Stereochemistry 1. Stereoisomerism 2. Chirality Chapter 3 Stereochemistry 1. Stereoisomerism 2. Chirality 3. Naming stereocenters - R/S configuration - working with R/S [Home Page -Practice ] 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 21

Looking for a change in the polarized plane achiral sample no change in the plane

Looking for a change in the polarized plane  CHIRAL rotates the plane

R-(+)-2-methyl-1-butanol S-(-)-2-methyl-1-butanol  20 D D 20  50/50 mixture of S and R 50% S(-5.75o) with 50% R(+5.75o) net rotation = 0 RACEMIC MIXTURE

Specific Rotation  Observed  dependent on (conc.), (cell length), (temp.) Specific Rotation []t = (degrees) l (dm) c (g/mL)  t = temperature  = wavelength l = path length (dm) c = concentration (g/mL)

Example: A sample of 2 g in 10 mL of solution Specific Rotation []t =  l c  Example: A sample of 2 g in 10 mL of solution measured in a 25 cm long cell gives an observed  of +134o The specific rotation is? (+134o) 2.5 (0.2) []t =  []t =  +268o (actually deg/cc2g-1)

Optical purity Absolutely pure (100%) cholesterol has a specific rotation of -39o. synthetic sample may contain: the enantiomer -  (or < -39o) or a diastereomer -  (or < -39o) or other junk -  (or < -39o)

Optical purity Absolutely pure cholesterol has a specific rotation of -39o.  () 1dm (1g pure) observe  = -39o () 1dm (?g+crap ) [-]t =   = less than -39o  1dm ( ) [-]t = -38.6o  = -38.6o 0.99g+0.01g (-35.1) 1dm ( ) [-]t =   = -35.1o 0.9g+0.1g (-31.2) 1dm ( ) [-]t =   = -31.2o 0.8g+0.2g

Mix is between100% S and 50/50 (S/R) Pure (S)-(+)-2-bromobutane specific rotation - +23.1o But what if observe optical rotation = +9.2? Not pure, possibly a mix of R and S!!!! +23.1o > +9.2o < 0o Mix is between100% S and 50/50 (S/R) optical purity

Pure (S)-(+)-2-bromobutane specific rotation - +23.1o But what if observe optical rotation = +9.2? Not pure, possibly a mix of R and S!!!! observed (100%)  of pure enantiomer = +9.2(100%) +23.1 optical purity = ---------------------- = 40% 40% optical purity i.e. 40% excess of S isomer 40% excess = 40%S + (60%S/R mixture) + (30%S+30%R) The sample has 70%S and 30%R

enantiomeric excess or ee (= optical purity) (moles 1 isomer) - (moles of other) (moles of both enantiomers) X 100% (.70) - (.30) (1.00) ee = X 100% ee = 40%

Solution of 10 mL of 0.1 M R enantiomer 30 mL of 0.1 M S enantiomer observed rotation = +4.8 What is the specific rotation of each enantiomer?

Solution of 10 mL of 0.1 M R enantiomer 30 mL of 0.1 M S enantiomer observed rotation = +4.8 What is the specific rotation of each enantiomer? opt. purity = mole S - mole R (moles of S + R) 3 - 1 3 + 1 2 4 opt. purity = = 50% = 50% +4.8 X X = + 9.6 (S) observed +,  S

What is the optical rotation of a sample of (+)-2-bromobutane ([]25 = +23.1) that is 75% optically pure? What percentage of (+) and (-) enantiomers are present in this sample?

opt pure rotation mix (+)%/(-)% 75% +17.3 87.5/12.5 What is the optical rotation of a sample of (+)-2-bromobutane that is 75% optically pure? What percentage of (+) and (-) enantiomers are present in this sample? ([]25 = +23.1)  []  23.1 75% = opt. purity = ee = 25o D  (+)75% + racemic(+/-) or (+)75% + (12.5%(+) +12.5%(-)) or (+)87.5% / (-)12.5% opt pure rotation mix (+)%/(-)% 75% +17.3 87.5/12.5

These similar “S” compounds rotate light in the opposite direction. (S)-(+)-2-bromobutane, = +5.75 (+) or (-) a measured physical property - not predictable These similar “S” compounds rotate light in the opposite direction. NaOH (S)-(+)-lactic acid sodium (S)-(-)-lactate

Resolution (separation): Convert mixture of enantiomers - same properties TO diastereomers - different physical properties, can be separated.

Resolution R S S R R R S S 2 equivalents R1 + R1 pure R1 R1 pure new compounds diastereiomeric mixture S + enantiomeric mixture different compound 2 equivalents R1 S R non-separable separate remove R1 R R1 S R pure pure S

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

Resolution Examples of enantiomerically pure bases R CH =CH H CH =CH H 2 =CH H CH 2 =CH H H H H R HO H N N H HO H CH3O N N (+)-cinchonine [R=H] (+)-quinidine [R = OCH3] (-)-quinine

[]D = -127o HCCl3 from Strycnos seeds (S nux-vomica) brucine Strychnine no methoxy groups

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

CHEMICAL & ENGINEERING NEWS Oct 23, 2000 pg 55 Chiral Drugs Sales top $100 Billion C&E NEWS Oct 1, 2001 pg 79 40% of all dosage-form drug sales in 2000 were single enantiomers. (Now >>50% single enantiomer)

Some drugs are racemic mixtures, e.g. antidepressants: Wellbutrin (bupropion, in Zyban) Effexor (venlafaxine hydrochloride)

Ibuprofen Naproxen - S isomer S isomer particularly active, but R slowly converted to S Naproxen - S isomer (R enantiomer liver toxin)

R-ketamine hallucinogenic S-ketamine anaesthetic R|S

analgesic DarvoN | NovraD antitussive 2S,3R-propoxyphen | 2R,3S-propoxyphen R / S R \ S

Thalidomide R- sedative, anti-inflammatory, Crohn’s disease S -teratogenic (but thalidomide racemized in the body)