1. Stereoisomerism 2. Chirality 3. Naming stereocenters - R/S configuration

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 21

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

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

20 20   D D R-(+)-2-methyl-1-butanol S-(-)-2-methyl-1-butanol 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)

 l c []t =  (+134o) 2.5 (0.2) []t =  +268o []t =  Specific Rotation 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? (actuallydeg/cc2g-1)

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

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

+23.1o > +9.2o < 0o Mixisbetween100% 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 ofRand S!!!! optical purity

observed (100%) +9.2(100%) = +23.1  of pure enantiomer Pure (S)-(+)-2-bromobutane specific rotation - +23.1o But what if observe optical rotation =+9.2? Not pure, possibly a mix ofR and S!!!! optical purity= ---------------------- = 40% 40% optical purity i.e. 40% excessof S isomer 40% excess= 40%S + (60%S/Rmixture) + (30%S+30%R) The sample has 70%S and30%R

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

mole S - mole R (moles of S + R) opt. purity = 2 4 3 - 1 3 + 1 50% opt. purity = = = +4.8 50% = X 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? 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?

 23.1 opt. purity = ee = 75% = 25o D 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)  []  (+)75% + racemic(+/-) or (+)75% + (12.5%(+) +12.5%(-)) or (+)87.5% / (-)12.5% opt pure rotation mix (+)%/(-)% 75% +17.3 87.5/12.5

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

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

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

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

CH =CH CH =CH 2 2 Resolution H H • Examples of enantiomerically pure bases H H H R H N HO 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

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

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

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

lipase >69%ee 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&ENEWS 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)

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

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

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

1. Stereoisomerism 2. Chirality 3. Naming stereocenters - R/S configuration