Isomers Have same molecular formula,

but different structures

Constitutional Isomers Differ in the order of attachment of atoms

(different bond connectivity)

Stereoisomers Atoms are connected in the

same order, but differ in spatial orientation Diastereomers

Not related as image and mirrorimage stereoisomers

Enantiomers Image and mirrorimage are not superimposable

Functional Group Isomers Isomers that contain different

functional groups

Positional Isomers Isomers that differ by

connectivity, but have same functional groups

H3C

CH3

CH3H H3C

CH3

H3CCH3

OH

H3C O CH3CH3

Br

H

ClF Br

H

ClF

H3C CH3H

HH3C

CH3

HH

Stereochemistry

140  

Stereochemistry

The types of stereoisomers can in fact be further delineated

1) Conformational

Two different conformers of the same compound may have nonsuperimposable mirror images

H

H ClBr

HHH

Cl HBr

HH

Cl

H

HHH

Br

The two conformers can be interconverted by a bond rotation

If the energy of interconversion is low (< ~20-25 kcal/mol) the two conformers cannot be separated and thus not considered chiral

Can also observe with conformational enantiomers if the energy to interconvert is

too high NO2

CO2HHO2C

O2NO2N

HO2CCO2H

NO2

141  

Stereochemistry

2) Configurational

Typically when an organic chemist refers to stereoisomers, they generally mean configurational stereoisomers where the two isomers can only be interconverted by breaking

a covalent bond (cannot be made equivalent by rotation about any bond)

H3C

Br

ClH CH3

Br

ClH

Enantiomers Nonsuperimposable mirror

image compounds

H3CCH3

Br H

Cl HH3C

CH3Br H

ClH

Diastereomers Stereoisomers that are not related by a mirror plane

H3CCH3

H Br

HCl

diastereomers

enantiomers With diastereomers, often have multiple chiral centers

present which yield a variety of stereoisomers

A chiral compound can have only 1 enantiomer,

but the number of diastereomers is dependent

upon number of chiral centers

142  

Stereochemistry Chiral compounds thus have a three dimensional shape,

in order to represent these three dimensional objects in a two dimensional page a number of drawing conventions have been adopted

Organic chemists use a wedge and dash line system to designate stereochemistry

Wedge line – object is pointing out of the plane Dash line – object is pointing into the plane

H

H HH

To draw a tetrahedral carbon: 1) Make a V with an angle approximately at 109.5˚ 2) Place the wedge and dashed lines in the obtuse angle space

Common errors: 1) placing dashed and wedge lines in acute space 2) Placing either two bonds as wedge or dashed with two bonds in plane 3) Placing dashed and wedge bonds on opposite sides of bonds in plane

143  

Stereochemistry

Another method to represent three dimensional structures is to indicate whether a hydrogen is pointing out of the plane or into a plane by using a solid dot approach

(primarily only used in fused ring type structures)

H

H

HH

Trans-Decalin Cis-Decalin

H

H

H

H

Using dash and wedge to represent bridgehead hydrogens can become cumbersome (especially as structure becomes larger)

Another method is to represent whether the hydrogen

is coming out of plane

A solid dot means hydrogen is coming out of

plane toward viewer (absence of dot means

going into plane) 144  

Another convenient way to represent stereochemistry is with a Fischer projection

To draw a Fischer projection: 1) Draw molecule with extended carbon chain in continuous trans conformation

2) Orient the molecule so the substituents are directed toward the viewer

** Will need to change the view for each new carbon position along the main chain

3) Draw the molecule as flat with the substituents as crosses off the main chain

Fischer Projection

CO2H

CH3

HOH

CO2HHHO

CH3

145  

Important Points

- Crosses are always pointing out of the page

- Extended chain is directed away from the page

Fischer Projection

CO2HHHO

CH3

CO2HHHO

CH3

A Fischer projection can be rotated 180˚, but not 90˚

A 90˚ rotation changes whether substituents are coming out or going into the page It changes the three dimensional orientation of the substituents

CO2HHHO

CH3

CH3OHH

CO2H

Convention is to place more oxidized carbon at

top, but obtain same stereoisomer

180˚ OHCO2HH3C

H

90˚

146  

Fischer projections are extremely helpful with long extended chains with multiple stereocenters

An enantiomer is easily seen with a Fischer projection

Fischer Projection

H3C

CH3

BrH

ClH

Orient view at each chiral center

CH3BrH

CH3BrHClH

CH3

Merely consider the “mirror” image of the Fischer projection

CH3HBrHCl

CH3

CH3BrHClH

CH3

147  

Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms

A chiral carbon is classified as being either R or S chirality

Br

H CH2CH3CH=CH2

12

3

4

In this method the substituents are “ranked” by priority

To rank priority: 1)  Consider the atomic number of the atom directly attached

(higher the atomic number, higher the priority)

2) For isotopes, atomic mass breaks the tie in atomic number

3) If still tied, consider the atoms bonded to the tied atoms. Continue only until the tie is broken.

4) Multiple bonds attached to an atom are treated as multiple single bonds. An alkene carbon therefore would consider as two bonds to that carbon

148  

After ranking substituents, place lowest priority substituent towards the back and draw an arrow from the highest priority towards the second priority

If this arrow is clockwise it is labeled R (Latin, rectus, “upright) If this arrow is counterclockwise it is labeled S (Latin, sinister, “left”)

Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms

Br

H CH2CH3CH=CH2

12

3

4Br

H CH=CH2CH2CH3

1

2

34

Br

CH=CH2H3CH2C

1

23

Br

CH2CH3H2C=HC

1

2 3

R S

149  

Using Cahn-Ingold-Prelog in Assigning Alkenes

-substituents are prioritized

-if the highest priorities are on the same side called Z

1 1

2 2 Z – zusammen – “together”

Z-2-bromo-2-butene

-if the highest priorities are on the opposite side called E

1

1 2

2

E – entgegen – “opposite”

E-2-bromo-2-butene

Consider each end of the alkene separately

H3C H

Br CH3

H3C CH3

Br H

150  

Meso Compounds

Sometimes there are compounds that are achiral but have chiral carbon atoms (called MESO compounds)

Maximum number of stereoisomers for a compound is 2n

(where n is the number of chiral atoms)

This compound has only 3 stereoisomers even though it has 2 chiral atoms

CH3HHOOHH

CH3

CH3OHHHHO

CH3

CH3HHOHHO

CH3

CH3OHHOHH

CH3

Enantiomers (nonsuperimposable

mirror images)

Diastereomers (not mirror related)

Identical (meso)

151  

The meso compounds are identical (therefore not stereoisomers) therefore this compound has 3 stereoisomers

Meso compounds are generally a result of an internal plane of symmetry bisecting two (or more) symmetrically disposed chiral centers

Meso Compounds

CH3HHOHHO

CH3

2,3-(2R,3S)-butanediol has an internal plane of symmetry as shown

Any compound with an internal plane of symmetry is achiral

152  

Other Stereochemical Descriptors

The R/S designation is used to describe the absolute configuration at a chiral atom

There are cases, however, where this does not completely describe the system (especially if the molecule is chiral, but there are no chiral atoms)

Have already seen an example of this with a conformational chirality

O2N

Br

Br

NO2There are no chiral atoms, but the molecule is chiral

An example of helical chirality

In these cases, the viewer looks down the chiral helical axis

O2N Br

Br

NO2The substituents are prioritized on the front and back

Draw a circle from the highest priority on front to highest priority

on back

1

1

Clockwise rotation: P (positive)

Counterclockwise rotation: M (minus)

(P) chirality 153  

Other Stereochemical Descriptors

An important point with the helical P/M descriptors is that it doesn’t matter which end of the helical axis the viewer chooses as the end point

O2N

Br

Br

NO2

O2N Br

Br

NO21

1

(P) chirality

NO2

Br

Br NO2

1 1

(P) chirality

Helical chirality is present in a number of different systems

C C CH3C

Cl CH3H H3C H

Cl

CH31

1

(M) chirality Allenes α-helix

Shown as clockwise rotation,

(P) chirality

154  

Other Stereochemical Descriptors

In bicyclic systems, substituents are labeled as endo or exo describing their orientation relative to the bicyclic system

Endo or Exo refer to position relative to larger ring of bicyclic system

Endo: towards larger ring Exo: away from larger ring

This bicyclic system has a 6-membered and 5-membered ring

Chlorine is towards 6-membered ring, while H is away from larger ring

Cl: endo H: exo Cl

H

H HHO

Brexo

exo endo

endo 155  

Other Stereochemical Descriptors

With sugars and amino acids the designation D/L is often used

Name is a result of the Fischer projection for these types of compounds

CHOOHHHHOOHHOHH

CH2OH

By convention in a Fischer projection, the most oxidized carbon is placed at the top of drawing

The chirality of the highest numbered chiral carbon (thus the chiral carbon near the bottom of the Fischer) is labeled D if higher priority

substituent is pointed toward the right (from latin dextro- [to the right]) or L if pointed to the left (from latin levo- [to the left])

D-glucose

CO2HHH2N

CH3

L-alanine

Same system is used in amino acids

Naturally occurring sugars have a D chirality, while naturally occurring amino acids have a L chirality

156  

Other Stereochemical Descriptors

CHOOHHHHOOHHOHH

CH2OH

In sugars and steroids, another common descriptor used is the α or β terminology

In sugars the open chain form can form a hemiacetal by reacting with a hydroxy group

OHOHO

HOH

OH

OHO

HOHO

OHOH

H

OH

This creates a new chiral carbon (called the anomeric carbon) which can place the new OH group either above the plane of the ring (β isomer) or below the plane (α isomer)

α-D-glucopyranose β-D-glucopyranose

HO3α-Cholestanol

157  

Other Stereochemical Descriptors

Another term that is used to distinguish two diastereomers is epimer

When two compounds with multiple chiral centers differ in the configuration at only one chiral center (thus would be diastereomers), the two compounds are called epimers

(the carbon site would thus be the epimeric carbon)

OHOHO OH

OH

OH

Consider two sugar molecules again

β-D-glucopyranose

Anomeric carbon O

HOOH

OH

OH

OHEpimeric carbon

Differ at only one carbon site

β-D-allopyranose

If more than one carbon site changes configuration, then compounds are not called epimers

If all chiral atoms change configuration then would be enantiomers

If some other combination of centers change configuration then would have diastereomers 158  

Other Stereochemical Descriptors

Another stereochemical term refers back to the structure of open chain aldotetroses in a Fischer projection

CHOOHHOHH

CH2OHD-Erythrose

CHOHHOOHH

CH2OHD-Threose

In Erythrose, the two higher priority substituents (OH groups) are on the same side of the Fischer while in Threose the OH groups are on the opposite side of the Fischer projection

In other structures with two chiral atoms, if the two higher priority substituents are on the same side of the Fischer, then it is called an erythro isomer

while if on opposite sides it is a threo isomer

O

OHH2N

Br CO2HHH2NHBr

PhErythro-2-amino-3-bromo-3-

phenylpropionic acid

(would still need R and S to know if amino and bromine are on right or

left side of Fischer)

159  

Stereochemical Relationships

The stereochemical relationship between two stereoisomers determines the relationship in physical properties between the two compounds

Enantiomers must have the same physical properties (e.g. melting point, boiling point, solubility, etc.)

Diastereomers, on the other hand, can have quite different physical properties

Same is true for mixtures of stereoisomers Consider a phase diagram representing a molar fraction of different stereoisomers

Solubility

N

R S

Enantiomeric mixture

The racemic need not be identical to pure R, but the shape must be symmetrical

Solubility

N

R,R R,S

Diastereomeric mixture

With diasteromers, the physical properties can be quite different 160  

Stereochemical Relationships

One way to distinguish between enantiomers is the optical rotation

Chiral compounds will rotate plane polarized light

Achiral compounds do not rotate plane polarized light

Enantiomers rotate plane polarized light the exact same amount, but in opposite directions

If the rotation occurs in a clockwise rotation it is labeled as (+) [a smaller case d is

sometimes used to distinguish from capital D in sugars or amino acids (both mean dextro)]

Labeled (-) if counterclockwise (or l from levro)

161  

Enantiomeric Excess (or optical purity)

For many cases where there is an abundance of one enantiomer relative to the other the sample is characterized by its enantiomeric excess (e.e.)

The enantiomeric purity is defined by this e.e.

Therefore if a given solution has 90% of one enantiomer (say R) and 10% of the other enantiomer (S) then the enantiomeric excess is 80%

[(90 – 10) / (90 + 10)](100%) = 80%

[(R – S) / (R + S)] (100%) = e.e.

162  

Prochirality

Sometimes replacement of one ligand from an achiral center generates a chiral center (this ligand is thus called prochiral)

Homotopic ligands

Ligands (substituents) present in a molecule which when substituted independently generate identical molecules

HO OHH1H2 Substitute H1

HO OHDH2

Substitute H2 HO OHH1D

Identical compounds are obtained

The H1 and H2 substituents are considered homotopic, and are not prochiral

163  

Prochirality

Hetereotopic substituents

HO OH

H1 H2

Substitute H1

Substitute H2

HO OH

D H2

HO OH

H1 D

Enantiomers are obtained

H1 and H2 at this position are called enantiotopic (enantiotopic substituents have the same chemical shift in a NMR)

H1 and H2 will have different environments when placed in a chiral field (e.g. enzymes), therefore need to be able to name the two positions unambiguously

Prioritize substituents using C-I-P naming scheme assuming one prochiral position is prioritized higher than other

(R)

H1 is therefore called pro-R (S)

H2 is therefore called pro-S

164  

Prochirality

Hetereotopic substituents

Substitute H1

Substitute H2

Diastereomers are obtained

(R)

H1 is therefore called pro-R

(S)

H2 is therefore called pro-S

HO OH

H1 H2

HO OH

D H2

HO OH

H1 D

(S)

(S)

H1 and H2 at this position are called diastereotopic (diastereotopic substituents have different chemical shifts in a NMR)

The chemical environment is different for the H1 and H2 hydrogens (thus why they are diastereotopic and not enantiotopic),

therefore they will each have a different chemical shift and they will split each other

165  

Prochirality

The differences in electronic environments for the heterotopic hydrogens can be used to distinguish isomers

H1 H2

HO H3HO OH

H1 H2

H3 OH

In this meso compound, H1 and H2 are diastereotopic (the electronic environment of

H1 pointed towards both OH groups is different than H2 pointed away from OH

groups), therefore they split each other and will split H3 with different coupling

In this diastereomer, H1 and H2 are homotopic (the electronic environment of H1 and H2 are identical due to a two fold axis),

therefore they will split H3 the same

Signal for H3 in stereoisomers

J.-P. Despres, C. Morat, J. Chem. Educ., 1992, (69) A232-A239 166  

Prochirality

Can use diastereotopic hydrogens to distinguish chirality

RO

OHHS HR

RO

OHS HR

H

O

OCH3

Chiral ester

HS and HR are enantiotopic (same signal in NMR)

HS and HR are diastereotopic (different signal in NMR)

RO

OHD HR

RO

OHHS D

What if one of the α-hydrogens in the acid is replaced with a deuterium stereoselectively, but do not know which one

Synthesize the chiral ester and take a 1H NMR to distinguish 167  

Prochirality

Blast from the past! (Old scheme from Biewer’s thesis!)

H

O

DSS

LiSS

HSS

D

O

OEt

OD

OEt

O

OH

OTBS OTBS

OH OH

OH

O

H D

HO

HO

D HO

HO

D

HO

HO

D TsO

TsO

D

TsO

TsO

D D

H

D

D

DD

SH SH

Wittig

AD-MIX-b LAH

DMAP

HF/PYR LAD

JONES

BuLi

HgCl2

TBSCl TsCl

D2O

How do we know that this chirality of the α-deuterated

acid was obtained? 168  

Prochirality

Had to form chiral ester, and then take NMR

O

OHS HR

H

O

OCH3R

D D

O

OHS D H

O

OCH3R

D D

Pro-R

Pro-S

With this chiral ester it is known that the Pro-S hydrogen is always

shifted more upfield

In the stereoselective α-deuteration, the more upfield position remains and thus the pro-S hydrogen remains

169  

Prochirality

Prochirality can also refer to trigonal centers (which must be achiral) that become chiral after a reaction

The most common case for organic compounds concerns reactions at carbonyls

H

O

CH3

RMgBr

H

OH

RCH3

sp2 hybridized carbons are achiral

If R is different than CH3, then chiral

Depending upon which face the Grignard reacts, two enantiomers are obtained

H

OH

CH3Ror

O

HCH3R R H

O

CH3H

O

H3C

Naming is a result of the face of approach for the nucleophile 1

2 3

1

2 3

Si face (first two letters of Sinister)

Re face (first two letters of Rectus) 170