is brought together with an enantiomerically pure reagent, wherein one enantiomer reacts more rapidly than the other. Is the difference in the reaction speed is high enough, an enantiomer remains unchanged back, the other enantiomer is converted into a new compound (possibly also chiral ). This Trennprizip makes you look, for example, in the enzymatic resolution with hydrolases to use. The more common type of applied kinetic resolution makes use of catalysis, wherein an enantiomerically pure catalyst is used instead of a reagent which converts an enantiomer of the starting material faster than the others.

Indirect principles: a) temporary covalent binding to excipients or b ) asymmetric synthesis within a synthetic route.

Specific rotation Jean-Baptiste Biot European Journal of Clinical Pharmacology Digital Object Identifier

668409