Racemate

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Is z. B. the left and the right molecule in a 1: 1 mixture, one speaks of a racemate.

A racemate [ rat͡seˈmaːt ] (also racemate ) or racemic (racemic) mixture is a substance mixture in stereochemistry that consists of two different chemical substances , the molecules of which are built up like an image and a mirror image (figure) and which are present in an equimolar mixture means in a ratio of 1: 1. Another prerequisite is that the image and the mirror image cannot be made to coincide. Such molecules, which are mirror images of one another, are called enantiomers and their respective chemical compounds are called chiral (Greek: manual ). They resemble or differ like two finger gloves that belong together, each of which gives room for a thumb and four fingers in the same way, only differently with regard to left and right .

The name “racemate” is derived from the Latin acidum racemicum = grape acid , the substance with which the first separation of a racemate into its two enantiomers was possible. This process is also called racemate resolution .

The physical properties of a racemic mixture can differ significantly from the properties of the associated enantiomers. For example, a racemate does not rotate the plane of polarization of polarized light and is optically inactive , so the rotation value α is 0 °.

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

properties

The distinction between whether a compound is present as a racemate or as one of the pure enantiomers is important insofar as enantiomers have the same physical properties, but often completely different physiological properties. Thus smells D - (+) - carvone by caraway , while L - (-) - carvone according mint smell. D - (-) - Leucine tastes sweet, while L - (+) - Leucine tastes bitter. The properties are important in pharmacology, where, for example, the ( S ) -configured β-blocker ( beta-receptor blocker ) can act 100 times more strongly than the ( R ) -enantiomer. One enantiomer of thalidomide , the active ingredient in the sleeping pill Contergan , is a teratogen (has a teratogenic effect, see Contergan scandal ). Separation of the enantiomers is useless here, since each individual enantiomer is converted into a mixture of ( S ) and ( R ) enantiomers when taken orally in vivo . 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 therefore specialized in a certain enantiomer according to the lock and key principle . Racemates of medicinally or nutritionally active substances, as they usually arise in a chemical synthesis , are therefore undesirable, since these are often not as specifically effective as pure enantiomers. Biotechnological processes, the use of enantiomerically pure starting substances or enantioselective syntheses usually lead directly to enantiomerically pure drugs. Alternatively, enantiomerically pure drugs are produced by resolution. Older drugs are still often used as racemates to this day, even if the different pharmacological effects of enantiomers are now generally known. Recently, some enantiomeric drugs have been developed to replace high-volume racemates as eutomers (see also: enantiomerically pure drug synthesis ).

The complete or partial degradation of an existing enantiomeric excess is called racemization . A racemate is separated into the individual enantiomers by resolution of the racemate .

The melting point of a racemate usually deviates from the melting point of the pure enantiomers. The melting point of the racemate can be lower or higher than that of the pure enantiomers. This phenomenon, unexpected at first glance, can be explained: If the racemate crystallizes as a racemic mixture (conglomerate), the crystals of the (+) - and (-) - form are present separately, i.e. the (+) - enantiomer has a higher one Affinity for (+) - molecules and the (-) - enantiomer has a higher affinity for (-) - molecules. During the crystallization, pure (+) and (-) crystals are created next to each other . The melting point of the racemic mixture is well below the melting point of the pure enantiomers. Example: Both pure (+) - and (-) - enantiomers of the drug glutethimide melt at 102–103 ° C. In contrast, (±) - glutethimide , i.e. the racemic mixture, has a melting point of 84 ° C.

The situation is different if the (+) - enantiomers during crystallization preferentially crystallize together with the (-) - enantiomers. Then each crystal contains the same number of molecules of both enantiomers. This case is called a racemic compound . The racemic compound differs in its physical properties from the pure enantiomers. The melting point can be higher, equal to or lower than that of the pure enantiomers. Example: The pure enantiomers of the drug ibuprofen have a melting point of 50-52 ° C, racemic ibuprofen has a melting point of 75-77.5 ° C. Racemic ibuprofen thus crystallizes as a racemic compound.

history

D and L tartrate crystals that behave like an image and a mirror image

In 1848, at the age of 26, Louis Pasteur had an aqueous solution of the sodium ammonium salt of grape acid crystallize out and separated individual crystals from it due to their asymmetrical shape ("hemihedral surfaces"). A solution of the crystals of one variety showed optical activity in one direction, the other in the opposite direction - the racemate was separated into enantiomers. Pasteur's work was doubted and he had to repeat it under the supervision of Jean-Baptiste Biot , which he succeeded. Pasteur was lucky: if it had been warmer in the laboratory, the experiment would have failed. In the case of sodium ammonium tartrate, spontaneous racemate splitting (crystallization as a conglomerate) only occurs below 28 ° C, above which only one type of crystal would have formed - the racemic compound.

The research work of the Dutch physical chemist Hendrik Willem Bakhuis Roozeboom (1854–1907) extended significantly to the field of thermodynamics and the study of multi-phase systems. Even before Pasteur, he contributed to the understanding of the thermodynamics of mixtures of enantiomers.

Crystallization

There are three different ways in which a racemate can crystallize. This has a particular impact on the resolution of racemates through crystallization. HWB Roozeboom clearly defined how to differentiate between these species as early as 1899.

Racemic compound

A crystalline racemate that forms a single phase in which the two enantiomers occur in a well-ordered 1: 1 ratio in the unit cell is called a racemic compound. The majority of all chiral compounds crystallize in this way.

conglomerate

A conglomerate (racemic mixture) is a crystalline racemate that consists of a 1: 1 mixture of separate crystals of the pure enantiomers. The unit cells of each individual crystal consist either exclusively of the (+) - enantiomer or of the (-) - enantiomer. This crystalline type is less common than the racemic compound.

Pseudoracemat

This is a crystalline racemate in which the two enantiomers form mixed crystals, i.e. the enantiomers are statistically distributed in the crystal lattice. Unequal amounts of both enantiomers can cocrystallize in any ratio. Very few chiral compounds crystallize in this way.

Resolution

As resolution method for separation of racemates into their enantiomers designated. The separation principles are:

Separation as enantiomers

  • manual sorting of separately grown crystals. The classic method according to Louis Pasteur , which is practically insignificant, is the manual sorting out of crystals under the microscope. A prerequisite for this is that the racemate forms crystals that contain only one of the enantiomers (spontaneous splitting). Such crystals also differ macroscopically like image and mirror image.
  • Separation of racemates by inoculating supersaturated racemate solutions with a small amount of an enantiomer of the same racemate and subsequent fractional crystallization. Prerequisite for this separation method: crystallization as a conglomerate. In the meantime, however, a process for the separation of connection-forming systems has been researched.

Separation after formation of diastereomers

  • Formation of diastereomeric salts by adding an enantiomerically pure auxiliary substance and subsequent separation by fractional crystallization using their different physical properties
  • The usual method in the organic chemical laboratory is to bring them into contact with chiral materials. Chromatographically, either the mobile (eluence) or the stationary phase is optically active. This leads to different retention of two enantiomers. A thin-layer chromatographic separation of enantiomers using an enantioselective stationary phase is also known.

Fermentative resolution

  • This process was also demonstrated for the first time by Pasteur in 1858, who let the mold Penicillium glaucum grow with racemic tartaric acid as a nutrient. While one enantiomer was being metabolized by the fungus, the other enantiomer remained in solution.

Kinetic resolution

  • Another method is the kinetic resolution. A racemic substance is combined with an enantiomerically pure reagent , with one enantiomer reacting faster than the other. If the difference in the reaction rate is large enough, one enantiomer remains unchanged; the other enantiomer is converted into a new (possibly also chiral) compound. This separation principle makes you z. B. in the enzymatic resolution with hydrolases benefit. The more frequently used type of kinetic resolution makes use of catalysis, in which, instead of a reagent, an enantiomerically pure catalyst is used that converts one enantiomer of the starting material faster than the other.

See also

Web links

Commons : Racemat  - collection of images, videos and audio files

Sources and Notes

  1. ↑ IUPAC rule E-4.5 ( PDF )
  2. ↑ For more easy-to-understand examples of left and right in nature and elsewhere, see: Henri Brunner: Rechts oder links - in der Natur und elsewhere , Wiley-VCH Verlag GmbH, Weinheim 1999 ( ISBN 3-527-29974-2 ), as well as in Brunner's “chiral gallery” .
  3. ^ Ernst Mutschler: drug effects , 5th edition, Wissenschaftlichen Verlagsgesellschaft Stuttgart, 1986, p. 277, ISBN 3-8047-0839-0 .
  4. ^ EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology , In: European Journal of Clinical Pharmacology 26 (1984) 663-668.
  5. ↑ Bernard Testa, Pierre-Alain Carrupt, Joseph Gal: The so-called "interconversion" of stereoisomeric drugs: An attempt at clarification . In: Chirality . tape 5 , no. 3 , 1993, p. 105-110 , doi : 10.1002 / chir.530050302 .
  6. ↑ Entry on resolution of racemates. In: Römpp Online . Georg Thieme Verlag, accessed on May 25, 2014.
  7. ↑ Hermann J. Roth, Christa E. Müller and Gerd Folkers: Stereochemie & Arzneimittel , Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998, ISBN 3-8047-1485-4 , pp. 161–162.
  8. ↑ HD Flack (2009) "Louis Pasteur's discovery of molecular chirality and spontaneous resolution in 1848, together with a complete review of his crystallographic and chemical work," ( Memento of the original from September 6, 2012) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 815 kB) Acta Crystallographica , Section A, Vol. 65, pp. 371-389. @1@ 2Template: Webachiv / IABot / crystal.flack.ch
  9. ^ Robert T. Morrison, Robert N. Boyd: Textbook of organic chemistry . 3rd edition, VCH, Weinheim 1986, p. 158, ISBN 3-527-26067-6 .
  10. ↑ Hans Beyer, Wolfgang Walter: Textbook of organic chemistry . 22nd edition, S. Hirzel Verlag, Stuttgart 1991, p. 347, ISBN 3-7776-0485-2 .
  11. ↑ Louis Fieser, Mary Fieser: Organische Chemie , Verlag Chemie Weinheim, 2nd edition, 1972, pp. 82-83, ISBN 3-527-25075-1 .
  12. ↑ Bernhard Testa: Fundamentals of Organic Stereochemistry , Verlag Chemie, Weinheim, 1983, pp. 162–167, ISBN 3-527-25935-X .
  13. ↑ Entry on Racemate. In: Römpp Online . Georg Thieme Verlag, accessed on May 25, 2014.
  14. ↑ Axel Kleemann and Jürgen Martens : Optical Resolution of Racemic S- (Carboxymethyl) cysteine , Liebigs Annalen der Chemie 1982, 1995-1998.
  15. ^ Kurt Günther, Jürgen Martens and Maren Schickedanz: Thin-layer chromatographic separation of enantiomers by means of ligand exchange , Angewandte Chemie 96 (1984) 514-515; Angewandte Chemie International Edition in English 23 (1984) 506.
  16. ↑ Bernd Schäfer: Natural substances of the chemical industry , Elsevier GmbH, Spektrum Verlag, 2007, page 155, ISBN 978-3-8274-1614-8 .
  17. ↑ Pasteur, ML (1858): CR Hebd. Seances Acad. Sci. Vol. 46, pp. 615-618.