Chapter 9: Stereochemistry Two forms of Thalidomide -One is a sedative used in 1960’s -One caused birth defects O O H H N N O O N N O O O O O H N O N O O Chapter 9: Stereochemistry Stereoisomers of Limonene: Lemons vs Oranges S-(-) Limonene R-(+) Limonene (lemons) (oranges) Stereochemistry Vocabulary Enantiomers = non- superimposable mirror images (stereoisomers) Chiral molecules = molecules tha t are not superi mposabl e with mirror image (handedness) Achiral molecules = molecules that are superimposable with mirror image (have some symmetry element) a a ** Chiral Centers = tetrahedral C d d sp3 bonded to four different c b b c groups (stereocenter) Configurational Isomers = How do we differentiate stereoisomers that differ in these two enantiomers? their configuration of a - By name? chiral center - Chemically? Enantiomers have same physical properties (mp, bp, etc) Configurations of Chiral Centers IUPAC sequence rules for R and S Configuration 1. Ass ign pr ior ity l ett ers t o th e f our groups (A -D) us ing same rules we used for E & Z alkenes (based on atomic number of atoms connected to chiral center, if same find first point of difference; multiple bonds count multiple times). 2. View molecule so group D points away from you. 3. Trace from group A to B to C: Clockwise = R Counterclockwise = S Cl Cl (2R) – 2-chloropentane (2S) – 2-chloropentane a * • easy when group D already R d c b points away from you a • note the wedge and dash are * always next to each other S d b c Configurations of Chiral Centers What do you do when group D does not point away from you? 1. View from a different perspective: view (behind board) a view a b c d c b d a a RR cb cb 2. Shortcut – if you sw itch two groups (on paper ) you invert stereocenter (go from R to S and vice versa) a a b d d c b c S So original must be R! (Note that a second switch would give you the R enantiomer again) Configurations of Chiral Centers CH3 CH3 (R) Br HO H (original = S) H HO Br O O CH3 OH (S) OH CH3 (original = R) O H N 2 OH (R)-Phenylalanine (-amino acid) Optical Activity: Rotation of Plane Polarized Light How do you physically tell the two enantiomers apart? • Clock wi se = d ext rorot at ory (+) • Counterclockwise = levorotatory (-) • Enantiomers rotate equally in opposite direction = observed rotation (o) Specific Rotation []D = c = concentration (g/mL) c x l l = path length (dm) Br Br (2R) – 2-bromobutane (2S) – 2-bromobutane o o []D =- 23. 1 []D = +231+ 23.1 Note: No correlation between R & S with (+) and (-) Optical Activity and Enantiomeric Excess (% ee) Can we determine the amounts of each enantiomer present? • 11(1:1 (equa l) m ix tures of enanti omers - optically inactive (does not rotate plane polarized light) - referred to as a racemic mixture (racemate) (100% pure referred to as optically pure) • Unequal mixtures: enantiomeric excess (% ee) [] observed % ee = x 100% [] pure enantiomer %R - %S = x 100% %R + %S Ex: Mixture of R & S 2-bromobutane [] = - 11.55o -11. 55 % ee = x 100% = 50% 23.10 50% excess (-) R enantiomer Total 75% R 50% racemic 25% S Compounds with Multiple Chiral Centers Now how many stereoisomers are possible? • For n chiral centers, 2n possible stereoisomers Br 22 = 4 stereoisomers * * Cl (2R, 3R) (2S, 3S) 2-bromo-3-chlorobutane (2R, 3S) (2S, 3R) Br Br Br Cl Cl Cl (2R, 3R) (2S, 3S) (2S, 3S) • For enantiomers, configuration at every chiral center inverted Br Br Cl Cl (2S, 3R) (2R, 3S) • How are these last two related to the first two? Diastereomers A new type of stereoisomers Definition = stereoisomers NOT related as an object and its non-superimposable mirror image (not enantiomers) 1. cis / trans diastereomers Cl Cl Cl Cl 2. configurational (R and S) diastereomers Br Br Br Cl Br Cl Cl Cl Br Cl Br Br Cl Cl (2R, 3R) (2S, 3R) • Do not have opposite configuration at every chiral center • Unlike enantiomers, diastereomers have completely different physical properties (i.e. mp, bp, [], etc) Resolution If enantiomers have the same properties, can you separate them? 1. Convert enantiomers into diastereomers 2. Separate diastereomers 3. Convert diastereomers back into pure enantiomers 2. Pure 1R, 2S Pure 1R 1R 1. 1R, 2S 3. 1S 1S, 2S Pure 1S, 2S Pure 1S Meso Compounds Molecules with chiral centers, but are achiral due to symmetry R R S * * * * S R S Plane of Symmetry Chiral (Achiral) (no symmetry plane) Br Br R S S S R S Br Br Br Br Br Enantiomers Br Br Br S R R S S R Br Br Br Br Meso (identical!) 2 identical chiral centers with opposite configuration Fischer Projections Alternative way to draw chiral centers a a a d c d c d b c b b view horizontal = coming out of page vertical = going into page To assign R/S configuration, place group “D” on top and trace from A to B to C - Only certain ‘rotations’ allowed (180o) -- Easier to use method that switches groups a d d d c a c a b b b c (S) (R) (so original R) Fischer Projections: Multiple Chiral Centers d H H c a R * H3C OH b H3C OH bottom d H C * H b H C H 3 c b 3 R OH c d OH a a What does the enantiomer look like? H H * * H3C OH HO CH3 Confirm that this is the * * H3C H H CH3 S, S stereoisomer OH OH Any other stereoisomers possible? Two chiral centers , 2 2 = 4 possible (maximum) H MESO! Only other stereoisomer possible H3C OH (total of three stereoisomers) H3C OH H (R, S an d S, R are iden tica l) Stereochemistry of Reactions Part I: Reactions that make a chiral center Achiral intermediates give achiral (racemic) products - Carbocation intermediates - Nuc can attack from ‘top’ or ‘bottom’ HBr 50% (R) * 50% (S) Br Racemic Mixture • The two transition states are enantiomeric, thus have equal energy so products form in equal amounts • Achiral reagents lead to optically inactive products Stereochemistry of Reactions Part II: Chiral reactants that make new chiral centers Chiral intermediates give chiral products - form unequal mixtures of diastereomers - transition states are now diastereotopic (l(unequal energy so filt)form in unequal amounts) • Optically active reactants leads to optically active products Stereochemistry of Reactions Examples Br2 Br Br + Br Br Equal amounts (racemate) (optically inactive) Br2 Br Br + Br Br Uneqq(ual amounts (diastereomers) (optically active) 1. OsO4 OH OH 2. NaHSO3 + OH OH Meso – same product! (optically inactive) Stereochemistry of Reactions Stereoselectivity – predominant formation of one of several possible stereoisomeric products Cis an d trans 2-btbutene pro duce different st ereoi someri c prod uct s Chirality at Atoms Other than Carbon Requires tetrahedral atom with four unique groups Chirality without chiral centers: a c c a CCC CCC b d d b Prochirality If an achiral molecule can be turned into a chiral molecule in a single chemical step it is “Prochiral” sp2 Prochiral Centers: Re and Si Faces O H OH Produce a Racemic Mixture Prochiral Chiral Note Re does not necessarily give (R) product! sp3 Prochiral Centers: Pro-R and Pro-S.