Constitutional Isomers
Differ in the order of
attachment of atoms
(different bond connectivity)
Stereochemistry
Functional Group Isomers
OH
CH3
Isomers that contain different
CH3
CH3
H3C
H3C
O
functional groups
Positional Isomers
Isomers that differ by
connectivity, but have same
functional groups
CH3
H3C
H
CH3
CH3
H3 C
Isomers
Have same molecular formula,
but different structures
Stereoisomers
Atoms are connected in the
same order, but differ in spatial orientation
Enantiomers
Image and mirrorimage are not superimposable
H
Br
H
F
Cl
F
Cl
Br
CH3
H
Diastereomers
H3 C
Not related as image and
H
mirrorimage stereoisomers
CH3
H3 C
H
H
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
Cl Br
The two conformers can be
interconverted by a bond rotation
H
H
If the energy of interconversion is
low (< ~20-25 kcal/mol) the two
conformers cannot be separated
and thus not considered chiral
H
H
Br
Br
H
Cl
Cl
H
H
H
H
H
H
Can also observe with conformational
enantiomers if the energy to interconvert is
too high
H
CO2H
HO2C
HO2C
CO2H
O 2N
NO2
NO2
O 2N
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)
Enantiomers
Nonsuperimposable mirror
image compounds
Br
Br
H3 C
A chiral compound can
have only 1 enantiomer,
but the number of
diastereomers is dependent
upon number of chiral
centers
H
Cl
H
Cl
CH3
diastereomers
Diastereomers
Stereoisomers that are not
related by a mirror plane
Br H
Br H
H3 C
CH3
H3 C
Cl H
With diastereomers, often have multiple chiral centers
present which yield a variety of stereoisomers
H Br
CH3
H3 C
H Cl
enantiomers
CH3
Cl H
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
H
H
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
H
H
Trans-Decalin
Cis-Decalin
Using dash and wedge to represent bridgehead hydrogens can become cumbersome
(especially as structure becomes larger)
H
H
H
Another method is to represent whether the hydrogen
is coming out of plane
H
A solid dot means
hydrogen is coming out of
plane toward viewer
(absence of dot means
going into plane)
144 Fischer Projection
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
HO
H
CO2H
CH3
** 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
CO2H
H
HO
CH3
145 Fischer Projection
Important Points
- Crosses are always pointing out of the page
- Extended chain is directed away from the page
CO2H
H
HO
CH3
CO2H
H
HO
CH3
A Fischer projection can be rotated 180˚, but not 90˚
OH
H3C
CO2H
H
90˚
CO2H
H
HO
CH3
180˚
CH3
H
OH
CO2H
Convention is to place
more oxidized carbon at
top, but obtain same
stereoisomer
A 90˚ rotation changes whether substituents are coming out or going into the page
It changes the three dimensional orientation of the substituents
146 Fischer Projection
Fischer projections are extremely helpful with long extended chains with multiple stereocenters
Orient view at each chiral center
H3 C
H
Cl
Br
H
CH3
CH3
H
Br
H
Cl
CH3
An enantiomer is easily seen with a Fischer projection
CH3
H
Br
H
Cl
CH3
CH3
Br
H
H
Cl
CH3
Merely consider the “mirror” image of the Fischer projection
147 Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms
A chiral carbon is classified as being either R or S chirality
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
1
Br 2
4
CH=CH2
H
CH2CH3
3
148 Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms
After ranking substituents, place lowest priority substituent towards the back and draw an arrow from the highest priority towards the second priority
1
Br 2
4
CH=CH2
H
CH2CH3
3
1
Br 3
4
CH2CH3
H
CH=CH2
2
1
Br
1
Br
H3CH2C
3
CH=CH2
2
R
H2C=HC
CH2CH3
2
3
S
If this arrow is clockwise it is labeled R (Latin, rectus, “upright)
If this arrow is counterclockwise it is labeled S (Latin, sinister, “left”)
149 Using Cahn-Ingold-Prelog in Assigning Alkenes
-substituents are prioritized
Consider each end of the alkene separately
-if the highest priorities are on the same side called Z
2
H C
3
1
Br
H
2
CH3 1
Z – zusammen – “together”
Z-2-bromo-2-butene
-if the highest priorities are on the opposite side called E
2
H C
3
1
Br
CH3 1
H
2
E – entgegen – “opposite”
E-2-bromo-2-butene
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)
Enantiomers
(nonsuperimposable
mirror images)
CH3
H
HO
H
OH
CH3
Diastereomers
(not mirror related)
CH3
H
OH
H
HO
CH3
CH3
H
HO
H
HO
CH3
Identical
(meso)
CH3
H
OH
H
OH
CH3
This compound has only 3 stereoisomers even though it has 2 chiral atoms
151 Meso Compounds
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
CH3
H
HO
H
HO
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 There are no chiral atoms, but the molecule is chiral
NO2
Br
An example of helical chirality
O2N
Br
In these cases, the viewer looks down the chiral helical axis
The substituents are prioritized on the front and back
Draw a circle from the highest
priority on front to highest priority
on back
NO2
1
Br
O2N
Br 1
(P) chirality
Clockwise rotation: P (positive)
Counterclockwise rotation: M (minus)
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
NO2
Br
NO2
Br
1
NO2
NO2
Br 1
Br
O2N
O2N
Br
Br
(P) chirality
1
1
(P) chirality
Helical chirality is present in a number of different systems
H3 C
C C C H
CH3
Cl
Allenes
1
Shown as
clockwise rotation,
(P) chirality
CH3
H
H3C
Cl 1
(M) chirality
α-helix
154 Other Stereochemical Descriptors
In bicyclic systems, substituents are labeled as endo or exo describing their orientation relative to the bicyclic system
This bicyclic system has a 6-membered
and 5-membered ring
H
Chlorine is towards 6-membered ring,
while H is away from larger ring
Cl: endo H: exo
Cl
Endo or Exo refer to position relative to larger ring of bicyclic system
Endo: towards larger ring
Exo: away from larger ring
exo
Br
H exo
endo
H
HO
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
H
HO
H
H
CHO
OH
H
OH
OH
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
CO2H
H2N
H
CH3
Same system is used in amino acids
Naturally occurring sugars have a D chirality, while naturally occurring amino acids have a L chirality
L-alanine
156 Other Stereochemical Descriptors
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
OH
HO
HO
H
HO
H
H
O
H
OH
OH
α-D-glucopyranose
CHO
OH
H
OH
OH
CH2OH
OH
HO
HO
O
OH
H
OH
β-D-glucopyranose
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)
HO
3α-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)
Consider two sugar molecules again
OH
HO
HO
Anomeric O carbon
OH
OH
β-D-glucopyranose
Differ at only one
carbon site
OH
HO
Epimeric
carbon
OH
O
OH
OH
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
CHO
H
OH
H
OH
CH2OH
CHO
H
HO
H
OH
CH2OH
D-Erythrose
D-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
Br
O
OH
H2 N
CO2H
H2N
H
Br
H
Ph
(would still need R and S to know if
amino and bromine are on right or
left side of Fischer)
Erythro-2-amino-3-bromo-3phenylpropionic acid
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
Enantiomeric mixture Diastereomeric mixture R R,R S Solubility N The racemic need not be identical to pure R,
but the shape must be symmetrical
R,S Solubility N With diasteromers, the physical properties
160 can be quite different
Stereochemical Relationships
One way to distinguish between enantiomers is the optical rotation
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)
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
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.
[(R – S) / (R + S)] (100%) = 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%
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
H2 H1
HO
OH
Substitute H1
Substitute H2
H2 D
HO
OH
D H1
HO
Identical compounds are obtained
OH
The H1 and H2 substituents are considered homotopic, and are not prochiral
163 Prochirality
Hetereotopic substituents
(R)
HO
OH
Substitute H1
H1 H2
H1 is therefore
called pro-R
HO
OH
D H2
H2 is therefore
called pro-S
(S)
Substitute H2
HO
Enantiomers
are obtained
OH
H1 D
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
164 Prochirality
Hetereotopic substituents
(S)
HO
OH
Substitute H1
H1 H2
H1 is therefore
called pro-R
HO
(R)
OH
D H2
Diastereomers
are obtained
H2 is therefore
called pro-S
Substitute H2
HO
(S)
H1 D
OH
(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
OH H3 OH
HO HO H3
H1 H2
H1 H2
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
O
O
R
Chiral ester
R
OH
O
HS HR
HS HR
HS and HR are enantiotopic
(same signal in NMR)
O
H OCH
3
HS and HR are diastereotopic
(different signal in NMR)
What if one of the α-hydrogens in the acid is replaced with a deuterium stereoselectively, but do not know which one
O
R
HS D
O
OH
R
OH
D HR
Synthesize the chiral ester and take a 1H NMR to distinguish
167 Prochirality
Blast from the past! (Old scheme from Biewer’s thesis!)
SH
O
BuLi
SH
S
H
D2O
S
AD-MIX-b
S
D
HgCl2
S
H
Wittig
O
D
HO
LAH
O
HO
O
D
OH
HO
HO
D
D
TsO
TsCl
OTBS
HF/PYR
D
OEt
HO
DMAP
S
Li
D
OEt
TBSCl
S
OTBS
HO
TsO
TsO
D
D
LAD
D
OH
OH
TsO
JONES
H
D
D
O
OH
H
D
D
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
Pro-R
D D
Pro-S
O
R
O
O
HS HR
H OCH
3
With this chiral ester it is known
that the Pro-S hydrogen is always
shifted more upfield
D D
O
R
O
O
HS D
H OCH
3
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
O
H
CH3
H
sp2 hybridized
carbons are achiral
OH
OH
RMgBr
or
CH3
R
H
R
CH3
If R is different than
CH3, then chiral
Depending upon which face the Grignard reacts, two enantiomers are obtained
Naming is a result of the face of approach for the nucleophile
1
1
O
2
H3 C
O
O
3
H
Si face
(first two letters of Sinister)
3
R
H CH3
R
H
2
CH3
Re face
(first two letters of Rectus)
170