9.

Stereochemistry

Based on McMurry’s Organic Chemistry, 7th edition

McMurry Organic Chemistry 6th edition Ch 9 (c) 1

2003
Stereochemistry
 Some objects are not the s
ame as their mirror images
(technically, they have no p
lane of symmetry)
 A right-hand glove is diff
erent than a left-hand gl
ove. The property is co
mmonly called “handed
ness”
 Organic molecules (includin
g many drugs) have hande
dness that results from sub
stitution patterns on sp3 hyb
ridized carbon

2
Why this Chapter?

 Handedness is important in organic and bioch

emistry

 Other types of stereoisomers besides cis/tran

s

 Molecular handedness makes possible specif

ic interactions between enzymes and substrat
es—effecting metabolism and pharmaceutical
s

3
 Examples of Enantiomers
 Molecules that have one carbon with 4 different substituents ha
ve a non-superimposable mirror image
 Enantiomers = non-superimposable mirror image stereoisomer
s
 Enantiomers have identical physical properties (except for one)
 Build molecular models to see this

4
 Chirality
 If an object has a plane of symmetry it’s the same as its mirror image
 A plane of symmetry divides an entire molecule into two pieces that
are exact mirror images
 Achiral means that the object has a plane of symmetry

 Molecules that are not superimposable with their mirror images are c
hiral (have handedness)
 Hands, gloves are prime examples of chiral object
 They have a “left” and a “right” version
 Organic molecules can be Chiral or Achiral

5
Chiral Centers

 A point in a molecule where four different groups (or atom

s) are attached to carbon is called a chiral center
 There are two nonsuperimposable ways that 4 different dif
ferent groups (or atoms) can be attached to one carbon at
om
 If two groups are the same, then there is only one way
 A chiral molecule usually has at least one chiral center

6
Chiral Centers in Chiral Molecules

 Groups are considered “different” if there is any struct

ural variation (if the groups could not be superimpose
d if detached, they are different)
 In cyclic molecules, we compare by following in each
direction in a ring

7
 9.3 Optical Activity
 Light restricted to pass through a plane is plane-polarized
 A polarimeter measures the rotation of plane-polarized light that h
as passed through a solution
 Rotation, in degrees, is []
 Clockwise (+) = dextrorotatory; Anti-clockwise (-) = levorotatory

 Plane-polarized light that passes through solutions of achiral compo

unds remains in that plane ([] = 0, optically inactive)
 Solutions of chiral compounds rotate plane-polarized light and the
molecules are said to be optically active
8
Measurement of Optical Rotation
 The more molecules of a chiral sample are present the greater the r
otation of the light = concentration dependent
 To have a basis for comparison, define specific rotation, []D for a
n optically active compound
 Specific rotation is that observed for 1 g/mL in solution in a cell with


a 10 cm path using light from sodium metal vapor (589 nm)


[
]
D
(observe
rotation
in
degre


(pathleng
h
in
dm)(con
tration
in
g/ml
lC

 The specific rotation of the enantiomer is equal in magnitude but op

posite in sign (+)-lactic acid = +3.82; (-)-lactic acid = -3.82

9
9.4 Pasteur’s Discovery of Enantiomers
 Louis Pasteur discovered that sodium ammonium salts of tart
aric acid crystallize into right handed and left handed forms
 The solutions contain mirror image isomers, called enantiom
ers and they crystallized in distinctly different shapes – such a
n event is rare
 A (50:50) racemic mixture of both crystal types dissolved tog
ether was not optically active
 The optical rotations of equal concentrations of these forms h
ave opposite optical rotations

10
Sequence Rules for Specification of Configuration
 A general method applies to determining the configuration at each c
hiral center (instead of to the whole molecule)
 The configuration is specified by the relative positions of all the gro
ups with respect to each other at the chiral center
 The groups are ranked in an established priority sequence and com
pared—use the same priority ranking as we did for E/Z names
 The relationship of the groups in priority order in space determines t
he label applied to the configuration, according to a rule

Method
• Assign each group priority 1-4 according to Cahn-Ingold-Prelog
• Rotate the assigned molecule until the lowest priority group (4) is in t
he back, look at remaining 3 groups in a plane
• Clockwise 1-2-3 movement is designated R (from Latin for “right”)
• Counterclockwise is designated S (from Latin word for “left”)
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12
Priority (Cahn-Ingold-Prelog) Rules [REVIEW CH. 6]

Rule 1:
 Look at the atoms directly attached to the chiral carbon and ass
ign priority based on highest atomic number (O > N > C > H)
Rule 2:
 If decision can’t be reached by ranking the first atoms in the sub
stituents, look at the second, third, or fourth atoms until differen
ce is found
Rule 3:
 Multiple-bonded atoms are equivalent to the same number of si
ngle-bonded atoms

13
 9.6 Diastereomers
 Molecules with more than one chiral center have mirror image ste
reoisomers that are enantiomers
 In addition they can have stereoisomeric forms that are not mirror
images, called diastereomers

14
 Diastereomers
 Diastereomers are similar, but they aren’t mirror images
 Enantiomers have opposite configurations at all chiral centers; Diaste
reomers are opposite at some, but not all chiral centers
 Diastereomers have different physical properties

 Epimers are diastereomers different at only 1 chiral center

15
 9.7 Meso Compounds
 Tartaric acid has two chiral centers and two diastereomeric forms
 One form is chiral and one is achiral, but both have two chiral centers
 An achiral compound with chiral centers is called a meso compound
– it has a plane of symmetry
 The two structures on the right in the figure are identical so the comp
ound (2R, 3S) is achiral
 Identical substitution on both chiral centers

16
9.8 Racemic Mixtures and The Res
olution of Enantiomers
 A 50:50 mixture of two chiral compounds that are mirr
or images does not rotate light – called a racemic mi
xture (named for “racemic acid” that was the double
salt of (+) and (-) tartaric acid
 The pure compounds need to be separated or resolv
ed from the mixture (called a racemate)
 To separate components of a racemate (reversibly) w
e make a derivative of each with a chiral substance th
at is free of its enantiomer (resolving agent)
 This gives diastereomers that are separated by their
differing solubility
 The resolving agent is then removed

17
Using an Achiral amine doesn’t change the relationship of the products
Still can’t separate the Enantiomeric Salts

18
Using a Chiral amine changes the relationship of the products
Now we can separate the Diastereomeric Salts

19
9.9 A Review of Isomerism

 The flowchart summarizes the types of isomers we h

ave seen

20
Constitutional Isomers

 Different order of connections gives different carbon

backbone and/or different functional groups

21
Stereoisomers
 Same connections, different spatial arrangement of atoms
 Enantiomers (nonsuperimposable mirror images)
 Diastereomers (all other stereoisomers)
 Includes cis, trans and configurational

22
9.10 Stereochemistry of Reactions: Ad
dition of H2O to Alkenes
 Many reactions can produce new chiral centers from
compounds without them
 What is the stereochemistry of the chiral product?
 What relative amounts of stereoisomers form?
 Example addition of H2O to 1-butene

23
Achiral Intermediate Gives Racemic Product
 Addition via carbocation
 Top and bottom are equally accessible
 Achiral reactant + Achiral reactant = Optically Inactive Product
 Optical Activity doesn’t come from nowhere

24
 Addition of H2O to a Chiral Alkene
 What is the sterochemical result of the addition of H2O to a chiral al
kene R-4-methyl-1-hexene
 Product has 2 chiral centers

-Chiral + Achiral = Optically Active

-Chiral Intermediate has different top

and bottom sides

-Amounts of the two products will be

different

-Product will have optical activity

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9.12 Chirality at Nitrogen, Phosphoru
s, and Sulfur
 N, P, S commonly found in organic compounds, and
can have chiral centers
 Trivalent nitrogen is tetrahedral
 Does not form a chiral center since it rapidly flips
 Individual enantiomers cannot be isolated = Achiral

26
 Also applies to phosphorus but it flips more slowly
 Can isolate individual enantiomers = Chiral

 Trivalent Sulfur Cations are also Chiral

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 9.13 Prochirality
 A molecule that is achiral but that can become chiral by a single alterat
ion is a prochiral molecule

 Re and Si are used to describe the faces of the prochiral sp2 reactant

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Prochiral distinctions, paired atoms or groups
 An sp3 carbon with two groups the same is also a prochiral center

 The two identical groups are distinguished by considering either and

seeing if it was increased in priority in comparison with the other

 If the center becomes R the group is pro-R and pro-S if the center be
comes S

29
Prochiral Distinctions in Nature

 Biological reactions often involve making distinctions

between prochiral faces or or groups
 Chiral entities (such as enzymes) can always make s
uch a distinction
 Example: addition of water to fumarate

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Chirality in Nature and Chiral Environments
 Enantiomers have same physical properties, different biological ones
 Stereoisomers are readily distinguished by chiral receptors in nature

 Properties of drugs depend on stereochemistry

 Think of biological recognition as equivalent to 3-point interaction
 Enzymes can make only one enantiomer from an achiral reactant
 In the chiral environment, pro-R and pro-S are chemically different

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