Stereochemistry

1. Stereochemistry

2. Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: 2-methylhexame is superimposable with its mirror image

3. Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: 2-methylhexame is superimposable with its mirror image

4. Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: • Compounds that are not superimposable with their mirror image are called chiral (in Greek, chiral means "handed") 3-methylhexane is a chiral molecule. • Compounds that are superimposable with their mirror image are called achiral. 2-methylhexane is an achiral molecule. • An atom (usually carbon) with 4 different substituents is called a stereogenic center or stereocenter.

5. Enantiomers Two compounds that are non-superimposable mirror images (the two "hands") are called enantiomers.

6. Introduction To Stereochemistry Structural (constitutional) Isomers - Compounds of the same molecular formula with different connectivity (structure, constitution) Conformational Isomers - Compounds of the same structure that differ in rotation around one or more single bonds Configurational Isomers or Stereoisomers - Compounds of the same structure that differ in one or more aspects of stereochemistry (how groups are oriented in space - enantiomers or diastereomers)

7. Types of isomerism and isomers Department of Pharmaceutical Analysis Chalapathi Institute of Pharmaceutical Sciences

8. Many things in nature look similar, but they are completely different ! The image is Derived from cesardogfoodadvertisments

9. TYPES OF ISOMERISM CHAIN ISOMERISM STRUCTURAL ISOMERISM POSITION ISOMERISM Same molecular formula but different structural formulae FUNCTIONAL GROUP ISOMERISM GEOMETRICAL ISOMERISM Occurs due to the restricted rotation of C=C double bonds... two forms - CIS and TRANS STEREOISOMERISM Same molecular formula but atoms occupy different positions in space. OPTICAL ISOMERISM Occurs when molecules have a chiral centre. Get two non-superimposable mirror images.

11. Configuration:A particular three-dimensional arrangement is called as configuration .. Isomers: Isomers are compounds having the same molecular formula but different linkages or spatial arrangements of atoms or different compounds with the same molecular formula Constitutional/structural isomers: Isomers having atoms bonded to different carbons. have different IUPAC names, the same or different functional groups, different physical properties and different chemical properties. Stereo isomers : Stereo isomers are isomers which differ in 3D arrangement or isomers differ in the way the atoms are oriented in space. They have identical IUPAC names (except for a prefix like cis or trans). They always have the same functional group(s). Stereo isomers differ in configuration

12. Comparison of constitutional isomers with stereo isomers

13. Sub classes of structural / constitutional isomerism • Compounds have the same molecular formula, but different structural formula • Chain different arrangements of the carbon skeleton • similar chemical properties • slightly different physical properties • more branching = lower boiling point • Positional same carbon skeleton • same functional group • functional group is in a different position • similar chemical properties - slightly different physical properties • FunctionalGroup different functional group • different chemical properties • different physical properties • Metamers and tautomers are the other sub classes of structural isomers • Sometimes more than one type of isomerism occurs in the same molecule. • The more carbon atoms there are, the greater the number of possible isomers

14. CHAIN ISOMERS Example 1 C4H10 Butane -straight chain 2-methylpropane- branched Differences between above chain isomers ChemicalIsomers show similar chemical properties because the same functional group is present. Physical Properties such as density and boiling point show trends according to the of the degree of branching Boiling Point“straight” chain isomers have higher values than branched ones the greater the degree of branching the lower the boiling point branching decreases the effectiveness of intermolecular forces less energy has to be put in to separate the molecules greater branching = lower boiling point 2-Methylpropane B.P is - 11.7°C N-Butane B.P . Is - 0.5°C

15. Example 2 C6H14

16. POSITIONAL ISOMERS Example 1 2 3 Pent-1-ene or 1-pentene double bond between carbons 1 and 2 Pent-2-ene or 2-pentene double bond between carbons 2 and 3 Example 1 shows positional isomerism in alkenes Example 2 BUT 1 2 1-Chlorobutane halogen on carbon 1 2-Chlorobutane halogen on carbon 2 is NOT 3-Chlorobutane Example 2 shows positional isomerism in halo alkanes. Moving the chlorine along the chain makes new isomers; the position is measured from the end nearest the functional group... the third example is 2- NOT 3-chlorobutane. There are 2 more structural isomers of C4H9Cl but they have a longest chain of 3

17. Position isomers Example 3 1,2-Dichlorobenzene ortho dichlorobenzene 1,3-Dichlorobenzene meta dichlorobenzene 1,4-Dichlorobenzene paradichlorobenzene Example 3 shows positional isomerism in aromatic compounds C5H10 Chain isomers

18. Functional group isomers The fallowing functional groups shows Functional group isomerism Alcohols and Ethers Aldehydes and Ketones Acids and Esters

19. Example 1 Alcohols and Ethers NameETHANOL METHOXYMETHANE ClassificationALCOHOLETHER Functional GroupR-OHR-O-R Physical propertiespolar O-H bond gives rise No hydrogen bonding to hydrogen bonding. low boiling point get higher boiling point insoluble in water and solubility in water Chemical properties Lewis base Inert Wide range of reactions

20. Example 2 Aldehydesand Ketones Name PROPANAL PROPANONE ClassificationALDEHYDEKETONE FunctionalGroupR-CHOR-CO-R Physicalpropertiespolar C=O bond gives polar C=O bond gives dipole-dipole interaction dipole-dipole interaction Chemical properties easily oxidised to acids of undergo oxidation under same number of carbons extreme conditions only reduced to 1° alcohols reduced to 1° alcohols

21. Example 3 Carboxylic acids and Esters NamePROPANOIC ACID METHYL ETHANOATE ClassificationCARBOXYLIC ACIDESTER Functional GroupR-COOHR-COOR Physical propertiesO-H bond gives rise No hydrogen bonding to hydrogen bonding. insoluble in water get higher boiling point and solubility in water Chemical properties acidic fairly unreactive reacts with alcohols hydrolysed to acids

22. e.g.Methoxypropane and ethoxyethane (molecular formula: C4H10O) Metamerism e.g. Pentan-2-one and pentan-3-one (molecular formula: C5H10O) can also be considered as position isomers

23. functional group isomers C4H10O Metamers

24. Tautomerism enol – keto tautomerism

25. ethenolethanal Enol is a structure with –OH attached directly to doubly-bonded C Not an enol But-2-en-1-ol Does not exhibit tautomerism

26. GEOMETRICAL ISOMERISM Free rotation of c-c bonds Single covalent bonds can easily rotate. What appears to be a different structure in an alkane is not. Due to the way structures are written out, they are the same. ALL THESE STRUCTURES ARE THE SAME BECAUSE C-C BONDS HAVE ‘FREE’ ROTATION

27. Restricted rotation of c=c bonds C=C bonds have restricted rotation so the groups on either end of the bond are ‘frozen’ in one position; it isn’t easy to flip between the two. This produces two possibilities. The two structures cannot interchange easily so the atoms in the two molecules occupy different positions in space.

28. Geometrical isomerism exists in fallowing cases i.e due to the restricted rotation about double bond Two different atoms/groups attached Two different atoms/groups attached  GEOMETRICAL ISOMERISM  Two similar atoms/groups attached Two similar atoms/groups attached Once you get two similar atoms/groups attached to one end of a C=C, you cannot have geometrical isomerism  Two similar atoms/groups attached Two different atoms/groups attached Two different atoms/groups attached Two different atoms/groups attached  GEOMETRICAL ISOMERISM

29. where a b and c  d If there are three or four different groups attached to the Cs of C=C double bond E/Znotation rather than the cis/trans notation is used to name the stereoisomers of a molecule. E : in opposition to  trans Z : together  cis

30. Geometrical isomerism in alkenes • an example of stereoisomersim • found in some, but not all, alkenes • occurs due to the RESTRICTED ROTATION OF C=C bonds • get two forms.... CIS Groups/atoms are on the SAME SIDE of the double bond TRANS Groups/atoms are on OPPOSITE SIDES across the double bond Isomers - have different physical properties - e.g. boiling points, density - have similar chemical properties - in most cases

31. Isomerism in butene There are 3 structural isomers of C4H8 that are alkenes*. Of these ONLY ONE exhibits geometrical isomerism. BUT-1-ENE 2-METHYLPROPENE cis BUT-2-ENE trans BUT-2-ENE * YOU CAN GET ALKANES WITH FORMULA C4H8 IF THE CARBON ATOMS ARE IN A RING

32. Geometric Isomers in Cycloalkanes • Ring structures like alkenes (C=C) restrict rotation and therefore can result in cis and trans isomers

33. Properties of Geometrical Isomers The chemical properties of geometrical isomers tend to be similar but their physical properties are different Zero net dipole moment van der Waals’ forces : cis > trans b.p. depends on v.d.w. forces ONLY  b.p. : cis > trans b.p. 60C 48C

34. more symmetrical less symmetrical Three planes of symmetry Two planes of symmetry lower packing efficiency higher packing efficiency m.p. is more affected by symmetry of molecules.  m.p. : trans > cis m.p. 80C 50C

35. The trans isomer has a much higher melting point. Unlike the cis isomer there is little intra-molecular hydrogen bonding

36. OPTICAL ISOMERISM Occurrenceoccurs when compounds have non-superimposable mirror images or handedness or chirality Isomers the two different forms are known as optical isomers or enantiomers they occur when molecules have a chiral centre a chiral centre contains an asymmetric carbon atom an asymmetric carbon has four different atoms (or groups) arranged tetrahedrally around it. CHIRAL CENTRES There are four different colours arranged tetrahedrally about the carbon atom 2-chlorobutane exhibits optical isomerism because the second carbon atom has four different atoms/groups attached

37. Spatial differences between isomers exists in optical isomerism • two forms exist which are NON-SUPERIMPOSABLE MIRROR IMAGES of each other • non-superimposable means you you can’t stack one form exactly on top of the other • Some common objects aremirror images and superimposablespoons • superimposable but not mirror images books • non-superimposable mirror images hands • NB For optical isomerism in molecules, both conditions must apply... • they must be mirror images AND be non-superimposable

38. Properties of optical isomers • isomers differ in their reaction to plane-polarised light • plane polarised light vibrates in one direction only • one isomer rotates light to the right, the other to the left • rotation of light is measured using a polarimeter • rotation is measured by observing the polarised light coming out towards the observer • If the light appears to haveturned to the rightturned to the left • DEXTROROTATORY LAEVOROTATORY • d or + form l or - form • Racematea 50-50 mixture of the two enantiomers (dl) or (±) is a racemic mixture. • The opposite optical effects of each isomer cancel each other out • ExamplesOptical activity is common in biochemistry and pharmaceuticals • • Most amino acids exhibit optical activity • • many drugs must be made of one optical isomer to be effective • - need smaller doses (safer and cost effective) • - get reduced side effects • - improved pharmacological activity

39. Enantiomers: Non superimposable mirror images are called as enantiomers. . Mirror images of each other but non-superimposablewith each other

40. The direction of optical rotation cannot be predicted from the structural formulae. It can only be determined experimentally

41. Properties of enantiomers: Enantiomers have the same or identical physical properties(melting point, boiling point, density, etc) except their optical activities. They heve identical chemical properties except their reactions with optically active substances or with chiral non-racemic reagents . As the enantiomers have identical physical properties theycannot be separated by normal separation techniques like distillation, etc.

42. They rotate plane-polarized light to the same extent but in opposite directions and because of external cancelation of rotation equimolar mixture of enantiomers becomes optically inactive. But the properties that depend on shape of molecule (biological-physiological properties) can be different for enantiomers So usually enantiomeric acids or bases can be reacted with an optically active base or acid to form salts that are diastereomers. Since diastereomers have different physical properties they can be separated by physical methods. The salts can then be converted back into the free acids or bases.

43. Example 1 Enantiomers of Carvone present in different volatile oils and show different odour CH3 CH3 Odor H3C H3C CH2 CH2 (–)-Carvonespearmint oil (+)-Carvonecaraway seed oil

44. Example 2 (+)butan-2-ol (-)butan-2-ol m.p. 99.5C 99.5C (-)-limonene lemon (+)-limonene orange Example 3 (R) (S)

45. Example 4 Example 5

46. Example 6

47. Example 7

48. THALIDOMIDE The drug, THALIDOMIDE is a chiral molecule and can exist as two enantiomers. In the 1960’s it was used to treat anxiety and morning sickness in pregnant women. Tragically, many gave birth to children with deformities and missing limbs. It turned out that only one of the enantiomers(the structure on the left i.e R isomer) was effective and safe; its optically active counterpart was not. The major problem was that during manufacture a mixture of the isomers was produced. The drug was banned world-wide, but not after tens of thousands of babies had been affected.  ‘R' is sedative  'S' enantiomer was tetragenic

49. Diastereomers: Non superimposable non mirror images mp = 158oC mp = 256oC • Properties of diastereomers: Diastereomers have different physical properties (BP, MP, density, refractive index, solubility etc.). They can be separated through conventional means distillation, recrystallization, chromatography)