Topic 5F Stereochemistry

Stereochemistry Study of three-dimensional shape of molecules and how this affects their chemical and physical properties Very important in biology Isomers that have the same formula and connectivity but differ only in the way the atoms are arranged in space are STEREOISOMERS Constitutional isomers having different connectivity and are joined up in a different way are NOT stereoisomers 71

Optical isomerism Optical isomers: differ in the way they rotate plane polarised light. –Enantiomers: isomers that are nonsuperimposable mirror images of each other. –Diastereomers: stereoisomers that are not enantiomers. Isomers with more than one chiral carbon that are not enantiomers but differ only in configurations about chiral carbons. 72

Optical Isomerism Carvone and the essence of spearmint are optical isomers or ENANTIOMERS They possess CHIRAL carbon and they are chiral molecules They interact with plane-polarised light differently 72 O CH 3 H O 3 H Spearmint essence Carvone (caraway)

Mirror images Mirror images that can be superimosed are ACHIRAL 73 The mirror image of this fork can be stacked on top of the real thing since the fork is symmetrical. It is achiral. Mirror image Real fork

Chirality or handedness From the Greek word “cheir” — hand Hands are non-superimposable — they are chiral 73 Any molecule that cannot be superimposed on its mirror image is said to be chiral

Chiral carbons Have four different substituents attached to them Chiral carbons have no symmetry they are asymmetric 74

Achiral molecules Carbons bearing two identical substituents are ACHIRAL They can be superimposed upon their mirror image 74 Real molecule Mirror image Mirror B A D D D D B A A B D D A B D D Mirror image

Examples of achiral molecules Each have two identical substituents 75 OH CH 2 OH CH 2 OH H H CO 2 H NH 2 H OH CH hydroxy-2- methylbutane Glycine 1,2,3-propanetriol (glycerol)

Chiral molecules A chiral molecule is unique and can not be superimposed upon its mirror image 75 B D C C D A B Mirror Mirror imageReal molecule Mirror image C D B A C B D A C D B A A D B C A

Examples of chiral molecules 76

Ranking groups (1)Higher atomic number of atom bonded to the chiral carbon means higher priority. H C N O F S Cl Br I, Increasing priority 77 (2)If two atoms are the same, proceed to the second atom or even farther along the chain to the first point of difference. (3)Groups with pi bonds are given single-bond equivalents by duplication or triplication of multiply bonded atoms. You will learn to use this rule in second year. (4)E/Z isomers use the same priority rule

(R) and (S) nomenclature Cahn-Ingold-Prelog system Align smallest group away from you 77 Steps: Assign priorities to all groups attached to the chiral centre Determine in what direction priorities decrease, clockwise or anticlockwise (S) (R)

Assigning (R) or (S) If groups descend in priority clockwise then (R) “R” from Latin word “rectus” 78 If groups descend in priority anticlockwise then (S) “S” from Latin word “sinister”

Examples 78 I C H CH 2 3 HO * OH C H CH * I C H 2 3 HO * OH C H CH * C OH CH R (R)-2-butanol C I HOCH S ( S )- 1-iodopropanol

Enantiomeric pairs Enantiomers (from Greek enantio, “opposite” and merso, “part”) have opposite configuration 78 Enantiomers Cl I Br I H H Mirror

Examples of enantiomers Enantiomers come in pairs: 79 CH NH 2 H CH NH 2 H CH 3 Mirror Enantiomers of 2-aminopentane * * CO 2 H H NH 2 CH 3 CO 2 H H NH 2 CH 3 Mirror Enantiomers of alanine * *

Fischer projections Configurations at carbon can be represented on paper by Fischer projections 79 A C C D B A C C DB Fischer projection

Example Enantiomers of glyceraldeyde as Fischer projections: 80 C C H OH HOCH 2 C C H HO CH 2 OH O H OH C H CHO CH 2 OH CHHO CHO CH 2 OH * * Enantiomers of glyceraldehyde Mirror HOH CHO CH 2 OH HHO CHO CH 2 OH Fischer projections

More than one chiral carbon Each chiral carbon treated separately 81 (2R,3R)-2,3,4-Trihydroxybutanal

Numbers of isomers 2 n Isomers, n = number of chiral centres

Numbers of isomers 2 n Isomers, n = number of chiral centres Isomers NOT mirror images are DIASTEREOMERS

Numbers of isomers 2 n Isomers, n = number of chiral centres Isomers NOT mirror images are DIASTEREOMERS

Meso compounds Two centres but possess a plane of symmetry Tartaric acid has only three streoisomers 83

Properties of enantiomers They behave differently in chiral environments –Chiral reactants –Chiral catalysts –Biological environments Interaction with plane-polarised light –The name optical isomerism stems from this 83

1815 Jean-Baptiste Biot discovered that some substances rotate the plane of polarised light. Sugar cane rotates light through 60° Such compounds are OPTICALLY ACTIVE All such compounds contain chirality. 84 Interaction with polarised light Plane Polarised light:

Interaction with polarised light 85

Dextro- and levorotation Compounds that rotate the plane of polarised light to the LEFT are LEVOROTATORY or the (–) form 85 Compounds that rotate the plane of polarised light to the RIGHT are DEXTROROTATORY or the (+) form  polarising filter Plane polarised light Sample solution cell Rotated light Unpolarised light  =-20° Counterclockwise Levorotatory  =+35° Clockwise Dextrorotatory

Specific rotation Magnitude of rotation depends upon –Nature of substance –Concentration of the solution –Temperature –Wavelength of light –Solvent Enables comparison of measurements under different conditions 85 []D[]D T

Specific rotation  is the observed rotation in degrees T is the temperature at measurement D is the sodium D line (589.3 nm) l is the cell length in decimeters (dm) c is the concentration in g/mL 85 [  ] D = T  l x c (solvent)

Solution:  = -14.4° l = 5/10 = 0.5 dm c = 1.8/10 =0.18 g/mL [  ] T D = -14.4/0.5 x 0.18 = ° (chloroform) Example 85 Specific rotation of cocaine: 1.80g dissolved in 10.0 mL of chloroform in a 5.0 cm cell gave an observed rotation at 20° with (sodium D line) of -14.4°

Configuration There is no relationship between the actual configuration at a carbon and the direction of rotation of plane polarised light For instance: 86 Same configuration C C H HO CH 2 OH O H CO 2 H CH 2 OH (-) Glyceric acid * oxidation C C H HO CH 2 OH O H H CHO CH 2 OH (+) Glyceraldehyde *

Racemic mixtures Enantiomers rotate the plane of polarised light by equal amounts but in opposite directions. A 50:50 mixture of enantiomers does not rotate the plane of polarised light. No net rotation RACEMIC MIXTURE : 50 No net rotation

Chirality in the biological world Example: Only one form of the amino acid alanine (S) is incorporated into protein molecules. The enantiomer (R) is oxidised and metabolised 88 Enantiomers of alanine CO 2 H H R-doesn't fit protein shape Chiral protein too big too small * R CH 3 NH 2 CO 2 H NH 2 S-fits protein shape Chiral protein S * CH 3 H

Chiral drugs Radically different roles of enantiomers. 89 (S) form is an analgesic (R) form inactive (S) form is a Teratogen (auses foetal deformities) (R) form is anAnti-depressant (S)(S) (S)(S)