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STEREOCHEMISTRY 8 M. C. E, D H,

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STEREOCHEMISTRY8

M. C. E!"#$%, D%&'()* H&)+!, ,-./

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITYFigure 8.1 Objects and Their Mirror ImagesIn (a), the chair and its mirror image are identical. !ey can be superimposed. In (b), the mirror image, side-arm chairs cannot be superimposed. One chair has a “right-handed” arm, the other has a “left-handed” arm. (!ese particular chairs were designed by the renowned woodworker George Nakashima.)

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITY

Figure 8.2 Nonsuperimosable Mirror ImagesA left and a right hand are nonsuperimposable mirror images. (M. C. Escher, Drawing Hands)

C CH H

Cl Cl

F FBrBr

mirror

HH

ClCl

BrFF

mirror

Br

(b)

(a)

Figure 8.3 Nonsuperimosable Mirror Image MoleculesBromochloro!uoromethane does not have a plane of symmetry. "erefore, it is chiral, and it exists as a pair of nonsuperimposable mirror image isomers. (a) Schematic diagram; (b) Ball-and-stick molecular models.

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITY

HH

ClH

ClCl

planes of symmetry

Figure 8.4 Planes of Symmetry in DichloromethaneDichloromethane, which has not one, but two planes of symmetry can be superimposed on its mirror image. It is achiral.

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITY

plane of symmetry

Cl

Br

HH

Figure 8.4 Planes of Symmetry in DichloromethaneDichloromethane, which has not one, but two planes of symmetry can be superimposed on its mirror image. It is achiral.

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITY

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITY

Figure 8.5 Plane of Symmetry in BromochloromethaneBromochloromethane has a plane of symmetry, and therefore it can be superimposed on its mirror image. It is achiral.

plane of symmetry

Cl

Br

HH

8.2 MIRROR IMAGE OBJECTS, MIRROR IMAGE MOLECULES AND CHIRALITYMirror Image Isomers

C CH3

Br

H 2-bromobutane(a chiral molecule)

stereogenic center

CH3 C CH3

Br

H 2-bromopropane(an achiral molecule)

not a stereogenic center

CH3CH2

CH2 C

Br

H

butyl group pentyl group

butyl group butenyl group

CH2CH2CH3

CH2 C

Br

H

CH2CH2CH3 CH2 CH CH2CH2

CH3CH2CH2CH2CH2

5-bromodecane

5-bromo-1-nonene

Figure 8.6 Schematic Diagram of a PolarimeterPlane-polarized light is obtained by passing light through a polarizing !lter. Any chiral compound in the sample tube rotates the plane-polarized light. "e direction and magnitude of the rotation are determined by rotating the analyzer to allow the light to pass through with maximum brightness. In a modern instrument this is all done electronically, but the basic principle is the same.

Sodium lamp

Polarizer

Plane ofpolarized light

Sample tube

Rotated planeof polarized light

Analyzer rotated to passlight with scale to read angle

8.3 OPTICAL ACTIVITYPlane Polarized Light

Table 8.1 Specific Rotations of Common CompoundsCompound [!]D

azidothymidine (AZT) +99!cefotaxin (a cephalosporin) +55!cholesterol "31.5!cocaine "16!codeine "136!epinephrine (adrenaline) "5.0!levodopa "13.1!monosodium glutamate (MSG) +25.5!morphine "132!oxacillin (a penicillin) +201!progesterone +172!sucrose +66!testosterone +109!

8.3 OPTICAL ACTIVITYSpecific Rotation

[!]D = !obs

l x c

Figure 8.6 Schematic Diagrams of Plane and Circularly Polarized Light(a) In plane polarized light, the electric !eld vectors of the light all oscillate in a single plane. (b) In circularly polarized light, the electric !eld vec-tor can rotate in a right-handed (clockwise) or left-handed (counterclockwise) direction. (c) If right-handed and left-handed phases of circularly polarized light are superimposed, the electric !eld vectors in the +x- "x directions cancel, and the y-components are additive, and directed along the y-axis. #e net result is plane-polarized light.

Mirror image helices

(b)

Plane polarized light (side view)

E

B

x

(a)

(c)

right-handed phase

left-handed phase

x

y

8.3 OPTICAL ACTIVITYCircularly Polarized Light and Optical Rotation

8.3 OPTICAL ACTIVITYOptical Purity

optical purity =observed rotation

rotation of pure enantiomerx 100%

Figure 8.7 Fischer Projection Structures of Glyceraldehyde(a) Perspective structures of glyceraldehyde. (b) Projection structures. (c) Fisher projection structures of the enantiomers glyceraldehyde. !e chiral center is located at the point where the bond lines intersect. !e carbon atom is not usually shown. !e vertical lines extend away from the viewer, behind the plane of the page; horizontal lines extend toward the viewer, out of the plane of the page, as shown in part (b).

Mirror

Perspective Structures

C

CHO

OHH

HOCH2

A

C

CHO

CH2OHH

HO

B

CHO

C OHH

CHO

C

CH2OH

HHO

A B

Fischer projection structures

H OH

CHO

CH2OH

HO H

CHO

CH2OH

A B

CH2OH

(a)

(b)

(c)

8.4 FISCHER PROJECTION FORMULAS

Figure 8.8 Kahn-Ingold-Prelog System of Configurational NomenclaturePlace the lowest priority atom or group away from your eye, and view the chiral site along the axis of the carbon-bond to the lowest priority group. (!e diagram of the eye in this "gure is from a drawing in the notebooks of Leonardo da Vinci.)

C

1

423 C

1

234

lowest priority atom Clockwise rotation from 1, to 2,to 3 gives R configuration.

8.5 ABSOLUTE CONFIGURATIONR,S Configurations: The Kahn-Ingold-Prelog System of Configurational Nomenclatur

Figure 8.10 Enantiomers and DiastereomersA molecule that contains two nonequivalent chiral centers, such as 2,3-4-trihydroxybutanal, can exist as four stereoisomers. !ey exist as two pairs of enantiomers. Stereoisomers that are not enantiomers are diastereomers.

Enantiomers

H OH

CHO

OHH

CH2OH

HO H

CHO

HHO

CH2OH

H OH

CHO

HHO

CH2OH

HO H

CHO

OHH

CH2OHI II III IV

[!]D -21.5 +21.5 -29.1 +29.1

Enantiomers

8.6 MOLECULES WITH TWO !OR MORE" STEREOGENIC CENTERSNonequivalent Stereogenic Centers

Figure 8.11 Configurations of Enantiomers and Diastereomers

CHO

CH OH

OH

CH

CHO

CH OH

H

COHHOCH2 HOCH2

Diastereomers

I (2R,3R)[!]D = -21.5o

III (2R,3S)[!]D =-29.1o

CHO

CHO H

H

COH

CHO

CH OH

OH

CHHOCH2 HOCH2

Diastereomers

II (2S,3S)[!]D = + 21.5o

IV (2S,3R)[!]D = +29.1o

Enantiomers Enantiomers

8.6 MOLECULES WITH TWO !OR MORE" STEREOGENIC CENTERSNonequivalent Stereogenic Centers

Figure 8.12 Configurations of Optically Active Tartaric Acids and Meso CompoundsOnly three stereoisomers exist for tartaric acid because it has two equivalent chiral centers. Two of the stereoisomers are enantiomers. !e third has a plane of symmetry, is optically inactive, and is called a meso compound; i.e. meso-tartaric acid.

C

COHH

CO2H

CO2H

OHHC

COHH

CO2H

CO2H

HHO

(2S,3S)

1 11

1

C

CHHO

CO2H

CO2H

HHOC

CHHO

CO2H

CO2H

HHO

(2R,3S)(2R,3S)

Enantiomers Same compound

(2S,3R)

C

CHHO

CO2H

CO2H

HHO

(2R,3S)

rotate 180o

C

CHHO

CO2H

CO2H

HHO

(2S,3R)

2 2 2 2

1

1

2 2

4

3

4

3

3 3 3 3

4 4 4 4

8.6 MOLECULES WITH TWO !OR MORE" STEREOGENIC CENTERSNonequivalent Stereogenic Centers

methylcyclohexane

CH3H

methylcyclohexane

CH3

plane of symmetry

(R)-4-methylcyclohexene

CH3H

8.7 Cyclic Molecules with Stereogenic CentersCyclic Structures with One Stereogenic Center

Br

H

H

Cl

R S

R

Br

H

H

ClS

(b) Diastereomers of 1,2-dibromocyclobutane

Br

H

Br

H

R

S

Meso compound

Mirror

Br

H

H

Cl

R S

R

Br

H

H

ClS

Br

H

Cl

H

R

R

S

Br

H

Cl

HS

(a) Diastereomers of 1-bromo-2-chlorocyclobutane

8.7 Cyclic Molecules with Stereogenic CentersCyclic Structures with Two Stereogenic Centers: Disubstituted Cyclobutanes

Figure 8.13 Diastereomers of 1,2-Disubstituted Cyclobutanes(a) A 1,2-disubstituted cyclobutane with two nonequivalent chiral centers has four diastereomers. (b) However, a 1,2-disubstituted cyclobutane with two equivalent chiral centers has only three diastereomers, one of which is a meso compound.

Figure 8.14 Stereoisomers of 1,4-Dimethylcyclohexane!e cis and trans isomers of 1,4-dimethylcyclohexane are achiral because each has a plane of symmetry.

cis-1,4-dimethylcyclohexane

H3C

CH3

CH3

CH3

Symmetry plane

H3C CH3

CH3

CH3

Symmetry plane

trans-1,4-dimethylcyclohexane

8.7 Cyclic Molecules with Stereogenic CentersCyclic Structures with Two Stereogenic Centers: Dimethyl Cyclohexanes

Mirror

CH3

H3C

H3C

CH3

same asmeso-cis-1,3-dimethylcyclohexane

CH3

H3C

CH3

CH3

Symmetry plane Symmetry plane

Mirror

H3C CH3

enantiomerstrans-1,3-dimethylcyclohexane

CH3

H3C

CH3

CH3

CH3 CH3

8.7 Cyclic Molecules with Stereogenic CentersCyclic Structures with Two Stereogenic Centers: Dimethyl Cyclohexanes

Figure 8.15 Diastereomers of 1,3-Dimethylcyclohexanecis-1,3-Dimethylcyclohexane is a meso compound. It is achiral because it has a plane of symmetry. trans-1,3-Dimethylcyclohexane exists as a pair of enantiomers.

Figure 8.16 Enantiomers of trans-1,2-Dimethylcyclohexanetrans-1,2-Dimethylcyclohexane exists as a pair of enantiomers. !ere is no a plane of symmetry.

Mirror

enantiomerstrans-1,2-dimethylcyclohexane

CH3

H3C

H3C

CH3

CH3

CH3

H3C

CH3

8.7 Cyclic Molecules with Stereogenic CentersCyclic Structures with Two Stereogenic Centers: Dimethyl Cyclohexanes

Figure 8.17 cis-1,2-Dimethylcyclohexane!e mirror images of cis-1,2-dimethylcyclohexane are not superimposable. However, chair-chair interconversion is very fast, so the enantiomers cannot be separated.

Mirror

CH3 H3CCH3 CH3

H3CCH3

very fast

8.7 Cyclic Molecules with Stereogenic CentersCyclic Structures with Two Stereogenic Centers: Dimethyl Cyclohexanes

Figure 8.18 General Method for Resolving Enantiomers

AR,ASRacemic mixture

XR

AR-XR AS-XR+Diastereomers

separateAR-XR AS-XR

cleave cleave

AR + XR AS + XR

separate separate

ASAROptically pure Optically pure

8.8 SEPARATION OF ENANTIOMERSGeneral Principles

8.8 SEPARATION OF ENANTIOMERSChiral Chromatography

(±)-mexiletine (an antiarrhythmic drug)

OCH2 CH

NH2

CH3

CH3

CH3

OCH2 CH

NH3

CH3

CH3

CH3

conjugate acid of mexiletine (pH 7)

O

column support (matrix)

NCO2

-

H

CO2-H

chiral ligand(S)-aspartate

8.9 CHEMICAL REACTIONS AT STEREOGENIC CENTERSPreview: Stereochemistry of a Substitution Reaction at a Stereogenic Center

C

H CH3

CH2(CH2)4CH3

HO Br !! !

Transition state for inversion of configuration

C Br

HCH3

CH3(CH2)5

(R)-2-bromooctane

NaOHCHO

H CH3

(CH2)5CH3

(S)-2-octanol

8.9 CHEMICAL REACTIONS AT STEREOGENIC CENTERSStereochemistry of a Free Radical Reaction

C CH2Cl

HCH3

CH3CH2

(S)-1-chloro-2-methylbutane

Br2 C CH2Cl

Br

CH3

CH3CH2light

+ C CH2Cl

CH3

BrCH3CH2

Figure 8.19 Free Radical Reaction at a Stereogenic Center A free radical intermediate is achiral because it has a plane of symmetry. A bromine molecule can therefore attack with equal probability from above or below the plane to give a 50:50 mixture of enantiomers. !e 2p orbital is half-occupied, and there is a 50% probability of "nding an electron above or below the nodal plane of the orbital.

C CH2ClCH3CH2

CH3

Br

C

Br

CH3CH2

CH3

CH2Cl

C

Br

CH3CH2

CH3

Br

BrBr

CH2Cl

Planar free radical

8.9 CHEMICAL REACTIONS AT STEREOGENIC CENTERSStereochemistry of a Free Radical Reaction

Figure 8.20 Stereochemistry of Markovnikov Addition of HBr to 1-ButeneA proton adds to the double bond of 1-butene to give an intermediate secondary carbocation. It is achiral because it has a plane of symmetry. Bromide ion can attack with equal probability from the top or the bottom to give a racemic mixture.

C CH3CH3CH2

HPlanar carbocation

C

Br

CH3CH2 CH3

H

(S)-2-bromobutane

C

Br

CH3CH2H

(R)-2-bromobutane

Br

Br

CH3

8.10 REACTIONS THAT PRODUCE STEREOGENIC CENTERSStereochemistry of Markovnikov Addition to Alkenes

Figure 8.21 Stereochemistry of Bromine Addition to Alkenes !e reaction of bromine with an alkene produces a bromonium ion intermediate. !is intermediate reacts with bromide ion in a process that results in net anti addition of bromine. !e stereochemical consequences for adding bromine to cis-2-butene and trans-2-butene are di"erent. cis-2-Butene yields a pair of enantiomers; trans-2-butene yields a meso compound.

Mirror plane

(2S,3S)-dibromobutane

C C

Br

H3C

H H

CH3

C C

Br

Br

H3C

CH3

HH

bromonium ion from cis-2-butene

a

Br

a

(2R,3R)-dibromobutane

C CCH3

Br

H3C Br

HH

(a)

Mirror plane

(2S,3R)-dibromobutane

C C

Br

H3C

H CH3

H

C C

Br

Br

H3C

HCH3

H

bromonium ion from trans-2-butene

a

Br

a

(2R,3S)-dibromobutane

C C HBr

H3C Br

CH3H

(b)

8.10 REACTIONS THAT PRODUCE STEREOGENIC CENTERSStereochemistry of Alkene Bromination

8.12 PROCHIRAL CENTERS

C

CH3

HO H

D

(S)-1-deuteroethanol

C

CH3

HO HR

HS

ethanol

C

CH3

HO D

H

(R)-1-deuteroethanol

add H from aboveC

CH3

OHHD

(R)-1-deuteroethanol

C

CH3

OD

1-deuteroethanol

add H from belowC

CH3

OHDH

(S)-1-deuteroethanol

oleic acid (R)-10-hydroxystearic acid

CH3(C6H2)6CH2

CCH2(CH2)6CO2H

OHH

C CCH2(CH2)6CO2H

HH

CH3(CH2)6CH2H2O

enzyme

HR

CH3

HS

CH3

OHH

(R)-2-butanol

D

CH3

H

CH3

OHH

(2R,3R)

H

CH3

D

CH3

OHH

(2R,3S)