Stereochem 2011-Pharm

INTRODUCTION TO STEREOCHEMISTRY

Isomers are compounds with the same molecular formula but not identical structures

Constitutional isomers are isomers which have the same molecular formula but differ in the way their atoms are connected

Constitutional Isomers

H3C

CH2

H2C

CH3

butaneChemical Formula: C4H10

CH3

CH

CH3H3C

2-methylpropaneChemical Formula: C4H10

Constitutional isomers are isomers which have the same molecular formula but differ in the way their atoms are connected

Stereoisomers have the same molecular formula, maintain the same connectivity, but differ in the way their atoms are arranged in space

Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about single bonds, and are often rapidly interconverting at room temperature

Conformations of Alkanes and Cycloalkanes

Conformations of Ethane

H3C CH3ethane

Staggered conformation of

ethane

Eclipsed conformation of

ethane

H

H H

H

HH

H

H

H

H

HH

H

H H

H

H H

H

H H

H

HH

Sawhorse Representation

Sawhorse Representation

Newman Projection

Newman Projection

ethane

Staggered conformation of

ethane

Eclipsed conformation of

ethane

H

H H

H

HH

H

H

H

H

HH

H

H H

H

H H

H

H H

H

HH

Sawhorse Representation

Sawhorse Representation

Newman Projection

Newman Projection

Configurational Isomers are stereoisomers that do not readily interconvert at room temperature and can (in principle at least) be separated.

Geometric isomers are configurational isomers that differ in the spatial position around a bond with restricted rotation (e.g. a double bond):

Geometric (Cis and Trans) Isomers

Geometric (Cis and Trans) Isomers result from restriction rotation

Compounds with double bonds cis isomer – have same substituents on the same side of the double bond (= Z with more complex molecules having high priority groups on the same side)

trans isomer – have the same substituents on the opposite side of the double bond (= E with more complex molecules having high priority groups on opposite sides)

Compounds with bonds in a ring: cis isomer – have the same substituents on the same side of the ring trans isomer - have the same substituents on the opposite side of the ring

Cis-trans (Geometric) isomerism in Alkenes

C C

ClCl

H H

cis-1,2-dichloroethene

C C

ClH

Cl H

trans-1,2-dichloroethene

(E)-1,2-dichloroethene(Z)-1,2-dichloroethene

Cis-trans (Geometric) isomerism in Alkenes

C C

ClH

H Cl

1,1-dichloroethene

*If one of the two carbon atoms of the double bond has two identical substituents, there are no cis-trans isomers for that molecule

Identifying cis and trans isomers of Alkenes

Example 11.3Two isomers of 2-butene are shown below. Which is the cis isomer and which is the trans isomer

C C

H

H3C

H

CH3

C C

H

H3C

CH3

H

cis-2-butene trans-2-butene

Naming cis and trans compounds

Example 11.4Name the following geometric isomers.

trans-3,4-dichloro-3-heptene cis-3,4-dimethyl-3-octene

H3C

H2C

CH2

C

C

Cl

Cl

H2C

CH3

H3C

CH2

C

H3C C

H2C

CH2

H2C

CH3

CH3

Identifying Geometric Isomers

Example 11.5Determine whether each of the following molecules can exist as cis-trans isomers:(1) 1-pentene(2) 3-ethyl-3-hexene(3) 3-methyl-2-pentene

1-pentene 3-ethyl-3-hexene

CH2CH3

CC

H3CH2C CH2CH3

H

C C

CH2CH2CH3H

H H

cis-3-methyl-2-pentene

C C

CH3H3C

H3CH2C H

C C

HH3C

H3CH2C CH3

trans-3-methyl-2-pentene

cis-9-octadecenoic acid

Cis and Trans Fatty Acids

O

OH

H H

O

OH

H

H

trans-9-octadecenoic acid

Cis-trans (Geometric) isomerism in Cycloalkanes

Cis-trans isomers are molecules having the same arrangement of atoms but differ in the spatial orientation of their substituents.

H

H

H

H

H

ClCl

H

HH

H H

cis-1,2-dichlorocyclohexane

H

H

H

H

H

ClH

Cl

HH

H H

trans-1,2-dichlorocyclohexane

Naming cis-trans Isomers of Substituted Cycloalkanes

Example 10.6Determine whether the following susbstituted cycloalkanes are cis or trans isomers.

trans-1,2-dimethylcyclopentane cis-1,2-dimethylcyclopentane

H

H

H

H

H CH3

HCH3 H

H

CH3

CH3

H

H

H

H

CH3CH3

HH H

H

CH3 CH3

Conformations of Alkanes and Cycloalkanes

Conformations of Cyclohexane

cyclohexaneChair

conformation of cyclohexane

Boat conformation of

cyclohexane

H

H

H

H

H

HH

H

HH

H H

A E

A

E

A

A

E

E

A

E

A

E

A

E

A

E

A

A

E

A

E

A

E

E

Chair conformation of

cyclohexane

Boat conformation of

cyclohexane

A E

A

E

A

A

E

E

A

E

A

E

A

E

A

E

A

A

E

A

E

A

E

E

Chair-Chair Interconversion

Optical isomers are configurational isomers that differ in the 3D relationship of the substituents about one or more atoms.

Diastereomers are optical isomers (stereoisomers) that are not enantiomers.

Enantiomers are optical isomers that are non-superimposable mirror images.

Chirality

Chiral objects are objects with left-handed and right-handed forms

Achiral objects - objects that have superimposable mirror images

Nonsuperimposable mirror images - a mirror image that is not the same as the image itself - chiral objects have nonsuperimposable mirror images

Assymetric Center

Chirality is not reserved just for objects - molecules can be chiral

Chiral molecules - generally molecules containing an asymmetric center

Asymmetric (chiral) center - tetrahedral atom bonded to four different groups - indicated with an asterisk (*)

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

Chiral Molecules with One Asymmetric Center

Molecules with one chiral center would have 2 enantiomers*Chiral molecules would have 2n enantiomers (where n is the number of chiral centers)

Chiral vs Achiral

How to Represent Enantiomers: Perspective Formulas

Perspective Formulas - shows two bonds of the asymmetric center as lines in the plane of the paper, another bond as a solid wedge protruding forward out of the paper, and the fourth bond as a hatched wedge extending behind the paper

Fischer Projections

Fisher Projection - representation of an asymmetric center as the point of intersection of two perpendicular lines

Horizontal lines represent bonds that project out of the plane of the paper

Vertical lines represent bonds that extend back from the plane of the paper away from the viewer

Fischer Projections

Br

H

CH3H3CH2C

Br

H

CH2CH3H3C

Naming Enantiomers -R,S System

STEP 1. Rank the groups/atoms bonded to the asymmetric center in order of priority. - rank in terms of atomic mass. Higher atomic mass, higher priority. - let’s have 1-chloro-1-ethanol as an example.

1. Chlorine = 36 amu 2. Oxygen = 16 amu 3. Carbon = 12 amu4. Hydrogen = 1 amu

STEP 2. Rotate the molecule so that the lowest priority group is pointing away from thereader.

Naming Enantiomers -R,S System

Step 3. Trace your finger around the three highest priority groups in order of the priority.

- If the circle is moving counterclockwise the CIP designation is “S”. If the circle is moving clockwise the CIP designation is “R”.

Step 4. Name the enantiomer in terms of its R or S configuration.- the name for this isomer is (S)-1-chloro-1-ethanol

Naming Enantiomers -R,S System

Assigning Priorities to Groups

1. Oxygen (from CH2OH) = 162. Carbon (from CH2CH3) = attached to carbon3. Carbon (from CH3) = attached to hydrogen4. Hydrogen = 1

Naming Enantiomers -R,S System

Lactic Acid

(S) (R)

4

3 2

1

4

32

1OH

CH3 CO2HH

OH

CH3HO2CH

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 a = 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 [a] # * centersPenicillin V +233.0 3Sucrose +66.5 10 Camphor +44.3 2MSG +25.5 1Cholesterol -31.3 8Morphine -132.0 5

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

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 AcidsCO2H

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 Carbohydrate

CHO

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

BrominationTrans is formed exclusively

No Meso is formed (cis)

racemic mixture

S SR RBr BrBr Br

Br2

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

a-(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