7.6 The Cahn-ingold-Prelog R-S Notational System TABLE 7.1 Absolute Configuration According to the Cahn-Ingold-Prelog Notational System Step number Example CHaCH Given that the absolute configuration of (+)-2-butanol is H3C 1. Identify the substituents at the stereogenic center, In order of decreasing precedence, the four substitu and rank them in order of decreasing precedence ents attached to the stereogenic center of 2-butanol according to the system described in Section 5.4 Precedence is determined by atomic number, work- outward from the point of attachment at th stereogenIc center. 2. Orient the molecule so that the lowest ranked sub- As represented in the wedge-and-dash drawing at stituent points away from you the top of this table the molecule is already appro- stituent attached to the stereogenic center and 46. priately oriented. Hydrogen is the lowest ranked points away from us. 3. Draw the three highest ranked substituents as they CHaC the lowest ranked group points away from you. that ppear to you when the molecule is oriented so 4. If the order of decreasing precedence of the three The order of decreasing precedence is anticlockwise highest ranked substituents appears in a clockwise The configuration at the stereogenic center is s ense, the absolute configuration is R(Latin rectus, right, ""correct"). If the order of decreasing prece- CH3 k OH(highest dence is anticlockwise, the absolute configuration is S Latin sinister, "left") Often, the R or S configuration and the sign of rotation are incorporated into the name of the compound, as in(R)-(-)-2-butanol and (S)-(+)-2-butanol PROBLEM 7.7 Assign absolute configurations as r or S to each of the following (a) H3C -CH2OH CHC CH3CH2 (+)-2-Methyl-1-butanol (+)-1-Bromo-2-methylbutane H3 (d) H3c CHF CHaCI (+)-1-Fluoro-2-methylbutane (+)-3-Buten-2-oI Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Often, the R or S configuration and the sign of rotation are incorporated into the name of the compound, as in (R)-()-2-butanol and (S)-()-2-butanol. PROBLEM 7.7 Assign absolute configurations as R or S to each of the following compounds: (a) (c) (b) (d) ()-3-Buten-2-ol C H HO H3C CH CH2 ()-1-Fluoro-2-methylbutane C H CH3CH2 H3C CH2F ()-1-Bromo-2-methylbutane C CH3 CH3CH2 H CH2Br ()-2-Methyl-1-butanol C H CH3CH2 H3C CH2OH 7.6 The Cahn–Ingold–Prelog R–S Notational System 269 TABLE 7.1 Absolute Configuration According to the Cahn–Ingold–Prelog Notational System Step number 1. Identify the substituents at the stereogenic center, and rank them in order of decreasing precedence according to the system described in Section 5.4. Precedence is determined by atomic number, working outward from the point of attachment at the stereogenic center. 2. Orient the molecule so that the lowest ranked substituent points away from you. 4. If the order of decreasing precedence of the three highest ranked substituents appears in a clockwise sense, the absolute configuration is R (Latin rectus, “right,” “correct”). If the order of decreasing precedence is anticlockwise, the absolute configuration is S (Latin sinister, “left”). Example In order of decreasing precedence, the four substituents attached to the stereogenic center of 2-butanol are As represented in the wedge-and-dash drawing at the top of this table, the molecule is already appropriately oriented. Hydrogen is the lowest ranked substituent attached to the stereogenic center and points away from us. The order of decreasing precedence is anticlockwise. The configuration at the stereogenic center is S. 3. Draw the three highest ranked substituents as they appear to you when the molecule is oriented so that the lowest ranked group points away from you. HO± CH3CH2± CH3± (highest) H± (lowest) CH3CH2 OH CH3 CH3CH2 OH CH3 (highest) (second highest) (third highest) ()-2-Butanol C H H3C CH3CH2 Given that the absolute configuration of ()-2-butanol is OH Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
270 CHAPTER SEVEN Stereochemistry SAMPLE SOLUTION (a) The highest ranking substituent at the stereogenic cen ter of 2-methyl-1-butanol is CH2OH; the lowest is H of the remaining two, ethyl outranks methyl Order of precedence: CH2OH CH3CH2> CH3>H The lowest ranking substituent (hydrogen)points away from us in the drawing The three highest ranking groups trace a clockwise path from CH2OH- CH3CH2 H2 his compound therefore has the r configuration. It is(R)-(+)-2-methyl-1-butanol Compounds in which a stereogenic center is part of a ring are handled in an anal gous fashion. To determine, for example, whether the configuration of (+)-4-methyl cyclohexene is R or S, treat the right- and left-hand paths around the ring as if they were Lower Higher is treated priority( H2C priorty H H,C (+)-4-Methylcyclohexene with the lowest ranked substituent(hydrogen) directed away from us, we see that the order of decreasing sequence rule precedence is clockwise. The absolute configuration R PROBLEM 7.8 Draw three-dimensional representations or make molecular mod els of (a) The R enantiomer of (b) The S enantiomer of l3C SAMPLE SOLUTION (a)The stereogenic center is the one that bears the bromine. In order of decreasing precedence, the substituents attached to the stereogenic center are >-CH2C> CH3 When the lowest ranked substituent (the methyl group) is away from us, the order of decreasing precedence of the remaining groups must appear in a clockwise sense in the r enantiomer Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
SAMPLE SOLUTION (a) The highest ranking substituent at the stereogenic center of 2-methyl-1-butanol is CH2OH; the lowest is H. Of the remaining two, ethyl outranks methyl. The lowest ranking substituent (hydrogen) points away from us in the drawing. The three highest ranking groups trace a clockwise path from CH2OH → CH3CH2 → CH3. This compound therefore has the R configuration. It is (R)-()-2-methyl-1-butanol. Compounds in which a stereogenic center is part of a ring are handled in an analogous fashion. To determine, for example, whether the configuration of ()-4-methylcyclohexene is R or S, treat the right- and left-hand paths around the ring as if they were independent substituents. With the lowest ranked substituent (hydrogen) directed away from us, we see that the order of decreasing sequence rule precedence is clockwise. The absolute configuration is R. PROBLEM 7.8 Draw three-dimensional representations or make molecular models of (a) The R enantiomer of (b) The S enantiomer of SAMPLE SOLUTION (a) The stereogenic center is the one that bears the bromine. In order of decreasing precedence, the substituents attached to the stereogenic center are When the lowest ranked substituent (the methyl group) is away from us, the order of decreasing precedence of the remaining groups must appear in a clockwise sense in the R enantiomer. Br O C CH2C CH3 H F F H3C Br H3C O is treated as CH3 H H H ()-4-Methylcyclohexene Lower priority path Higher priority path CH3 H CH2 C C H2C H2C C C H H3C CH2OH CH3CH2 Order of precedence: CH2OH CH 3CH2 CH3 H 270 CHAPTER SEVEN Stereochemistry Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
7.7 Fischer Projections CH which leads to H2c c the structure (R)-2-Bromo-2-methylcyclohexanone Since its introduction in 1956, the Cahn-Ingold-Prelog system has beco standard method of stereochemical notation 7.7 FISCHER PROJECTIONS Stereochemistry deals with the three-dimensional arrangement of a molecules atoms, and we have attempted to show stereochemistry with wedge-and-dash drawings and computer-generated models. It is possible, however, to convey stereochemical informa tion in an abbreviated form using a method devised by the german chemist Emil Fischer. Lets return to bromochlorofluoromethane as a simple example of a chiral mole- ganic chemist of the late cule. The two enantiomers of BrCIFCH are shown as ball-and-stick models, as wedge and-dash drawings, and as Fischer projections in Figure 7.6. Fischer projections are the 1902 Nobel Prize in always generated the same way: the molecule is oriented so that the vertical bonds at work in carbohydrate and the stereogenic center are directed away from you and the horizontal bonds point toward protein you. A projection of the bonds onto the page is a cross. The stereogenic carbon lies at the center of the cross but is not explicitly shown. It is customary to orient the molecule so that the carbon chain is vertical wit lowest numbered carbon at the top as shown for the Fischer projection of (R)-2-but CH H The Fischer project ction HO resp onds to HO-C-H CH,CH CH2CH3 (R)-2-Butanol 3●m Cl BI FIGURE 7.6 Ball-and and-dash drawings(center) and Fischer projections (right) of the R and s enan- tiomers of bromochlorofluo- (S)-Bromochlorofluoromethane romethane Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Since its introduction in 1956, the Cahn–Ingold–Prelog system has become the standard method of stereochemical notation. 7.7 FISCHER PROJECTIONS Stereochemistry deals with the three-dimensional arrangement of a molecule’s atoms, and we have attempted to show stereochemistry with wedge-and-dash drawings and computer-generated models. It is possible, however, to convey stereochemical information in an abbreviated form using a method devised by the German chemist Emil Fischer. Let’s return to bromochlorofluoromethane as a simple example of a chiral molecule. The two enantiomers of BrClFCH are shown as ball-and-stick models, as wedgeand-dash drawings, and as Fischer projections in Figure 7.6. Fischer projections are always generated the same way: the molecule is oriented so that the vertical bonds at the stereogenic center are directed away from you and the horizontal bonds point toward you. A projection of the bonds onto the page is a cross. The stereogenic carbon lies at the center of the cross but is not explicitly shown. It is customary to orient the molecule so that the carbon chain is vertical with the lowest numbered carbon at the top as shown for the Fischer projection of (R)-2-butanol. The Fischer projection HO H CH2CH3 CH3 (R)-2-Butanol corresponds to CH3 CH2CH3 HO C H Br O H2C C (R)-2-Bromo-2-methylcyclohexanone Br CH3 which leads to O the structure 7.7 Fischer Projections 271 Br Cl H C F H H C H (R)-Bromochlorofluoromethane (S)-Bromochlorofluoromethane Cl Br F Br Cl F Cl Br F Fischer was the foremost organic chemist of the late nineteenth century. He won the 1902 Nobel Prize in chemistry for his pioneering work in carbohydrate and protein chemistry. FIGURE 7.6 Ball-andstick models (left), wedgeand-dash drawings (center), and Fischer projections (right) of the R and S enantiomers of bromochlorofluoromethane. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SEVEN Stereochemistry Edward Siloac, an under- fying a configuration as R or S, the safest procedure is to convert a Fischer graduate organic chemistry ee-dimensional representation, remembering that the horizontal bonds always Virginia, published a paper in the june 1999 issue of the PROBLEM 7.9 Write Fischer projections for each of the compounds of prob- tion(pp. 798-799)that de- em7.7. scribed how to use your SAMPLE SOLUTION (a)The structure of (R)-(+)-2-methyl-1-butanol is shown in projections to R and S the structure that follows at the left. view the structural formula from a position figuration. chosen so that the HoCH2-C-CH2 CH3 segment is aligned vertically, with the ver- tical bonds pointing away from you. replace the wedge-and-dash bonds by lines to give the Fischer projection shown at the right. I CH -CH,0H sathe as H-f-CH, which becomes the CH,OH) CHOH scher p CH3CH CH2 CH3 CH2CHE 7.8 PHYSICAL PROPERTIES OF ENANTIOMERS The usual physical properties such as density, melting point, and boiling point are iden- cal within experimental error for both enantiomers of a chiral compound Enantiomers can have striking differences, however, in properties that depend on the arrangement of atoms in space. Take, for example, the enantiomeric forms of car vone.(R)-(-)-Carvone is the principal component of spearmint oil. Its enantiomer. (S)-(+)-carvone, is the principal component of caraway seed oil. The two enantiomers do not smell the same: each has its own characteristic odor H2C CH2 3C CH (R)-(-)-Carvone (S)-(+)-Carvone The difference in odor between(R)-and(S)-carvone results from their different behavior toward receptor sites in the nose. It is believed that volatile molecules occupy only those odor receptors that have the proper shape to accommodate them. Because the receptor sites are themselves chiral, one enantiomer may fit one kind of receptor while entitled"When the other enantiomer fits a different kind. An analogy that can be drawn is to hands and Mirror in the june 1996 is. gloves. Your left hand and your right hand are enantiomers. You can place your left hand sue of the Journal of Chemi. into a left glove but not into a right one. The receptor(the glove) can accommodate one cal Education(pp 481-484) enantiomer of a chiral object(your hand) but not the other. The term"chiral recognition"refers to the process whereby some chiral receptor which the two enantiomers or reagent interacts selectively with one of the enantiomers of a chiral molecule. Very have different biological high levels of chiral recognition are common in biological processes.(-)-Nicotine, for example, is much more toxic than(+)-nicotine, and (+)-adrenaline is more active in the Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
When specifying a configuration as R or S, the safest procedure is to convert a Fischer projection to a three-dimensional representation, remembering that the horizontal bonds always point toward you. PROBLEM 7.9 Write Fischer projections for each of the compounds of Problem 7.7. SAMPLE SOLUTION (a) The structure of (R)-()-2-methyl-1-butanol is shown in the structure that follows at the left. View the structural formula from a position chosen so that the HOCH2±C±CH2CH3 segment is aligned vertically, with the vertical bonds pointing away from you. Replace the wedge-and-dash bonds by lines to give the Fischer projection shown at the right. 7.8 PHYSICAL PROPERTIES OF ENANTIOMERS The usual physical properties such as density, melting point, and boiling point are identical within experimental error for both enantiomers of a chiral compound. Enantiomers can have striking differences, however, in properties that depend on the arrangement of atoms in space. Take, for example, the enantiomeric forms of carvone. (R)-()-Carvone is the principal component of spearmint oil. Its enantiomer, (S)-()-carvone, is the principal component of caraway seed oil. The two enantiomers do not smell the same; each has its own characteristic odor. The difference in odor between (R)- and (S)-carvone results from their different behavior toward receptor sites in the nose. It is believed that volatile molecules occupy only those odor receptors that have the proper shape to accommodate them. Because the receptor sites are themselves chiral, one enantiomer may fit one kind of receptor while the other enantiomer fits a different kind. An analogy that can be drawn is to hands and gloves. Your left hand and your right hand are enantiomers. You can place your left hand into a left glove but not into a right one. The receptor (the glove) can accommodate one enantiomer of a chiral object (your hand) but not the other. The term “chiral recognition” refers to the process whereby some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule. Very high levels of chiral recognition are common in biological processes. ()-Nicotine, for example, is much more toxic than ()-nicotine, and ()-adrenaline is more active in the (R)-()-Carvone (from spearmint oil) O H3C CH2 CH3 C (S)-()-Carvone (from caraway seed oil) O H3C CH2 CH3 C C H CH3CH2 CH3 CH2OH is the same as which becomes the Fischer projection CH2OH CH2CH3 H C CH3 H CH3 CH2CH3 CH2OH 272 CHAPTER SEVEN Stereochemistry An article entitled “When Drug Molecules Look in the Mirror” in the June 1996 issue of the Journal of Chemical Education (pp. 481–484) describes numerous examples of common drugs in which the two enantiomers have different biological properties. Edward Siloac, an undergraduate organic chemistry student at the University of Virginia, published a paper in the June 1999 issue of the Journal of Chemical Education (pp. 798–799) that described how to use your hands to translate Fischer projections to R and S configurations. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
7.8 Physical Properties of Enantiomers CHIRAL DRUGS recent estimate places the number of prescr A much more serious drawback to using chiral drug tion and over-the-counter drugs marketed as racemic mixtures is illustrated by thalidomide throughout the world at about 2000. Approx- briefly employed as a sedative and antinausea drug imately one-third of these are either naturally occur- in Europe and Great Britain during the period ring substances themselves or are prepared by chemi 1959-1962. The desired properties are those of (R)- cal modification of natural products. Most of the thalidomide (S)-Thalidomide, however, has a very drugs derived from natural sources are chiral and are different spectrum of biological activity and was almost always obtained as a single enantiomer rather shown to be responsible for over 2000 cases of seri than as a racemic mixture Not so with the over 500 ous birth defects in children born to women who chiral substances represented among the more than took it while pregnant 1300 drugs that are the products of synthetic organic hemistry. Until recently, such substances were, with few exceptions, prepared, sold, and administered as racemic mixtures even though the desired therapeuti activity resided in only one of the enantiomers. Spurred by a number of factors ranging from safety and efficacy to synthetic methodology and econom- ics, this practice is undergoing rapid change as more and more chiral synthetic drugs become available in enantiomerically pure form. Basic research directed toward understanding Because of the high degree of chiral the factors that control the stereochemistry of chem tion inherent in most biological processes ical reactions has led to new synthetic methods that make it practical to prepare chiral molecules in enan- drug will exhibit the same level, or even the same tiomerically pure form. Recognizing this, most major kind, of effect. At one extreme, one enantiomer has harmaceutical companies are examining their exist the desired effect, and the other exhibits no biologi- ing drugs to see which ones are the best candidates cal activity at all. in this case, which is relatively rare, for synthesis as single enantiomers and, when prepar and contains 50%"inert ingredients. "Real cases are only the desired enantiomer. In 1992, the United more complicated. For example it is the S enan. States Food and Drug Administration(FDA)issued tiomer that is responsible for the pain- relieving prop- guidelines that encouraged such an approach, but erties of ibuprofen, normally sold as a racemic mix left open the door for approval of new drugs as ture. The 50% of racemic ibuprofen that is the r racemic mixtures when special circumstances war enantiomer is not completely wasted, however, be. rant. One incentive to developing enantiomerically cause enzyme-catalyzed reactions in our body con pure versions of existing drugs is that the novel pro- vert much of it to active (S)-ibuprofen luction methods they require may make them eligi- ble for patent protection separate from that of the iginal drugs. Thus the temporary monopoly posi- (CH3)2CHCH2 tion that patent law views as essential to fostering in novation can be extended by transforming a success- ful chiral, but racemic, drug into an enantiomerically Ibuprofen pure version. constriction of blood vessels than(-)-adrenaline()-Thyroxine is an amino acid of the thyroid gland, which speeds up metabolism and causes nervousness and loss of weight Its enantiomer, (+)-thyroxine, exhibits none of these effects but is sometimes given to heart patients to lower their cholesterol levels. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
constriction of blood vessels than ()-adrenaline. ()-Thyroxine is an amino acid of the thyroid gland, which speeds up metabolism and causes nervousness and loss of weight. Its enantiomer, ()-thyroxine, exhibits none of these effects but is sometimes given to heart patients to lower their cholesterol levels. 7.8 Physical Properties of Enantiomers 273 CHIRAL DRUGS Arecent estimate places the number of prescription and over-the-counter drugs marketed throughout the world at about 2000. Approximately one-third of these are either naturally occurring substances themselves or are prepared by chemical modification of natural products. Most of the drugs derived from natural sources are chiral and are almost always obtained as a single enantiomer rather than as a racemic mixture. Not so with the over 500 chiral substances represented among the more than 1300 drugs that are the products of synthetic organic chemistry. Until recently, such substances were, with few exceptions, prepared, sold, and administered as racemic mixtures even though the desired therapeutic activity resided in only one of the enantiomers. Spurred by a number of factors ranging from safety and efficacy to synthetic methodology and economics, this practice is undergoing rapid change as more and more chiral synthetic drugs become available in enantiomerically pure form. Because of the high degree of chiral recognition inherent in most biological processes (Section 7.8), it is unlikely that both enantiomers of a chiral drug will exhibit the same level, or even the same kind, of effect. At one extreme, one enantiomer has the desired effect, and the other exhibits no biological activity at all. In this case, which is relatively rare, the racemic form is simply a drug that is 50% pure and contains 50% “inert ingredients.” Real cases are more complicated. For example, it is the S enantiomer that is responsible for the pain-relieving properties of ibuprofen, normally sold as a racemic mixture. The 50% of racemic ibuprofen that is the R enantiomer is not completely wasted, however, because enzyme-catalyzed reactions in our body convert much of it to active (S)-ibuprofen. O (CH3)2CHCH2 CHCOH CH3 Ibuprofen A much more serious drawback to using chiral drugs as racemic mixtures is illustrated by thalidomide, briefly employed as a sedative and antinausea drug in Europe and Great Britain during the period 1959–1962. The desired properties are those of (R)- thalidomide. (S)-Thalidomide, however, has a very different spectrum of biological activity and was shown to be responsible for over 2000 cases of serious birth defects in children born to women who took it while pregnant. Basic research directed toward understanding the factors that control the stereochemistry of chemical reactions has led to new synthetic methods that make it practical to prepare chiral molecules in enantiomerically pure form. Recognizing this, most major pharmaceutical companies are examining their existing drugs to see which ones are the best candidates for synthesis as single enantiomers and, when preparing a new drug, design its synthesis so as to provide only the desired enantiomer. In 1992, the United States Food and Drug Administration (FDA) issued guidelines that encouraged such an approach, but left open the door for approval of new drugs as racemic mixtures when special circumstances warrant. One incentive to developing enantiomerically pure versions of existing drugs is that the novel production methods they require may make them eligible for patent protection separate from that of the original drugs. Thus the temporary monopoly position that patent law views as essential to fostering innovation can be extended by transforming a successful chiral, but racemic, drug into an enantiomerically pure version. N O O O N H O Thalidomide Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website