Chemistry
Enantiomers
Enantiomers are pairs of molecules that are non-superimposable mirror images of each other. They have the same physical and chemical properties, but they interact differently with other chiral molecules. Enantiomers are important in pharmaceuticals, as one enantiomer may have a desired therapeutic effect while the other may be inactive or even harmful.
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12 Key excerpts on "Enantiomers"
eBook - PDFDrug Stereochemistry
Analytical Methods and Pharmacology, Third Edition
- Krzysztof Jozwiak, W. J. Lough, Irving W. Wainer, Krzysztof Jozwiak, W. J. Lough, Irving W. Wainer(Authors)
- 2012(Publication Date)
- CRC Press(Publisher)
Such modern aspects of stereochemistry are the focal point of this volume. TYPES OF STEREOISOMERS When molecules composed of the same constituents have the same structural formulae but differ only with respect to the spatial arrangement of certain atoms or groups of atoms, they are defined as stereoisomers. Chiral stereoisomers are those that are optically active. A group of chiral stereoisomers constitutes at least one pair of Enantiomers: nonsuperimposable molecules, which relates to each other as their mirror images. Stereoisomers that are not related to each other as Enantiomers are diastereomers or diastereoisomers. In some cases, a diaster-eoisomer may acquire an element of symmetry forbidden for a chiral molecule and, thus, lose its optical activity. Enantiomers The largest class of chiral molecules is compounds in which the asymmetric center (called a center of chirality) is a tetravalent carbon atom, as in Figure 2.2. The tetrahedral orientation of the bonds to a tetravalent carbon is such that when four nonidentical ligands are present, the mirror image of the molecule is nonsuperimposable, the molecule is enantiomeric and chiral. When two of the moieties are identical, the mirror image is superimposable, and the molecule is achiral. Several examples of chiral drug molecules are presented in Figure 2.4. 20 DRUG STEREOCHEMISTRY: ANALYTICAL METHODS AND PHARMACOLOGY Chirality is not necessarily associated with tetrahedral hybridization of valencies. Interesting example is the metal-complex compound tris(2,2’-bipyr-idine)ruthenium(II) (Fig. 2.4). In this case the octahedral Ru 2 þ cation is a center of chirality. It coordinates three planar and achiral bipyridine molecules and the spatial arrangement of these planes predicates dissymmetry of the complex. The structure resembles a three-winged propeller with two possible rotations: clock-wise (the D enantiomer) or counterclockwise (the L enantiomer).
eBook - ePubStereochemistry and Stereoselective Synthesis
An Introduction
- Mihály Nógrádi, László Poppe, József Nagy, Gábor Hornyánszky, Zoltán Boros(Authors)
- 2016(Publication Date)
- Wiley-VCH(Publisher)
14Enantiomer: one among those nonsuperposable stereoisomers that are related as mirror images (Enantiomers thus form pairs of mirror images). Enantiomers must be chiral. Scalar physical properties of Enantiomers are identical; they only differ in vectorial physical properties, such as optical rotation. Their chemical behavior toward achiral agents is identical, while it may differ toward chiral agents [2–4].[This definition is in accord with IUPAC recommendation [2–4] on stereochemistry stating that Enantiomers are pairs of molecular entities, which are not superposable and are related as mirror images.]15Possible forms of isomerism.Figure 2.6Conformation/configuration and isomeric relationships are illustrated by the isomers of cyclohexane (C6 H12 ) (Figure 2.7 ). It follows from the definitions and examples in Figure 2.7 that it depends on the type of isomerism under which conditions components of a mixture of isomers can be separated. Constitutional isomers and diastereomers are differing in most of their chemical and physical properties, while Enantiomers can only be differentiated by direction-dependent (vectorial) properties and exhibit different chemical reactivities only toward chiral partners. Examples in Figure 2.7 well illustrate the necessity of giving exact definitions and justify taking into consideration the criterion of isolability.Conformation, configuration, and various types of isomerism. The molecules shown all have the same molecular formula (C6 H12 ). Molecules placed into a common box are either identical (≡) or exist as a set of conformations capable to interconversion ( ). (c.i.: constitutional isomers; D: diastereomers; and E: Enantiomers).Figure 2.7By the example of cyclohexane shown in Figure 2.7 , it can be seen that its different conformational states cannot be isolated and are not separable molecular entities. Here, the imprecision of the IUPAC definition of conformation becomes apparent since the three states differ not only by rotation around single bonds. In the chair and the half-chair conformations, C–C–C bond angles are also different. The two states of methylcyclopentane shown are related as mirror images, but these are superposable and therefore achiral
eBook - PDF- Allan Blackman, Steven E. Bottle, Siegbert Schmid, Mauro Mocerino, Uta Wille(Authors)
- 2022(Publication Date)
- Wiley(Publisher)
trans-1,2-dimethylcyclopentane H 3 C CH 3 H 3 C CH 3 cis-1,2-dimethylcyclopentane 878 Chemistry FIGURE 17.10 Relationships among isomers. (Note: This description excludes conformers, which can interconvert without breaking bonds.) Isomers different compounds with the same molecular formula. Bonds would have to be broken and reformed to convert from one to another. Constitutional isomers isomers with a different order of attachment of their atoms Stereoisomers isomers with the same order of attachment of atoms, but a different orientation of their atoms in space Enantiomers stereoisomers that are nonsuperimposable mirror images of each other Diastereomers stereoisomers that are not mirror images 17.2 Enantiomerism LEARNING OBJECTIVE 17.2 Recognise Enantiomers as non-equivalent mirror images. As we have learned above, Enantiomers are stereoisomers that are nonsuperimposable mirror images of each other. Except for inorganic compounds and a few simple organic compounds, the vast majority of molecules in the biological world show enantiomerism, including carbohydrates, lipids, amino acids and proteins, and nucleic acids. Further, approximately half of all pharmaceuticals show enantiomerism. To understand the significance of enantiomerism, recall that Enantiomers have some different properties. While they have the same boiling points, melting points and solubilities, each of a pair of Enantiomers reacts differently towards other chiral molecules. This is especially important in biology. For example, one form of thalidomide acts in the body to produce a sedative/hypnotic effect that controls the symptoms of morning sickness, whereas the other form acts to produce birth defects or to destroy some types of rapidly growing cancer cells. As the structure of thalidomide is relatively complicated, we will start by looking at a simpler example.
eBook - PDF- Harry G. Brittain(Author)
- 2018(Publication Date)
- CRC Press(Publisher)
When the mirror images of a compound are not superimposable, these mirror images are denoted as Enantiomers. Numerous techniques exist that permit the physical separation of Enantiomers in a mixture (8), and such methodologies have become important in the large-scale preparation of separated Enantiomers for pharmaceutical purposes. Individual enantiomeric molecules are completely equivalent in their molecular properties, with the exception of their interaction with circularly polarized light. An equimolar mixture of two Enantiomers is termed a racemic mixture. The generally accepted configurational nomenclature for tetrahedral carbon Enantiomers was devised by Cahn, Ingold, and Prelog, and is based on sequencing rules (9). Enantiomers are identified as being either R or S , depending on the direction (clockwise or counterclockwise) of substituents after they have been arranged according to increasing atomic mass. Compounds con-taining more than one center of dissymmetry are identified as diastereomers, and in compounds containing n dissymmetric centers the number of diastereomers will equal 2 n . Although not quite fitting the formal definition of polymorphic solids, the relationship between racemic mixtures and resolved Enantiomers presents an intriguing parallel. By virtue of symmetry constraints, a resolved enantiomer must crystallize in a non-centrosymmetric space group. Racemic mixtures are under no 15 Structural Aspects of Molecular Dissymmetry 561 analogous constraint, but over 90% of all racemic mixtures (which are merely equimolar mixtures of the Enantiomers) are found to crystallize in a centrosymmetric space group (10). This consequence of molecular dissymmetry results in the situa-tion where differing crystal structures can be obtained for the same chemical com-pound, depending only on the degree of resolution.
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
The signifi- cance of enantiomerism is that, except for inorganic and a few simple organic com- pounds, the vast majority of molecules in the biological world show this type of isomerism, including carbohydrates (Chapter 17), lipids (Chapter 19), amino acids and proteins (Chapter 18), and nucleic acids (DNA and RNA, Chapter 20). Further, approximately one‐half of the medications used in human medicine also show this type of isomerism. Enantiomers Stereoisomers that are nonsuperposable mirror images; the term refers to a relationship between pairs of objects. 6.1 6.2 6 . 2 What Are Enantiomers? 161 162 C H A P T E R 6 Chirality: The Handedness of Molecules As an example of a molecule that exhibits enantiomerism, let us consider 2‐butanol. As we go through the discussion of this molecule, we focus on carbon 2, the carbon bearing the OH group. What makes this carbon of interest is that it has four different groups bonded to it. The most common cause of enantiomerism among organic molecules is a carbon bonded to four different groups. OH CH 3 CHCH 2 CH 3 2-Butanol the four different “groups” bonded to this carbon are H, OH, CH 3 , and CH 2 CH 3 The structural formula we have just drawn does not show the shape of 2‐butanol or the orientation of its atoms in space. To do this, we must consider the molecule as a three‐ dimensional object. On the left are a ball‐and‐stick model of 2‐butanol and a perspective drawing of what we will call the “original” molecule. See Table 1.7 to review the meaning of the dashes and wedges in perspective drawings. Original OH C CH 2 CH 3 H CH 3 Mirror image C CH 3 CH 2 H CH 3 HO To the right in the preceding diagram is the mirror image of the original molecule. Every molecule and, in fact, every object in the world around us, has a mirror image.
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2016(Publication Date)
- Wiley(Publisher)
6.1 Stereoisomers Isomers that have the same molecular formula and the same connectivity, but different orientations of their atoms in space. cis -2-Butene or Z -2-Butene trans -2-Butene or E -2-Butene CH 3 H C C CH 3 H and H C C H CH 3 CH 3 William H. Brown The horns of this African gazelle show chirality and are mirror images of each other. Isomers Different compounds with the same molecular formula Constitutional Isomers Isomers with a different connectivity of their atoms Stereoisomers Isomers with the same connectivity of their atoms, but a different orientation of their atoms in space Enantiomers Stereoisomers whose molecules are nonsuperposable mirror images Diastereomers Stereoisomers whose molecules are not mirror images OH O OH OH CH 3 CH 3 CH 3 CH 3 FIGURE 6.1 Relationships among isomers and some examples. 6.2 What Are Enantiomers? Enantiomers are stereoisomers that are nonsuperposable mirror images. The signifi- cance of enantiomerism is that, except for inorganic and a few simple organic com- pounds, the vast majority of molecules in the biological world show this type of isomerism, including carbohydrates (Chapter 17), lipids (Chapter 19), amino acids and proteins (Chapter 18), and nucleic acids (DNA and RNA, Chapter 20). Further, approximately one‐half of the medications used in human medicine also show this type of isomerism. 6.2 Enantiomers Stereoisomers that are nonsuperposable mirror images; the term refers to a relationship between pairs of objects. 162 C H A P T E R 6 Chirality: The Handedness of Molecules As an example of a molecule that exhibits enantiomerism, let us consider 2‐butanol. As we go through the discussion of this molecule, we focus on carbon 2, the carbon bearing the OH group. What makes this carbon of interest is that it has four different groups bonded to it. The most common cause of enantiomerism among organic molecules is a carbon bonded to four different groups.
eBook - PDF- David R. Klein(Author)
- 2020(Publication Date)
- Wiley(Publisher)
For this reason, Chiral Drugs Thousands of drugs are marketed throughout the world. The origins of these drugs fall into three categories: 1. natural products—compounds isolated from natural sources, such as plants or bacteria, 2. natural products that have been chemically modified in the labora - tory, or 3. synthetic compounds (made entirely in the laboratory). Most drugs obtained from natural sources consist of a single enantiomer. It is important to realize that a pair of enan- tiomers will rarely exhibit the same potency. We have seen in previous chapters that drug action is usually the result of drug- receptor binding. If the drug binds to the receptor in at least three places (called three-point binding), then one enantiomer of the drug may be more capable of binding with the receptor: C R H H + NH 3 CO 2 – H H H + NH 3 CO 2 – C R The first compound (left) can bind with the receptor, while its enantiomer (right) cannot bind with the receptor. For this reason, 5.4 Optical Activity 195 5.4 OPTICAL ACTIVITY Enantiomers exhibit identical physical properties. For example, compare the melting and boiling points for the Enantiomers of carvone: O (R)-Carvone Melting point = 25°C Boiling point = 231°C O (S)-Carvone Melting point = 25°C Boiling point = 231°C This should make sense, because physical properties are determined by intermolecular interactions, and the intermolecular interactions of one enantiomer are just the mirror image of the intermolecular interactions of the other enantiomer. Nevertheless, Enantiomers do exhibit different behavior when exposed to plane-polarized light. To explore this difference, let’s first quickly review the nature of light. Enantiomers will rarely produce the same biological response. As an example, consider the Enantiomers of ibuprofen: OH O (S)-Ibuprofen OH O (R)-Ibuprofen Ibuprofen is an analgesic (painkiller) with anti-inflammatory properties. The S enantiomer is the active agent, while the R enantiomer is inactive.
- Frederick Bettelheim, William Brown, Mary Campbell, Shawn Farrell(Authors)
- 2019(Publication Date)
- Cengage Learning EMEA(Publisher)
416 | Chapter 14 Chirality: The Handedness of Molecules Copyright 2020 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. If an object and its mirror image are superposable, then they are identi-cal and enantiomerism is not possible. We say that such an object is achiral (without chirality); that is, it has no handedness. Examples of achiral ob-jects include an undecorated cup, an unmarked baseball bat, a regular te-trahedron, a cube, and a sphere. To repeat, the most common cause of chirality in organic molecules is a tetrahedral carbon atom with four different groups bonded to it. We call such a chiral carbon atom a stereocenter . 2-Butanol has one stereocenter; 2-propanol has none. As another example of a molecule with a stereocenter, let us consider 2-hydroxypropanoic acid, more commonly named lactic acid. Lactic acid is a product of anaerobic glycolysis. (See Section 27.2 and Chem-ical Connections 27A.) It is also what gives sour cream its sour taste. Figure 14.4 shows three-dimensional representations of lactic acid and its mirror image. In these representations, all bond angles about the cen-tral carbon atom are approximately 109.5° and the four bonds from it are directed toward the corners of a regular tetrahedron. Lactic acid displays enantiomerism or chirality; that is, the original molecule and its mirror image are not superposable but rather are different compounds.
eBook - ePub- C. Brown(Author)
- 2013(Publication Date)
- Academic Press(Publisher)
et al., 1988). Because of potential pharmacological, pharmacokinetic and toxicological issues, some scientists suggest that only single isomers should be considered for drug development and regulatory approval. In support of racemic drug development, proponents cite examples of racemic compounds that have been administered for years without untoward effects, and the technical difficulties associated with large-scale production of single isomers.Fig. 1 Structure of quinidine and quinine.In the past few decades pharmacological and toxicological investigations have clearly demonstrated significant differences in the biological activity of some isomeric pairs. Recently, pharmacokinetic investigations into the disposition of Enantiomers have enhanced our understanding of racemic drug action and have helped us to understand previously inexplicable pharmacodynamic outcomes following administration of racemates to patients.2 Terminology
A myriad of terms in stereochemistry are used to define molecules and to describe the relationship between molecules and receptors in the body (Wainer and Marcotte, 1988 ;Caldwell et al. , 1988). This section is not meant to be an exhaustive review of the field, but to cover the major terms and concepts to be used.Isomers are unique molecular entities composed of the same chemical constituents with common structural characteristics. Stereoisomers are those isomers whose atoms, or groups of atoms, differ with regard to spatial arrangement of the ligands. Stereoisomers can be either geometric or optical isomers. Geometric isomers are stereoisomers without optically active centres; for these compounds terminology such as cis or Z isomer (meaning together or same side), and trans or E isomer (meaning opposite side) are used to describe the spatial arrangement.Optical isomers are a subset of stereoisomers, from which at least two isomers are optically active; these compounds are said to possess chiral or asymmetrical centres. The most common chiral centre is carbon, but phosphorus, sulphur and nitrogen can also form chiral centres. If the isomer and its mirror image are not superimposable, the pair are referred to as Enantiomers or optical antipodes . A mixture of equal portions (50/50) of each enantiomer is called a racemate. Optical isomers that are not Enantiomers are called diastereoisomers or diastereomers
eBook - PDF- T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
In this instance both structures are (R )-1-bromo-1-chloroethane. Another method for assigning (R ) and (S ) configurations using one’s hands as chiral templates has been described (Huheey, J. E., J. Chem. Educ. 1986, 63, 598–600). Groups at a chirality center are correlated from lowest to highest priority with one’s wrist, thumb, index finger, and second finger, respectively. With the ring and little finger closed against the palm and viewing one’s hand with the wrist away, if the correlation between the chirality center is with the left hand, the configuration is (S ), and if with the right hand, (R ). ANSWER: A and B are two molecules of the same compound oriented differently. 5.8 PROPERTIES OF Enantiomers: OPTICAL ACTIVITY 209 (−)-tartaric acid. An equal mixture of tartaric acid Enantiomers, (+/−)-tartaric acid, has a melting point of 210–212 °C, however. • Enantiomers show different behavior only when they interact with other chiral substances, including their own enantiomer. This is evident in the melting point data above. Enantiomers also show different rates of reaction toward other chiral molecules—that is, toward reagents that consist of a single enantiomer or an excess of a single enantiomer. And, Enantiomers show different solubili- ties in solvents that consist of a single enantiomer or an excess of a single enantiomer. One easily observable way in which Enantiomers differ is in their behavior toward plane-polarized light. • When a beam of plane-polarized light passes through an enantiomer, the plane of polarization rotates. • Separate Enantiomers rotate the plane of plane-polarized light equal amounts but in opposite directions. • Separate Enantiomers are said to be optically active compounds because of their effect on plane-polarized light. In order to understand this behavior of Enantiomers, we need to understand the nature of plane-polarized light. We also need to understand how an instrument called a polarimeter operates.
eBook - PDFOrganic Chemistry
A Mechanistic Approach
- Penny Chaloner(Author)
- 2014(Publication Date)
- CRC Press(Publisher)
Diastereoisomers are different compounds, with different chemical and physical proper- ties. Enantiomers have the same physical properties other than their ability to rotate the plane of plane-polarized light and the same chemical reactivity unless they are reacting with a chiral reagent. 7.53 ent-7.53 7.54 ent-7.54 Cl Me H Ph Me Et (S) (R) Cl H Me Ph Me Et (S) (S) Cl Me H Ph Me Et (S) (R) Cl H Me Ph Me Et (R) (R) The difference in physical properties of diastereoisomers suggests a route that we might use to separate Enantiomers (a process described as resolution)—we will convert them, by some revers- ible process, into separable diastereoisomers. If we consider the reduction of 7.55 using sodium borohydride (we’ll meet this reaction in Chapter 14), the ketone is planar and can be approached from either face by Na[BH 4 ]. These approaches are equally likely, so the product obtained will be racemic. If this alcohol is then reacted with a chiral carboxylic acid (Equation 7.3), then two dis- tinct esters will be formed, with R, R- and R, S-stereochemistries. The two esters are diastereoiso- mers, which may be separated by physical techniques. Once the esters have been separated, then they can be hydrolyzed to obtain the separated alcohols and recover the chiral acid: H 3 C COOEt O (1) Na[BH 4 ] (2) H 2 O H 3 C (R) COOEt H OH 7.55 Racemic product H 3 C (S) COOEt H OH + 50 % 50 % (7.3) R S R R S R , -alcohol -acid , -ester , -ester + → + R Chapter 7 – Stereochemistry 245 Separations may also be accomplished using chiral biological reagents, such as enzymes. Most enzymes, since they are composed of chiral amino acids, will accept only one enantiomer of a molecule as their substrate. Thus, the enzyme hog kidney acylase hydrolyzes only the natural enantiomer of amides. We will develop this idea further in Chapter 15, when we consider the reactions of carboxylic acid derivatives in more detail.
eBook - PDF- Scott E. Denmark(Author)
- 2009(Publication Date)
- Wiley-Interscience(Publisher)
In short, any discussion of molecular chirality requires the approximation inherent in the classical model, that is, the Born-Oppenheimer approximation. In this model it is assumed that the atomic nuclei in the molecule behave like classical particles whose spatial positions are fixed, and that it is only the electrons that are smeared out as matter waves. This assumption of a molecular structure, which has A A A A 14 MOLECULAR CHIRALITY its origin in traditional chemistry, allows us to account for the existence of Enantiomers and to rationalize chirality observables. 2. Motion-Dependent Chirality Time reversal, mentioned above in connection with CPT-Enantiomers, is also at the heart of a distinction between time-dependent and time-independent enantiomorphism. In a series of p ~ b l i c a t i o n s , ~ ~ - ~ ~ Laurence Barron has provided the basis for his argument that “The only compelling reason for generalizing Kelvin’s definition is to encompass absolute asymmetric synthesis and the concept of chirality in elementary particle physics by including motion-dependent ~hirality.”~~ According to B a r r ~ n ~ ~ : A A A The essential characteristic of a chiral object is that it is found in two distinct enantiomeric states that cannot be interconverted by time reversal combined with any proper spatial rotation. Barron subsequently reformulated this definition as follows34: True chirality is exhibitedpossessed by systems that exist in two distinct enantiomeric states that are interconverted by space inversion, but not by time reversal combined with any proper spatial rotation.
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