Stereochemistry- Chapter 3 1. Stereoisomerism 2. Chirality 3. Naming stereocenters - R/S configuration 4. Acyclic Molecules with 2 or more stereocenters 5. Cyclic Molecules with 2 or more stereocenters 6. Properties of Stereocenters 7. Optical activity 8. Separation of Enantiomers, Resolution 9. Significance of Chirality in the biological world Lect 6, Sept 17, 2002 Lecture 6, Feb 11, 2003 Lecture 7 Fall 03 February 6 04

Isomers - same molecular formula - different compounds constitutional isomers - different connectivity stereoisomers - same connectivity - different orientation in space (recall cis/trans)

Chirality handedness not superposable on its mirror image symmetry = superposable types: plane imaginary plane through an object one half is the mirror image of the other center identical parts on an axis equidistant from a point

If symmetry is present, the substance is achiral. Elements of Symmetry Conformations of 2,3-butanediol* syn - plane of symmetry anti - point of symmetry . . If symmetry is present, the substance is achiral. *meso or R,S (later)

Elements of Symmetry Plane of symmetry achiral

Chiral Center chiral center - carbon (atom) with 4 different groups common source of chirality - tetrahedral (sp3) carbon (atom) - bonded to 4 different groups chiral center - carbon (atom) with 4 different groups Enantiomers: stereoisomers nonsuperposable mirror images All chiral centers are stereocenters Not all stereocenters are chiral centers

Enantiomers representation of mirror image or enantiomer 2-Butanol - 1 chiral center different representations for this enantiomer representation of mirror image or enantiomer

Enantiomers 3-Chlorocyclohexene

Enantiomers A nitrogen chiral center

Enantiomers 2-Chlorobutane How is handedness designated?

Enantiomers Enantiomers of lactic acid another representation

R,S Convention - Priority rules Each atom bonded to the chiral center assigned a priority by atomic number higher atomic number, higher the priority increasing priority Same atoms bonded to the chiral center look to the next set of atoms priority assigned to 1st point of difference increasing priority

R,S Convention double (triple) bond atoms viewed as bonded to an equivalent number of atoms by single bonds

Naming Chiral Centers 1. Locate the chiral center, prioritize four substituents 1 (highest) to 4 (lowest) 2. Orient molecule so that lowest priority (4) group is directed away ( behind ) 3. Read three groups toward you (in front) (1) to (3) Clockwise R configuration; counterclockwise S

Naming Chiral Centers ( )-3-Chlorocyclohexene R ( )-mevalonic acid R

Stereochemistry- Chapter 3 1. Stereoisomerism 2. Chirality 3. Naming stereocenters - R/S configuration 4. Acyclic Molecules with 2 or more stereocenters 5. Cyclic Molecules with 2 or more stereocenters 6. Properties of Stereocenters 7. Optical activity 8. Separation of Enantiomers, Resolution 9. Significance of Chirality in the biological world Lect 6, Sept 17, 2002 Lecture 6, Feb 11, 2003 Lecture 7 Fall 03 February 6 04

Ibuprofen Naproxen S isomer S isomer particularly active, but R slowly converted to S Naproxen S isomer

Assign R/S to stereogenic carbon in coniine Assign R or S to carvone S caraway/dill R spearmint Assign R/S to stereogenic carbon in coniine Golden pitcher plant R-(-)-coniine poison hemlock

Enantiomers & Diastereomers molecule with 1 chiral center: 21 = 2 stereoisomers are possible molecule with 2 chiral centers: a max of 22 = 4 stereoisomers “possible” molecule with n chiral centers: 2n = maximum stereoisomers are possible

2n 256 (ignore sugar)

Enantiomers & Diastereomers 2,3,4-trihydroxybutanal 2 chiral centers 22 = 4 stereoisomers “possible” & exist 2 pairs of enantiomer (Erythrose) Diastereomers: stereoisomers that are not mirror images

Enantiomers & Diastereomers 2,3-Dihydroxybutanedioic acid (tartaric acid) 2n = 4 “possible” but only three stereoisomers exist Meso compound: achiral but possessing 2 or more chiral centers enantiomers symmetry plane-superposable (same compound)

Enantiomers & Diastereomers 2-Methylcyclopentanol cis-2-Methylcyclopentanol enantiomers left right diastereomers top bottom trans-2-Methylcyclopentanol

Enantiomers & Diastereomers 1,2-cyclopentanediol diastereomers trans-1,2-cyclopentanediol (enantiomers) cis-1,2-cyclopentanediol (a meso compound)

Enantiomers & Diastereomers cis-3-methylcyclohexanol flip: axial-equatorial reverse but still cis

Enantiomers & Diastereomers trans-3-methylcyclohexanol flip: axial-equatorial reverse but still trans

Isomers

Properties of Stereoisomers Enantiomers: identical physical and chemical properties in achiral environments m. pt. 174o 174o pK1 2.98 2.98 Diastereomers: different compounds different physical and chemical properties m. pt. 146o 174o pK1 3.23 2.98

Plane-Polarized Light optical activity Light vibrating in all planes  to direction of propagation Plane-polarized light: light vibrating only in parallel planes Plane-polarized light the vector sum of left and right circularly polarized light

Optically Activity Enantiomers (chiral) interact with circularly polarized light rotating the plane one way with R center and opposite way with S result: rotation of plane-polarized light clockwise (+) or counterclockwise (-)

Plane-Polarized Light (polarimeter) Change in the polarized plane? achiral sample no change in the plane

Plane-Polarized Light (polarimeter) Change in the polarized plane?  CHIRAL rotates the plane

Stereochemistry- Chapter 3 1. Stereoisomerism 2. Chirality 3. Naming stereocenters - R/S configuration 4. Acyclic Molecules with 2 or more stereocenters 5. Cyclic Molecules with 2 or more stereocenters 6. Properties of Stereocenters 7. Optical activity 8. Separation of Enantiomers, Resolution 9. Significance of Chirality in the biological world Lect 6, Sept 17, 2002 Lecture 6, Feb 11, 2003 Lecture 7 Fall 03 February 6 04

Optical Activity ( )-(+)-lactic acid ( )-(-)-lactic acid observed rotation: , degrees a compound rotates polarized light - dextrorotatory (+) right - levorotatory (-) left T specific rotation []D = ( )-(+)-lactic acid ( )-(-)-lactic acid S R

R-enantiomer is (-); R or S above? Example: 0.5g (-)-epinephrine-HCl in 10mL H2O measured in 20 cm cell (25o/D) obs = -5.0o, []D =? 25o R-enantiomer is (-); R or S above? [a] = deg (cm2g-1 )

Optical Activity Racemic mixture: equal amounts of (+) and (-) enantiomers - rotation is 0o For a 50/50 mixture of S and R,  = ? 0o

optical purity = 40% (S)-(+)-2-bromobutane, []D=+23.1o But from the obs, []D= +9.2? 21o It’s not pure; possibly some R present! If some R, what percent? Mix is between 100% S and 50/50 (S/R) +23.1o > +9.2o < 0o optical purity = 40% 40% excess = 40%S + (60%S/R mixture) 40% excess = 40%S + (30%S + 30%R)  the sample has 70%S and 30%R

Optical Purity: composition of a mixture of enantiomers enantiomeric excess (ee): difference between the percent of 2 enantiomers in a mixture ee = optical purity

e.g. 6g of (+)-2-butanol plus 4g of (-)-2-butanol, ee = ? ee = x100% 6 - 4 6 + 4 = 20% []D of (+)-2-butanol = +13.5o; obs sample = ? rt opt pure = = ee obs pure 20% = obs +13.5pure obs = (.20)(+13.5%) = +2.7o

Enantiomeric Excess 100% sample = 97%S + (3%S and R) Example: A commercial synthesis of naproxen (Aleve) gives the S enantiomer in 97% ee. What are the percentages of the R & S in this mixture? 100% sample = 97%S + (3%S and R) 97%S + (1.5%S+1.5%R) 98.5%S + 1.5%R

Resolution - separation of enantiomers One strategy: convert enantiomeric pair into 2 diastereomers diastereomers - different compounds different physical properties Common - reaction forming salt separate diastereomers remove :B leaves pure enantiomers 4

Resolution racemic acids - resolved w/ available chiral bases, e.g. (S)- and (R)-1-phenylethanamine

Resolution by acid-base reactions Pure-Sb ----resolved---- racemic mix

Resolution Examples of enantiomerically pure bases   CH =CH H CH =CH 2 =CH H CH 2 =CH H H H H HO H N N H HO H CH3O N N (+)-Cinchonine (-)-Quinine 23 [  ] = +228 D 25 [  ] = -165 D

racemic bases with chiral acids like: []D = -127o HCCl3 from Strycnos seeds (S nux-vomica) brucine Strychnine no methoxy groups racemic bases with chiral acids like:

Resolution [] = 0 enantiomeric mixture pure enantiomer + R S S R S S

Resolution [] = 0 enantiomeric mixture []25 = -8.2 pure enantiomer D [] = 0 pure enantiomer R S Resolution S []25 = +8.2 D

lipase >69%ee 50/50 mix R-Enzyme

lipase >69%ee R-Enzyme A 50/50 enantiomeric mixture of esters forms R-acid and recover S-ester. R-Enzyme

Enzymes as resolving agents racemic mix ethyl ester of (S)- and (R)-naproxin (R)-ester - no effect (S)-now acid different functional gp.

CHEMICAL & ENGINEERING NEWS Oct 23, 2000, pg 55 Chiral Drugs Sales top $100 Billion carbohydrates deoxynucleic acid amino acids

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 Chapter 5