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Chapter 5 Chiral Molecules

Ch. 5 - 1 1. & Stereochemistry

 An object is achiral (not chiral) if the object and its mirror image are identical

Ch. 5 - 2  A chiral object is one that cannot be superposed on its mirror image

Ch. 5 - 3 1A. The Biological Significance of Chirality  Chiral molecules are molecules that cannot be superimposable with their mirror images

O O ● One NH causes birth defects, N O the other cures morning sickness O Ch. 5 - 4 HO

NH HO OMe Tretoquinol OMe OMe

● One enantiomer is a bronchodilator, the other inhibits platelet aggregation

Ch. 5 - 5  66% of all drugs in development are chiral, 51% are being studied as a single enantiomer

 Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs

Ch. 5 - 6 2. Isomerisom: Constitutional & Stereoisomers 2A. Constitutional Isomers

 Isomers: different compounds that have the same molecular formula ● Constitutional isomers: isomers that have the same molecular formula but different connectivity – their atoms are connected in a different order Ch. 5 - 7  Examples Molecular Constitutional Formula Isomers

C4H10 and Butane 2-Methylpropane

Cl Cl C3H7Cl and 1-Chloropropane 2-Chloropropane

Ch. 5 - 8  Examples Molecular Constitutional Formula Isomers

CH O CH C H O OH and 3 3 2 6 Ethanol Methoxymethane

O OCH and 3 C H O OH 4 8 2 O Butanoic acid Methyl propanoate Ch. 5 - 9 2B. Stereoisomers

 Stereoisomers are NOT constitutional isomers

 Stereoisomers have their atoms connected in the same sequence but they differ in the arrangement of their atoms in space. The consideration of such spatial aspects of molecular structure is called stereochemistry

Ch. 5 - 10 2C. &

 Stereoisomers can be subdivided into two general categories: enantiomers & diasteromers ● Enantiomers – stereoisomers whose molecules are nonsuperposable mirror images of each other ● Diastereomers – stereoisomers whose molecules are not mirror

images of each other Ch. 5 - 11  Geometrical isomers (cis & trans isomers) are: ● Diastereomers e.g. Ph Ph Ph and Ph (cis) (trans)

Cl Cl Cl H and H H H Cl (cis) (trans) Ch. 5 - 12 Subdivision of Isomers

Isomers (different compounds with same molecular formula)

Constitutional Isomers Stereoisomers (isomers that have the same (isomers whose atoms have a connectivity but differ in spatial different connectivity) arrangement of their atoms)

Enantiomers Diastereomers (stereoisomers that are (stereoisomers that are nonsuperposable mirror NOT mirror images of images of each other) each other)

Ch. 5 - 13 3. Enantiomers and Chiral Molecules  Enantiomers occur only with compounds whose molecules are chiral  A chiral molecule is one that is NOT superposable on its mirror image  The relationship between a chiral molecule and its mirror image is one that is enantiomeric. A chiral molecule and its mirror image are said to be enantiomers of each other Ch. 5 - 14 OH (2-Butanol)

(I) and (II) are nonsuperposable H OH HO H mirror images of each other (I) (II)

Ch. 5 - 15 4. A Single Chirality Center Causes a Molecule to Be Chiral

 The most common type of chiral compounds that we encounter are molecules that contain a carbon atom bonded to four different groups. Such a carbon atom is called an asymmetric carbon or a chiral center and is usually designated with an asterisk (*)

Ch. 5 - 16 Cl Me C* Et H

H Cl Cl H Me Et Et Me (III) (IV)

mirror (III) and (IV) are nonsuperposable mirror images of each other Ch. 5 - 17 Cl Me C Me H

H Cl Cl H Me Me Me Me (V) (VI)

mirror (V) and (VI) are superposable ⇒ not enantiomers ⇒ achiral Ch. 5 - 18 4A. Tetrahedral vs. Trigonal Stereogenic Centers

 Chirality centers are tetrahedral stereogenic centers

H OH HO H Me * Et Et * Me (A) (B) Tetrahedral stereogenic mirror (A) & (B) are center enantiomers ⇒ chiral Ch. 5 - 19  Cis and trans alkene isomers contain trigonal stereogenic centers

Ph H H Ph

H Ph Ph H Trigonal (C) (D) stereogenic mirror center ⇒ achiral (C) & (D) are identical

Ch. 5 - 20 4A. Tetrahedral vs. Trigonal Stereogenic Centers

 Chirality centers are tetrahedral stereogenic centers

 Cis and trans alkene isomers contain trigonal stereogenic centers

Ch. 5 - 21 5. More about the Biological Importance of Chirality

(+)- (-)-Limonene (limonene enantiomer (limonene enantiomer found in oranges) found in lemons)

Ch. 5 - 22 Thalidomide

 The activity of drugs containing chirality centers can vary between enantiomers, sometimes with serious or even tragic consequences

 For several years before 1963 thalidomide was used to alleviate the symptoms of morning sickness in pregnant women

Ch. 5 - 23  In 1963 it was discovered that thalidomide (sold as a mixture of both enantiomers) was the cause of horrible birth defects in many children born subsequent to the use of the drug O O O O NH NH N O N O

O O Thalidomide enantiomer of (cures morning sickness) Thalidomide (causes birth defects)

Ch. 5 - 24 6. How to Test for Chirality: Planes of Symmetry

 A molecule will not be chiral if it possesses a plane of symmetry  A plane of symmetry (mirror plane) is an imaginary plane that bisects a molecule such that the two halves of the molecule are mirror images of each other  All molecules with a plane of symmetry in their most symmetric conformation

are achiral Ch. 5 - 25 Plane of symmetry Cl

Me Me

H achiral

Cl

Me Et

H No plane of symmetry chiral Ch. 5 - 26 7. Naming Enantiomers: R,S-System

OH H OH HO H Recall: (I) (II)

 Using only the IUPAC naming that we have learned so far, these two enantiomers will have the same name: ● 2-Butanol  This is undesirable because each compound must have its own distinct name Ch. 5 - 27 7A. How to Assign (R) and (S) Configurations

 Rule 1 ● Assign priorities to the four different groups on the from highest to lowest (priority bases on atomic number, the higher the atomic number, the higher the priority)

Ch. 5 - 28  Rule 2 ● When a priority cannot be assigned on the basis of the atomic number of the atoms that are directly attached to the chirality center, then the next set of atoms in the unassigned groups is examined. This process is continued until a decision can be made.

Ch. 5 - 29  Rule 3 ● Visualize the molecule so that the lowest priority group is directed away from you, then trace a path from highest to lowest priority. If the path is a clockwise motion, then the configuration at the asymmetric carbon is (R). If the path is a counter-clockwise motion, then the configuration is (S)

Ch. 5 - 30 H  Example HO (2-Butanol)

① ④ O H Step 1: C C ② or ③ ② or ③

① ④ O H ③ C ② Step 2: CH3 H3C C H2 (H, H, H) (C, H, H) Ch. 5 - 31 ① OH OH ④ H ③ ② Me Et Et Me OH OH HO H = H Me Et Me Et Et Arrows are clockwise Me (R)-2-Butanol

Ch. 5 - 32  Other examples ① Cl Cl Counter- clockwise ④ H ③ CH3 HO CH3 (S) HO ② Clockwise ② OCH3 OCH3 ④ (R) ③ H3C CH2CH3 Br CH2CH3 Br ① Ch. 5 - 33  Other examples ● Rotate C–Cl bond such that H is pointed to the back ② Cl Cl ④ ③ Br H H OH HO Br ①

Cl Clockwise

Br OH (R) Ch. 5 - 34  Other examples

● Rotate C–CH3 bond such that H is pointed to the back ② H OCH3 ④ I H ① OCH3 I H3C H3C ③

Counter-clockwise OCH3

H3C I (S) Ch. 5 - 35  Rule 4 ● For groups containing double or triple bonds, assign priorities as if both atoms were duplicated or triplicated

e.g. C O as C O O C

C C as C C C C C C C C as C C

C C Ch. 5 - 36  Example ③ CH3 ④ (S) H ② CH=CH2 HO ① Compare CH3 & CH CH2 : H H

CH CH2 equivalent to C C H C C

Thus, CH3 ⇒ (H, H, H)

CH CH2 ⇒ (C, C, H) Ch. 5 - 37  Other examples ② (R) OH ④ CH H ③ 3 Cl ① O

③ OH H2C ④ CH ② C ⇒ (O, O, C) H ② 3 Cl ① O (S) ③ C ⇒ (O, H, H) Ch. 5 - 38 8. Properties of Enantiomers: Optical Activity

 Enantiomers ● Mirror images that are not superposable

H H

* * Cl Cl CH3 H3C H3CH2C CH2CH3

mirror Ch. 5 - 39  Enantiomers have identical physical properties (e.g. melting point, boiling point, refractive index, solubility etc.) Compound bp (oC) mp (oC) (R)-2-Butanol 99.5 (S)-2-Butanol 99.5 (+)-(R,R)- 168 – 170 (–)-(S,S)-Tartaric Acid 168 – 170 (+/–)-Tartaric Acid 210 – 212

Ch. 5 - 40  Enantiomers ● Have the same chemical properties (except reaction/interactions with chiral substances) ● Show different behavior only when they interact with other chiral substances ● Turn plane-polarized light on opposite direction

Ch. 5 - 41  Optical activity ● The property possessed by chiral substances of rotating the plane of of plane-polarized light

Ch. 5 - 42 8A. Plane-Polarized Light  The electric field (like the magnetic field) of light is oscillating in all possible planes  When this light passes through a polarizer (Polaroid lens), we get plane- polarized light (oscillating in only one plane) Polaroid lens Ch. 5 - 43 8B. The

 A device for measuring the optical activity of a chiral compound

α =observed

Ch. 5 - 44 8C. observed temperature rotation 25 α [α] = D c x ℓ wavelength concentration length of cell of light of sample in dm (e.g. D-line solution (1 dm = 10 cm) of Na lamp, in g/mL λ=589.6 nm)

Ch. 5 - 45  The value of α depends on the particular experiment (since there are different concentrations with each run) ● But specific rotation [α] should be the same regardless of the concentration

Ch. 5 - 46  Two enantiomers should have the same value of specific rotation, but the signs are opposite

CH3 CH3 * * H H CH2CH3 H3CH2C HO OH

25 25 [α] = + 13.5o [α] = − 13.5o D mirror D

Ch. 5 - 47 9. The Origin of Optical Activity

Ch. 5 - 48 Ch. 5 - 49 Two circularly- Two circularly-polarized polarized beams beams counter-rotating counter-rotating at at different velocities, the same velocity such as after interaction (in phase), and with a chiral molecule, their vector sum and their vector sum Ch. 5 - 50 9A. Racemic Forms  An equimolar mixture of two enantiomers is called a (or racemate or racemic form)  A racemic mixture causes no net rotation of plane-polarized light equal & opposite rotation by the rotation enantiomer

CH3 H3C H OH HO H C2H5 C2H5 (R)-2-Butanol (S)-2-Butanol (if present) Ch. 5 - 51 9B. Racemic Forms and

 A sample of an optically active substance that consists of a single enantiomer is said to be enantiomerically pure or to have an enantiomeric excess of 100%

Ch. 5 - 52  An enantiomerically pure sample of (S)-(+)- 2-butanol shows a specific rotation of +13.52 25 [α] = +13.52 D

 A sample of (S)-(+)-2-butanol that contains less than an equimolar amount of (R)-(–)-2- butanol will show a specific rotation that is less than 13.52 but greater than zero  Such a sample is said to have an enantiomeric excess less than 100%

Ch. 5 - 53  Enantiomeric excess (ee) ● Also known as the optical purity

mole of one moles of other % enantiomeric enantiomer enantiomer = x 100 excess total moles of both enantiomers

● Can be calculated from optical rotations

% enantiomeric observed specific rotation = x 100 excess * specific rotation of the pure enantiomers

Ch. 5 - 54  Example ● A mixture of the 2-butanol enantiomers showed a specific rotation of +6.76. The enantiomeric excess of the (S)-(+)- 2-butanol is 50%

% enantiomeric +6.76 = x 100 = 50% excess * +13.52

Ch. 5 - 55 10. The Synthesis of Chiral Molecules 10A. Racemic Forms

Ni CH3CH2CCH3 + H H ( −+ )-CH3CH2CHCH3 O OH

Butanone Hydrogen ( −+ )-2-Butanol (achiral (achiral (chiral molecules) molecules) molecules; but 50:50 mixture (R) & (S))

Ch. 5 - 56 Ch. 5 - 57 10B. Stereoselective Syntheses

 Stereoselective reactions are reactions that lead to a preferential formation of one stereoisomer over other stereoisomers that could possibly be formed ● enantioselective – if a reaction produces preferentially one enantiomer over its mirror image ● diastereoselective – if a reaction leads preferentially to one over others that are possible

Ch. 5 - 58 O + O H , H2O + EtOH OEt heat OH F F racemate ( −+ ) racemate ( −+ )

O O H2O OEt lipase OH F F racemate ( −+ ) (−) (> 69% ee) O

+ OEt + EtOH F (+) (> 99% ee) Ch. 5 - 59 11.

 Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs

NC HO NH O 3 NMe CO2 2 HO H Escitalpram L-DOPA (anti-depressant ) (treatment for Parkinson's) F

Ch. 5 - 60 Naproxen (anti-inflammatory drug) CO2H

CH3 MeO

NaO C 2 CH HO 3 S CH3 Cl N

Singulair (asthma and allergy treatment) Ch. 5 - 61 12. Molecules with More than One Chirality Center

 Diastereomers ● Stereoisomers that are not enantiomers

● Unlike enantiomers, diastereomers usually have substantially different chemical and physical properties

Ch. 5 - 62 Br Br C H H C (I) Cl Cl (II) HO C H H C OH CH3 CH3

Br Br C H H C (III) Cl Cl (IV) CH3 C H H C CH3 HO OH Note: In compounds with n tetrahedral , the maximum number of stereoisomers is 2n. Ch. 5 - 63 Br Br C H H C (I) Cl Cl (II) HO C H H C OH CH3 CH3

Br Br C H H C (III) Cl Cl (IV) CH3 C H H C CH3 HO OH

 (I) & (II) are enantiomers to each other  (III) & (IV) are enantiomers to each other Ch. 5 - 64 Br Br C H H C (I) Cl Cl (II) HO C H H C OH CH3 CH3

Br Br C H H C (III) Cl Cl (IV) CH3 C H H C CH3 HO OH

 Diastereomers to each other: ● (I) & (III), (I) & (IV), (II) & (III), (II) & (IV) Ch. 5 - 65 12A. Meso Compounds  Compounds with two stereocenters do not always have four stereoisomers (22 = 4) since some molecules are achiral (not chiral), even though they contain stereocenters  For example, 2,3-dichlorobutane has two stereocenters, but only has 3 stereoisomers (not 4)

Ch. 5 - 66 H H C Br Br C (I) CH3 CH3 (II) CH3 C Br Br C CH3 H H

H H C Br Br C (III) CH3 CH3 (IV) H C Br Br C H CH3 CH3 Note: (III) contains a plane of symmetry, is a , and is achiral ([α] = 0o). Ch. 5 - 67 H H C Br Br C (I) CH3 CH3 (II) CH3 C Br Br C CH3 H H

H H C Br Br C (III) CH3 CH3 (IV) H C Br Br C H CH3 CH3

 (I) & (II) are enantiomers to each other and chiral  (III) & (IV) are identical and achiral Ch. 5 - 68 H H C Br Br C (I) CH3 CH3 (II) CH3 C Br Br C CH3 H H

H H C Br Br C (III) CH3 CH3 (IV) H C Br Br C H CH3 CH3

 (I) & (III), (II) & (III) are diastereomers  Only 3 stereoisomers: ● (I) & (II) {enantiomers}, (III) {meso} Ch. 5 - 69 12B. How to Name Compounds with More than One Chirality Center Ha Br  2,3-Dibromobutane Br Hb 2 3

1 4 ● Look through C2–Ha bond a ④ ①Br H

③ 2 ② C2: (R) configuration C1 C3 (H, H, H) (Br, C, H) Ch. 5 - 70 ● Look through C3–Hb bond ④ ① b Br Hb Br H Ha 3 4 ③ 3 ② 2 CH C4 C2 Br 3 1 CH3 (H, H, H) (Br, C, H) C3: (R) configuration

● Full name:  (2R, 3R)-2,3-Dibromobutane

Ch. 5 - 71 13. Fischer Projection Formulas 13A. How To Draw and Use Fischer Projections Fischer Projection COOH COOH Et Br HO Ph Br Ph Br Ph Et OH Et OH H3C COOH CH3 CH3

Ch. 5 - 72 H Me COOH Me OH H H Ph H OH Ph COOH

COOH COOH

HO H HO H Fischer Me H Projection Me H

Ph Ph Ch. 5 - 73 Cl H H Cl H Cl Cl H

H3C CH3 H3C CH3 (I) (II) (2S, 3S)-Dichlorobutane (2R, 3R)-Dichlorobutane

CH CH3 3 H Cl Cl H enantiomers Cl H H Cl CH CH3 3 mirror  (I) and (II) are both chiral and they are

enantiomers with each other Ch. 5 - 74 CH3 H H Cl Cl H Cl H Cl H3C CH3 (III) CH3 (2S, 3R)-Dichlorobutane Plane of symmetry

 (III) is achiral (a meso compound)  (III) and (I) are diastereomers to each other Ch. 5 - 75 14. of Cyclic Compounds a meso compound mirror achiral

H Me H Me Me Me

Me H Me H H H

enantiomers Plane of symmetry Ch. 5 - 76 14A. Cyclohexane Derivatives  1,4-Dimethylcyclohexane Plane of • Both cis- & trans- Me symmetry Me 1,4-dimethylcyclo- hexanes are achiral and optically inactive Me Me Me H • The cis & trans forms are Me H Me Me diastereomers H H cis-1,4-dimethyl trans-1,4-dimethyl cyclohexane cyclohexane Ch. 5 - 77  1,3-Dimethylcyclohexane Plane of symmetry

Me Me Me * * Me cis-1,3-dimethyl H cyclohexane H (meso)

● cis-1,3-Dimethylcyclohexane has a plane of symmetry and is a meso compound Ch. 5 - 78  1,3-Dimethylcyclohexane

NO plane of symmetry

Me Me Me Me * * H H H H Me Me trans-1,3-dimethyl cyclohexane enantiomers

● trans-1,3-Dimethylcyclohexane exists as a pair of enantiomers

Ch. 5 - 79  1,3-Dimethylcyclohexane ● Has two chirality centers but only three stereoisomers

cis-1,3-dimethyl trans-1,3-dimethyl cyclohexane cyclohexane

Me Me Me Me H H H H H H Me Me

(meso) enantiomers Ch. 5 - 80  1,2-Dimethylcyclohexane mirror H H Me Me Me Me H H

enantiomers

● trans-1,2-Dimethylcyclohexane exists as a pair of enantiomers

Ch. 5 - 81  1,2-Dimethylcyclohexane ● With cis-1,2-dimethylcyclohexane the situation is quite complicated mirror Me Me H H Me Me (I) H H (II) ● (I) and (II) are enantiomers to each other

Ch. 5 - 82 ● However, (II) can rapidly be interconverted to (III) by a ring flip mirror Me Me 2' H H 2 1' Me Me 1 (I) H H (II)

Me 2 Me 1 H H (III) Ch. 5 - 83 ● Rotation of (III) along the vertical axis gives (I) Me Me 2' H H 2 1' Me Me 1 (I) H H (II)

C1 of (II) and (III) become C2’ of (I) & Me 1 (III) C2 of (II) and (III) Me 2 become C1’ of (I) H H Ch. 5 - 84 Me Me 2' H H 2 1' Me Me 1 (I) H H (II)

Although (I) and (II) Me are enantiomers to 1 (III) Me 2 each other, they can H interconvert rapidly H ⇒ (I) and (II) are achiral Ch. 5 - 85 15. Relating Configurations through Reactions in Which No Bonds to the Chirality Center Are Broken

 If a reaction takes place in a way so that no bonds to the chirality center are broken, the product will of necessity have the same general configuration of groups around the chirality center as the reactant

Ch. 5 - 86 Same configuration

O OH NaBH4 H H MeOH H Me H Me H

Me H NaCN Me H Ph Br DMSO Ph CN

Same configuration Ch. 5 - 87 15A. Relative and Absolute Configurations  Chirality centers in different molecules have the same relative configuration if they share three groups in common and if these groups with the central carbon can be superposed in a pyramidal arrangement

Y The chirality centers in I and II have the X A C B same relative A C I configuration. Their B common groups and II central carbon can be superposed. Ch. 5 - 88  The of a chirality center is its (R) or (S) designation, which can only be specified by knowledge of the actual arrangement of groups in space at the chirality center

(R)-2-Butanol (S)-2-Butanol

HO H H OH

enantiomers Ch. 5 - 89 16. Separation of Enantiomers: Resolution

 Resolution – separation of two enantiomers O O OH OMe OMe e.g. O O CF3 + CF3 R * R' O Ph Ph R R' R R' (racemic) OMe Cl ( 1 : 1 ) Ph CF3 (Mosher acid diastereomers chloride) usually separable either by flash column chromatography or recrystallization etc. Ch. 5 - 90 

OH OH OH R1 R1 R1 R * R * + R *

R2 R2 O R2 (racemic)

● One enantiomer reacts “fast” and another enantiomer reacts “slow”

Ch. 5 - 91  e.g. Me Si Me3Si Me3Si 3 tBuOOH, Ti(OiPr) 4 O OH + OH * OH (-)-DET C H C H C5H11 HO COOEt 5 11 5 11 (racemic) (-)-DET: HO COOEt 42% 43% (D)-(-)-Diethyl Tartrate (99%ee) (99%ee)

× 

Me3Si Me3Si

R' S OH H R OH

H R' * stop reaction at ≤ 50% * maximum yield = 50% Ch. 5 - 92 17. Compounds with Chirality Centers Other than Carbon

R4 R3 H R3 Si Ge R1 R2 R1 R2

R4 R3 R2 R1 N X S R1 R2 O

Ch. 5 - 93 18. Chiral Molecules That Do Not Possess a Chirality Center

P(Ph)2 (Ph)2P

P(Ph)2 (Ph)2P

(S)-BINAP (R)-BINAP

enantiomers Ch. 5 - 94 mirror

H H H H C C C C C C Cl Cl Cl Cl

enantiomers

Ch. 5 - 95  END OF CHAPTER 5 

Ch. 5 - 96