Stereochemistry Dr. A. G. Nikalje Dept. Of Pharmaceutical Chemistry Stereochemistry refers to the 3dimensional properties and reactions of molecules. It has its own language and terms that need to be learned in order to fully communicate and understand the concepts. Chiral carbon, optical activity, R/S forms Definitions Stereoisomers compounds with the same connectivity, different arrangement in space Enantiomers stereoisomers that are nonsuperimposible mirror images; only properties that differ are direction (+ or -) of optical rotation Diastereomers stereoisomers that are not mirror images; different compounds with different physical properties More Definitions Asymmetric center sp3 carbon with 4
different groups attached Optical activity the ability to rotate the plane of plane polarized light Chiral compound a compound that is optically active (achiral compound will not rotate light) Polarimeter device that measures the optical rotation of the chiral compound Plane-Polarized Light Plane-Polarized Light through an Achiral Compound Plane-Polarized Light through a Chiral Compound Polarimeter Measures Optical Rotation Specific Rotation, []]] []]] = ] / cl = observed rotation c = concentration in g/mL l = length of tube in dm
Dextrorotary designated as d or (+), clockwise rotation Levorotary designated as l or (-), counterclockwise rotation Specific Rotations of some Common Organic Compounds Compound []] # * centers Penicillin V +233.0 3 Sucrose +66.5 10 Camphor +44.3 2 MSG +25.5 1 Cholesterol -31.3 8 Morphine -132.0 5 Chirality Center Carbon has four different groups attached
Enantiomers nonsuperimposible mirror images mirror plane OH H HO2C OH CH3 (S)(+) lactic acid from muscle tissue o [] = +13.5 CH3 H CO 2H (R)(-) lactic acid from milk o [] = -13.5
Enantiomeric Excess (Optical Purity) observed rotation rotation of pure enantiomerx 100 = enantiomeric excess (e.e.) o observed rotation = +109 109.0 e.e. = 123.0 x 100 = 88.6% e.e. H H (S)-(-) Limonene o [= from lemons (R)(+) Limonene o
[] = +123.0 from oranges 88.6% (+) 11.4% racemic actually 94.3% (+) Biological Activity (R)(+) Thalidomide O O N H (S)(-) Thalidomide O H N O a sedative and hypnotic O
O H N O a teratogen H N O SSRI Efficacy depends on Stereochemistry NC O * N(CH3)2 (+/-) Celexa (-) Lexapro F
Absolute Configuration Use Cahn, Ingold, Prelog priorities Place the lowest priority group back (focus down C - 4 bond) draw arrow from 1-2-3 1 1 clockwise counterclockwise 4 4 2 2 3 3 (R) (S) Assign Priority to each Group on Asymmetric Center I Cl H I
rotate F 4 H F3 1 Cl 2 focus down C-4 bond Lactic Acid 4 H HO2C 2 1
OH 1 OH CH3 3 (S) 4 H CO2H 2 CH3 3 (R) C.I.P. Priorities Low High CH2CH2CH3
CH(CH 3)2 O CH2CH2OH CH 2CH CH2CH2CH3 CH=CH 2 CO2H CH 2Cl CH2CH2Br CH(CH3)2 Fischer Projections H HO 2C
CH3 OH OH OH H CO 2H CH3 H CO 2H CH3 Horizontal bonds approach you (wedge bonds) Vertical bonds move away (dashed bonds) Assigning Absolute Configuration to Fischer Projections H
HO2C H CH3 (S) OH OH OH rotate CO2H H CO2H CH3 CH3
(S) (S) Rotation of the Projection 90o Reverses Absolute Configuration OH H 90 CO2H CH3 (S) H o CH3 OH CO2H (R)
90 CH3 o HO2C H OH (S) 90 o CO2H HO CH3 H (R) Diastereomers
Stereoisomers That Are Not Mirror Images H OH 3 2 CO2H H OH 3 2 CO2H Br H H Br (2S,3S) (2S,3R) same stereochemistry at C2 (S) opposite stereochemistry at C3 Fischer Projections with 2 Chiral Centers
CO2H H 2 Br 3 OH H CO2H H 2 OH H 3 Br
CH3 CH3 (2S,3S) (2S,3R) 2 Chiral Centers 4 Stereoisomers Identical, Enantiomers or Diastereomers? CH2CH3 H a) Br CH3 & H CH2CH3
b) Br HO H C CH3 CH3 C H CH3 NH2 CH3 & H NH2 H
OH CH3 Tartaric Acids R,R CO2H H HO OH H S,S CO2H HO H H OH CO2H CO2H
R,S CO2H S,R CO2H H OH HO H H OH HO H CO2H CO2H
Racemic Mixture R,R S,S CO2H CO2H H OH HO H CO2H HO H H OH CO2H
Racemic Mixture (Racemate): 50/50 mixture of enantiomers o m.p. C [] (degrees) (g/mL) (R,R) Tartaric acid 168-170 - 12 1.7598 (S,S) Tartaric Acid 168-170 + 12 1.7598 (+/-) Tartaric acid 210-212 0 1.7723 Meso Compound Internal Plane of Symmetry
Optically Inactive R,S CO2H mirror plane S,R CO2H H OH HO H H OH HO H
CO2H CO2H o superimposible rotate 180 2,3,4-trichlorohexane How many stereoisomers? Cl * * * Cl Cl 3 asymmetric centers 2n, n= # asymmetric centers (3) 8 stereoisomers n = 3; 2n = 8 CH3
CH3 CH3 CH3 S H Cl Cl H R H Cl Cl H S H Cl
Cl H R H Cl Cl H RH Cl Cl H S H H
Cl H Cl CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH3 CH3 CH3 Cl Cl
H H Cl CH2CH3 Cl H Cl H H H Cl H Cl
Cl H H H Cl Cl H Cl CH2CH3 CH2CH3 Cl CH2CH3
A Carbohydrate CHO OH R H S H OH R H OH R H HO
CH2OH (+) D-Glucose Internal Planes of Symmetry Both are Meso CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Asymmetric Centers on Rings Br Br
Br Br A Br Br B 1(R),2(S) cis 1,2-dibromocyclohexane nonsuperimposible but A flips into B Meso Allenes can be Chiral H Cl H C C H
C C CH3 CH3 C C H Cl Mycomycin, an antibiotic H C C H C C H C
C Nocardia acidophilus C CH=CHCH=CHCH2CO 2H []D = -130 o Reactions that Generate Chirality Centers Hydrogenation, syn CH3 CH2CH3 CH3 H H2, Pt/C
CH3 CH2CH3 CH2CH3 H CH3 CH2CH3 CH2CH3 product is meso H CH3 H CH3 CH2CH3 Bromination Trans is formed exclusively No Meso is formed (cis) Br2 Br Br R R
Br Br S S racemic mixture Bromonium Ion is Opened Equally from Both Sides Br2 + Br Br Br Br R R Br Br
S S racemic mixture Br Br Br Br trans alkene + anti addition = MESO CH2CH3 H H CH2CH3 Br2 CH2CH3 H Br CH2CH3
H meso Br Br H CH2CH3 CH2CH3 H Br cis Alkene + anti addition = racemic mixture Br CH2CH3 H a CH2CH3 H CH2CH3 H CH2CH3 H
Br2 Br CH2CH3 CH2CH3 H H a Br CH2CH3 H Br b H HCH CH 2 3 CH CH 2 3 CH2CH3 H
Br CH2CH3 H b Br Br R R Br Br CH2CH3 H S S Br Brominations Often Generate Asymmetric Centers CH3 H
CH3 Br2 CH3 H Br H CH3 CH3 CH3 H Br H Br S S H Br R R
racemic mixture CH3 H H CH3 Br2 CH3 H Br Br H CH3 CH3 CH3 H Br H
Br S R meso Asymmetric Center is Generated Racemic Mixture Formed Br H-Br H a) (R) H Br a) H Br b) H
Br b) (S) Asymmetric Induction PPh2 RuCl2 PPh2 CH3 OH H2 Ru(BINAP)Cl2 H CH3 OH 96% e.e. Noyori and Knowles shared Nobel Prize in Chemistry, 2001 Preparation of (L)-Dopa for Treatment of Parkinsons HO
HO C=C H NH2 CO2H H2 Rh(DIOP)Cl 2 CO2H HO CH2C HO l-(-) Dopa H NH2 enz. HO HO
CH2CH2NH2 Dopamine cannot cross blood-brain barrier Relevance of Stereochemistry EPHEDRA from Ma Huong OH * * NHCH3 CH3 2 asymmetric centers 4 stereoisomers d-pseudoephedrine and l-ephedrine (R,S) (S,S) useful decongenstants One-step synthesis Pseudophed
* NHCH3 CH3 "desoxyephedrine" (methamphetamine) l-(R) - Vicks d-(S)- "Meth" -(p-isobutylphenyl)propionic acid CH3 H CO 2H (S)(+) ibuprofen anti-inflammatory H HO 2C CH3
(R)(-) ibuprofen 80-90% metabolized to (S)(+) Model of Thalidomide How Sweet it is! OH Cl CH2OH O CH2OH O HO OH O HO Sucrose HO
CH2OH O CH2Cl O HO OH CH2OH O HO CH2Cl HO Sucralose or Splenda Sucralose is 600 times sweeter and does not get metabolized. Sildenafil (Viagra) and Caffeine CH3
CH3 O N CH3 H N N N CH3 S N N O O N
N N CH3CH2O O O N CH3 Radiosensitizer of Choice Until 2004 HOOC O O OH O OH
H H OH O O H O H Okadaic acid 17 asymmetric centers O OH
