Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson 3-1 Stereoisomerism and Chirality Chapter 3 3-2 Isomers Isomers: different compounds with the same molecular formula Constitutional isomers: isomers with a different connectivity Stereoisomers: isomers with the same connectivity but a different orientation of their atoms in space 3-3 Chirality Chiral: from the Greek, cheir, hand • an object that is not superposable on its mirror image Achiral: an object that lacks chirality; one that lacks handedness • an achiral object has at least one element of symmetry • plane of symmetry: an imaginary plane passing through an object dividing it so that one half is the mirror image of the other half • center of symmetry: a point so situated that identical components are located on opposite sides and equidistant from that point along the axis passing through it 3-4 Elements of Symmetry Symmetry in objects 3-5 Elements of Symmetry Plane of symmetry (cont’d) mirror plane HO OH 3-6 Chiral Center The most common (but not the only) cause of chirality in organic molecules is a tetrahedral atom, most commonly carbon, bonded to four different groups A carbon with four different groups bonded to it is called a chiral center • all chiral centers are stereocenters, but not all stereocenters are chiral centers (see Figure 3.5) Enantiomers: stereoisomers that are nonsuperposable mirror images • refers to the relationship between pairs of objects 3-7 Enantiomers 2-Butanol • has one chiral center • here are four different representations for one enantiomer OH C H H3 C CH2 CH3 (1) H H3 C OH C CH2 CH3 (2) H OH OH (3) (4) • using (4) as a model, here are two different representations for the enantiomer of (4) OH (4) OH OH representations for the enantiomer of (4) 3-8 Enantiomers The enantiomers of lactic acid • drawn in two different representations O OH HO O C C C C H CH3 OH HO O O OH OH H CH3 HO OH 3-9 Enantiomers 2-Chlorobutane Cl CH3 CHCH2 CH3 H Cl Cl H 3-10 Enantiomers 3-Chlorocyclohexene Cl Cl 3-11 Enantiomers A nitrogen chiral center + + N H3 C N CH2 CH3 CH3 CH2 CH3 A pair of enantiomers 3-12 R,S Convention Priority rules 1. Each atom bonded to the chiral center is assigned a priority based on atomic number; the higher the atomic number, the higher the priority (1) (6) -H -CH3 (7) -N H2 (8) (16) (17) - OH - SH - Cl (35) (53) - Br -I Increasing priority 2. If priority cannot be assigned per the atoms bonded to the chiral center, look to the next set of atoms; priority is assigned at the first point of difference (1) - CH 2 -H (6) - CH 2 -CH 3 (7) - CH 2 -NH2 (8) - CH 2 -OH Increasing priority 3-13 R,S Convention 3. Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds -CH=CH2 O -CH is treated as is treated as C C -CH-CH2 O C C O H C CH is treated as C C C C H C C 3-14 Naming Chiral Centers 1. Locate the chiral center, identify its four substituents, and assign priority from 1 (highest) to 4 (lowest) to each substituent 2. Orient the molecule so that the group of lowest priority (4) is directed away from you 3. Read the three groups projecting toward you in order from highest (1) to lowest priority (3) 4. If the groups are read clockwise, the configuration is R; if they are read counterclockwise, the configuration is S H Cl (S)-2-Chlorobutane S 2 1 3 3-15 Naming Chiral Centers • (R)-3-Chlorocyclohexene Cl 3 1 H 2 R • (R)-Mevalonic acid 1 1 4 HO CH3 O HO 3 2 R OH 3 2 3-16 Enantiomers & Diastereomers a molecule with 1 chiral center, 21 = 2 stereoisomers are possible For a molecule with 2 chiral centers, a maximum of 22 = 4 stereoisomers are possible For a molecule with n chiral centers, a maximum of 2n stereoisomers are possible For 3-17 Enantiomers & Diastereomers 2,3,4-Trihydroxybutanal • two chiral centers • 22 = 4 stereoisomers exist; two pairs of enantiomers CHO CHO H C OH HO C H H C OH HO C H CH2 OH CH2 OH A pair of enantiomers (Erythreose) CHO CHO H C OH HO C H HO C H C OH CH2 OH H CH2 OH A pair of enantiomers (Threose) Diastereomers: • stereoisomers that are not mirror images • refers to the relationship among two or more objects 3-18 Enantiomers & Diastereomers 2,3-Dihydroxybutanedioic acid (tartaric acid) • two chiral centers; 2n = 4, but only three stereoisomers exist COOH COOH H C OH HO C H H C OH HO C H COOH COOH A meso compound (plane of symmetry) Meso COOH COOH H C OH HO C H HO C H C OH COOH H COOH A pair of enantiomers compound: an achiral compound possessing two or more chiral centers that also 3-19 has chiral isomers Enantiomers & Diastereomers 2-Methylcyclopentanol CH 3 OH HO H 3 C H H H H cis-2-Methylcyclopentanol (a pair of enantiomers) CH3 H diastereomers H H3 C H OH H HO trans-2-Methylcyclopentanol (a pair of enantiomers) 3-20 Enantiomers & Diastereomers 1,2-Cyclopentanediol OH HO H OH HO H H H cis-1,2-Cyclopentanediol (a meso compound) OH H H diastereomers HO OH H H HO trans-1,2-Cyclopentanediol (a pair of enantiomers) 3-21 Enantiomers & Diastereomers cis-3-Methylcyclohexanol H3 C OH HO CH3 3-22 Enantiomers & Diastereomers trans-3-Methylcyclohexanol H3 C CH3 OH HO 3-23 Isomers rotation about single bonds Compounds with the same molecular formula same connectivity different connectivity Cis,Trans (E,Z) Isomers (can be called diastereomers) rotation restricted Constitutional Isomers Stereoisomers stereoisomers but no chiral centers Conformations Conformational Isomers with chiral centers m ore than one chiral center achiral Meso Compounds Atropisomers one chiral center chiral not mirror images Diastereomers mirror images Enantiomers Enantiomers 3-24 Properties of Stereoisomers Enantiomers have identical physical and chemical properties in achiral environments Diastereomers are different compounds and have different physical and chemical properties • meso tartaric acid, for example, has different physical and chemical properties from its enantiomers (see Table 3.1) 3-25 Plane-Polarized Light Ordinary light: light vibrating in all planes perpendicular to its direction of propagation Plane-polarized light: light vibrating only in parallel planes Optically active: refers to a compound that rotates the plane of plane-polarized light 3-26 Plane-Polarized Light • plane-polarized light is the vector sum of left and right circularly polarized light • circularly polarized light reacts one way with an R chiral center, and the opposite way with its enantiomer • the result of interaction of plane-polarized light with a chiral compound is rotation of the plane of polarization 3-27 Plane-Polarized Light Polarimeter: a device for measuring the extent of rotation of plane-polarized light 3-28 Optical Activity • observed rotation: the number of degrees, , through which a compound rotates the plane of polarized light • dextrorotatory (+): refers to a compound that rotates the plane of polarized light to the right • levorotatory (-): refers to a compound that rotates of the plane of polarized light to the left • specific rotation: observed rotation when a pure sample is placed in a tube 1.0 dm in length and concentration in g/mL (density); for a solution, concentration is expressed in g/ 100 mL COOH C H H3 C OH (S)-(+)-Lactic acid 21 [] D = +2.6° COOH H C CH3 HO (R)-(-)-Lactatic acid 21 [] D = -2.6° 3-29 Optical Purity Optical purity: a way of describing the composition of a mixture of enantiomers Percent optical purity = []sample []pure enantio mer x 100 Enantiomeric excess: the difference between the percentage of two enantiomers in a mixture [R] - [S] x 100 = %R - %S Enantiomeric excess (ee) = [R] + [S] • optical purity is numerically equal to enantiomeric excess, but is experimentally determined 3-30 Enantiomeric Excess Example: a commercial synthesis of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), gives the S enantiomer in 97% ee CH3 COOH H3 CO (S)-Naproxen Calculate the percentages of the R and S enantiomers in this mixture 3-31 Resolution Racemic mixture: an equimolar mixture of two enantiomers • because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific rotation is zero Resolution: the separation of a racemic mixture into its enantiomers 3-32 Resolution One means of resolution is to convert the pair of enantiomers into two diastereomers • diastereomers are different compounds and have different physical properties A common reaction for chemical resolution is salt formation + :B RCOOH (R,S)-Carboxylic (R)-Base acid - + RCOO HB (R,R)-Salt + (S,R)-Salt) • after separation of the diastereomers, the enantiomerically pure acids are recovered 3-33 Resolution • racemic acids can be resolved using commercially available chiral bases such as 1-phenylethanamine NH2 NH2 (S)-1-Phenylethanamine (R)-1-Phenylethanamine • racemic bases can be resolved using chiral acids such as OH O HO H3 C CH3 O OH HO OH HOOC COOH CH3 O OH O OH (2R,3R)-(+)-Tartaric acid (S)-(-)-Malic acid (1S,3R)-(+)-Camphoric acid 3-34 3-35 Resolution Enzymes as resolving agents O OEt EtO CH3 H3 C H3 CO + O OCH3 Ethyl ester of (S)-naproxen 1. esterase NaOH, H2 O 2 . HCl, H2 O O Ethyl ester of (R)-naproxen (not affected by the esterase) OH CH3 H3 CO (S)-Naproxen 3-36 Amino Acids • the 20 most common amino acids have a central carbon, called an -carbon, bonded to an NH2 group and a COOH group • in 19 of the 20, the -carbon is a chiral center • 18 of the 19 -carbons have the R configuration, one has the S configuration • in the D,L system, all have the L configuration • at neutral pH, an amino acid exists as an internal salt • in this structural formula, the symbol R = a side chain side chain O H3 N - O R Ionized or zwitterion form of an amino acid 3-37 Proteins • proteins are long chains of amino acids covalently bonded by amide bonds formed between the carboxyl group of one amino acid and the amino group of another amino acid R O H N H3 N O R R N H O H N n O OR for most proteins, n= 10-750 3-38 Chirality in the Biological World Except for inorganic salts and a few lowmolecular-weight organic substances, the molecules of living systems are chiral Although these molecules can exist as a number of stereoisomers, generally only one is produced and used in a given biological system It’s a chiral world! 3-39 Chirality in the Biological World Consider chymotrypsin, a protein-digesting enzyme in the digestive system of animals • chymotrypsin contains 251 chiral centers • the maximum number of stereoisomers possible is 2251 • there are only 238 stars in our galaxy! 3-40 Chirality in the Biological World Enzymes are like hands in a handshake • the substrate fits into a binding site on the enzyme surface • a left-handed molecule will only fit into a left-handed binding site and • a right-handed molecule will only fit into a righthanded binding site • enantiomers have different physiological properties because of the handedness of their interactions with other chiral molecules in living systems 3-41 Chirality in the Biological World • a schematic diagram of an enzyme surface capable of binding with (R)-glyceraldehyde but not with (S)glyceraldehyde 3-42 Stereoisomerism and Chirality End Chapter 3 3-43