Stereochem-2012-ques

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Stereochemistry
Arrangements of
Atoms in 3-d Space
Stereochemistry
• Stereochemistry:
The study of the three-dimensional structures of
molecules, particularly stereoisomers
• Structural isomers:
Have the same molecular formula, same types of
bonds, but different bonding sequences,
“connectivity”
• Stereoisomers:
Have the same molecular formula, same bonding
sequences, but different spatial arrangements &
relative orientations
Stereochemistry
CHIRALITY: If an object’s mirror image (i.e. a
molecule’s 3-d reflected shape) … “cannot be brought to
coincide with itself” (i.e. It is non-superimposable), it is
chiral.
Stereochemical cis-trans
Isomers
• To maintain orbital overlap
in the pi bond, C=C double
bonds cannot freely rotate.
• Although the two molecules
below have the same
connectivity, they are NOT
identical.
Naming Alkene Stereoisomers :
the E-Z Notational System
vs. “cis-trans”
Triglycerides & Unsaturated Fatty Acids
Saturated & Unsaturated: cis- vs. trans-
Stereochemical Notation
CH2(CH2)6CO2H
CH3(CH2)6CH2
C
H
C
Oleic acid
H
cis and trans are useful when
substituents are identical or analogous
Oleic acid, an unsaturated fatty acid, has a cis double
bond; (Hs are identical.)
cis and trans references are ambiguous
when analogies are not obvious
Cl
When there are four
different substituents, cis
and trans does not work.
Br
C
H
C
F
Example
A systematic body of rules for ranking
substituents must be used, which is
related to, but different from the cis and
trans references.
The E-Z Notational System
E : higher ranked substituents on opposite sides
Z :higher ranked substituents on same side
higher
C
lower
C
Consider each sp2 carbon
of the double bond
separately.
Rank the pair of
substituents relative to
each other.
The E-Z Notational System
E : higher ranked substituents on opposite sides
Z : higher ranked substituents on same side
lower
C
C
higher
Consider each sp2 carbon
of the double bond
separately.
Rank the pair of
substituents relative to
each other.
The E-Z Notational System
Compare the pairs
E : higher ranked substituents on opposite sides
Z : higher ranked substituents on same side
higher
lower
C
lower
higher
C
higher
(E) Entgegen
higher
C
lower
C
lower
(Z) Zusammen
The E-Z Notational System
Ranking
The substituents are ranked in order of
decreasing atomic number on each carbon.
higher
lower
C
lower
higher
C
higher
(E) Entgegen
higher
C
lower
C
lower
(Z) Zusammen
The Cahn-Ingold-Prelog
(CIP) System
The system used was devised by
R. S. Cahn
Sir Christopher Ingold
Vladimir Prelog
Their rules for ranking groups were
devised for another kind of
stereochemistry, chirality, but have been
adapted to alkene stereochemistry.
Example
Higher atomic number outranks lower
atomic number
Br > F
Cl > H
higher Br
C
lower
F
Cl
higher
H
lower
C
Example
Higher atomic number outranks lower
atomic number
Br > F
Cl > H
higher Br
C
lower
F
Cl
higher
H
lower
C
(Z )-1-Bromo-2-chloro-1-fluoroethene
CIP Rules
When two atoms are identical, compare the
atoms attached to them on the basis of their
atomic numbers. Precedence is established
at the first point of difference.
—CH2CH3 outranks —CH3
—C(C,H,H)
—C(H,H,H)
higher
lower
CIP Rules
Work outward from the point of attachment,
comparing all the atoms attached to a
particular atom before proceeding further
along the chain.
—CH(CH3)2 outranks —CH2CH2CH3
—C(C,C,H)
higher
—C(C,H,H)
lower
CIP Rules
higher
lower
—CH(CH3)2 outranks —CH2CH2CH3
—C(C,C,H)
higher
—C(C,H,H)
lower
CIP Rules
higher
lower
higher
lower
—CH2CH(CH3)2 outranks —CH2CH2CH(CH3)2
higher
lower
(Z)- configuration
CIP Rules
Evaluate substituents one by one.
The ranking is not cumulative:
Do not add atomic numbers within groups.
—CH2OH outranks —C(CH3)3
—C(O,H,H)
higher
—C(C,C,C)
lower
CIP Rules
An atom that has double or triple bonds to
another atom is considered to be replicated
as a substituent on that atom. See oxygen:
—CH=O outranks —CH2OH
—C(O,O,H)
higher
—C(O,H,H)
lower
Question
The molecules above are (E) configurations.
True (A) False (B)
Question
The molecules above are (Z) configurations.
True (A) False (B)
Disubstituted Cyclohexanes
cis-trans Isomerism
Cyclic Stereoisomers
In cyclic structures (rings) cis and trans notation is
used to distinguish between stereoisomers just as
in C=C double bonds,
 Cis— identical groups are positioned on the SAME side
of a ring -drawn as being planar.
 Trans— identical groups are positioned on OPPOSITE
sides of a ring -drawn as being planar.
Cycloalkane Stereochemistry
cis -trans Isomers
Cyclohexane Stereochemistry
Drawings: cis isomers & the need for perspective
Are the methyl groups axial or equatorial?
What is the actual conformational shape of the cyclohexane ring?
Chair Conformers
cis-1,4-dimethylcyclohexane
H
H
ring-flip
H
CH3
CH3
H3C
cis-1,4-dimethylcyclohexane
H
CH3
Cyclohexane Stereochemistry
Trans isomers
Chair Conformers
trans-1,4-dimethylcyclohexane
CH3
H
H 3C
CH3
H
ring-flip
H
trans-1,4-dimethylcyclohexane
H
CH3
Stereochemistry
cis-1,2-disubstituted-cyclohexane
axial
equatorial
Stereochemistry
trans-1-tert-Butyl-3-Methylcyclohexane
Cyclohexane Stereochemistry
Cis -Trans Isomers
Position
1,2
cis
trans
e,a or a,e e,e or a,a
1,3
e,e or a,a
a,e or e,a
1,4
e,a or a,e
e,e or a,a
a = axial; e = equatorial
Question
Indicate the relationship of the pair of molecules shown.
A. same molecules
B. mirror images
C. different molecules
D. constitutional isomers
E. cis and trans isomers
Question
Consider the molecule below. What is the maximum number of
methyl groups that can be in the equatorial position at the same
time?
A. 0
B. 1
C. 2
D. 3
E. 4
Conformations of Fused Rings
Stability of Fused Rings
Trans-fused cyclohexane rings are more stable than
cis-fused
Conformations of Fused Rings
Worksheet 7 (Part 2): Ambrox
Many Bicyclic Systems
•
There are many important structures that result
when one ring is fused to another.
.
•
Camphor, which you smelled the first day of class,
and camphene are fragrant natural products
isolated from evergreens.
Bicyclic Compounds
Nomenclature
Representing compounds with two fused rings.
To name a bicyclic compound, include the prefix
“bicyclo” in front of the total carbon alkane name.
For example, the compounds below could both be
named, bicycloheptane.
Bicyclic Compounds
Nomenclature
The two molecules are not identical, therefore they
cannot have the same name.
Count the number of carbons connecting the
bridgeheads.
Bicyclic Compounds
Nomenclature
1. Start numbering at a bridgehead carbon and
number the longest carbon chain connecters first.
1. Then give the substituents the lowest numbers
possible.
• Practice with SKILLBUILDER 4.5.
Bicyclic Compounds
Nomenclature
Decalin = Bicyclo[4.4.0]decane
Structure of Steroids
C
Decalin-like
A
D
B
• Fundamental framework of steroids is a
tetracyclic carbon framework.
Steroids
Structure of Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Cholesterol is an important steroid
endogenously produced in all plants and
animals.
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
• Cholesterol is essential to life. It is the
biosynthetic precursor of a large number of
important molecules: Sex hormones, Vitamin
D, Bile acids, Corticosteroids
Hormonal Steroids
•
There are many biologically important steroids,
two related to primary sex traits are:
Vitamin D3
CH3
CH3
CH3
CH3
H
HO
• Insufficient sunlight can lead to a deficiency of
vitamin D3, interfering with Ca2+ transport and
bone development. Rickets may result; as
well as very bad moods.
Cholesterol: Biochemical
Reactions
CH3
CH3
CH3
H
HO
CH3
CH3
H
H
+ H2 
Cholic Acid
H2
H
H2
H
Cholic Acid
O
•What
functions are
present?
HO CH3
CH3
CH3
H
H
HO
H
|
H
H
OH
• Is the A/B
ring system
cis or trans?
OH
•Oxidation in the liver degrades cholesterol to
produce Cholic acid which is the most abundant of
the bile acids.
Cortisone
O
CH3
OH
O
CH3
H
O
OH
H
H
•What
principal
functions are
present?
•Corticosteroids are involved in maintaining electrolyte levels, in
the metabolism of carbohydrates, and in mediating allergic
reactions by suppressing the immune system.
Progesterone
•What
principal
functions are
present?
O
H3C
H3C
H
H
H
O
• Supresses ovulation during pregnancy.
Conformations of Multi-fused Rings
• Trans-fused cyclohexane ring is more stable than
cis-fused cyclohexane ring. DIAMOND:
Molecular Chirality:
Enantiomers
Chirality
Chirality
“I call any geometrical figure, or group of points, chiral, and
say that it has chirality, if its image in a plane mirror … cannot
be brought to coincide with itself. Two equal and similar right
hands are homochirally similar.”
Sir William Thomson (Lord Kelvin)
The Baltimore Lectures, 1904
Chirality
A molecule is chiral if its two mirror image
forms are not superimposable upon one another.
A molecule is achiral if its two mirror image
forms are superimposable.
Tetrahedral Atoms
Achiral:
Chirality in Three Dimensions
Bromochlorofluoromethane is chiral
Cl
Br
H
F
It cannot be
superimposed point
for point on its mirror
image.
Bromochlorofluoromethane is chiral
Cl
Cl
Br
Br
H
F
H
F
To show
nonimsuperposability,
rotate this model 180°
around a vertical axis.
Enantiomers
Chirality & nonsuperimposable mirror images
Isomers
constitutional
isomers
stereoisomers
Isomers
constitutional
isomers
enantiomers
stereoisomers
diastereomers
Stereochemistry
• Two types of stereoisomers:
enantiomers
• pairs of compounds that are nonsuperimposable
mirror images of each other
diastereomers
• stereoisomers that are not mirror images of each
other
– Eg. geometric isomers (cis-trans, E-Z isomers)
Stereochemistry
• Many molecules and objects are achiral:
– identical to its mirror image
– not chiral
Stereochemistry
• Cis-1,2-dichlorocyclopentane is achiral even
though it contains 2 chiral carbon atoms:
– It contains an internal mirror plane of symmetry
• Any molecule that has an internal mirror plane of
symmetry is achiral even if it contains chiral
carbon atoms.
Question
Both cis- and trans-1,2-dimethylcyclohexane are
chiral.
True (A)
False (B)
Question
How many of the following compounds contain
an internal mirror plane of symmetry?
A) 1
B) 2
C) 3
D) 4
Question
Which of the following molecules is chiral?
B
A
C
D
The chiral carbon atom
a carbon atom with four
different groups attached to it
w
x
C
z
y
also called:
chiral center; chiral carbon
asymmetric center
asymmetric carbon
stereocenter
stereogenic center
Stereoisomers
• There are 8 chiral carbon atoms in chlolesterol,
which can have a total of 28 stereoisomers.
• SEE: SKILLBUILDER 5.7.
Symmetry and Chirality
• Molecules with an even number of chiral
centers that have a plane of symmetry are
achiral and called MESO compounds.
• Another way to test if a compound is a MESO
compound is to see if it is identical to its mirror
image. If identical, it is NOT chiral. It is achiral.
• Meso compounds have less than the predicted
number of stereoisomers based on the 2n formula.
• SEE: SKILLBUILDER 5.8.
Enantiomers
Stereochemistry
• Enantiomers are different stereochemical
compounds:
They have the same boiling point, melting
point, density. Their physical/chemical
properties are identical.
They differ in rotation of plane polarized light,
doing so in equal but opposite directions.
(polarimetry)
They behave differently with other chiral
molecules
• Enzymes
• Receptors: eg. taste and scent
Importance of Stereochemistry
• Enzymes are
capable of
distinguishing
between
stereoisomers
:
Red Wine / Stereochemistry
Absolute Configuration
In 1847, Louis Pasteur performed the first
resolution of enantiomers from a racemic
mixture of tartaric acid salts.
The different enantiomers formed different
shaped crystals, which he microscopically
separated with tweezers.
Smells
CH3
O
H3C
CH3
O
CH2
(–)-Carvone
spearmint oil
H3C
CH2
(+)-Carvone
caraway seed oil
Chiral drugs
Ibuprofen is chiral, but normally sold as
a racemic mixture, which is 50% of each
enantiomer
H
H3C
C
HO
CH2CH(CH3)2
C
O
The enantiomer above is responsible for its
analgesic and anti-inflammatory properties.
Stereochemistry
• The pharmacological activity of many
drugs depends on their stereochemistry:
(S)-(+)-ketamine
anesthetic
(R)-(-)-ketamine
hallucinogen
Stereochemistry
A Sedative or a Potent Teratogen?
Chirality and Chiral Carbon Atoms
A molecule with a single stereogenic
center is chiral. A carbon atom with four different
substituents is a stereogenic center and chiral.
2-Butanol is an example.
H
CH3
C
OH
CH2CH3
Examples of molecules with 1 chiral carbon
CH3
CH3CH2CH2
C
CH2CH2CH2CH3
CH2CH3
a chiral alkane
Examples of molecules with 1 chiral carbon
OH
Linalool, a naturally occurring chiral alcohol
Examples of molecules with 1 chiral carbon
H2C
CHCH3
O
1,2-Epoxypropane: a chiral carbon
can be part of a ring
attached to the chiral carbon are:
—H
—CH3
—OCH2
—CH2O
Examples of molecules with 1 chiral carbon
Limonene: a chiral
carbon can be part of a
ring
CH3
H
C
CH3
CH2
attached to the
chiral carbon are:
—H
—CH2CH2
—CH2CH=
—C=
Examples of molecules with 1 chiral carbon
H
D
C
CH3
T
Chiral as a result of isotopic substitution
Optical Rotation
Relative Configuration
and
Absolute Configuration
Optical Activity
• Chiral compounds are optically active:
– capable of rotating the plane of polarized light
• Enantiomers rotate the plane of polarized light
by exactly the same amount but in opposite
directions.
(S)-(+)-d-2-butanol
+13.5o rotation
(R)-(-)-l-2butanol
-13.5o rotation
Optical Activity
• Compounds that rotate the plane of polarized
light to the right (clockwise) are called
dextrorotary.
•d
• (+) IUPAC convention
• Compounds that rotate the plane of polarized
light to the left (counterclockwise) are called
levorotary.
•l
• (-)
IUPAC convention
Optical Activity
Configuration
Relative configuration compares the
arrangement of atoms in space of one compound
with those of another.
Absolute configuration is the precise
arrangement of atoms in space.
Configuration
Relative configuration compares the
arrangement of atoms in space of one compound
with those of another.
Until the 1950s, all configurations were relative
Absolute configuration is the precise
arrangement of atoms in space.
Now, the absolute configuration of almost any
compound can be determined
Relative configuration: Optical Rotation
Pd
CH3CHCH
CH2
OH
[a] + 33.2°
CH3CHCH2CH3
OH
[a] + 13.5°
No bonds are made or broken at the chiral carbon
in this experiment. Therefore, when (+) d-3-buten-2-ol
and (+) d -2-butanol have the same sign of rotation, the
arrangement of atoms in space at the chiral carbon atom
is analogous. The two have the same relative configuration.
Two possibilities
HO
H
H
OH
H2, Pd
HO
H2, Pd
H
H
OH
But in the absence of additional information, we can't
tell which structure corresponds to
(+) d -3-buten-2-ol, and which one to (–) l-3-buten-2-ol.
Two possibilities
HO
H
H
OH
H2, Pd
HO
H2, Pd
H
H
OH
Nor can we tell which structure corresponds to
(+)-2-butanol, and which one to (–)-2-butanol.
Absolute configurations
HO
H
H2, Pd
OH
[a] –13.5°
H
[a] +33.2°
[a] +13.5°
H
HO
H2, Pd
H
OH
[a] –33.2°
Relative configuration
HBr
CH3CH2CHCH2OH
CH3
[a] -5.8°
CH3CH2CHCH2Br
CH3
[a] + 4.0°
Not all compounds that have the same relative
configuration have the same sign of rotation. No bonds
are made or broken at the chiral carbon in the
reaction shown, so the relative positions of the atoms
are the same. Yet the sign of rotation can change.
Absolute Configuration
The R,S system of nomenclature
Rank the 4 groups (atoms) bonded to the chirality center
There is NO DIRECT
CORRELATION
between (R) and (S)
configurations, and the
relative configuration /
the optical rotation:
(+)/(-)
The Cahn-Ingold-Prelog (CIP) Rules
Treat the single carbon atom as a double bond, but
taking into account the tetrahedral geometry
1. Rank the substituents at the stereogenic
carbon center according to their atomic number.
2. Orient the molecule so that lowest-ranked
substituent points away from you.
3. If the order of decreasing precedence traces
a clockwise path, the absolute configuration
is R. If the path is anticlockwise, the
configuration is S.
Orient the lowest priority (4) away from you:
[Highest is (1)]
Switch any 2
substituents and the
new configuration is
opposite
R S; S  R
Clockwise = R configuration
Counterclockwise = S configuration
Designating Configurations
• The groups attached to the chiral center are the
same (-CH2-) below.
• Analyze the atomic numbers of the next atoms in
the bonding sequence.
4
1
Adjacent atoms:
Tie
Next atoms::
2
3
Designating Configurations
• Double bonds count as two single bonds.
Question
• Is the following molecule is R or S?
A = RB = S-
Naming from the Perspective Formula
1. Rank the groups bonded to the asymmetric carbon
1
4
2
3
2. If the group (or atom) with the lowest priority is
bonded by hatched wedge,
3. If necessary, rotate the molecule so that the lowest
priority group (or atom) is bonded by a hatched wedge
4.
Enantiomers of 2-butanol
H
H
CH2CH3
CH3CH2
C
OH
H3C
(S)-2-Butanol
HO
C
CH3
(R)-2-Butanol
Question
What is the stereochemical designation
of the following molecule?
A. (R)
B. (S)
C. non-chiral (achiral)
Question
Indicate the relationship of the pair of molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers
Question
Indicate the relationship of the pair of
molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers
Question
Indicate the relationship of the pair of
molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers
Question
Indicate the relationship of the pair
of molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers
Question
Indicate the relationship of the pair
of molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers
chiral carbon in a ring
H3C
H
R
H
H
—CH2C=C > —CH2CH2 > —CH3 > —H
Question
H
A
B
The S-isomer is an effective sedative. The R- is a
teratogen in humans, but not rats.
In the structures above, which is the R-isomer,
A or B?
Question
What is the stereochemical designation of
the following molecule?
A. (R)
B. (S)
C. non-chiral (achiral)
Fischer Structures
“The Horizontal Bonds Point Towards You!”
Emil Fischer, 1815-1919
(the second) Nobel Prize in Chemistry, 1902
Rules for Fischer projections
H
Cl
Br
F
Arrange the molecule so that horizontal bonds at
chiral carbon point toward you and vertical bonds
point away from you.
Rules for Fischer projections
H
Br
Cl
F
Projection of molecule on page is a cross. When
represented this way it is understood that horizontal
bonds project outward, vertical bonds are back.
Rules for Fischer projections
H
Br
Cl
F
Projection of molecule on page is a cross. When
represented this way it is understood that horizontal
bonds project outward, vertical bonds are back.
Question
What is the stereochemical designation of the
indicated chirality center?
A. (R)
B. (S)
C. non-chiral (achiral)
Disubstituted Cyclohexanes
Stereoisomerism
Question
Indicate the relationship of the pair
of molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers
Question
Indicate the relationship of the pair
of molecules shown.
A. same molecules
B. enantiomers
C. diastereomers
D. different molecules
E. constitutional isomers

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