10/4/2010. Sequence Rules for Specifying Configuration. Sequence Rules for Specifying Configuration. 5.5 Sequence Rules for Specifying.

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1 5.5 Sequence Rules for Specifying Configuration Configuration The three-dimensional arrangement of substituents at a chirality center Sequence rules to specify the configuration of a chirality center: 1. Look at the four atoms directly attached to the chirality center and assign priorities in order of decreasing atomic number The atom with the highest atomic number is ranked first; the atom with the lowest atomic number (usually hydrogen) is ranked fourth Heavier isotopes of the same element rank higher than the lighter isotopes 2. If a decision cannot be reached by ranking the first atoms in the substituents, look at the second, third, or fourth atoms outward until a difference is found 3. Multiple-bonded atoms are equivalent to the same number of single-bonded atoms 1

2 Stereochemical configuration around the carbon Once priorities have been assigned to the four groups attached to the chiral carbon, orient the molecule so that the group of lowest priority (4) points directly back Look at the three remaining substituents R configuration If a curved arrow drawn from highest to lowest priority (1 2 3) through substituents is clockwise S configuration If a curved arrow drawn from highest to lowest priority (1 2 3) through substituents is counterclockwise 2

3 (-)-Lactic acid Rule 1 -OH has priority 1 -H has priority 4 Rule 2 -CO 2 H is higher in priority than CH 3 O (the highest second atom in CO 2 H) outranks H (the highest second atom in CH 3 ) (-)-Glyceraldehyde S configuration (+)-Alanine S configuration Both have the S configuration, although one is levorotatory and the other is dextrorotatory The sign of optical rotation, (+) or (-) is not directly correlated to the R,S designation Absolute configuration The exact three-dimensional structure of a chiral molecule They are specified verbally by the Cahn-Ingold- Prelog R,S convention In 1951, an X-ray spectroscopic method for determining the absolute spatial arrangement of atoms in a molecule was found Based on these results, it can be said with a certainty that the R,S conventions are correct 3

4 Worked Example 5.3 Assigning Configuration to Chirality Centers Orient each of the following drawings so that the lowest-priority group is toward the rear, and then assign R or S configuration: Worked Example 5.4 Drawing the Three-Dimensional Structure of an Enantiomer Draw the tetrahedral representation of (R)-2-chlorobutane. 5.6 Molecules with more than one chirality center A molecule with n chirality centers can have up to 2 n stereoisomers (although it may have fewer) Amino acid threonine (2-amino-3-hydroxybutanoic acid) CH 3 CH(OH)CH(NH 2 )COOH Two chirality centers (C2 and C3) Four possible stereoisomers 4

5 The four stereoisomers of 2-amino-3-hydroxybutanoic acid The four stereoisomers of 2-amino-3-hydroxybutanoic acid can be grouped into two pairs of enantiomers The 2R, 3R stereoisomer is the mirror image of 2S, 3S The 2R, 3S stereoisomer is the mirror image of 2S, 3R Stereoisomers that are not mirror images Enantiomers have opposite configurations at all chirality centers have opposite configurations at one or more of the chirality centers but the same configuration at others 2R, 3R stereoisomer and 2R, 3S stereoisomer are diastereomers because they have the same configuration at C2 but different configurations at C3. Of the four stereoisomers of threonine, only the 2S, 3R isomer [ ] D = occurs naturally in plants and animals and is an essential human nutrient Most biological molecules are chiral, and usually only one stereoisomer is found in nature 5

6 Epimers Two diastereomers that differ at only one chirality center but are the same at all the others Cholestanol and coprostanol are both found in human feces and both have nine chirality centers Eight of the nine chirality centers are identical, but the one at C5 is different Cholestanol and coprostanol are epimeric at C5 5.7 Meso Compounds Tartaric acid A compound with more than one chirality center Meso Compounds 2R, 3R and 2S, 3S structures represent a pair of enantiomers because they are not identical 2R, 3S and 2S, 3R structures are identical The molecule has a plane of symmetry Achiral 6

7 Meso Compounds Meso compounds Molecule that are achiral, yet contain chirality centers Tartaric acid exists as only three stereoisomers: two enantiomers and one meso form Meso Compounds The (+)- and (-)-tartaric acids Have identical melting points, solubilities, and densities Differ in sign of their rotation of plane-polarized light The meso isomer is diastereomeric with the (+) and (-) forms It has no mirror-image relationship to (+)- and (-)-tartaric acids Is a different compound Has different physical properties Worked Example 5.5 Distinguishing Chiral Compounds from Meso Compounds Does cis-1,2-dimethylcyclobutane have any chirality centers? Is it chiral? 7

8 5.8 Racemic Mixtures and the Resolution of Enantiomers Racemate or racemic mixture Denoted by either the symbol ( ) or the prefix d,l to indicate an equal mixture of dextrorotatory and levorotatory forms Show no optical rotation because the (+) rotation form one enantiomer exactly cancels the (-) rotation from the other Pasteur started with a 50 : 50 mixture of the two chiral tartaric acid enantiomers He was able to resolve, or separate, the racemic tartaric acid into its (+) and (-) enantiomers Racemic Mixtures and the Resolution of Enantiomers The most common method of resolution uses an acid-base reaction between the racemate of a chiral carboxylic acid (RCO 2 H) and an amine base (RNH 2 ) to yield an ammonium salt Reaction of the racemate of a chiral acid, lactic acid, and an achiral amine base, methylamine, CH 3 NH 2 The product is an unresolvable 50 : 50 mixture of methylammonium (+)- lactate and methylammonium (-)-lactate Racemic Mixtures and the Resolution of Enantiomers Reaction of the racemate of lactic acid and a single enantiomer of a chiral amine base (R)-1-phenylethylamine (+)- and (-)-lactic acids react with (R)-1-phenylethylamine to give an R,R ammonium salt and an S,R ammonium salt Ammonium salts are separated as two different diastereomers with different chemical and physical properties 8

9 Worked Example 5.6 Predicting the Chirality of a Product We ll see in Section 16.3 that carboxylic acids (RCO 2 H) react with alcohols (R OH) to form esters (RCO 2 R ). Suppose that ( )-lactic acid reacts with CH 3 OH to form the ester, methyl lactate. What stereochemistry would you expect the product(s) to have? What is the relationship of the products? 9