1. Chirality & Stereochemistry

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1 hapter 5 Stereochemistry hiral Molecules reated by Professor William Tam & Dr. illis hang h. 5 - About The Authors These Powerpoint Lecture Slides were created and prepared by Professor William Tam and his wife Dr. illis hang. Professor William Tam received his B.Sc. at the University of ong Kong in 990 and his.d. at the University of Toronto (anada) in 995. e was an NSER postdoctoral fellow at the Imperial ollege (UK) and at arvard University (USA). e joined the Department of hemistry at the University of Guelph (ntario, anada) in 998 and is currently a Full Professor and Associate hair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top % most cited hemists worldwide. e has published four books and over 80 scientific papers in top international journals such as J. Am. hem. Soc., Angew. hem., rg. Lett., and J. rg. hem. Dr. illis hang received her B.Sc. at New York University (USA) in 99, her M.Sc. and.d. in 997 and 00 at the University of Guelph (anada). She lives in Guelph with her husband, William, and their son, Matthew. h hirality & Stereochemistry An object is achiral (not chiral) if the object and its image are identical A chiral object is one that cannot be superposed on its image h. 5 - h. 5 - A. The Biological Significance of hirality hiral molecules are molecules that cannot be superimposable with their images N Thalidomide N ne enantiomer causes birth defects, the other cures morning sickness h. 5-5 Tretoquinol N ne enantiomer is a bronchodilator, the other inhibits platelet aggregation h. 5-6

2 66% of all drugs in development are chiral, 5% are being studied as a single enantiomer f the $75 billion in world-wide sales of formulated pharmaceutical products in 008, $05 billion was attributable to single enantiomer drugs h Isomerisom: onstitutional Isomers & Stereoisomers A. onstitutional Isomers Isomers: different compounds that have the same molecular formula onstitutional isomers: isomers that have the same molecular formula but different connectivity their atoms are connected in a different order h. 5-8 Examples Examples Molecular Formula onstitutional Isomers Molecular Formula onstitutional Isomers 0 Butane and -thylpropane 6 and hanol thoxymethane 7 l l -hloropropane and l -hloropropane h Butanoic acid and thyl propanoate h. 5-0 B. Stereoisomers Stereoisomers are NT 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 h Enantiomers & Diastereomers Stereoisomers can be subdivided into two general categories: & diasteromers Enantiomers stereoisomers whose molecules are nonsuperposable images of each other Diastereomers stereoisomers whose molecules are not images of each other h. 5 -

3 Geometrical isomers (cis & trans isomers) are: Diastereomers e.g. (cis) l l (cis) and and (trans) l l (trans) h. 5 - Subdivision of Isomers onstitutional Isomers (isomers whose atoms have a different connectivity) Isomers (different compounds with same molecular formula) Enantiomers (stereoisomers that are nonsuperposable images of each other) Stereoisomers (isomers that have the same connectivity but differ in spatial arrangement of their atoms) Diastereomers (stereoisomers that are NT images of each other) h Enantiomers and hiral Molecules Enantiomers occur only with compounds whose molecules are chiral A chiral molecule is one that is NT superposable on its image The relationship between a chiral molecule and its image is one that is enantiomeric. A chiral molecule and its image are said to be of each other h. 5-5 (-Butanol) and are nonsuperposable images of each other h A Single hirality enter auses a Molecule to Be hiral 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 () h. 5-7 l l l (IV) and (IV) are nonsuperposable images of each other h. 5-8

4 l l l (V) (VI) (V) and (VI) are superposable not achiral h. 5-9 A. Tetrahedral vs. Trigonal Stereogenic enters hirality centers are tetrahedral stereogenic centers (A) Tetrahedral stereogenic center chiral (B) (A) & (B) are h. 5-0 is and trans alkene isomers contain trigonal stereogenic centers A. Tetrahedral vs. Trigonal Stereogenic enters hirality centers are tetrahedral stereogenic centers Trigonal stereogenic center achiral () (D) () & (D) are identical is and trans alkene isomers contain trigonal stereogenic centers h. 5 - h More about the Biological Importance of hirality (+)-Limonene (limonene enantiomer found in oranges) (-)-Limonene (limonene enantiomer found in lemons) h. 5 - Thalidomide The activity of drugs containing chirality centers can vary between, sometimes with serious or even tragic consequences For several years before 96 thalidomide was used to alleviate the symptoms of morning sickness in pregnant women h. 5 -

5 In 96 it was discovered that thalidomide (sold as a mixture of both ) was the cause of horrible birth defects in many children born subsequent to the use of the drug N N N N Thalidomide (cures morning sickness) enantiomer of Thalidomide (causes birth defects) h ow to Test for hirality: Planes of Symmetry A molecule will not be chiral if it possesses a plane of symmetry A plane of symmetry ( plane) is an imaginary plane that bisects a molecule such that the two halves of the molecule are images of each other All molecules with a plane of symmetry in their most symmetric conformation are achiral h. 5-6 Plane of symmetry l 7. Naming Enantiomers: R,S-System l No plane of symmetry achiral chiral h. 5-7 Recall: Using only the IUPA naming that we have learned so far, these two will have the same name: -Butanol This is undesirable because each compound must have its own distinct name h A. ow to Assign (R) and (S) onfigurations Rule 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) Rule 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. h. 5-9 h. 5-0

6 Rule 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) h. 5 - Example Step : or or Step : (,, ) (,, ) (-Butanol) h. 5 - = Arrows are clockwise (R)--Butanol h. 5 - ther examples l l ounterclockwise (S) lockwise (R) h. 5 - ther examples Rotate l bond such that is pointed to the back l l l lockwise ther examples Rotate bond such that is pointed to the back I I ounter-clockwise (R) I (S) h. 5-5 h. 5-6

7 Rule For groups containing double or triple bonds, assign priorities as if both atoms were duplicated or triplicated e.g. as as as h. 5-7 Example = ompare & : equivalent to Thus, (,, ) (,, ) (S) h. 5-8 ther examples (R) 8. Properties of Enantiomers: ptical Activity l Enantiomers Mirror images that are not superposable l (S) (,, ) (,, ) h. 5-9 l l h. 5-0 Enantiomers have identical physical properties (e.g. melting point, boiling point, refractive index, solubility etc.) ompound bp ( o ) mp ( o ) (R)--Butanol 99.5 (S)--Butanol 99.5 (+)-(R,R)-Tartaric Acid ( )-(S,S)-Tartaric Acid (+/ )-Tartaric Acid 0 h. 5 - Enantiomers ave 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 h. 5 -

8 ptical activity The property possessed by chiral substances of rotating the plane of polarization of plane-polarized light h. 5-8A. Plane-Polarized 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 planepolarized light (oscillating in only one plane) Polaroid lens h. 5-8B. The Polarimeter A device for measuring the optical activity of a chiral compound α =observed optical rotation 8. Specific Rotation temperature wavelength of light (e.g. D-line of Na lamp, λ=589.6 nm) 5 [α] = α D c x concentration of sample solution in g/ml l observed rotation length of cell in dm ( dm = 0 cm) h. 5-5 h. 5-6 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 Two should have the same value of specific rotation, but the signs are opposite 5 [α] = +.5 o D [α] =.5 o 5 D h. 5-7 h. 5-8

9 9. The rigin of ptical Activity h. 5-9 h Two circularlypolarized beams counter-rotating at the same velocity (in phase), and their vector sum Two circularly-polarized beams counter-rotating at different velocities, such as after interaction with a chiral molecule, and their vector sum h A. Racemic Forms An equimolar mixture of two is called a racemic mixture (or racemate or racemic form) A racemic mixture causes no net rotation of plane-polarized light 5 (R)--Butanol rotation 5 (S)--Butanol (if present) equal & opposite rotation by the enantiomer h B. 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 00% h. 5-5 An enantiomerically pure sample of (S)-(+)- -butanol shows a specific rotation of [α] = +.5 D A sample of (S)-(+)--butanol that contains less than an equimolar amount of (R)-( )-- butanol will show a specific rotation that is less than.5 but greater than zero Such a sample is said to have an enantiomeric excess less than 00% h. 5-5

10 Enantiomeric excess (ee) Also known as the optical purity % enantiomeric excess % enantiomeric excess mole of one moles of other enantiomer enantiomer = x 00 total moles of both an be calculated from optical rotations = observed specific rotation specific rotation of the x 00 pure h Example A mixture of the -butanol showed a specific rotation of The enantiomeric excess of the (S)-(+)- -butanol is 50% % enantiomeric excess = x 00 = 50% +.5 h The Synthesis of hiral Molecules 0A. Racemic Forms Ni + ( + )- Butanone (achiral molecules) ydrogen (achiral molecules) ( + )--Butanol (chiral molecules; but 50:50 mixture (R) & (S)) h h B. 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 image diastereoselective if a reaction leads preferentially to one diastereomer over others that are possible h F racemate ( + ) F racemate ( + ) +, heat lipase + + F racemate ( + ) F ( ) (> 69% ee) + F (+) (> 99% ee) h. 5-60

11 . hiral Drugs f the $75 billion in world-wide sales of formulated pharmaceutical products in 008, $05 billion was attributable to single enantiomer drugs Naproxen (anti-inflammatory drug) N F N Escitalpram (anti-depressant ) N L-DPA (treatment for Parkinson's) h. 5-6 l N Na Singulair (asthma and allergy treatment) S h Molecules with More than ne hirality enter Diastereomers Stereoisomers that are not Unlike, diastereomers usually have substantially different chemical and physical properties h. 5-6 l l l l (IV) Note: In compounds with n tetrahedral stereocenters, the maximum number of stereoisomers is n. h. 5-6 l l l l l l (IV) l l (IV) & are to each other & (IV) are to each other h Diastereomers to each other: &, & (IV), &, & (IV) h. 5-66

12 A. so ompounds ompounds with two stereocenters do not always have four stereoisomers ( = ) since some molecules are achiral (not chiral), even though they contain stereocenters For example,,-dichlorobutane has two stereocenters, but only has stereoisomers (not ) h (IV) Note: contains a plane of symmetry, is a meso compound, and is achiral ([α] = 0 o ). h (IV) (IV) & are to each other and chiral & (IV) are identical and achiral h &, & are diastereomers nly stereoisomers: & {}, {meso} h B. ow to Name ompounds with More than ne hirality enter,-dibromobutane a Look through a bond : (R) configuration a (,, ) (,, ) b h. 5-7 Look through b bond a b b (,, ) (,, ) : (R) configuration Full name: (R, R)-,-Dibromobutane h. 5-7

13 . Fischer Projection Formulas A. ow To Draw and Use Fischer Projections Fischer Projection h. 5-7 Fischer Projection h. 5-7 l l (S, S)-Dichlorobutane l l l l (R, R)-Dichlorobutane l and are both chiral and they are with each other l h l l (S, R)-Dichlorobutane is achiral (a meso compound) and are diastereomers to each other l l Plane of symmetry h Stereoisomerism of yclic ompounds a meso compound achiral Plane of symmetry h A. yclohexane Derivatives,-Dimethylcyclohexane cis-,-dimethyl cyclohexane Plane of symmetry trans-,-dimethyl cyclohexane Both cis- & trans-,-dimethylcyclohexanes are achiral and optically inactive The cis & trans forms are diastereomers h. 5-78

14 ,-Dimethylcyclohexane Plane of symmetry cis-,-dimethyl cyclohexane (meso) cis-,-dimethylcyclohexane has a plane of symmetry and is a meso compound h. 5-79,-Dimethylcyclohexane N plane of symmetry trans-,-dimethyl cyclohexane trans-,-dimethylcyclohexane exists as a pair of h. 5-80,-Dimethylcyclohexane as two chirality centers but only three stereoisomers cis-,-dimethyl cyclohexane (meso) trans-,-dimethyl cyclohexane h. 5-8,-Dimethylcyclohexane trans-,-dimethylcyclohexane exists as a pair of h. 5-8,-Dimethylcyclohexane With cis-,-dimethylcyclohexane the situation is quite complicated and are to each other h. 5-8 owever, can rapidly be interconverted to by a ring flip ' ' h. 5-8

15 Rotation of along the vertical axis gives ' ' of and become of & of and become of h ' ' Although and are to each other, they can interconvert rapidly and are achiral h Relating onfigurations through Reactions in Which No Bonds to the hirality enter Are oken 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 Same configuration NaB NaN DMS N h Same configuration h A. Relative and Absolute onfigurations hirality 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 X A B II Y A B I The chirality centers in I and II have the same relative configuration. Their common groups and central carbon can be superposed. h 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)--Butanol (S)--Butanol h. 5-90

16 6. Separation of Enantiomers: Resolution Resolution separation of two e.g. R R' (racemic) l F (Mosher acid chloride) F R R' + ( : ) diastereomers F R R' usually separable either by flash column chromatography or recrystallization etc. h. 5-9 Kinetic Resolution R R R (racemic) R ne enantiomer reacts fast and another enantiomer reacts slow R R + R R R h. 5-9 e.g. Si t Bu, Ti( i Pr) (-)-DET Si + Si 7. ompounds with hirality enters ther than arbon 5 (racemic) (-)-DET: (D)-(-)-Diethyl Tartrate 5 % (99%ee) 5 % (99%ee) R R R R Si R Ge R R Si R' S Si R R' R R R R R N X S R stop reaction at 50% maximum yield = 50% h. 5-9 h hiral Molecules That Do Not Possess a hirality enter P() P() () P () P l l l l (S)-BINAP (R)-BINAP h h. 5-96

17 END F APTER 5 h. 5-97