Stereochemistry: Chiral Molecules PDF

Chapter 5 Stereochemistry Chiral Molecules Chapter 5 In this chapter we will consider:  How to identify, codify, and name the three-dimensional arrangement of atoms and molecules  How such arrangements can lead to unique properties and behaviors...

Chapter 5 Stereochemistry Chiral Molecules Chapter 5 In this chapter we will consider:  How to identify, codify, and name the three-dimensional arrangement of atoms and molecules  How such arrangements can lead to unique properties and behaviors Chapter 5 1. Chirality & Stereochemistry  An object is achiral (not chiral) if the object and its mirror image are identical Chapter 5  A chiral object is one that cannot be superposed on its mirror image Chapter 5 1A. The Biological Significance of Chirality  Chiral molecules are molecules that cannot be superposed onto their mirror images O O One enantiomer NH causes birth defects, N O the other cures morning sickness O Thalidomide Chapter 5  HO NH HO OMe Tretoquinol OMe OMe One enantiomer is a bronchodilator, the other inhibits platelet aggregation Chapter 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 Chapter 5 2. Isomerism: Constitutional Isomers & 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 Chapter 5  Examples Molecular Constitutional Formula Isomers C4H10 and Butane 2-Methylpropane Cl C3H7Cl Cl and 1-Chloropropane 2-Chloropropane Chapter 5  Examples Molecular Constitutional Formula Isomers OH and CH3 O CH3 C2H6O Ethanol Methoxymethane O OCH3 OH and C4H8O2 O Butanoic acid Methyl propanoate Chapter 5 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 Chapter 5 2C. Enantiomers & Diastereomers  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 Chapter 5  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) Chapter 5 Subdivision of Isomers Isomers (different compounds with same molecular formula) Constitutional Isomers Stereoisomers (isomers whose atoms (isomers that have the same have a different connectivity but differ in spatial 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) Chapter 5 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 Chapter 5  OH (2-Butanol) (I) and (II) are nonsuperposable H OH HO H mirror images of each other (I) (II) Chapter 5 4. Molecules Having One Chirality Center Are Chiral  A chirality center is a tetrahedral carbon atom that is bonded to four different groups  A molecule that contains one chirality center is chiral and can exist as a pair of enantiomers Chapter 5  The presence of a single chirality center in a molecule guarantees that the molecule is chiral and that enantiomeric forms are possible  An important property of enantiomers with a single chirality center is that interchanging any two groups at the chirality center converts one enantiomer into the other Chapter 5  Any atom at which an interchange of groups produces a stereoisomer is called a stereogenic center (if the atom is a carbon atom it is usually called a stereogenic carbon)  If all of the tetrahedral atoms in a molecule have two or more groups attached that are the same, the molecule does not have a chirality center. The molecule is superposable on its mirror image and is achiral Chapter 5  Cl Me C* Et H same H Cl Cl H as Me Et Et Me (III) (IV) mirror (III) and (IV) are nonsuperposable mirror images of each other Chapter 5  same as mirror (V) and (VI) are superposable ⇒ not enantiomers ⇒ achiral Chapter 5 4A. Tetrahedral vs. Trigonal Stereogenic Centers  Chirality centers are tetrahedral stereogenic centers H OH HO H Me * Et Et * Me (A) (B) Tetrahedral stereogenic (A) & (B) are center mirror enantiomers ⇒ chiral Chapter 5  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 Chapter 5 5. More about the Biological Importance of Chirality Chapter 5 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 Chapter 5  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) Chapter 5 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 Chapter 5 Plane of symmetry Cl Me Me H achiral Cl No plane of Me Et symmetry H chiral Chapter 5 7. Naming Enantiomers: The 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 Chapter 5 7A. How to Assign (R) and (S) Configurations  Rule 1 Assign priorities to the four different groups on the stereocenter from highest to lowest (priority bases on atomic number, the higher the atomic number, the higher the priority) Chapter 5  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. Chapter 5  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) Chapter 5  HO H  Example (2-Butanol) ① ④ O H Step 1: C C ② or ③ ② or ③ ① ④ O H Step 2: ③ C ② CH 3 H3C C H2 (H, H, H) (C, H, H) Chapter 5  ① OH OH ④ H ③ ② Me Et Et Me OH OH H HO = H Me Et Me Et Et Arrows are clockwise Me (R)-2-Butanol Chapter 5  Other examples ① Cl Cl Counter- ④ clockwise ③ H CH3 HO CH3 (S) HO ② Clockwise ② OCH3 OCH3 ④ ③ (R) H 3C CH2CH3 Br CH2CH3 Br ① Chapter 5  Other examples Rotate C–Cl bond such that H is pointed to the back ② Cl Cl ④ ③ Br H H OH HO ① Br Cl Clockwise Br OH (R) Chapter 5  Other examples Rotate C–CH3 bond such that H is pointed to the back ② H OCH3 ④ I H ① OCH3 I H3C H 3C ③ Counter-clockwise OCH3 H3C I (S) Chapter 5  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 Chapter 5  Example ③ CH3 ④ (S) H ② CH=CH 2 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) Chapter 5  Other examples ② (R) OH ④ ③ CH3 H Cl ① O ③ OH H2C ④ ② C  (O, O, C) ② CH3 H ① Cl O (S) ③ C  (O, H, H) Chapter 5 8. Properties of Enantiomers: Optical Activity  Enantiomers Mirror images that are not superposable H H * * Cl CH3 H3C Cl H3CH2C CH2CH3 mirror Chapter 5  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)-Tartaric Acid 168 – 170 (–)-(S,S)-Tartaric Acid 168 – 170 (+/–)-Tartaric Acid 210 – 212 Chapter 5  Enantiomers Have the same chemical properties (except reaction/interactions with chiral substances) Show different behavior only when they interact with other chiral substances Rotate plane-polarized light in opposite direction Chapter 5  Optical activity The property possessed by chiral substances of rotating the plane of polarization of plane-polarized light Chapter 5 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 Chapter 5 8B. The Polarimeter  A device for measuring the optical activity of a chiral compound a = observed optical rotation Chapter 5 8C. Specific Rotation observed temperature rotation 25 a [a]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 l=589.6 nm) Chapter 5  The value of a depends on the particular experiment (since there are different concentrations with each run) But specific rotation [a] should be the same regardless of the concentration Chapter 5  Two enantiomers should have the same value of specific rotation, but the signs are opposite CH3 CH3 * * H CH2CH3 H3CH2C H HO OH 25 o 25 o [a] = + 13.5 [a] =  13.5 D mirror D Chapter 5 9. The Origin of Optical Activity Chapter 5 9. The Origin of Optical Activity Chapter 5 9. The Origin of Optical Activity Chapter 5 9A. Racemic Forms  An equimolar mixture of two enantiomers is called a racemic mixture (or racemate or racemic form)  A racemic mixture causes no net rotation of plane-polarized light equal & opposite rotation by the rotation enantiomer CH3 H 3C H OH HO H C2 H 5 C2H 5 (R)-2-Butanol (S)-2-Butanol (if present) Chapter 5 9B. Racemic Forms and Enantiomeric Excess  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% Chapter 5  An enantiomerically pure sample of (S)-(+)- 2-butanol shows a specific rotation of +13.52 25 [a]D = +13.52  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% Chapter 5  Enantiomeric excess (ee) Also known as the optical purity Can be calculated from optical rotations % enantiomeric observed specific rotation = x 100 excess * specific rotation of the pure enantiomers Chapter 5  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 Chapter 5 10. The Synthesis of Chiral Molecules 10A. Racemic Forms Ni CH3CH2CCH 3 + H H ( )-CH3CH2CHCH 3 O OH Butanone Hydrogen (  )-2-Butanol (achiral (achiral (chiral molecules) molecules) molecules; but 50:50 mixture (R) & (S)) Chapter 5 Chapter 5 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 diastereomer over others that are possible Chapter 5  O + O H , H2O OEt heat OH + EtOH F F racemate (  ) racemate (  ) O O H2O OEt lipase OH F F racemate (  ) () (> 69% ee) O + OEt + EtOH F (+) (> 99% ee) Chapter 5 11. Chiral Drugs  Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs Chapter 5 Chapter 5 12. Molecules with More than One Chirality Center  In compounds with n tetrahedral stereocenters, the maximum number of stereoisomers is 2n Chapter 5 12A. How to Draw Stereoisomers for Molecules Having More than One Chirality Center Chapter 5  Start by drawing the portion of the carbon skeleton that contains the chirality centers in such a way that as many of the chirality centers are placed in the plane of the paper as possible, and as symmetrically as possible Chapter 5  Next we add the remaining groups that are bonded at the chirality centers in such a way as to maximize the symmetry between the chirality centers Chapter 5  To draw the enantiomer of the first stereoisomer, we simply draw its mirror image Chapter 5  To draw another stereoisomer, we interchange two groups at any one of the chirality centers All of the possible stereoisomers for a compound can be drawn by successively interchanging two groups at each chirality center Chapter 5  Next we examine the relationship between all of the possible pairings of formulas to determine which are pairs of enantiomers, which are diastereomers Chapter 5  Structures 1 and 2 are enantiomers; structures 3 and 4 are also enantiomers  Structures 1 and 3 are stereoisomers and they are not mirror images of each other. They are diastereomers Diastereomers have different physical properties - different melting points and boiling points, different solubilities, and so forth Chapter 5  Diastereomers Stereoisomers that are not enantiomers Unlike enantiomers, diastereomers usually have substantially different chemical and physical properties Chapter 5  Br Br (I) Cl C H H C Cl (II) HO C H H C OH CH3 CH3 Br Br Cl C H H C Cl (III) (IV) CH3 C H H C CH3 HO OH  (I) & (II) are enantiomers of each other  (III) & (IV) are enantiomers of each other Chapter 5  Br Br (I) Cl C H H C Cl (II) HO C H H C OH CH3 CH3 Br Br Cl C H H C Cl (III) (IV) CH3 C H H C CH3 HO OH  Diastereomers of each other: (I) & (III), (I) & (IV), (II) & (III), (II) & (IV) Chapter 5 12B. 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) Chapter 5  H H CH3 C Br Br C CH (I) 3 (II) CH3 C Br Br C CH3 H H H H CH C Br Br C CH (III) 3 3 (IV) H C Br Br C H CH3 CH3 Note: (III) contains a plane of symmetry, is a meso compound, and is achiral ([a] = 0o). Chapter 5  H H CH3 C Br Br C CH (I) 3 (II) CH3 C Br Br C CH3 H H H H CH C Br Br C CH (III) 3 3 (IV) H C Br Br C H CH3 CH3  (I) & (II) are enantiomers of each other and chiral  (III) & (IV) are identical and achiral Chapter 5  H H CH3 C Br Br C CH (I) 3 (II) CH3 C Br Br C CH3 H H H H CH C Br Br C CH (III) 3 3 (IV) H C Br Br C H CH3 CH3  (I) & (III), (II) & (III) are diastereomers  Only 3 stereoisomers: (I) & (II) {enantiomers}, (III) = (IV) {meso} Chapter 5 12C. How to Name Compounds with More than One Chirality Center a H Br  2,3-Dibromobutane Br H b 2 3 1 4 Look through C2–Ha bond a④ ① Br H ③ 2 ② C2: (R) configuration C1 C3 (H, H, H) (Br, C, H) Chapter 5  Look through C3–Hb bond ④ Br b ① b H H Br a H 3 4 ③ 3 ② 2 CH3 C4 C2 Br 1 CH3 (H, H, H) (Br, C, H) C3: (R) configuration Full name:  (2R, 3R)-2,3-Dibromobutane Chapter 5 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 Chapter 5  H Me COOH Me OH H H Ph H OH Ph COOH COOH COOH HO H HO H Fischer Me H Me H Projection Ph Ph Chapter 5  Cl H H Cl H Cl Cl H H3C CH3 H3C CH3 (I) (II) (2S, 3S)-Dichlorobutane (2R, 3R)-Dichlorobutane CH3 CH3 H Cl Cl H Cl H enantiomers H Cl CH3 CH3  (I) and (II) are both chiral and they are enantiomers of each other Chapter 5  CH3 H H Cl Cl H Cl H Cl H3 C CH3 (III) CH3 (2S, 3R)-Dichlorobutane Plane of symmetry  (III) is achiral (a meso compound)  (III) and (I) are diastereomers of each other Chapter 5 14. Stereoisomerism of Cyclic Compounds a meso compound mirror achiral H Me H Me Me Me Me H Me H H H enantiomers Plane of symmetry Chapter 5  14A. Cyclohexane Derivatives  1,4-Dimethylcyclohexane Plane of Both cis- & trans- Me symmetry Me 1,4-dimethylcyclo- hexanes are achiral and Me Me optically inactive Me H The cis & trans Me H Me Me forms are H H diastereomers cis-1,4-dimethyl trans-1,4-dimethyl cyclohexane cyclohexane Chapter 5  1,3-Dimethylcyclohexane Plane of symmetry Me Me Me * * cis-1,3-dimethyl Me H cyclohexane H (meso) cis-1,3-Dimethylcyclohexane has a plane of symmetry and is a meso compound Chapter 5  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 Chapter 5  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 Chapter 5  1,2-Dimethylcyclohexane mirror H H Me Me Me Me H H enantiomers trans-1,2-Dimethylcyclohexane exists as a pair of enantiomers Chapter 5  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 Chapter 5  However, (II) can rapidly be interconverted to (III) by a ring flip Me Me 2' H H 2 1' Me Me 1 (I) H H (II) Me Me 2 1 H H (III) Chapter 5  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 C2 of (II) and (III) 2 1 (III) Me become C1’ of (I) H H Chapter 5  Me Me 2' H H 2 1' Me Me 1 (I) H H (II) Although (I) and (II) are enantiomers to Me 2 1 (III) each other, they can Me H interconvert rapidly H  (I) and (II) are achiral Chapter 5 15. Relating Configurations through Reactions in Which No Bonds to the Chirality Center Are Broken  A reaction is said to proceed with retention of configuration at a chirality center if no bonds to the chirality center are broken. This is true even if the R,S designation for the chirality center changes because the relative priorities of groups around it changes as a result of the reaction Chapter 5  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 Chapter 5 15A. Relative & 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 superimposed in a pyramidal arrangement Chapter 5  The absolute configuration 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 Chapter 5 16. Separation of Enantiomers: Resolution  Resolution – separation of two enantiomers O O OH OMe OMe e.g. O O C F3 + C F3 R * R' O Ph Ph (racemic) R R' R R' OMe Cl (1 : 1) Ph CF3 (Mosher acid diastereomers chloride) usually separable either by flash column chromatography or recrystallization etc. Chapter 5  Kinetic Resolution OH OH OH R1 R1 R1 R * R * + R * R2 R2 O R2 (racemic) One enantiomer reacts “fast” and another enantiomer reacts “slow” Chapter 5  e.g. Me3Si t i Me3Si Me3Si BuOOH, Ti(O Pr)4 O OH (-)-DET OH + OH * C5H11 HO COOEt C5H11 C5H11 (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% Chapter 5 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 Chapter 5 18. Chiral Molecules That Do Not Possess a Chirality Center Chapter 5  mirror H H H H C C C C C C Cl Cl Cl Cl enantiomers Chapter 5  END OF CHAPTER 5  Chapter 5