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