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

StereochemistryStereochemistryOH

CH

H3C F

HO

CH

H3CF

21

Chapter 3

Looking for a change in the polarized plane

no change in the plane

achiral sample

rotates the plane

Looking for a change in the polarized plane

20

D

R-(+)-2-methyl-1-butanol

CH CH2OH

H3CH2C

H3C

D

20

S-(-)-2-methyl-1-butanol

CHHOH2C

CH2CH3

CH3

50/50 mixture of S and R 50% S(-5.75o) with 50% R(+5.75o)

net rotation = 0RACEMIC MIXTURE

Observed dependent on (conc.), (cell length), (temp.)

Specific Rotation

[]t = (degrees) l (dm) c (g/mL)

t = temperature = wavelengthl = path length (dm)c = concentration (g/mL)

Specific Rotation

[]t =l c

Example: A sample of 2 g in 10 mL of solutionmeasured in a 25 cm long cell gives an observed of +134o

The specific rotation is?

Specific Rotation

[]t =

[]t =

+268o

(+134o)2.5 (0.2)

(actually deg/cc2g-1)

Optical purity Absolutely pure (100%)

cholesterol has a specific rotation of -39o.

HO

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.

[-]t =

()1dm (1g pure)

observe = -39o

= -38.6o

= -35.1o

()1dm (?g+crap )[-]t =

= less than -39o

= -31.2o

(-35.1)1dm ( )[-]t =

(-31.2)1dm ( )[-]t =

1dm ( )[-]t = -38.6o

0.99g+0.01g

0.9g+0.1g

0.8g+0.2g

Pure (S)-(+)-2-bromobutanespecific rotation - +23.1o

But what if observe optical rotation = +9.2? Not pure, possibly a mix of R and S!!!!

CBrH

CH3

CH2CH3

+23.1o > +9.2o < 0o

Mix is between100% S and 50/50 (S/R)optical purity

optical purity = ----------------------observed (100%)

of pure enantiomer=

+9.2(100%)

+23.1

40% optical purity i.e. 40% excess of S isomer

40% excess = 40%S + (60%S/R mixture)

The sample has 70%S and 30%R

= 40%

Pure (S)-(+)-2-bromobutanespecific rotation - +23.1o

But what if observe optical rotation = +9.2? Not pure, possibly a mix of R and S!!!!

CBrH

CH3

CH2CH3

+ (30%S+30%R)

enantiomeric excess or ee (= optical purity)

ee =(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 enantiomerobserved rotation = +4.8What is the specific rotation of each enantiomer?

Solution of 10 mL of 0.1 M R enantiomer 30 mL of 0.1 M S enantiomerobserved 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

24

opt. purity = = = 50%

X = + 9.6 (S) observed +, S

=50%+4.8

X

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?

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)

[]

opt. purity = ee = 25o

D

23.1

75% =

(+)75% + racemic(+/-)

opt pure rotation mix (+)%/(-)% 75% +17.3 87.5/12.5

or (+)75% + (12.5%(+) +12.5%(-))or (+)87.5% / (-)12.5%

(S)-(+)-2-bromobutane, = +5.75

(+) or (-) a measured physical property - not predictable

NaOH

CO2H

C

CH3

HHOCO2

- +Na

C

CH3

HHO

(S)-(+)-lactic acid sodium (S)-(-)-lactate

These similar “S” compounds rotate light in the opposite direction.

Convert mixture of enantiomers - same properties

Resolution (separation):Resolution (separation):

TO diastereomers - different physical properties, can be separated.

R

R1

S

R1

ResolutionResolution

Rnon-separable

enantiomeric mixture

separate

S R

R1

new compoundsdiastereiomeric mixture

S

R1

+differentcompound

2 equivalentsR1

remove R1

remove R1

pure S

Rpure

Resolution by acid-base reactions

Pure-Sb

racemic mix

+

NH

C

H

H3CPh

H

CH3

CH

CF3

CO O

H

CH3C

CF3

CO O

NH

C

H

H3CPh

H

H

H

CH3C

H

CO O

NH

C

H

H3CPh

H

H

F3C

+

CH3C

F3C

CO

ON

H

CH

CH3

Ph

HHH

C

H3C

H

C

O

ON

H

CH

CH3

Ph

HHF3C

CH3 C

H

CF3

CO

O

CH3C

H

CF3C

O

O

remove amine

remove amine

Examples of enantiomerically pure bases

ResolutionResolution

(+)-cinchonine [R=H](+)-quinidine [R = OCH3]

H

N

HCH2=CH

N

HHO

CH2=CH

(-)-quinine

HHO

N

N

CH3O

H H

H

H

R

[]D = -127o HCCl3 from Strycnos seeds (S nux-vomica)

brucine

Strychnine no methoxy groups

N

N

O

H

H

O

H

H3CO

H3COH

H

N HH

H

O

HF

HOS

enantiomeric mixture

OHH

[] = 0

OHH

OHH

R

S

pure enantiomer

O

HF

ClS

OHH

S

OHH

R

R

S

S

S+

O

O

HFH

O

HFO

H

O

O

HFH

R

O

HFO

H

S

enantiomeric mixture

[] = 0

OHH

OHH

R

S

pure enantiomer

O

HF

ClS

[]25 = -8.2DOHH

R

O

HF

HO

+

OHH

S

O

HF

HO+

[]25 = +8.2D

H3C

CH2

H2C

CH2

H2C

C

C

OO

CH2

FH

CH3

OHH O

H

O

H

lipase

R-Enzyme

H3C

CH2

H2C

CH2

H2C

C

CO

OH

FH

>69%ee

CH3

H2C

CH2

H2C

CH2

C

CO

OH2C

FH

H3C

50/50 mix

H3C

CH2

H2C

CH2

H2C

C

CO

OCH2

FH

CH3

OHH O

H

O

H

lipase

R-Enzyme

H3C

CH2

H2C

CH2

H2C

C

CO

OH

FH

>69%ee

CH3

H2C

CH2

H2C

CH2

C

CO

OH2C

FH

H3C

CH3

H2C

CH2

H2C

CH2

C

CO

OH2C

FH

H3C

CH3

H2C

CH2

H2C

CH2

C

CO

OH2C

FH

H3C

CH3

H2C

CH2

H2C

CH2

C

CO

OH2C

FH

H3C A 50/50 enantiomeric mixture of esters

forms R-acid and recover S-ester.

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)

Cl

O

NtBuH

H3CO

(H3C)2N

OH.HCl

IbuprofenCH3C

CH3

C

H3C H

C

O

OH

H

S isomer particularly active, but R slowly converted to S

C CH3

H3C

C

CH3H

C

O

OH

H

Naproxen - S isomer

OCH3

CH3

-O2CH

Na+

(R enantiomer liver toxin)

R / S

N

H2C C C

H2C

CH3H3C

OH3C

C

O

CH2CH3

H N

CH2CC

CH2

H3C CH3

OCH3

C

O

H3CH2C

H

R \ S

analgesic DarvoN | NovraD antitussive2S,3R-propoxyphen | 2R,3S-propoxyphen

SS

R

N

O

O

NO H

OH

Thalidomide R- sedative, anti-inflammatory, Crohn’s disease S -teratogenic

N

O

ON

O H

O

N

O

O

NO

H

O H

(but thalidomide racemized in the body)