Chemistry
Racemic mixture
A racemic mixture is a combination of equal amounts of two enantiomers, which are mirror-image molecules that cannot be superimposed onto each other. These enantiomers have the same physical and chemical properties but differ in their interaction with polarized light. Racemic mixtures are optically inactive due to the cancellation of the optical activity of the individual enantiomers.
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7 Key excerpts on "Racemic mixture"
- Morris Hein, Scott Pattison, Susan Arena, Leo R. Best(Authors)
- 2014(Publication Date)
- Wiley(Publisher)
26.5 Racemic mixtureS Explain the biological and pharmacological significance of Racemic mixtures. A mixture containing equal amounts of a pair of enantiomers is known as a Racemic mixture. Such a mixture is optically inactive and shows no rotation of polarized light when tested in a polarimeter. Each enantiomer rotates the plane of polarized light by the same amount but in opposite directions. Thus, the rotation by each isomer is canceled. The ( { ) symbol is often used to designate Racemic mixtures. For example, a Racemic mixture of lactic acid is written as ( { )-lactic acid because this mixture contains equal molar amounts of ( + )-lactic acid and ( - )-lactic acid. Racemic mixtures are usually obtained in laboratory syntheses of compounds in which a chiral carbon atom is formed. Thus, catalytic reduction of pyruvic acid (an achiral compound) to lactic acid produces a Racemic mixture containing equal amounts of ( + )- and ( - )-lactic acid: � H 2 O pyruvic acid CH 3 CCOOH CH 3 CHCOOH Ni OH (�)-lactic acid As a general rule, in the biological synthesis of optically active compounds, only one of the isomers is produced. For example, ( + )-lactic acid is produced by reactions occurring in muscle tissue, and ( - )-lactic acid is produced by lactic acid bacteria in the souring of milk. These stereospecific reactions occur because biochemical syntheses are enzyme catalyzed. The preferential production of one isomer over another is often due to the configuration (shape) of the specific enzyme involved. Returning to the hand analogy, if the “right-handed” enan- tiomer is produced, then the enzyme responsible for the product can be likened to a right- handed glove. The mirror-image isomers (enantiomers) of a Racemic mixture are alike in all ordinary physical properties, except in their action on polarized light. It is possible to separate or resolve Racemic mixtures into their optically active components.
eBook - ePub- C. Brown(Author)
- 2013(Publication Date)
- Academic Press(Publisher)
2Racemic Therapeutics—Problems all Along the Line
E.J. ARIENS, Groenewoudseweg 45, 6524 TP Nijmegen, The NetherlandsPublisher Summary
Racemic therapeutics is fixed ratio mixtures of stereoisomers, biologically to be regarded as different compounds. Usually only one of the isomers fully contributes to the therapeutic action whereas the other often is classified as a medicinal pollutant. Because of the differences in the turnover, in pharmacokinetics the proportion of the enantiomers continuously changes in plasma. The implications of the neglect of stereoselectivity at the various levels in the investigation of racemic drugs are discussed. For new chiral drugs the choice between using the racemate or the single compound is based on a critical evaluation of the chiral characteristics both therapeutically and toxicologically. This chapter states that whether violation of fundamental rights of patients as formulated in the Helsinki conventions largely depends on the ethical attitude of clinical investigators and their pharmaceutical and industrial informants.1 Introduction
The concept of stereochemistry and stereoselectivity in biological processes goes back to Pasteur and van’t Hoff–Le Bel about 100 years ago. In their memoirs (Pasteur, 1901 ) Pasteur stated:Most natural organic products, the essential products of life are asymmetric and possess such asymmetry that they are not superposable on their images … This establishes perhaps the only well marked line of dermarcation that can at present be drawn between the chemistry of dead matter and the chemistry of living matter.Chirality, stereoselectivity and stereospecific production of chemicals are characteristics of nature. Many of the xenobiotics obtained by organic synthesis are also chiral. Contrary to natural products, synthetic chiral compounds are usually obtained as isomeric mixtures such as racemates. This situation rapidly changed with the development of stereospecific catalytic methods and the application of biotechnological methods which rely on the help of enzymes as catalysts. Stereospecific syntheses and/or separation of stereoisomers were, and to a certain extent still are, laborious tasks. As a consequence, most of the synthetic chiral agents applied as drugs are marketed as Racemic mixtures or, in general, as mixtures of isomers, which illustrates that the line of demarcation between the chemistry of dead and living matter postulated by Pasteur still holds largely true for producers of drugs and pesticides (Fig. 1 ) (Ariens, 1990
eBook - PDF- T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
If the (R ) and (S ) enantiomers were present in equal amounts, there would be no net rotation of the plane of polarized light. • An equimolar mixture of two enantiomers is called a Racemic mixture (or racemate or racemic form). A Racemic mixture causes no net rotation of plane-polarized light. PRACTICE PROBLEM 5.14 Albuterol, shown here, is a commonly prescribed asthma medication. For either enantiomer of albuterol, draw a three-dimensional formula using dashes and wedges for bonds that are not in the plane of the paper. Choose a perspective that allows as many carbon atoms as possible to be in the plane of the paper, and show all unshared electron pairs and hydrogen atoms (except those on the methyl groups labeled Me). Specify the (R,S) configuration of the enantiomer you drew. Me Me Me N H OH HO HO Albuterol 214 CHAPTER 5 STEREOCHEMISTRY: Chiral Molecules On the other hand, a sample of (S )-(+)-2-butanol that contains less than an equimolar amount of (R)-(−)-2-butanol will show a specific rotation that is less than +13.52 but greater than zero. Such a sample is said to have an enantiomeric excess less than 100%. The enantiomeric excess (ee), also known as the optical purity, is defined as follows: % Enantiomeric excess = moles of one enantiomer − moles of other enantiomer total moles of both enantiomers × 100 The enantiomeric excess can be calculated from optical rotations: % Enantiomeric excess = observed specific rotation specific rotation of the pure enantiomer × 100 Let us suppose, for example, that a mixture of the 2-butanol enantiomers showed a specific rotation of +6.76. We would then say that the enantiomeric excess of the (S )-(+)-2-butanol is 50%: Enantiomeric excess = +6.76 +13.52 × 100 = 50% When we say that the enantiomeric excess of this mixture is 50%, we mean that 50% of the mixture consists of the (+) enantiomer (the excess) and the other 50% consists of the racemic form.
- H. John Smith, Hywel Williams(Authors)
- 2005(Publication Date)
- CRC Press(Publisher)
4.DRUG CHIRALITY AND ITS PHARMACOLOGICAL CONSEQUENCES
ANDREW J.HUTT4.1 INTRODUCTION
One in four of all therapeutic agents are marketed and administered to man as mixtures. These agents are not drug combinations in the accepted meaning of the term, i.e. two or more coformulated therapeutic agents, but combinations of isomeric substances the biological activity of which may well reside predominantly in one isomer. The majority of these mixed formulations arise due to the use of Racemic mixtures of synthetic chiral drugs and less frequently to mixtures of diastereoisomers. Over the last ten years there has been considerable interest in the area of drug chirality as a result of recent advances in the stereoselective synthesis and stereospecific analysis of chiral molecules. As a result of these advances and the realization of the significance of the pharmacodynamic and pharmacokinetic differences between the enantiomers of chiral drugs there has been increasing concern over the use of racemates, and other stereoisomeric mixtures, in therapeutics. The use of such mixtures may present problems particularly if the adverse effects, or toxicity of the drug is associated with the less active, or inactive isomer, or does not show stereoselectivity. Many authors regard racemates as “compounds which contain 50% impurity” and that their use is “polypharmacy” with the proportions of the materials being dictated by chemical rather than pharmacological or therapeutic criteria. As a result of these concerns drug stereochemistry has become an important consideration for both the pharmaceutical industry and the major drug regulatory authorities.The extent of the problem can be appreciated from the results of a survey of 1675 drugs carried out in the early 1980s. Of these agents 1200 (72%) were classified as synthetic and 475 (28%) as natural products or semisynthetic agents. Of the compounds classified as natural products or semisynthetics 469 were chiral and of these 461 (98%) were marketed as single isomers. In contrast 29% (480) of the synthetic compounds were chiral with only 3.5% (58) being available as single isomers the remainder (25%) being marketed as racemates. More recent investigations have indicated that the position regarding natural and semisynthetic agents has not changed greatly but that the proportion of synthetic agents available as single isomers had increased. From the above figures it is obvious that drug chirality is an “across-the-board” problem, mixtures of stereoisomers being found in the majority of therapeutic groups.
eBook - PDF- Indra K. Reddy, Reza Mehvar, Indra K. Reddy, Reza Mehvar(Authors)
- 2004(Publication Date)
- CRC Press(Publisher)
9 Bioequivalency Determination of Racemic Drug Formulations: Is Stereospecific Assay Essential? Aziz Karim Takeda Pharmaceuticals North America, Inc., Lincolnshire, Illinois, U.S.A. Cherukury Madhu Pfizer, Inc., Ann Arbor, Michigan, U.S.A. Chyung Cook Baxter Healthcare, Round Lake, Illinois, U.S.A. 1. INTRODUCTION Chemical synthesis results in the formation of an optically inactive racemate containing an equal amount of two stereoisomers with identical physico-chemical properties but differing in their property to rotate the plane of polarized light: one enantiomer will rotate the plane in the right direction, (dextrorotatory, d or +) while its antipode will rotate in the opposite direction with the same magnitude (levorotatory, l or −). This optical characteristic, however, does not reflect the three-dimensional configuration of the molecule. A preferred nomenclature system incorporating the three-dimensional configuration of the chiral molecule is based on assigning a priority to atoms attached to the racemic carbon according to the Cahn-Ingold-Prelog rules [1]. Prefixes R- (rectus) and S- (sinister) are assigned to the enantiomers on the basis of their absolute configuration. No relationships exist between the d and l versus R and S nomenclatures. For example, the active S-enantiomer of ibuprofen is dextrorotatory (d or +) while that of verapamil, also an S-enantiomer, is levorotatory (l or –). The more active enantiomer is termed the “eutomer,” and the less active the “distomer.” The distomer is often incorrectly viewed as a passive component of the racemate with little pharmacological or pharmacokinetic (PK) significance. However, in some cases, the distomer may act as an agonist or antagonist at the receptor site or compete for drug metabolizing enzymes and binding sites. In other cases, the two stereoisomers may have different pharmacological effects, and administration of a racemate would represent a combination drug product (e.g., indacrine [2]).
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
Specific rotation Observed rotation of the plane of polarized light when a sample is placed in a tube 1.0 dm long at a concentration of 1.0 g/mL. Racemic mixture A mixture of equal amounts of two enantiomers. Optically inactive Showing that a compound or mixture of compounds does not rotate the plane of polarized light. Filled sample tube Plane of polarized light Polarizing filter 180° 0° Light source 180° 0° α Analyzing filter needs to be rotated until darkness is again achieved FIGURE 6.6 Schematic diagram of a polarimeter with its sample tube containing a solution of an optically active compound. The analyzing filter has been turned clockwise by α degrees to restore the dark field. 6.9 176 C H A P T E R 6 Chirality: The Handedness of Molecules 6 . 10 How Can Enantiomers Be Resolved? 177 Because interactions between molecules in living systems take place in a chiral environment, it should come as no surprise that a molecule and its enantiomer or one of its diastereomers elicit different physiological responses. As we have already seen, (S)‐ibuprofen is active as a pain and fever reliever, whereas its R enantiomer is inactive. The S enantiomer of the closely related analge- sic naproxen is also the active pain reliever of this compound, but its R enantiomer is a liver toxin! HOOC CH 3 H HOOC OCH 3 CH 3 H (S )-Ibuprofen (S )-Naproxen 6.10 How Can Enantiomers Be Resolved? Resolution is the separation of a Racemic mixture into its enantiomers. Because two enan- tiomers have the same physical properties, separating them, in general, is difficult, but sci- entists have developed a number of ways to do it. In this section, we illustrate the use of enzymes as chiral catalysts for separating one enantiomer from another. Resolution Separation of a Racemic mixture into its enantiomers. nature. Of course, instances do occur in which more than one stereoisomer is found, but these rarely exist together in the same biological system.
eBook - PDF- Rose Marie O. Mendoza(Author)
- 2020(Publication Date)
- Arcler Press(Publisher)
In the end, the chapter explain in detail the concept of racemization. 6.1. INTRODUCTION The creation of non-racemic samples of chiral organic compounds either from racemic precursors or from achiral by adopting any viable means is known as optical activation. It is usually seen that optical activation is not considered as satisfactory expression by many. It clearly positions as the formation of a physical property (which is called optical activity), while on the other hand, the portrayal of the process ought appropriately to highlight the enantiomerically enhanced composition of the preferred product quite apart by using rotation as a probe. Moreover, this term has lot of shortcomings primarily because of the fact that large number of samples of enantiomerically enhanced with chiral substances may carry meagre or even in some cases zero rotation. Unfortunately, it results in nonexistence of any alternative expression. If the isolation of chiral substances from either animal sources or plant sources and their alterations is debarred, there are majorly two key sets of optical activation methods: stereoselective syntheses and resolutions. There are various methods that may involve in resolution methods (a) physical processes only or (b) chemical reactions. In resolutions that are governed by the chemical reactions, it is generally seen that there is % Separation of Stereoisomers, Resolution, and Racemization 157 intervention of either diastereomeric products or diastereomeric transition states. While using such types of methods, one can be benefitted from the operations of either kinetic control or thermodynamic. It is widely assumed that whatever be the nature of the chemical alteration that occurs in context with a resolution, the reaction is either rescindable or, in some other case, the process eventually triggered back to the initial material parted into its enantiomer components.
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