Isomerism: Constitutional Isomers and Stereoisomers

Constitutional Isomers = same molecular formula, different connectedness Stereoisomers = same molecular formula, same connectivity of atoms but different arrangement of atoms in space

Chapter 5

Stereochemistry: Chiral Molecules

Constitutional Isomers - Review

1.

Two types of stereoisomers

Enantiomers: stereoisomers whose molecules are nonsuperposable mirror images Diastereomers: stereoisomers whose molecules are not mirror images of each other
Example: cis and trans double bond isomers

Same molecular formula different bond connectivities

Examp les of Constitutional Isomers formu la C3H8O C4H10 constitutional isomers OH CH3CH2CH2OH CH3CHCH3 CH3CH2CH2CH3 CH3CHCH3 CH3

2.

Example: cis and trans cycloalkane isomers

Always different properties Very different properties if different functional groups

Enantiomers and Chiral Molecules

t Chiral molecule - has the property of handedness
l Not superposable on its mirror image l Can exist as a pair of enantiomers

Mirror images = handedness

t Pair of enantiomers
l A chiral molecule and its mirror image

t Achiral molecule
l Superposable on its mirror image

Left hand cannot be superimposed on the right hand

A chiral molecule: 2-butanol

Mirror image = converts right hand into left

I and II are mirror images of each other I and II are not superposable and so are enantiomers

2- propanol is not chiral B is mirror image of A, but is superimposable by 180 o rotation

Chiral molecules and stereogenic centers

1. A molecule with a single tetrahedral carbon bonded to four

different groups will always be chiral

2. Switching two groups at the tetrahedral center leads to the

enantiomeric molecule
CH3 H C CH3 A OH HO CH3 C CH3 B H

3. A molecule with more than one tetrahedral carbon bonded to

four different groups is not always chiral

l Stereogenic center (stereo center)
An atom bearing groups of such nature that an interchange of any two groups will produce a stereoisomer Carbons at a tetrahedral stereogenic center are designated with an asterisk (*)

l Example: 2-butanol

rotate

Everything has a mirror image, the question is whether it is superimposable

Tests for achirality

Mirror images not superimposable = enantiomers
1. Draw mirror image. Is it superimposable?

2. Does the species have a bisecting plane of symmetry?

Plane of Symmetry = achiral

An imaginary plane that bisects a molecule in such a way that the two halves of the molecule are mirror images of each other A molecule with a plane of symmetry cannot be chiral
H Cl

2 -chlorobutane: no plane of Symmetry

Cl

*
H

Cl

H
2-chloropropane

Compounds with 4 different groups attached to one Carbon must be chiral unless a meso compound (2 stereocenters)

If any two groups on a C are identical, achiral

Many biological processes depend on chirality

t The binding specificity of a chiral receptor site for a

Nomenclature of Enantiomers: The R,S System Developed as the Cahn-Ingold-Prelog system (1956)

chiral molecule is usually only favorable in one way

1. 2.

The four groups attached to the stereogenic carbon are assigned priorities from highest (a) to lowest (d) Priorities are assigned as follows
Atoms directly attached to the stereogenic center are compared Atoms with higher atomic number are given higher priority

3.

If priority cannot be assigned based on directly attached atoms, the next layer of atoms is examined

2-butanol

R,S nomenclature, cont.

4.

R,S nomenclature, cont.

5. Groups with double or triple bonds are assigned

The molecule is rotated to put the lowest priority group back

If the groups descend in priority (a,b then c) in clockwise direction the enantiomer is R (R= rectus, right) If the groups descend in priority in counterclockwise direction the enantiomer is S (S=sinister, left)

priorities as if their atoms were duplicated or triplicated

R,S nomenclature, cont.

6.

If lowest priority group is not in back: 3 options

1. Rotate molecule to put lowest priority in back

With isotopes, higher atomic weight gets priority

H
2

OH
1

2. Move your eye to sight along bond toward group 4

If lowest priority group is not in back: third option 1. Swap any two groups and then assign the opposite of the new priority
This works because interchanging two groups automatically generates the enantiomer of the original
H
H3 C H

Name this enantiomer of 3 -chloro-3-methyl -1-pentene

(D) CH 3
Assign an (R ,S) label to this stereoisomer:

(B) C H2 =CH

(C )

C (A) Cl CH2 CH3

Step 1: Assign Priorities

C H3 OH

Step 2: Visualize along the axi s with the lowest priority group away from the viewer.
(B)

OH

Swap H and CH3

-------->

C H=C H2
(D) CH3

Cl CH 2 CH 3
(C)

(A)

This stereoisomer is (S).

counterclockwise

R
therefore: S

Step 3: Trace out the sequence A---->C.

Comparing molecules: Are A and B identical or enantiomers?

Properties of Enantiomers
t Enantiomers have almost all identical physical properties

(melting point, boiling point, density) Method 1:Rotate B to see if it will become superposable with A
Physical Properties of (R) and (S)-2-But anol (R) 99.5o C 0.808 (S) 99.5o C 0.808

boiling point density (g/mL, 20o C)

Method 2: Exchange 2 groups to try to convert B into A

l One exchange of groups leads to the enantiomer of B l Two exchanges of groups leads back to B

t However enantiomers rotate the plane of plane-polarized light

in equal but opposite directions

Properties of Enantiomers: Optical Activity

t Enantiomers rotate the plane of plane-polarized light in

Plane polarized light

equal but opposite directions

Oscillation of the electric field of ordinary light occurs in all possible planes perpendicular to the direction of propagation

Reflected light is largely horizontally polarized If the light is passed through a polarizer only one plane emerge s

Plane polarized light

Plane polarized light oscillates in a single plane

Schematic of a Polarimeter

Like a rope thru a picket fence

Specific Rotation a property of an enantiomer

An optically active substance (e.g. one pure enantiomer ) will rotate the plane-polarized light
l The amount the analyzer needs to be turned to permit light through

Specific rotation of enantiomers

l The specific rotation of the two pure enantiomers of 2-

is called the observed rotation l We need to calculate a standard value specific rotation [ ]

butanol are equal but opposite

l There is no straightforward correlation between the R,S

l If the analyzer is rotated clockwise the rotation is (+) and the

molecule is dextrorotatory (D) l If the analyzer is rotated counterclockwise the rotation is ( -) and the molecule is levorotatory (L)

designation of an enantiomer and the direction [(+) or (-)]in which it rotates plane polarized light

An example of specific rotation

A sample of a compound A in chloroform (0.500 g/mL) at 25.0 oC shows a rotation of +2.5 o in a 1.0 decimeter cell. What is the specific rotation?

Racemic Mixture = A 1:1 mixture of enantiomers

t No net optical rotation t Often designated as (+) t Racemic mixture = racemate

[] ltemp

LxC

+2.5o 1.0 dm x 0.5 (g/mL)

= +5.0o dm-1 (g/mL) -1

Wha t is the o bserv ed ro ta tio n o f A in a 0 .5 dm ce ll?

= []

x L x C = 5.0 o dm-1 (g/mL) -1 x 0.5 d m x 0.5 g/mL = + 1.25o

What is the observed r ot at ion if C = 0.050 g/mL?

= []

x L x C = 5.0 o dm -1 (g/mL)-1 x 1.0 d m x 0.050 g/ mL = +0.25 o

Equal amounts of each

Enantiomeric Excess
A mixture of enantiomers may be enriched in one enantiomer We can measure the enantiomeric excess (ee)

Enantiomeric Excess

ee of 50% = 50% of one enantiomer (+) 50% of racemate (+/-)

t Example : The optical rotation of a sample of 2-butanol is

+6.76o . What is the enantiomeric excess?

Equivalently 75% of (+)-enantiomer 25% of (-)-enantiomer

The Synthesis of Chiral Molecules

Most chemical reactions which produce chiral molecules generate the racemic mixture (50%R, 50% S)

Enantioselective Synthesis
If all starting materials and reactants are achiral, the products will be achiral or racemic If one of the reagents is chiral, as is common in biological systems, then the products may be chiral e.g.: picking out the left handed gloves from a racemic mixture of rights and lefts
H

O enzymatic reduction ClCH2CH2CH2CCH3 alcohol dehydrogenase 5-chloro-2- pentanone

OH CH 3

C ClCH 2CH 2CH 2

(S)-5-chloro-2 -pentanol ( 98% ee)

(achiral)

Top and bottom faces of the ketone bond are different to handed reagents

Enantioselective Synthesis in the lab

Synthetic chemists are designing chiral catalysts that mimic the en an tioselectivi ty of en zyme-catalyzed reaction s.

Chiral Drugs and Pharmaceutical Companies

Typically only one enantiomer of a drug is biologically active Preparation of only the desiredenantiomer saves material, costs, and possible side effects

O H
(achiral) (i) chiral catalyst (ii) acid workup

HO H

O O
H HO CH3 HO O (S) (active) O (R) (inactive) H CH 3

+ CH 2=C

OSi(CH 3) 3 OCH3

methyl 5 -phenyl pentan-3-ol-oate (98% ee) (S)

(achiral)

Ibuprofen

Molecules with More than One Stereogenic Center

Each new center may generate a potential pair of stereoisomers, so the theoretical number of possible stereoisomers is 2 n (May have fewer if symmetry elements are present)

Four stereoisomers of 2,3-dibromopentane

Relationship of 1 and 2 = enantiomers

l Enantiomers = same properties, cannot be separated

How many stereoisomers?

Relationship of 3 and 4 = enantiomers 1 and 3 (or 1 and 4) = diastereomers

l Diastereomers: stereoisomers not mirror images of each other l Have different physical properties and can be separated

Four stereoisomers of 2,3-dibromopentane

Meso compounds
Sometimes molecules with 2 or more stereogenic centers will have less than the maximum amount of stereoisomers

We cannot simply say that 1 is an enantiomer or a diasteromer Stereoisomerism refers to the relationship between two isomers

Meso compound are achiral

t Because superposable on its mirror image t Despite the presence of stereogenic centers t Not optically active t Has a plane of symmetry

Meso Compounds and Racemates

Under achiral conditions, a synthesis of 2,3-dibromobutane may create:
A and B in equal amounts (the racemate) C (the meso product) Some mixture of racemate (A/B) and meso compound C

+ {_____________} Definition: a meso compound is a compound that is achiral despite having stereogenic centers
racemate

meso

Naming Compounds with More than One Stereogenic Center

Using same rules, assign each stereogenic center separately Example: (2R, 3R)-2,3-dibromobutane

Fischer Projections
A 2-dimensional representation of chiral molecules
l Vertical lines represent bonds projecting behind the plane of the paper l Horizontal lines represent bonds projecting out of the plane of the

paper

Cannot rotate a Fischer projection about either vertical or horizontal axis

Widely used in carbohydrate chemistry

Relative Configurations: (D)- and (L)-Glyceraldehyde

Relating Configurations of StereogenicCenters

If no bonds to the stereogenic carbon are broken, the reaction proceeds with retention of configuration

In the la te 19th cent ury , Emil Fischer developed a method for assigning configurat io ns at stereocenters relativ e t o the enantiomers of glycera ldehyde. Fo r t he next 50 o r 6 0 years, config ura tions at stereocenters were la beled rela tive to the stereo centers in the stereoiso mers of glycera ldehyde.
The St ereoiso mers of Glycera ldehyde

O HO OH g lyceraldehy de H
H

O CH C OH CH 2OH (R) HO

O CH C H CH2OH ( S)

(+)
(D)

(-)
( L)

Note change of R to S despite retention

Over 10 0 years ago , Fischer assigned t he dextro rotat ory (+) st ereoiso mer, the config urat ion we call ( R) , and t he levoro tat ory (-) st ereoiso mer was a ssigned the (S) co nf ig ura tion .
The la bels Fischer a ssigned were ca lled (D) a nd (L) . These a ssignments were a g uess.

A n Example : Re lating (-)-Lac tic A cid to (+)-Glyc eraldeh yde

Absolute Configurati onal Assignments

O CH H C* OH
HgO oxidation
Retention

O COH H C* OH CH 2 OH (-)-glyceric acid

O
HNO 2 H 2O
Retention

COH H C* OH CH2NH2 (+ )-isoserine

HNO2 HBr Retention

CH 2OH (+ )-glyceraldeh yde

The series of chemical reactions involv ing retention of configuratio n at the stereo centers configurationally link (+)-glyceraldehyde and (-)-lactic acid .

O CH H C* OH configurationally the same

O COH H C* OH CH 3 (-)-lactic acid

This transformation shows that (+ )-isoserine has the same absolute con figuration as (+)-glyceraldehyde.

O COH H C* OH CH3 (-)-lactic acid

Zn, H +
Retention

O COH H C* OH

CH 2OH (+)-gly ceraldehyde

CH2Br (-)-3-bromo-2-h ydroxypropanoic acid

Before 1951 the absolute configurations were not known. Only these relative configurations were known from carefully designed chemical transformations linking the assignments to the configurations of the glyceraldehydes assumed by Emil Fis cher.
1951, X-ray crystal structure of (+) tartaric acid showed Fischer made the right guess!

This transformation shows that (+)-isoserine has the same absolute configuration as (-)-lactic acid.

Stereoisomerism of Cyclic Compounds

Consider 1,2-dimethylcyclopropane Two stereogenic centers
CH 3 I CH 3 trans CH3

Stereoisomerism of Cyclic Compounds

l 1,4-dimethylcyclohexane
Neither the cis not trans isomers is optically active Each has a plane of symmetry

II CH3

III H3C CH3 cis

Trans isomer has two enantiomers R,R and S,S

Cis isomer is a meso compound

t 1,3-dimethylcyclohexane
l The trans and cis compounds each have two

Separation of enantiomers = resolution

Cannot be separated directly Why not? Can be separated by chiral reagent which creates diastereomeric relationship

stereogenic centers
l The cis compound has a plane of symmetry and is meso l The trans compound exists as a pair of enantiomers

R S Racemic Form

R
reaction

R R
separate

- R

R
pure forms

+ S R
Dia stereo mers (different pro perties)

- R

(ide nt ical propert ies)

is a resolving agent. It is a single enant iomer (such as R) of a chiral compound.

Ring flip of (a) produces another (a), not the mirror image (b)

General Approach to Resolution

Often use organic acids or based which are found optically pure in nature Can form acid-base salts which usually assures a high melting point and the potential to separate by selective crystallization Easily regenerate starting acid or base

Resolution of a Carboxylic Acid

CH 3 C6 H * 5CCOOH H
( ra cemic form)

(+)(-)-Salt + (-)-alkaloid
(basic)

(-)(-)-Sal t diastereomer s
separate by fractional cryst allization

(+,- )-2-phenylpro panoic acid

CH 3O

HO H

H N

(+)(-)-S alt
H3O+

(-)(-)-Salt
H3O+

quinine
(primary alkaloid from various spec ie s of Cinchona)

wate r phase organic phase CH 3 (-)-alkaloid as (+ )- C6 H5* CCOOH ammonium salt H

organic phase water phase CH 3 (-)-alkaloid as * (-)- C 6H 5 CCOOH ammonium salt H

Chiral Molecules without a tetrahedral carbon

R1 R4 N
R1 R4 Si R3
silane

Chirality without tetrahedral atoms

l Atropoisomer: conformational isomers that are stable

+ R2

R2

R3
quaterna ry ammonium io n

Chir al Molecules withou t a Stereoce nter : Molec ular C hirality

Some molecules begin a helical chirality by restricted rotation

l Allenes: contain two consecutive double bonds
A A
B B A A A A B

B B

10