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Home , Chirality, Chirality (chemistry), Chirality (mathematics), Enantiomer, Optical rotation, Polarimeter

Symmetry

Monarch butterfly: bilateral = mirror symmetry

Whenever winds blow butterflies find a new place on the willow tree -Basho (~1644 - 1694)

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Chapter 7: - three-dimensional arrangement of atoms (groups) in space Stereoisomers: with the same connectivity but different arrangement of atoms (groups) in space

H C CH 3 3 H3C H

H H H CH3

cis-1,2-dimethylcyclopropane trans-1,2-dimethylcyclopropane

H H H CH3

H3C CH3 H3C H cis-2-butene trans-2-butene

geometric ()

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1 7.1: Molecular : Enantiomers: non-superimposable isomers. Enantiomers are related to each other much like a right hand is related to a left hand Enantiomers have identical physical properties, i.e., bp, mp, etc. Chirality (from the Greek word for hand). Enantiomers are said to be chiral.

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Molecules are not chiral if they contain a plane of symmetry: a plane that cuts a in half so that one half is the mirror image of the other half. Molecules (or objects) that possess a mirror plane of symmetry are superimposable on their mirror image and are termed achiral. 7.2: The Chirality Center - A molecule containing a carbon with four different groups results in a chiral molecule, and the carbon is referred to as a chiral, or asymmetric, or stereogenic center.

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2 Enantiomers: non-superimposable mirror image isomers

7.3: Symmetry in Achiral Structures - Any molecule with a plane of symmetry or a center of symmetry must be achiral. achiral chiral Not a symmetry symmetry plane plane O OH O H H H H H C O CH3 H C O C C H C C H H H O H H O

Chiral center (stereogenic, asymmetric) 157

7.4: Optical Activity - molecules enriched in an will rotate plane polarized are said to be optically active. The optical is dependent upon the substance, the concentration, the path length through the sample, and the of light.

589 nm - D-line of a sodium lamp

Plane polarized light: light that oscillates in only one plane

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3 H 0 ° + α - α 0 ° H HO C HO2C C CH3 CH3 HO2C HO

dextrorotatory (d): rotates light levororotatory (l): rotates light to the right (clockwise) to the left (counterclockwise) α : angle (# of degrees) plane polarized light is rotated by an optically active sample. Expressed in degrees. Enantiomers will rotate plane polarized light the same magnitude (α) but in opposite directions (+ or -) 90% (+) + 10% (-) will rotate light 80% of pure (+) 75% (+) + 25% (-) will rotate light 50% of pure (+) 50% (+) + 50% (-) will be optically inactive 50:50 mixture of enantiomers (+/-): racemate or Each individual molecule is chiral, however the bulk property of the substance is achiral, if it is in an achiral environment. 159

Specific Rotation [α]D : a standardized value for the

α = optical rotation in degrees l = path length in dm T 100 α [α] = c = concentration of sample in g/100 mL λ l • c T = temperature in °C λ = wavelength of light, usually D for the D-line of a sodium lamp (589 nm)

The is a physical constant of a chiral molecule

The [α]D may also depend upon , therefore the solvent is usually specified.

H NH2

for : HO2C 20 [α]D = +14.5° (c 10, 6N HCl) 160

4 CH3 CH3 H O H O H

CH3 CH3 O CH3

[α]D= +33.0 [α]D= -7.0

There is NO correlation between the sign of the optical rotation and the three-dimensional arrangement of atoms 161

7.6: The Cahn-Ingold-Prelog R-S Notational System Assigning the 1. Use the Cahn-Ingold-Prelog priority rules (Chapter 5) to assign priority (one through four) to the four groups on the “chiral” atom. 3. Orient the molecule so that the lowest priority atom is in the back (away from you). Look at the remaining three groups of priority 1-3. If the remaining three groups are arranged so that the priorities 1→2→3 are in a clockwise fashion, then assign the chiral center as R (“rectus” or right). If the remaining three groups are arranged 1→2→3 in a counterclockwise manner, then assign the chiral center as S (“sinister” or left)

1 1 1 1 OH OH OH 3 OH 2 orient lowest priority H orient lowest priority CO H CH3 H 4 H 2 group away 4 H group away H3C CO2H CO2H CH3 2 HO2C CH3 3 3 2 3 2 162 clockwise = R counter clockwise = S

5 3. Or use the “Hand Rule.” Orient the lowest priority group up. Point your thumb in the direction of the lowest priority group. If you need to use your right hand so that your fingers point in the direction of the group priorities in the order 1→2→3, then the stereogenic center is assigned R (“rectus” or right). If your left hand is required so that your fingers point in the direction of the group priorities 1→2→3, the the stereogenic center is assigned S (“sinister” or left).

4 4 H H 1 1 2 OH HO 2 HO2C CO2H CH3 H3C 3 3 (R)-(-)-Lactic (S)-(+)- (Right Hand) (Left Hand)

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You must be able to draw tetrahedral carbons properly!! In the plane of the paper Dash: projecting behind and in the same plane the plane of the paper Dash and Wedge are on as the tetrahedral carbon away from you adjacent position off the (adjacent position off the tetrahedral carbon tetrahedral carbon) H Wedge: projecting out C OH HO2C of the plane of the paper CH3 toward you

LINEAR : You should draw the carbon backbone in the plane of the paper, and draw substituents either coming towards you (with wedges) or going away from you (with dashes). Note that each carbon should look like a tetrahedron. Correct • • Incorrect • •

H H H Br C HO C C OH Br OH CO H HO C HO2C 2 2 CH CH3 H3C 3

Cl Br Cl OH OH

Cl O OH Cl Br H 164

6 Do the Double-Switch Dance!! In order to assign the stereochemistry you must be able to manipulate the structure on paper so that the lowest priority group is in the proper (back for the steering wheel rule or up for the hand rule) Interchanging any two groups inverts the stereochemistry. So switch the lowest priority group to the desired position. Then switch the other two groups. The “double-switch” does not change the stereochemistry. 3 CH3 CO2H CO2H switch the clockwise = R CH and CO H H C C switch the H and OH C 3 2 OH 1 HO H HO C H OH 2 2 H3C H3C inverts the inverts the stereochemistry stereochemistry

switch the CH3 H H switch the H and CH3 OH and CO2H 2 left hand = S C OH C OH C CO2H HO2C HO2C HO H CH3 1 CH3 inverts the 3 stereochemistry inverts the 165 stereochemistry

switch Br atomic # 35 priority 1 1 3 CH H 1 4 Br 3 O C 2 OH 4 6 - 8 2 2 H H C OH HO 4 C switch O O C Counterclockwise = S H3C Br 3 1 CH3 6 - 1 3

switch H atomic # 1 priority 4 1 4 1 OCH 8 - 6 - 1 1 4 H OCH3 3 H3CO H HO C 2 OH C OH 6 - 8 - 6 2 HO C OH Counterclockwise = S 3 O C 2 3 O O CH OH 6 - 8 - 1 3 switch 2

switch H atomic # 1 priority 4 switch 2 CH3 OH 8 1 CH2CH3 4 Clockwise = R C OH H H CH2CH3 6 - 6 2 1 HO CH2CH3 CH3 3 CH3 6 - 1 3

Note: assignment of R or S has NO relationship with the optical rotation (+) or (-). 166

7 7.7: Fischer Projections - representation of a three-dimensional molecule as a flat structure. A tetrahedral carbon is represented by two crossed lines:

horizontal line is coming vertical line is going back out of the plane of the behind the plane of the page (toward you) paper (away from you)

substituent carbon

CO H CO H CO2H 2 2 H OH H OH OH H3C (R)-lactic acid H CH3 CH3

CO2H CO2H CO2H H HO H HO H (S)-lactic acid H C 3 OH CH3 CH3

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Manipulation of Fischer Projections 1. Fischer projections can be rotated by 180° only!

CO2H CH3 CO2H CH3 180 ° H OH HO H 180 ° HO H H OH

CH3 CO2H CH3 CO2H (R) (R) (S) (S) a 90° rotation inverts the stereochemistry and is illegal! 90 ° CO2H OH H OH ≠ HO2C CH3

CH3 H (R) (S) 2. If one group of a Fischer projection is held steady, the other three groups can be rotated clockwise or counterclockwise. hold CO H CO H CO2H H steady 2 2 HO H HO2C OH H OH HO CH3 hold CH CH CH3 H steady 3 3 (R) (R) (S) (S) 168

8 Assigning R and S Configuration to Fischer Projections 1. Assign priorities to the four substitutents according to the Cahn-Ingold-Prelog rules 2. Perform the two allowed manipulations of the Fischer projection to place the lowest priority group at the top (or bottom). 3. If the priority of the groups 1→2→3 are clockwise then assign the center as R, if 1→2→3 are counterclockwise then assign the center as S. 2 place at the top 4 CO2H H 1 H2N H 4 2 HO2C NH2 1 hold steady CH3 CH3 rotate other 3 3 three groups counterclockwise 1-2-3 counterclockwise = S

2 4 2 CO2H H CO2H 4 1 2 H NH2 1 H2N CO2H H2N CH3 CH3 1 3 CH3 H 3 3 4 169 1-2-3 clockwise = R

7.8: Properties of Enantiomers In general, enantiomers have the same physical properties (bp, mp, density, etc). Enantiomers will rotate plane polarized light the same magnitude (α) but in opposite directions (+ or -).

O O R S HO CO2H HO2C OH H C 3 CH3 H NH2 H2N H CH HO OH 3 H3C D-DOPA L-DOPA no biological effect used for the treatment of (S)-(+)- (R)-(-)-carvone ParkinsonDisease caraway seeds (rye) spearmint oil

O O O O S R NH HN CH3 H3C N S O O R N H N CH3 H3C N H H H H H O O (S)-methampetamine (R)- (S)- (R)-Thalidomide no biological effect teratogen sedative

Enantiomers can have significantly different biological properties

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9 7.10: Chiral Molecules with Two Chirality Centers

CO2H CO2H CO2H CO2H OH O H2N H H NH2 H NH2 H2N H * * OH H OH HO H H OH HO H NH2 CH3 CH3 CH3 CH3 Threonine (2S, 3R) (2R, 3S) (2R, 3R) (2S, 3S)

mirror images mirror images (enantiomers) Natural threonine (enantiomers) possesses the 2S, 3R stereochemistry non-mirror image (diastereomers)

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Enantiomers must have the opposite configuration at all chiral centers. In general, enantiomers have identical physical properties except optical rotation (which is equal in magnitude but opposite in sign). Diastereomers may have completely different physical properties. For a molecule with n chiral centers, there are 2n number of stereoisomers possible, not including geometric stereoisomers of double bonds.

Erythro: substituents on same side of a Fischer projection i.e., (2R, 3R)- and (2S, 3S)-threonine Threo: substituents on opposite sides of a Fischer projection i.e., (2S, 3R)- and (2R, 3S)-threonine

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10 Br H H Br Br Cl Cl Br

H Cl Cl H H H H H (1S,2S)-1-bromo-2- (1R,2R)-1-bromo-2- (1S,2R)-1-bromo-2- (1R,2S)-1-bromo-2- chlorocyclopropane chlorocyclopropane chlorocyclopropane chlorocyclopropane

mirror images mirror images (enantiomers) (enantiomers)

non-mirror image (diastereomers) 7.11: Achiral Molecules with Two Chirality Centers

Br Br Br Br Br H H Br

H H H H H Br Br H meso (achiral) chiral Meso: molecules that contain chiral atoms but are achiral because they also possess a plane of symmetry. 173

CO2H CO2H CO2H CO2H R S R S H C OH HO C H H C OH HO C H rotate 180° R S S R HO C H H C OH H C OH HO C H

CO2H CO2H CO2H CO2H

mirror images Identical (enantiomers)

CO2H CO2H diastereomers R R H C OH H C OH S S H C OH H C OH

CO2H CO2H

meso : The groups on the top carbon reflect (through the symmetry plane) onto the groups on the bottom carbon

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11 7.12: Molecules with Multiple Chirality Centers Maximum number of stereoisomers = 2n. where n = number of structural units capable of stereochemical variation. Structural units include chiral centers and cis (E) and/or trans (Z) double bonds.

CH3 * H : eight chiral centers CH3 H * * 8 * * 2 = 256 possible stereoisomers * H *H HO * (only one of which is naturally occurring) H

H H (E) (E) (S) H3C (R) H3C H H OH H HO H OH H3CHC C C CH3 H H H (Z) H H (R) H (Z) (S) H C H OH HO H 175 3 H3C

A Brief Review of Isomerism

Isomers: compounds with the same chemical formula, but different arrangement of atoms Constitutional : have different connectivities (not limited to alkanes)

C5H12 C4H10O C4H11N NH O 2 OH NH2 butanol diethyl ether different carbon skeleton different functional group different position of FG Stereoisomers: Atoms connected in the same way, but different three-dimensional arrangement of atoms or groups (topology) enantiomers: non-superimposable mirror image isomers diastereomers: non-superimposable, non-mirror image isomer (more than one chiral center. geometric isomers (diastereomers): E / Z isomers 176

12 7.9: Reactions That Create a Chirality Center - reactions of achiral reactants may generate product with chiral centers H Br C H H-Br H3CH2C C H3CH2C C CH3 H H 1-butene 2-bromobutane (achiral) (chiral) However, the products of such reactions with be optically inactive (racemic) Br - Top Face bottom top Br H face H H CH C face C 3 2 C CH3 H3CH2C C H CH3 H3CH2C Br CH3

- (R)-2-bromobutane Br Bottom Face (S)-2-bromobutane (50%) (50%) There is an equal chance for Br- to add from the top face or the bottom face resulting in a 50:50 mixture. The two products are enantiomers. The two transitions states are enantiomeric and

have identical activation energies 177

O H3CCO3H * chiral but racemic

OH Br , H O 2 2 Br * chiral but racemic

H3C OH HBr H3C Br * *

racemic chiral but racemic

H3C OH H3C Br HBr (S)

chiral but racemic 178

13 Br Br H H Br 2 CH CH 3 3 + H3C H3C H3C CH3 Br Addition of Br2 Br to 2-butene (2R, 3R) (2S, 3S) (anti-addition) Br Br H CH3 Br 2 CH CH3 3 + H3C H3C H C H 3 Br Br Meso (identical)

O O H H H H H C H3CCO3H + 3 CH3 Epoxidation H3C CH H H3C CH3 3 H to 2-butene Meso (identical) (syn-addition) O H CCO H O H CH3 3 3 H CH H C 3 + 3 H H3C H H3C H H CH3 (2R, 3R) (2S, 3S) 179

A reaction of a chiral reactant with an achiral reagent may give diastereomeric products, which may or may not be formed in equal amounts. H3C H HBr H C H Br H H C H H Br 3 + 3 (R) (R) (S) (R) (R)

(R)-4-methyl-1-hexene (2S,4R)-2-bromo- (2R,4R)-2-bromo- 4-methylhexane 4-methylhexane

Br - Top Face bottom H C 3 H Br H face top H3C H CH H face C C 3 C H CH3 CH H CH3 Br 3

- (2R,4R)-2-bromo- Br Bottom Face (2S,4R)-2-bromo- 4-methylhexane 4-methylhexane 7.14: Resolution of Enantiomers (please read) - a process of separating a racemate into pure enantiomers. The enantiomers of the racemate must be temporarily converted into diastereomers. 50:50 mixture of enantiomers is a racemic mixture or racemate,

denoted by (±) or (d,l) 180

14 Resolution of a racemic amino by of their salts, using a chiral counter ion H H H NH2 H NH 2 H NH2 N H3O C C C CH3 CO2H CH CO H 3 2 CH3 CO2 N H (R)-(-) (±) (R)-(-) (-) + H + Diasteromeric salts N (separate)

N H H H H3N H H N H N (-)-sparteine 2 H3O C (chiral base) C CH3 CO2H CH3 CO2 N H (S)-(+) (-) (S)-(+) 7.15: Stereoregular (please read) 7.16: Chirality Centers Other Than Carbon (please read) Stereochemistry at atoms other than carbon: N, Si, P, S, and H H C CH2CH3 other atoms have the potential to be 3 N •• chiral (assymmetric, stereogenic) centers

Barrier to inversion is very low •• H N CH2CH3 181 H3C Inversion is a process

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