Transcript Chapter 1--Title - Imperial Valley College

Chapter 5
Stereochemistry: Chiral Molecules
1
Chapter 5
Stereochemistry: Chiral Molecules
Isomerism: Constitutional Isomers and Stereoisomers
Isomers are different structures with the same molecular formula.
Constitutional isomers, already examined, are isomers with
different bond connectivities.
Examples of Constitutional Isomers
formula
constitutional isomers
C3H8O
OH
CH3CH2CH2OH CH3CHCH3
C4H10
CH3CH2CH2CH3
CH3CHCH3
CH3
Stereoisomers
Stereoisomers are not constitutional isomers.
They have the same general atom connectivity, but they differ in the
arrangement of atoms in space. The cis-trans isomers of alkenes and
cycloalkanes are examples of stereoisomers.
Examples of Stereoisomers
2-butene
H3C
CH3
H cis H
H3C
H
H trans CH3
1,2-dichlorocyclopropane
H
H
H
Cl
Cl Cl
Cl H
cis
trans
Enantiomers and Diastereomers
Stereoisomers are divided into two general categories: enantiomers and
diastereomers.
Enantiomers are stereoisomers that are mirror
image related, and are not superimposable upon
one another.
Diastereomers are stereoisomers that are not
enantiomers. They are not mirror images of
one another.
Isomerism: Constitutional Isomers and
Stereoisomers
• Stereoisomers are isomers with the same
molecular formula and same connectivity of
atoms but different arrangement of atoms in
space
5
• Enantiomers: stereoisomers whose molecules are
nonsuperposable mirror images (R, S)
• Diastereomers: stereoisomers whose molecules are
not mirror images of each other (R/S, cis/trans)
• Example: cis and trans double bond isomers
• Example: cis and trans cycloalkane isomers
6
Enantiomers and Chiral Molecules
Enantiomers are possible only with molecules that are chiral.
If a molecule has two distinct stereoisomeric forms that are mirror
image related, it is chiral. These stereoisomeric forms are called
enantiomers.
Enantiomers and Chiral Molecules
• Chiral molecule
– Not superposable on its mirror image
– Can exist as a pair of enantiomers
• Pair of enantiomers
– A chiral molecule and its mirror image
• Achiral molecule
– Superposable on its mirror image
7
• Example: 2-butanol
– I and II are mirror images of each other (figures a and b)
– I and II are not superposable and so are enantiomers
(figure c)
– 2-butanol is a chiral molecule
8
Achiral Molecules
Achiral molecules do not exist in two unique stereoisomeric forms that
are mirror image related (enantiomers). The mirror image of an
achiral molecule can be superimposed upon the original structure.
• Example: 2-propanol
– Not chiral
9
Stereocenters
A stereocenter is an atom at which the exchange of any two groups
around the atom interconverts stereoisomers.
Tetrahedral Carbons as Stereocenters
A tetrahedral carbon with four different
groups attached can exist in enantiomeric
forms. It is a stereocenter because
exchange of any two groups around the
tetrahedral center interconverts
stereoisomers.
X
W C* Y
Z
a stereocenter with
four different groups
The asterisk indicates a
stereocenter.
• Chiral molecule
– A molecule with a single tetrahedral carbon bonded to four
different groups will always be chiral
– A molecule with more than one tetrahedral carbon bonded to
four different groups is not always chiral
– Switching two groups at the tetrahedral center leads to the
enantiomeric molecule in a molecule with one tetrahedral carbon
• Stereogenic 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 (*)
• Example: 2-butanol
11
Stereocenters in Alkenes
The cis and trans isomers of an alkene, such as 1,2-chloroethene, are
stereoisomers. Since they are not related as enantiomers, they are
diastereomers.
Cl
Cl
Cl
a stereocenter
trans
cis
Cl
Since exchange of the Cl and H around a carbon interconverts the cis
and trans stereoisomers, the carbons are stereocenters.
Find the Stereocenter
CH3
CH3CCH2CH3
H
Cl
CH3CCH2CH3
H
CH3
CH3CH2CCH2CH2CH3
H
achirall
chirall
chirall
2-methylbutane
2-chlorobutane
3-methylhexane
The Importance of Chirality in Biological Systems
Chirality or handedness is common in nature. On the macroscopic level,
helical seashells generally spiral like a right-handed screw and are chiral.
Climbing vines wind in a specific direction.
On the molecular level, most biologically important molecules are chiral.
The biological activity of chiral molecules is specifically associated with a
specific enantiomer. This specificity results from reaction between a
chiral molecule and a chiral receptor that only accomodates one
enantiomer. This enantioselectivity is a key factor in drug design.
The Biological Importance of Chirality
• The binding specificity of a chiral receptor site for a
chiral molecule is usually only favorable in one way
14
The History of Stereochemistry
In 1874 two young chemists, J.H. Van't Hoff (Utrech) and J.A. Le Bel
(Sorbonne) deduced a tetrahedral geometry for tetravalent carbon from
their observations of substituted methanes.
The Van't Hoff and Le Bel Argument
At that time, it was known that only one compound of the general formula
CH3Y had ever been found. For example, there is only one compound
with the formula CH3Br.
This observation
means that all 4 H in
CH4 are equivalent.
Possible Geometries for CH4
H
H
H C H
H
square planar
H C H
H H
H
pyramidal
tetrahedral
C
H
H
Disubstituted Methanes
Also, for the general formula CH2XY, there is only one known
compound. For example, only one compound exists with the
formula CH2BrCl.
This observation rules out the square planar and pyramidal geometries
for methane (and tetravalent carbon, in general) because stereoisomers
should exist for CH2XY with those geometries.
replace H
H C Y
X
H
H C H
Stereoisomers
X
H
square planar
(nonequivalent H)
X
replace H
H C H
Y
replace H
Y C X
H H
H C X
H H
pyrimidal
(nonequivalent H)
Stereoisomers
replace H
H C X
Y H
Stereochemical Properties of a Tetrahedral Carbon Atom
A tetrahedral geometry for methane is consistent with the
stereochemical observations on substituted methanes.
H
H
X
X
C
C
C
H
H
CH4
4 equivalent H
H
H
H
H
X
X
C
C
H
A
Y
H
Y
CH2XY
2 equivalent H
CH3X
3 equivalent H
CH2XY is achiral.
B may be
superimposed on A.
H
Y
H
B
H
The same stereostructure.
Two Stereoisomeric Forms of CWXYZ
Introduction of one
more group, Z, leads
to stereoisomers.
X
H
C
H
Y
replace H
replace H
X
X
Z
C
H
A
Y
not
superimposable
H
C
Z
B
Y
A and B are
stereoisomers that are
mirror image related.
They are enantiomers.
This analyis by Van't Hoff and Le Bel that led to their proposal of a
tetrahedral geometry for tetravalent carbon was not immediately
accepted. In fact, some of the leading organic chemists of that period
ridiculed the work of these two young scientists.
Kolbe's Lament
An excerpt of a letter written by Hermann Kolbe (University of
Leipzig) in 1877 in response to the work of the young J.H. van't Hoff.
"Not long ago, I expressed the view that the lack of general education and of
thorough training in chemistry was one of the causes of the deterioration of
chemical research in Germany.
Will anyone to whom my worries seem exaggerated please read , if he can,
a recent memoir by a Herr van't Hoff on 'The Arrangements of Atoms in
Space,' a document crammed to the hilt with outpourings of childish
fantasy......
This Dr. J.H. van't Hoff, employed by the veterinary college at Utrech, has, so it
seems, no taste for accurate chemicalresearch.
He finds it more convenient to mount his Pegasus (evidently taken from the
stables of the veterinary college) and to announce how, on his bold flight to
Mount Parnassus, he saw atoms arranged in space."
Despite such opposition, within 10 years of publishing their work,
the ideas of van't Hoff and Le Bel were verified by abundant evidence
and accepted by the chemical community.
Tests for Chirality: Planes of Symmetry
•
•
The absolute test for molecular chirality is the superimposability
test. Determine if a molecule and its mirror image are
superimposable on one another. If they are not, the molecule is
chiral.
A molecule is chiral if it possesses a single tetrahedral stereocenter
as in 2-chlorobutane.
*
CH3CHClCH
2CH3
•
If the molecule possesses a plane of symmetry that bisects the
structure, it is achiral. The presence of a plane of symmetry means
the two halves of the structure are mirror images of
each other.
OH
4-heptanol
CH3CH2CH2
C
H
CH2CH2CH3
plane of symmetry
achiral
Tests for Chirality: Planes of Symmetry
• Plane of symmetry
– 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
• Example
– 2-Chloropropane (a) has a plane of symmetry but 2-chlorobutane
(b) does not
21
Nomenclature of Enantiomers: The (R,S) System
Since chiral molecules can exist in two different stereoisomeric forms
(enantiomers), it is necessary to have a naming system that
unambiguously identifies each.
In 1956, three prominent chemists (R.S. Cahn, C.K. Ingold and V.
Prelog) devised a naming system for stereocenters. A stereocenter is
labeled either R (Rectus) or S (Sinister) according to the priority order
of the atoms or groups around the stereocenter.
(1) Each of the four atoms or groups attached to the stereocenter is
assigned a priority from A (highest) to D (lowest). Priority is
first determined by the atomic number of the atom attached to the
stereocenter. If H is attached, it automatically has the lowest priority
(D).
Example: 2-butanol
(B or C)
(A)
HO
CH3
C
(D)
H
CH2CH3
(B or C)
Nomenclature of Enantiomers: The R,S System
• Also called the Cahn-Ingold-Prelog system
• 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
• If priority cannot be assigned based on directly attached
atoms, the next layer of atoms (further out) is examined
• Example
23
• 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
• If the groups descend in priority in counterclockwise
direction the enantiomer is S
24
• Groups with double or triple bonds are
assigned priorities as if their atoms were
duplicated or triplicated
25
Example: An Enantiomer of 3-Chloro-3-methyl-1-pentene
(D)
CH3
Assign an (R,S) label to
this stereoisomer:
(B)
CH2=CH
C
(A)
Cl
CH2CH3
(C)
Step 1: Assign Priorities
Step 2: Visualize along the axis with the lowest
priority group away from the viewer.
(B)
CH=CH2
(D) CH3
C
(A)
Cl
CH2CH3
This stereoisomer is (S).
counterclockwise
(C)
Step 3: Trace out the sequence A---->C.
Quiz Chapter 5 Section 7
Provide complete IUPAC names for the compounds below.
(A)
Cl
(A)
OH
(D)
H C
CH2CH3
CH3
(B)
(C)
(D)
H C
CH3
H2C=CHCH2
(C)
(B)
(R)-2-chlorobutane
(S)-4-penten-2-ol
• Problem: Are A and B identical or enantiomers?
• Manipulate B to see if it will become superposable with A
• Exchange 2 groups to try to convert B into A
– One exchange of groups leads to the enantiomer of B
– Two exchanges of groups leads back to B
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Properties of Enantiomers: Optical Activity
Enantiomers are distinct stereoisomers. One structure cannot be
superimposed on the other. However, the two stereoisomers are
identical in all respects, except that they are mirror images of each
other. It is not surprising that enantiomers have identical properties,
except when they are in a chiral environment.
Physical Properties of (R) and (S)-2-Butanol
boiling point
(R)
99.5oC
(S)
99.5oC
density (g/mL, 20oC)
0.808
0.808
Optical Activity
However, when plane-polarized light is passed through a solution of (R)2-butanol, the plane is rotated in one direction and when planepolarized light is passed through a solution of (S)-2-butanol, the plane is
rotated in the opposite direction.
Some Early Studies of Optical Activity
In the early 19th century, experiments revealed the extraordinary
interaction between light and minerals. In 1808 the French scientist
Etienne Louis Malus discovered that light transmitted by a crystal of
iceland spar (CaCO3) was polarized in a single plane. (Described below)
A few years later, Jean Baptiste Biot (1774-1862, College de France)
found that a crystal of quartz (SiO2) rotated the plane of the
transmitted plane-polarized light. Biot further observed that some
quartz crystals rotate the plane in one direction, and other crystals
rotate the plane in the opposite direction. This property of rotation
was related to the hemihedral form of the quartz crystals that exists in
mirror image forms.
Hemihedral Quartz Crystals
Optically Active Materials in Nature
Biot showed in 1815 that certain naturally occurring organic
compounds rotate plane-polarized light in either the pure liquid or
dissolved state as a solution. Oil of turpentine, solutions of table sugar,
camphor, and tartaric acid all had this property. Biot correctly
concluded that this "optical activity" was inherent in the molecules.
Experiments with Tartaric Acid
Tartaric acid is a byproduct
of winemaking. It is present
in grapes as its potassium salt.
general structures
- +
COOH
CHOH
CHOH
COOH
CO2 K
CHOH
CHOH
COOH
tartaric acid
potassium tartrate
As the sugar in grape juice ferments to ethanol, the potassium
tartrate precipitates. Acidification of the salt yields tartaric acid.
The Experiments of Louis Pasteur
Louis Pasteur (1822-1895) was a student of Biot. In 1848, the young
scientist was working with tartaric acid supplied to him by a local
chemical company when he noticed something that had escaped earlier
workers.
The various salts of tartaric acid all showed evidence of crystallizing in
a hemihedral crystal of the same sense. Solutions of these salts were
optically active. But in experiments with sodium ammonium tartrate
(the double salt of tartaric acid), he made a dramatic discovery. This
tartrate double salt showed no optical activity in solution, and it
crystallized in two hemihedral forms similar to the two hemihedral
forms of quartz.
Pasteur carefully separated the two hemihedral forms with a tweezers.
Solutions of each hemihedral crystal were optically active in the
opposite sense. When equal weights of each hemihedral crystal were
mixed, the resulting solution was optically inactive.
Pasteur correctly speculated that the two forms may differ in
arrangement of atoms in space, and envisioned arrangements of
opposite senses. Louis Pasteur anticipated the importance of
"stereochemistry" as a feature of molecular structures
Jean Baptiste Biot studies the crystals prepared by Louis Pasteur.
Plane Polarized Light
Light is a moving wave of electric and magnetic fields called
electromagnetic radiation. The strengths of the electric and magnetic
fields oscillate in a repeating pattern as the wave moves through space.
Electric and Magnetic Fields
(electric and magnetic fields are perpendicular)
X
Oscillating electric and magnetic fields
moving in the X-direction.
Head-on view
of oscillating
electric or magnetic
field vector.
Ordinary and Plane-Polarized Light
Ordinary light is a bundle
of waves with electromagnetic
field vectors moving in all
directions around the
propagating axis.
Plane-polarized light is
a wave with only a single
oscillating electromagnetic
field vector
head-on view
head-on view
Plane-polarized light is obtained by passing ordinary light
through a polarizer (material such as Iceland spar).
ordinary light
polarizer
plane-polarized light
The Interaction of Plane-Polarized Light with Materials
When plane-polarized light is passed through certain materials
(gases, liquids or crystalline solids), the plane of the polarized light
rotates.
material
plane-polarized light
rotated plane of
polarized light
Solutions of certain organic compounds have this capability.
The rotatory power is characteristic of the compound and is
measured in a polarimeter.
Components of a Polarimeter
light
source
polarizer
view
polarizer
for analysis
The second polarizer is rotated to
match the degree of rotation of the
plane-polarized light. When a match is
achieved, light passes through the
polarizer.
The direction of rotation is either:

counterclockwise
"Levorotatory"
"l" or (-)
rotated
plane of
light ()
sample
cell

clockwise
"Dextrorotatory"
"d" or (+)
• The Polarimeter
38
Specific Rotation: A Measurement of Rotatory Power
The measured rotation, a, depends on how many molecules the
plane-polarized light interacts with in passing through the cell, and
experimental variables such as the wavelength of the light, solvent
and temperature.
In order to adjust for these
experimental variables, the
intrinsic rotatory power of a
compound is described by
its specific rotation, []:
[]
where
temp
l

=

LxC
is the observed rotation
L is the cell path length in
decimeters
C is the concentration in
g/mL
Some Examples
A sample of a compound A in chloroform (0.500 g/mL) at 25.0oC shows
a rotation of +2.5o in a 1.0 decimeter cell. What is the specific rotation?
[]
temp
l
=

LxC
=
+2.5o
1.0 dm x 0.5 (g/mL)
= +5.0o dm-1 (g/mL)-1
What is the observed rotation of A in a 0.5 dm cell?
 = 
x L x C = 5.0o dm-1 (g/mL)-1 x 0.5 dm x 0.5 g/mL = +1.25o
What is the observed rotation if C = 0.050 g/mL?
 = 
x L x C = 5.0o dm-1 (g/mL)-1 x 1.0 dm x 0.050 g/mL = +0.25o
• The specific rotation of the two pure enantiomers of 2butanol are equal but opposite
• There is no straightforward correlation between the R,S
designation of an enantiomer and the direction [(+) or (-)]in
which it rotates plane polarized light
• Racemic mixture
• A 1:1 mixture of enantiomers
• No net optical rotation
• Often designated as (+)
41
Some Examples of Specific Rotations
CH3
CH3
HO
C
H
CH2CH3
H
C
OH
CH2CH3
(S)-2-butanol
(R)-2-butanol
D25 = -13.52 o

25 = +13.52 o
D
CH 3
ClCH 2
CH 3
C
H
CH 2CH 3
H
(R)-(-)-1-chloro-2-methylbutane
 D25 = -1.64
The subscript "D"
refers to the sodium
D-line at 589.3 nm.
o
C
CH 2Cl
CH 2CH 3
(S)-(+)-1-chloro-2-methylbutane

25
D
= +1.64
o
NOTE: there is no direct correlation between (R,S) and
the sign (+ or -) of the rotation.
Racemic Forms and Enantiomeric Excess
• Often a mixture of enantiomers will be
enriched in one enantiomer
• One can measure the enantiomeric excess (ee)
• Example : The optical rotation of a sample of 2butanol is +6.76o. What is the enantiomeric
excess?
43
Optical Purity
Racemic Form or Racemate
A mixture of equal amounts of the two enantiomers of a chiral
compound is called a racemic form (or mixture) or simply racemate.
Because the rotatory power is balanced by the equal numbers of the
enantiomers, a racemic form shows no net rotation of plane-polarized
light.
Optical Purity and Enantiomeric Excess (ee)
If the specific rotation of a single enantiomer of a chiral compound is
known, it is possible to determine the enantiomeric mixture of samples
of the compound from polarimetric experiments.
A sample of a chiral compound that contains only a single enantiomer
is enantiomerically pure, and is said to have an enantiomeric excess
(ee) of 100%.
Example: (S)-(+)-1-chloro-2-methylbutane
A sample that is 100% of this enantiomer has a
specific rotation of [a]25 = +1.64o.
CH3
H
D
C
CH2Cl
CH2CH3
As the levorotatory (R) enantiomer is added to
the sample, it cancels the dextrorotatory power
of an equal number of (S) molecules.
The rotatory power of the sample is due only to
the enantiomers that are in excess.
Enantiomeric Excess (ee)
The enantiomeric excess of a sample is
(moles of one enantiomer -moles of other enantiomer)
%(ee) =
x 100
(total moles of both enantiomers)
and is directly calculated from the specific rotations by
(observed specific rotation)
%(ee) =
(specific rotation of pure enantiomer)
x 100
Optical Purity of (R)- and (S)-1-Chloro-2-methylbutane
observed specific
rotation in degrees
+1.64
optical purity
(ee) in %
%S
%R
100
100
0
+0.82
50
75
25
+0.41
25
62.5
37.5
50
0
50
0
0
-0.41
25
37.5
62.5
- 0.82
50
25
75
-1.64
100
0
100
Quiz Chapter 5 Section 9
A sample of 100% ee (R)-2-butanol shows [] = -13.5o. What is the
enantiomeric mixture of a sample of 2-butanol that shows [] =
+1.35o ?
%ee =
+1.35o
+13.5o
x 100 = 10% excess of S
This sample of 2-butanol is 90% racemic form and 10% excess S,
or S = (45 + 10) = 55% and R = 45%.
The Synthesis of Chiral Molecules
• Most chemical reactions which produce chiral
molecules produce them in racemic form
48
Symmetrical Reaction Pathways
Racemic forms of chiral products result whenever a reaction goes
through an achiral stage: starting point or chemical intermediate.
An achiral stage introduces symmetrical reaction pathways that
necessarily lead to 50% (S) and 50% (R) chiral products.
Example: Reduction of 2-Butanone
=
O
CH3CH2CCH3
+ H2
CH3
CH3CH2
C=O
O=C
H-H
H-H
CH3
CH2CH3
These and other mirror image
modes of reaction occur with
equal probability.
CH3
CH3CH2
OH
C
H
(R)
50%
Racemic Form
CH3
HO
C CH2CH3
H
(S)
50%
Enantioselective Reactions
A reaction that produces a stereocenter where one enantiomer is
favored over the other is enantioselective. This preference requires
some external chiral influence such as a chiral reagent, a chiral solvent,
or a chiral catalyst.
Enantioselectivity in Nature
There are many enantioselective reactions in natural systems where the
chiral influence is an enzyme. These biopolymers of amino acids
provide chiral reaction sites where one enantiomer generally reacts
much faster than the other because of stereochemical and electrostatic
factors.
H
=
O
enzymatic reduction
ClCH2CH2CH2CCH3
alcohol dehydrogenase
5-chloro-2-pentanone
(achiral)
OH
C
ClCH2CH2CH2
CH3
(S)-5-chloro-2-pentanol
(98% ee)
Enantioselectivity in the Laboratory
Synthetic chemists are designing chiral catalysts that mimic the
enantioselectivity of enzyme-catalyzed reactions.
O
HO H
H
O
O
(achiral)
(ii) acid workup
+
CH2=C
(i) chiral catalyst
OSi(CH3)3
OCH3
(achiral)
methyl 5-phenyl pentan-3-ol-oate
(98% ee) (S)
Chiral Drugs
The driving force behind the effort to design enantioselective
reactions is the pharmaceutical industry. Typically, only one
enantiomer of a chiral drug is active. One example is the
antiinflammatory drug ibuprofen (sold as advil, motrin, nuprin).
The (S) enantiomer is active while the (R) enantiomer is inactive.
H
CH3
HO
H
CH3
HO
O
(S)
(active)
O
(R)
(inactive)
Molecules with More than One Stereocenter
A compound with one stereocenter can exist in two
stereoisomeric forms (enantiomers) called (R) and (S). If there
are two stereocenters, each center may be (R) or (S). The
various stereocenter combinations are shown in the table.
Stereocenters
Possible Combinations
R
1
R
2
R
Stereoisomers
S
R
S
S
S
2
S
4
R
The maximum number of stereoisomers
is 2n, where n is the number of stereocenters.
The Stereoisomers of 2,3--Dibromopentane
* *
two stereocenters
2n = 4 stereoisomers
CH3CHCHCH2CH3
Br Br
What are the four stereoisomers and
how are they related to each other?
Possible Combinations of the Stereocenters
1
2
3
4
5
CH3-CHBr-CHBr-CH2CH3
(2R)
(2R)
(2S)
(2S)
(3R)
(3S)
(3R)
(3S)
The Four Stereoisomers of 2,3--Dibromopentane
CH3
CH3
H
H
C
Br
C
Br
CH2CH3
I
(2S,3R)
Br
Br
C
H
C
H
CH2CH3
II
(2R,3S)
CH3
CH3
Br
H
C
H
C
Br
CH2CH3
III
(2R,3R)
H
Br
C Br
C
H
CH2CH3
IV
(2S,3S)
(1) Use eclipsed conformations for easier assignment of (R) or (S).
(2) Add the groups around the stereocenters in one stereoisomer and
assign labels to the stereocenters.
(3) Draw the mirror image of I. That gives II. Each stereocenter
changes configuration.
(4) Change the configuration only at C-2 in I from S to R.
That gives III.
(5) Draw the mirror image of III. That gives IV.
The Relationships Among the Four Stereoisomers
of 2,3-Dibromopentane
CH3
H C
H C
Br
CH3
Br
C H
C H
Br
Br
CH2CH3
CH2CH3
2S, 3R
2R, 3S
I
II
CH3
CH3
C H
H C Br
H C Br
Br C H
CH2CH3
CH2CH3
2R, 3R
2S, 3S
III
IV
Br
Stereoisomer pairs I/II and III/IV are mirror image related. They are
enantiomers. Note that all stereocenters change in going from one
enantiomer to the other.
CH3
H
C
H
C
Br
Br
Br
CH2CH3
2S, 3R
I
CH3
CH3
Br
C H
C H
CH2CH3
2R, 3S
II
enantiomers
Br
H
CH3
C H
C Br
CH2CH3
H C Br
Br C H
CH2CH3
2R, 3R
III
2S, 3S
IV
enantiomers
Stereoisomers that are not Enantiomers are
Diastereomers of Each Other
Among the following four stereoisomers
CH3
H C
H C
Br
CH3
Br
C H
C H
Br
Br
CH2CH3
CH2CH3
2S, 3R
2R, 3S
I
II
the diastereomeric pairs are:
CH3
CH3
C H
H C Br
H C Br
Br C H
CH2CH3
CH2CH3
2R, 3R
2S, 3S
III
IV
Br
I/III, I/IV, II/III, II/IV
Note: In diastereomers, all the stereocenters are not mirror image
related as in enantiomers.
Unlike the mirror-image related enantiomers, diastereomers have
different physical and chemical properties. The diastereomeric
relationship between structures is an important and fundamental
principle in simple organic and biological systems.
Meso Compounds: A Special Stereochemical Situation
The maximum number of stereoisomers when there are
two stereocenters is 22= 4. But structural symmetry
influences this analysis.
Example: 2,3-dibromobutane
*
There are two stereocenters in this compound.
*
CH3-CH-CH-CH3
Br Br
The four possible stereoisomers of 2,3-dibromobutane are:
CH 3
H
C
Br
H
C
Br
CH 3
2S, 3R
I
CH 3
CH 3
Br C H
Br C H
Br C H
H C Br
CH 3
2R, 3S
II
CH 3
2R, 3R
III
CH 3
H
C
Br
Br C H
CH 3
2S, 3S
IV
At first view, it may appear that this compound exists in four unique
stereoisomeric forms as found in 2,3-dibromopentane, but..............
Structural Symmetry: The Meso Diastereomer
Symmetry reduces the number of stereoisomers from four to three.
CH3
H C
H C
CH3
Br
Br
Br
Br
CH3
2S, 3R
I
C H
C H
CH3
2R, 3S
II
CH3
C H
H C Br
CH3
2R, 3R
III
Br
CH3
H C Br
Br C H
CH3
2S, 3S
IV
A more careful inspection of the four possible stereoisomers reveals that
I and II are not different because one structure may be superimposed on
the other. They are the same stereoisomer.
Thus, 2,3-dibromobutane exists in only three unique stereoisomeric
forms: I=II, and the enantiomeric pair III and IV.
The Diastereomers of 2,3-Dibromobutane
Stereoisomer I=II is achiral and is called a meso diastereomer. The
meso diastereomer has an internal plane of symmetry that
necessarily makes it achiral.
Br
H C
CH3 R
Br
C H
S CH3
The meso diastereomer
of 2,3-dibromobutane
is achiral and does not
exist in enantiomeric forms.
The Chiral Diastereomer of 2,3-Dibromobutane
CH3
Stereoisomers III and IV
are the two enantiomers
of the chrial diastereomer
of 2,3-dibromobutane.
C H
H C Br
CH3
2R, 3R
III
Br
CH3
H C Br
Br C H
CH3
2S, 3S
IV
.
This diastereomer is sometimes
called the ( +- ) or (d,l) diastereomer,
meaning it exists in enantiomeric forms, to distinguish it from the
meso-diastereomer.
Meso Compounds
• Sometimes molecules with 2 or more
stereogenic centers will have less than the
maximum amount of stereoisomers
62
• Meso compound: achiral despite the presence
of stereogenic centers
• Not optically active
• Superposable on its mirror image
• Has a plane of symmetry
63
Quiz Chapter 5 Section 12
How many stereoisomers are possible for each structure below?
Identify each stereoisomer with its complete name and identify
enantiomeric and diastereomeric relationships.
CH3CHClCH2CHClCH3
2,4-dichloropentane
(S,S)-2,4-dichloropentane
enantiomers
(R,R)-2,4-dichloropentane
diastereomers
(S,R)-2,4-dichloropentane
CH3CHClCHClCH2CH3
2,3-dichloropentane
(2S,3S)-2,3-dichloropentane
(2R,3R)-2,3-dichloropentane
enantiomers
diastereomers
(2S,3R)-2,3-dichloropentane
(2R,3S)-2,3-dichloropentane
enantiomers
Naming Compounds with More than One
Stereogenic Center
• The molecule is manipulated to allow
assignment of each stereogenic center
separately
– This compound is (2R, 3R)-2,3-dibromobutane
65
Fischer Projection Formulas
Emil Fischer (1852-1919), one of the most prominent German
chemists of the late 19th and early 20th centuries, devised a
convention for representing three-dimensional structural
information in two dimensions. These "Fischer formulas" are
especially helpful in keeping track of stereochemical details in
structures with more than one stereocenter.
Example: (R)-2-chlorobutane
CH2CH3
CH2CH3
H
C
H
Cl
Cl
CH3
CH3
The Two-Dimensional Fischer Formula
Draw vertical and horizontal crossing lines. The
point of intersection is the stereocenter.
The horizontal line represents bonds projected towards the viewer.
The vertical line represents bonds projected away from the viewer.
How to Use Fischer Formulas: (S,R)-2,3-Dibromobutane
*
*
CH3-CH-CH-CH3
Br Br
By convention, Fischer
formulas are written with
the main chain extending
top to bottom.
(S,R)-2,3-Dibromobutane (meso)
CH3
CH3
H C
H C
Br
Br
CH3
3-dimensional
representation
H
Br
H
Br
CH3
Fischer Formula
Note: A plane of symmetry identifies this
stereoisomer as achiral in both representations.
The superimposability test may be used with Fischer formulas to
determine whether structures are identical or different.
Rules for the Superimposability Test with Fischer Formulas
(1) Fischer formulas only have meaning for structures with
stereocenters.
o
(2) Fischer formulas may be rotated 180 in the plane of
the paper, but no other angle.
(3) Any one exchange of groups around a stereocenter produces the
other configuration (R--->S or S--->R). Any even number of
exchanges produces the original configuration.
(4) If any of the above manipulations allows one Fischer formula to be
superimposed on a second, they are the same stereoisomer.
Example: Compare A and B as Fischer formulas
CH3
H C Br
C
H
Br
CH3
A
CH3
CH3
Br
H
H
Br
H
Br
Br
H
CH3
CH3
I
II
I and II are not superimposable
as drawn. Rotate II by 180o and
check again.
CH3
H C Br
C
H
Br
CH3
B
rotate in plane 180o
CH3
I and III are also not
H
Br
superimposable, so I and
II/III are different stereoisomers. Br
H
Since they are mirror image
CH3
related, they are enantiomers.
III
Fischer Projection Formulas
• Vertical lines represent bonds that project behind
the plane of the paper
• Horizontal lines represent bonds that project out of
the plane of the paper
70
Quiz Chapter 5 Section 13
Complete the Fischer projection formula for (R)-2-butanol.
CH3
HO
H
CH2CH3
solution
H
CH3
C
OH
CH2CH3
(R)
H
CH3
CH3
OH
CH2CH3
HO
H
CH2CH3
two exchanges of groups around
stereocenter retains configuration
Stereoisomerism in Cyclic Compounds
The stereochemical features of cyclic systems can be examined using
the (sometimes hypothetical) planar structures.
1,2-Dimethylcyclopropane
CH3
CH3
II
I
CH3
III
CH3
trans
Stereoisomers I and II are the
enantiomers of the chiral trans
diastereomer.
H3C CH3
cis
Stereoisomer III is the
meso diastereomer (achiral)
with a plane of symmetry.
Stereoisomerism of Cyclic Compounds
• 1,4-dimethylcyclohexane
• Neither the cis not trans isomers is optically active
• Each has a plane of symmetry
73
1,3-Dimethylcyclopentane
CH3 CH3
CH3
II
CH3 I
CH3
trans
Stereoisomers I and II are
the two enantiomers of the
chiral trans diastereomer.
CH3
III
cis
Stereoisomer III is the meso
cis diastereomer.
Even though cyclopentane has a nonplanar conformation, the
analyses of the planar geometries lead to correct stereochemical
conclusions.
Stereochemical Features of Dimethylcyclohexanes
An examination of hypothetical planar structures does provide quick
and correct conclusions about the stereochemical features of the
dimethylcyclohexanes. A thorough evaluation requires an examination
of the chair conformations.
1,3-Dimethylcyclohexane
I
I
III
cis
(meso)
trans
(chiral)
II
II
III
This quick analysis indicates that the trans diastereomer is chiral
because it exists in two non-superimposable mirror image
stereoisomeric forms (I and II). The cis diastereomer is achiral and is
meso because it has an internal plane of symmetry.
• 1,3-dimethylcyclohexane
• The trans and cis compounds each have two
stereogenic centers
• The cis compound has a plane of symmetry and is
meso
• The trans compound exists as a pair of enantiomers
76
A Conformational Analysis of the 1,3-Dimethylcyclohexanes
Draw a chair conformation of the trans diastereomer (axial-equatorial) and its
mirror image (enantiomer). These are stereoisomers I and II below.
Chair-chair interconversion leads to I' and II' that
are also mirror image related (enantiomers).
I'
I
mirror
II
mirror
II'
After rotations, I
superimposes on I' and
II superimposes on II'.
Therefore, chair-chair
interconversion gives
back the same
stereoisomer.
I/I' and II/II' are not superimposable. They are mirror image
isomers. They are the two enantiomers of the chiral trans
diastereomer.
cis-1,3-Dimethylcyclohexane: The Meso Diastereomer
Analysis of the (hypothetical) planar
structure quickly reveals a plane of
symmetry in the cis diastereomer, which
means this compound is achiral.
This conclusion is confirmed from an examination of
the two chair conformations.
III
chair 1
diaxial
IV
chair 2
diequatorial
(highly favored)
Although III and IV are different stereoisomers (more specifically
conformational stereoisomers), they are both meso, since each has a
plane of symmetry. Therefore, cis-1,3-dimethylcyclohexane exists in
two interconverting chair conformations that preserve the symmetry
features revealed in the planar structure.
Relative Configurations at Stereocenters
For many years before the development of x-ray crystallography,
configurations at stereocenters were assigned relatively. The
stereocenter in one chiral compound was related to one in another
compound through a stereochemically well-defined chemical
transformation.
CH3
H
C*
bond-breaking is remote from stereocenter
CH3
+
CH2OH
C2H5
HCl
(S)-(-)-2-methyl-1-butanol
o
25
[]D
= -5.756
heat
H
C*
CH2Cl
C2H5
+ H2O
(S)-(+)-1-chloro-2-methylbutane
o
25
[]D
= +1.64
Because the bonding changes are remote from the stereocenter, the
configuration of groups around the stereocenter in the product is the
same as in the reactant. This reaction proceeds with retention of
configuration.
Relative Configurations: (D)- and (L)-Glyceraldehyde
In the late 19th century, Emil Fischer developed a method for assigning
configurations at stereocenters relative to the enantiomers of
glyceraldehyde. For the next 50 or 60 years, configurations at
stereocenters were labeled relative to the stereocenters in the
stereoisomers of glyceraldehyde.
The Stereoisomers of
Glyceraldehyde
O
O
CH
CH
O
HO
H
OH
glyceraldehyde
H
C
OH
CH2OH
(R)
(+)
(D)
HO
C
H
CH2OH
(S)
(-)
(L)
Over 100 years ago, Fischer assigned the dextrorotatory (+)
stereoisomer, the configuration we call (R), and the levorotatory (-)
stereoisomer was assigned the (S) configuration.
The labels Fischer assigned were called (D) and (L). These assignments
were a guess.
Relating Configurations through Reactions in which
No Bonds to the Stereogenic Carbon are Broken
• A reaction which takes place in a way that no bonds
to the stereogenic carbon are broken is said to
proceed with retention of configuration
81
An Example: Relating (-)-Lactic Acid to (+)-Glyceraldehyde
O
CH
H C* OH
O
O
HgO
oxidation
HNO2
COH
H C* OH
Retention
H2O
Retention
CH2OH
(-)-glyceric acid
CH2OH
(+)-glyceraldehyde
COH
H C* OH
CH2NH2
(+)-isoserine
This transformation shows that (+)-isoserine has
the same absolute configuration as (+)-glyceraldehyde.
HNO2
HBr
Retention
O
COH
H C* OH
CH3
(-)-lactic acid
O
Zn, H+
Retention
COH
H C* OH
CH2Br
(-)-3-bromo-2-hydroxypropanoic acid
This transformation shows that (+)-isoserine has
the same absolute configuration as (-)-lactic acid.
Absolute Configurational Assignments
The series of chemical reactions involving retention of
configuration at the stereocenters configurationally link
(+)-glyceraldehyde and (-)-lactic acid.
O
CH
H C * OH
O
configurationally
the same
CH 2OH
(+)-gly ceraldehy de
COH
H C * OH
CH 3
(-)-lact ic 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 Fischer.
Absolute Configurations
In 1951 J.M. Bijvoet demonstrated the absolute configuration of
(+)-tartaric acid by X-ray analysis. Earlier work showed that
this compound was configurationally linked to (-)-glyceraldehyde. The
assumed assignments of Emil Fischer were shown to be correct.
O
CH
COOH
configurationally linked
*
HO C H
CH2OH
(S)-(-)-glyceraldehyde
The work of Bijvoet allows the
absolute assignments of
configurations in all chiral
compounds that had been
chemically linked to the
glyceraldehydes. In more recent
years, X-ray analysis has been
widely used to assign
configurations in other
compounds with stereocenters.
H C* OH
*
HO C H
CH2OH
(+)-tartaric acid
structure confirmed by X-ray
Absolute Configurations
O
O
CH
CH
*
HO C H
CH2OH
(S)-(-)-glyceraldehyde "L"
*
H C OH
CH2OH
(S)-(-)-glyceraldehyde "D"
The Separation of Enantiomers: Resolution
Because enantiomers have identical physical properties, they are
not separable by simple direct methods such as distillation,
chromatography or crystallization.
They may be separated in the presence of a chiral influence that
introduces diastereomeric relationships. The separation of the
enantiomers of a racemic form is called resolution.
Resolution Scheme
- R
S
reaction
Racemic Form
(identical properties)
R
R
R
R
R
R
R
separate
+
S
R
R
Diastereomers
(different properties)
S
pure forms
R
- R
S
is a resolving agent. It is a single enantiomer
(such as R) of a chiral compound.
The racemic form (R,S) is reacted with a single enantiomer (R) of
a resolving agent to produce diastereomers (R,R and S,R) that are
separable by physical means. The resolving agent is then removed
producing the pure enantiomers R and S.
Resolving Agents
Potential resolving agents are optically active acids and bases. Nature
provides a group of optically active amines (bases) called alkaloids in
plants. Many form crystalline salts when reacted with chiral organic
acids. The two diastereomeric salts produced from a racemic form of the
organic acid may be separated. Removal of the resolving agent yields the
pure enantiomers of the organic acid.
Examples of optically active alkaloids are (-)-quinine, (-)-strychnine and
(-)-brucine.
CH3O
HO
H
H N
H
N
H
CH3O
H
O=
H
quinine
(primary alkaloid from various
species of Cinchona)
H
H
N
N
H N
O
strychnine
(abundant in seeds of
Strychnos nux-vomica L.)
CH3O
H
N
H
O=
brucine
H
O
(from Strychnos seeds)
Resolution of a Carboxylic Acid
CH3
C6H5*CCOOH
H
(+)(-)-Salt
+
(-)-alkaloid
(-)(-)-Salt
(basic)
diastereomers
(+,-)-2-phenylpropanoic acid
(racemic form)
(+)(-)-Salt
H3O+
separate by
fractional
crystallization
(-)(-)-Salt
H3O+
water phase
organic phase
water phase
organic phase
CH3
CH3
*CCOOH (-)-alkaloid as
(-)-alkaloid as
C
H
(-)*
6
5
(+)- C6H5CCOOH
ammonium salt
ammonium
salt
H
H
Stereocenters other than Carbon
Any tetrahedral atom with four different groups is a stereocenter,
similar to carbon, with the potential to exist in two stereoisomeric forms.
R1
R1
R4
R2
R4
+ R2
Si
N
R3
R3
quaternary ammonium ion
silane
Chiral Molecules without a Stereocenter: Molecular Chirality
A molecule is chiral if it is not superimposable on its mirror image. It is
not required that there be a stereocenter in the structure. A chiral
structure without a stereocenter has molecular chirality.
Examples of Molecular Chirality
H
H
CH3
C
C
C
CH3
an allene
COOH
NO2
NO2
COOH
a biphenyl
Chiral Molecules that Do Not Possess a Tetrahedral
Atom with Four Different Groups
• Atropoisomer: conformational isomers that are
stable
• Allenes: contain two consecutive double bonds
90