Stereochemistry

Stereochemistry refers to the 3-dimensional 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.

Definitions

• Stereoisomers – compounds with the same connectivity, different arrangement in space

• Enantiomers – stereoisomers that are non-superimposible 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, [α]

[α] = α / cl = observed rotation

c = concentration in g/mLl = length of tube in dm

Dextrorotary designated as d or (+), clockwise rotation

Levorotary designated as l or (-), counter-clockwise 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 CenterCarbon has four different groups attached

Enantiomers nonsuperimposible mirror images

OH

CH3HO2CH

OH

CO2HCH3

H

mirrorplane

(S)(+) lactic acid (R)(-) lactic acid

from muscle tissue from milk[] = +13.5 [] = -13.5

oo

Enantiomeric Excess(Optical Purity)

actually 94.3% (+)

11.4% racemic88.6% (+)

= 88.6% e.e.

x 100 123.0109.0

e.e. =

oobserved rotation = +109

from oranges

o

[] = +123.0

H

from lemons

o[=

(S)-(-) Limonene (R)(+) Limonene

H

x 100 = enantiomeric excess (e.e.)rotation of pure enantiomerobserved rotation

Biological Activity

(R)(+) Thalidomide (S)(-) Thalidomide

N

NO

O

O

O

H

H

a sedative and hypnotic a teratogen

N

NO

O

O

O

H

H

SSRI Efficacy depends on Stereochemistry

ON(CH3)2

F

NC

*

(+/-) Celexa(-) Lexapro

Absolute Configuration

1

23

4

Use Cahn, Ingold, Prelog priorities

Place the lowest priority group back (focus down C - 4 bond)

(R)

clockwise

draw arrow from 1-2-31

2 34

(S)

counterclockwise

Assign Priority to each Group on Asymmetric Center

focus down C-4 bond

4

3

2

1I

ClHF

rotateI

FH

Cl

Lactic Acid

(S) (R)

4

3 2

1

4

32

1OH

CH3 CO2HH

OH

CH3HO2CH

C.I.P. Priorities

CH2CH2CH3 CH(CH3)2

CH2CH2OH CH2CH

O

CH2CH2CH3 CH=CH2

CO2H CH 2Cl

Low High

CH2CH2Br CH(CH3)2

Fischer Projections

Vertical bonds move away (dashed bonds)

Horizontal bonds approach you (wedge bonds)

OH

CO2H

CH3

HOH

CH3HO2CH

OH

CO2H

CH3

H

Assigning Absolute Configuration to Fischer

Projections

OH

CO2H

CH3

H

OH

CO2H

CH3

H

OH

CH3HO2CH

(S) (S) (S)rotate

Rotation of the Projection 90o

Reverses Absolute Configuration

90o

90oo

90

(S) (R) (S) (R)

CH3

H

OH

HO2C

CO2H

CH3

H

HO

H

OH

CO2H

CH3

OH

CO2H

CH3

H

DiastereomersStereoisomers That Are Not Mirror Images

3 322

opposite stereochemistry at C3

same stereochemistry at C2 (S)

CO2H

OHH

Br H

CO2H

OHH

BrH(2S,3S) (2S,3R)

Fischer Projections with 2 Chiral Centers

CO2H

CH3

H OH

Br H H Br

H OH

CO2H

CH3

(2S,3S) (2S,3R)

2

3

2

3

2 Chiral Centers4 Stereoisomers

Identical, Enantiomers or Diastereomers?

H

H

CH3

CH3

&

CH3

CH3

H

H CC

a)

CH2CH3

CH3

H

H

Br

Br

CH2CH3

CH3&

b)

OH

HO

NH2

NH2

Tartaric Acids

CO2H

CO2H

H OH

HO H H OH

HO H

CO2H

CO2H

CO2H

CO2H

H OH

H OH HO H

HO H

CO2H

CO2H

R,R S,S

R,S S,R

Racemic Mixture

o

(g/mL) 1.7598 1.7598 1.7723

m.p. C 168-170 168-170 210-212

[] (degrees) - 12 + 12 0

(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid

Racemic Mixture (Racemate): 50/50 mixture of enantiomers

CO2H

CO2H

H OH

HO H H OH

HO H

CO2H

CO2H

R,R S,S

Meso CompoundInternal Plane of Symmetry

Optically Inactive

orotate 180

superimposible

CO2H

CO2H

H OH

H OH HO H

HO H

CO2H

CO2H

R,S S,R

mirror plane

2,3,4-trichlorohexaneHow many stereoisomers?

Cl

Cl

Cl3 asymmetric centers

8 stereoisomers

* **

2n, n= # asymmetric centers (3)

n = 3; 2n = 8

CH3

CH2CH3

H Cl

Cl H

H Cl Cl H

H Cl

Cl H

CH3

CH2CH3

CH3

CH2CH3

Cl H

H Cl

H Cl Cl H

Cl H

H Cl

CH3

CH2CH3

H Cl

H Cl

H Cl

CH3

CH2CH3

Cl H

Cl H

Cl H

CH3

CH2CH3

Cl H

H Cl

H Cl

CH3

CH2CH3

H Cl

Cl H

Cl H

CH3

CH2CH3

S

S

R

R

R

S

A CarbohydrateCHO

CH2OH

H OH

HO H

H OH

H OH

(+) D-Glucose

R

S

R

R

Internal Planes of Symmetry

CH3CH3

CH3CH3

CH3CH3

CH3 CH3

Both are Meso

Asymmetric Centers on Rings

Br

Br

Br

Br

1(R),2(S) cis 1,2-dibromocyclohexane

nonsuperimposible but A flips into B

A B

BrBr

Meso

Allenes can be Chiral

C C C

H

CH3

C CClHC

CH3

H

ClH

Mycomycin, an antibiotic

C C C

H

CH=CHCH=CHCH2CO2HCCCCHH

Nocardia acidophilus []D = -130o

Reactions that Generate Chirality Centers

Hydrogenation, syn

CH3CH3

CH2CH3CH2CH3

H2, Pt/C

CH2CH3 CH2CH3

CH3CH3

HH

CH2CH3

CH2CH3

H CH3

H CH3

product is meso

BrominationTrans is formed exclusively

No Meso is formed (cis)

racemic mixture

S SR RBr BrBr Br

Br2

Bromonium Ion is Opened Equally from Both Sides

Br2

Br Br Br BrR R S S

racemic mixture

Br

Br

Br

Br

Br Br + -

trans alkene + anti addition = MESO

CH2CH3

CH2CH3 H

H

Br2

CH2CH3

CH2CH3

HH

Br

Br

Br Br

CH2CH3CH2CH3HH

meso

cis Alkene + anti addition = racemic mixture

H

CH2CH3 CH2CH3

H

Br2

Br Br

CH2CH3CH2CH3 H

HR R

CH2CH3

CH2CH3

H

H

Br

Br

CH2CH3CH2CH3 H

H

Br BrS S

Br

H HCH2CH3CH2CH3

Br

Br

BrH

H

CH2CH3

CH2CH3

a b

a b

Brominations Often Generate Asymmetric Centers

Br2

R RS S

racemic mixture

CH3CH3

H H

CH3CH3

Br BrH H

CH3CH3

Br BrH H

CH3

CH3 H

H CH3

CH3 H

H

Br

Br

CH3CH3

Br BrH H

S Rmeso

Br2

Asymmetric Center is Generated Racemic Mixture Formed

H-Br

HH

Br

Br

a)

b)

Br

H

a) Br

H

b)(R) (S)

Asymmetric Induction

PPh2

PPh2

RuCl2

CH3

OHH2

Ru(BINAP)Cl2

CH3H

OH

96% e.e.

Noyori and Knowles shared Nobel Prize in Chemistry, 2001

Preparation of (L)-Dopafor Treatment of Parkinson’s

HO

HO

CH2C

CO2H

NH2

H

l-(-) Dopa

HO

HO

CH2CH2NH2

Dopaminecannot cross blood-brain

barrier

C=CNH2

CO2HH

HO

HO

H2Rh(DIOP)Cl2

enz.

Relevance of Stereochemistry

(S,S)(R,S)useful decongenstants

d-pseudoephedrine and l-ephedrine

4 stereoisomers

**

2 asymmetric centers

EPHEDRA from Ma Huong

NHCH3

CH3

OH

One-step synthesis

Pseudophed

*

d-(S)- "Meth"l-(R) - Vicks

(methamphetamine)"desoxyephedrine"NHCH3

CH3

-(p-isobutylphenyl)propionic acid

CH3 CO2HH

(S)(+) ibuprofen (R)(-) ibuprofen

CH3HO2C

H

anti-inflammatory 80-90% metabolized to (S)(+)

Model of Thalidomide

How Sweet it is!

Sucrose

O

HOOH

O

CH2OH

OCH2OH

CH2OH

HO

HO

OH

Sucralose or Splenda

O

Cl

HOOH

O

CH2OH

OCH2Cl

CH2Cl

HO

HO

Sucralose is 600 times sweeter and does not get metabolized.

Sildenafil (Viagra) and Caffeine

NN

N

N

CH3

H

O

CH3CH2O

S

N

N

CH3

O

O

N

N

N

N

CH3

O

O

CH3

CH3

Radiosensitizer of Choice Until 2004

Okadaic acid17 asymmetric centers

O

OH

HOOC

OH

OH

O

OH

HO

OH

HOH

O

O