1

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

2

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.

3

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

4

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

5

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?

6

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

7

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

8

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

9

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

10

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

11

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