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StereochemistryThe Relative Arrangement of
Atoms in Space
Stereochemistry
• Stereochemistry:– The study of the three-dimensional structure of
molecules
• Structural isomers:– same molecular formula but different bonding
sequence
• Stereoisomers:– same molecular formula, same bonding sequence,
different spatial orientation
Importance of Stereochemistry
• Enzymes arecapable ofdistinguishingbetweenstereoisomers:
Molecular Molecular ChiralityChirality::EnantiomersEnantiomers
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Chirality
“I call any geometrical figure, or group of points, chiral, andsay that it has chirality, if its image in a plane mirror … cannot be brought to coincide with itself. Two equal and similar righthands are homochirally similar.”
Sir William Thomson (Lord Kelvin)The Baltimore Lectures, 1904
A molecule is A molecule is chiralchiral if its two mirror image if its two mirror image forms forms are not are not superimposable superimposable upon one another. upon one another.
A molecule is A molecule is achiralachiral if its two mirror image if its two mirror image forms forms areare superimposablesuperimposable..
ChiralityChirality
Tetrahedral Atoms
Achiral:
Chirality in Three Dimensions
BrBrClCl
HH
FF
Bromochlorofluoromethane Bromochlorofluoromethane is is chiralchiral
It cannot beIt cannot besuperimposed pointsuperimposed pointfor point on its mirrorfor point on its mirrorimage.image.
BrBrClCl
HH
FF
Bromochlorofluoromethane Bromochlorofluoromethane is is chiralchiral
HH
ClClBrBr
FFTo showTo shownonimsuperposabilitynonimsuperposability,,rotate this model 180rotate this model 180°°around a vertical axis.around a vertical axis.
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Chirality Chirality & & nonsuperimposable nonsuperimposable mirror images mirror images
EnantiomersEnantiomersIsomersIsomers
stereoisomersstereoisomersconstitutionalconstitutionalisomersisomers
IsomersIsomers
stereoisomersstereoisomersconstitutionalconstitutionalisomersisomers
diastereomersdiastereomersenantiomersenantiomers
Stereochemistry
• Two types of stereoisomers:– enantiomers
• pairs of compounds that are nonsuperimposablemirror 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
H H
ClCl
H H
ClCl
Stereochemistry
• Cis-1,2-dichlorocyclopentane is achiral eventhough it contains 2 chiral carbon atoms:– It contains an internal mirror plane of symmetry
• Any molecule that has an internal mirror plane ofsymmetry is achiral even if it contains chiralcarbon atoms.
H H
ClCl
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Question
Which of the following compounds does notcontain an internal mirror plane of symmetry?
CCCC
OOH
OOH
OHHH OH
CCCC
OOH
OOH
HOOHH
HC
C
CCCC
OOH
OOH
HOOHH
H
H
ClHF
CH3
H
H
H3C
F F
HH
A B C D
QuestionWhich of the following molecules is chiral?
C
CH3 C CH2CH2CH3
Cl
H
H
Cl
CH3CH2CH2CH3
CH3 C CH2CH3
CH3
Cl
CH3 C CH2CH3
CH3
Cl
H H
BrBr
BrH
Br H
CH3
H
H
H3C
F F
HH
A B
C D
Physical Properties ofPhysical Properties ofEnantiomersEnantiomers
Stereochemistry• Enantiomers are different stereochemical
compounds:– With the same boiling point, melting point,
density, and other physical/chemicalproperties being identical eg. the refractiveindex
– That rotate plane polarized light in oppositedirections (polarimetry)
– That behave differently with other chiralmolecules• Enzymes• Taste buds, scent
Physical properties are the same:Physical properties are the same: melting point, boiling point, density, etcmelting point, boiling point, density, etc
Others are differentOthers are different: : properties that depend on the shape of molecule properties that depend on the shape of molecule
egeg. . biological-physiological and optical properties,biological-physiological and optical properties, and their and their behavior in a beam of polarized lightbehavior in a beam of polarized light
Properties of Properties of enantiomersenantiomers
d- and l- tartaric acid
Pasteur - Wine andAbsolute Configuration
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Stereochemistry
• Stereochemistry plays an important role indetermining the properties and reactionsof organic compounds:
CH2H3CH
OCH3
CH2H3CH
OCH3
H2C CH3
OCH3
H
Caraway seed spearmint
OO OO
CHCH33 CHCH33
HH33CC HH33CCCHCH22 CHCH22
OdorOdor
((––)-)-CarvoneCarvonespearmint oilspearmint oil
(+)-(+)-CarvoneCarvonecaraway seed oilcaraway seed oil
IbuprofenIbuprofen is is chiralchiral, but normally sold as, but normally sold asa a racemic racemic mixture. The mixture. The enantiomer enantiomer belowbelowis the one responsible for its analgesic is the one responsible for its analgesic and and antiinflammatory antiinflammatory properties. properties.
Chiral Chiral drugsdrugs
CHCH22CH(CHCH(CH33))22
HHHH33CC
CC
OO
CC
HOHO
Stereochemistry
• The properties of many drugs depends ontheir stereochemistry:
CH3
HN
CH3O
Cl
NHO
Cl
NH
(S)-ketamine
CH3
HN
CH3O
Cl
NHO
Cl
NH
(R)-ketamine
anesthetic hallucinogen
A Sedative or a Potent Teratogen?
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a carbon atom with foura carbon atom with fourdifferent groups attached to itdifferent groups attached to it
also called:also called:chiral chiral center; center; chiral chiral carboncarbonasymmetric centerasymmetric centerasymmetric carbonasymmetric carbonstereocenterstereocenterstereogenic stereogenic centercenter
The The chiral chiral carbon atomcarbon atom
ww
xx yy
zz
CC
A molecule with a single A molecule with a single stereogenic stereogenic center is center is chiralchiral..
2-2-Butanol Butanol is an example.is an example.
Chirality Chirality and and chiral chiral carbonscarbons
CHCH33
OHOH
HH
CC CHCH22CHCH33
Examples of molecules with 1 Examples of molecules with 1 chiral chiral carboncarbon
CHCH33
CC
CHCH22CHCH33
CHCH22CHCH22CHCH22CHCH33CHCH33CHCH22CHCH22
a a chiral alkanechiral alkane
Examples of molecules with 1 Examples of molecules with 1 chiral chiral carboncarbon
Linalool, a naturally occurring Linalool, a naturally occurring chiral chiral alcoholalcohol
OHOH
Examples of molecules with 1 Examples of molecules with 1 chiral chiral carboncarbon
1,2-1,2-EpoxypropaneEpoxypropane: a : a chiral chiral carboncarboncan be part of a ringcan be part of a ring
OO
HH22CC CHCHCHCH33
attached to the attached to the chiral chiral carbon are:carbon are:
——HH
——CHCH33
——OCHOCH22
——CHCH22OO
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Examples of molecules with 1 Examples of molecules with 1 chiral chiral carboncarbon
Limonene: a Limonene: a chiralchiralcarbon can be part of acarbon can be part of aringring
CHCH33
HH CC
CHCH33
CHCH22
attached to theattached to thechiral chiral carbon are:carbon are:
——HH
——CHCH22CHCH22
——CHCH22CH=CH=
——C=C=
Examples of molecules with 1 Examples of molecules with 1 chiral chiral carboncarbon
Chiral Chiral as a result of isotopic substitutionas a result of isotopic substitution
CHCH33CCDD
TT
HH A molecule with a single A molecule with a single chiral chiral carboncarbonmust be must be chiralchiral..
But, as you saw earlier, a molecule with two or more But, as you saw earlier, a molecule with two or more
chiral chiral carbons may be carbons may be chiralchiral
or it may not.or it may not.
WeWe’’ll return to this when we consider molecules ll return to this when we consider molecules with more than onewith more than one chiral chiral carbon atom in detail.carbon atom in detail.
Optical Rotation Relative Configuration
and Absolute Configuration
Same:Same: melting point, boiling point, density, etc.melting point, boiling point, density, etc.
Different: Different: Optical Activity/ Optical RotationOptical Activity/ Optical Rotation
Physical Properties of EnantiomersPhysical Properties of Enantiomers
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Optical Activity• Chiral compounds are optically active:
– capable of rotating the plane of polarized light
• Enantiomers rotate the plane of polarized lightby exactly the same amount but in oppositedirections.
C
CH3
CH2CH3HHO
C
C
CH3
CH2CH3HHO
HOH
CH3
CH3CH2
(S)-(+)-d-2-butanol (R)-(-)-l-2butanol
+13.5o rotation -13.5o rotation
Optical Activity
• Compounds that rotate the plane of polarizedlight to the right (clockwise) are calleddextrorotary.
• d• (+) IUPAC convention
• Compounds that rotate the plane of polarizedlight to the left (counterclockwise) are calledlevorotary.
• l• (-) IUPAC convention
Optical Activity
• The direction and magnitude of rotation must bedetermined experimentally.– There is NO CORRELATION between (R)
and (S) configuration and the direction ofrotation.
Optical RotationOptical Rotation
Relative configurationRelative configuration compares the compares the arrangement of atoms in space of one compound arrangement of atoms in space of one compound with those of another.with those of another.
Absolute configurationAbsolute configuration is the precise is the precise arrangement of atoms in space.arrangement of atoms in space.
ConfigurationConfiguration
Relative configurationRelative configuration compares the compares the arrangement of atoms in space of one compound arrangement of atoms in space of one compound with those of another.with those of another.
until the 1950s, all configurations were relativeuntil the 1950s, all configurations were relative
Absolute configurationAbsolute configuration is the precise is the precise arrangement of atoms in space.arrangement of atoms in space.
we can now determine the absolute we can now determine the absolute configuration of almost any compoundconfiguration of almost any compound
ConfigurationConfiguration
No bonds are made or broken at the No bonds are made or broken at the chiral chiral carboncarbon
in this experiment. Therefore, when (+) in this experiment. Therefore, when (+) dd-3--3-butenbuten-2--2-ol ol
and (+) and (+) dd -2- -2-butanol butanol have the same sign of rotation, the have the same sign of rotation, the
arrangement of atoms in space at thearrangement of atoms in space at the chiral chiral carbon atom carbon atom
is analogous. The two is analogous. The two have have the same relative configuration.the same relative configuration.
CHCH33CHCHCHCH22CHCH33
OHOH
PdPd
[[αα] + 33.2] + 33.2°° [[αα] + 13.5] + 13.5°°
Relative configuration: Optical RotationRelative configuration: Optical Rotation
CHCH33CHCHCHCH
OHOH
CHCH22
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HHHOHO
HH OHOHHH22, Pd, Pd
HHHOHOHH22, Pd, Pd
HH OHOH
Two possibilitiesTwo possibilities
But in the absence of additional information, we can'tBut in the absence of additional information, we can'ttell which structure corresponds totell which structure corresponds to(+) (+) dd -3- -3-butenbuten-2--2-olol, and which one to (, and which one to (––) ) ll-3--3-butenbuten-2--2-olol..
HHHOHO
HH OHOHHH22, Pd, Pd
HHHOHOHH22, Pd, Pd
HH OHOH
Two possibilitiesTwo possibilities
Nor can we tell which structure corresponds toNor can we tell which structure corresponds to(+)-2-(+)-2-butanolbutanol, and which one to (, and which one to (––)-2-)-2-butanolbutanol..
HHHOHO
HH OHOHHH22, Pd, Pd
HHHOHOHH22, Pd, Pd
HH OHOH
Absolute configurationsAbsolute configurations
[[αα] +33.2] +33.2°°[[αα] +13.5] +13.5°°
[[αα] ] ––13.513.5°° [[αα] ] ––33.233.2°°
Not all compounds that have the same relativeNot all compounds that have the same relative
configuration have the same sign of rotation. No bondsconfiguration have the same sign of rotation. No bonds
are made or broken at the are made or broken at the chiral chiral carbon in thecarbon in the
reaction shown, so the relative positions of the atoms reaction shown, so the relative positions of the atoms
are the same. Yet the sign of rotation can change.are the same. Yet the sign of rotation can change.
CHCH33CHCH22CHCHCHCH22BrBr
CHCH33
HBrHBr
[[αα] -5.8] -5.8°° [[αα] + 4.0] + 4.0°°
Relative configurationRelative configuration
CHCH33CHCH22CHCHCHCH22OHOH
CHCH33
Absolute Configuration
Rank the groups (atoms) bonded to the chirality center
The R,S system of nomenclature
1. Rank the 1. Rank the substituents substituents at the at the stereogenic stereogenic center according to their atomic number.center according to their atomic number.
2. Orient the molecule so that lowest-ranked 2. Orient the molecule so that lowest-ranked substituent substituent points away from you.points away from you.
(The back in a 3d drawing.) (The back in a 3d drawing.) 3. If the order of decreasing precedence traces 3. If the order of decreasing precedence traces
a clockwise path, the absolute configuration a clockwise path, the absolute configuration is is RR. If the path is anticlockwise, the . If the path is anticlockwise, the
configuration is configuration is SS..
The The CahnCahn--IngoldIngold--Prelog Prelog RulesRules
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Orient the lowest priority (4) away from you
Clockwise = R configuration
Counterclockwise = S configuration
Switch any 2Switch any 2and it is theand it is theoppositeoppositeconfiguration.configuration.
Naming from the Perspective Formula
1
23
4
1. Rank the groups bonded to the asymmetric carbon
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.
CC OHOH
HH33CC
HHCHCH33CHCH22
Enantiomers of 2-butanolEnantiomers of 2-butanol
CCHOHO
CHCH33
HHCHCH22CHCH33
((SS)-2-Butanol)-2-Butanol ((RR)-2-Butanol)-2-Butanol
HHHH33CC
HH
HH
chiral chiral carbon in a ringcarbon in a ring
RR
——CHCH22C=C > C=C > ——CHCH22CHCH2 2 > > ——CHCH33 > > ——HH
Question: A Sleeping Pill or a Potent Teratogen?
The S-isomer is an effective sedative. The R- is aThe S-isomer is an effective sedative. The R- is a
teratogen teratogen in humans, but not rats.in humans, but not rats.
Which is R-isomer in the structures above, A or B?Which is R-isomer in the structures above, A or B?
HH
A B
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Agree That the HorizontalBonds Project Toward You
Emil Fischer, 1815-1919(the second) Nobel Prize in Chemistry, 1902
Rules for Fischer projectionsRules for Fischer projections
Arrange the molecule so that horizontal bonds atArrange the molecule so that horizontal bonds atchiral chiral carbon point toward you and vertical bondscarbon point toward you and vertical bondspoint away from you.point away from you.
Br Cl
F
H
Rules for Fischer projectionsRules for Fischer projections
Projection of molecule on page is a cross. WhenProjection of molecule on page is a cross. Whenrepresented this way it is understood that horizontalrepresented this way it is understood that horizontalbonds project outward, vertical bonds are back.bonds project outward, vertical bonds are back.
Br Cl
F
H
Rules for Fischer projectionsRules for Fischer projections
Projection of molecule on page is a cross. WhenProjection of molecule on page is a cross. Whenrepresented this way it is understood that horizontalrepresented this way it is understood that horizontalbonds project outward, vertical bonds are back.bonds project outward, vertical bonds are back.
BrBr ClCl
FF
HH
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