GROUP 7 ORGANIC CHEMISTRY ISOMERSM COPY.pptx

Isomerism of organic compounds

1. GROUP 7 ATEKANIZA DOREEN : VU-BPC-2307-0886-DAY OMONG INNOCENT : VU-BPC-2307-0419-DAY KAWALYA STEVEN : VU-BPC-2307-0639-DAY NTEGE ABDALLA : VU-BPC-2307-1132-DAY

2. Questions Discuss in details; Walden inversion Geometric isomerism Stereoisomerism in cyclic compounds Allene Isomerism

3. Walden inversion Defn ; method of racemic modification that involves reversal of a chiral center in the molecule in a chemical reaction. When an atom or group directly linked to chiral carbon atom is replaced, the reaction may proceed with inversion of configuration. This phenomenon was first of all observed by Walden (1895) and hence the name Walden inversion. Since a molecule can form two enantiomers around a chiral center, Walden inversion converts the configuration of the molecule from one enantiomeric form to another (known as optic inversion).

4. W.I occurs at a tetrahedral carbon atom. The backside attack by the nucleophile in an SN2 rxn gives rise to a product whose configuration is opposite to the reactant PRODUCTS REACTION

5. CONTN Therefore , This helps inverting the configuration of a carbon atom during the nucleophilic substitution rxn . Thus enhancing on the synthesis of drugs with a chiral center. E.g ketamine, Dopa , ethambutol , thalidomide

6. Sinc e SN 2 reactions always proc eed with inversion o f configuration , Walden i nversion is a type of SN2 reaction Walden inversion may also be defined as the conversion of the (+) form to (—) form or vice versa. Thus (+) malic acid may be converted to (— ) m alic acid as f ollows .

7. Formation of an inverted umbrella shape

8. CONTN MECHANISM OF SYNTHESIS

9. APPLICATION In production of active-ingredient enantiomers. The properties of many drugs depends on their stereochemistry : (S)- Ketamine (R )- Ketamine Anesthetic Hallucinogen

10. Geometric Isomerism

11. Geometrical isomers Geometrical isomer have same molecular formula and structural formula But it has different orientation of atoms in space due to presence of double bonds or rings. The geometrical isomerism arises when atoms or groups are arranged differently in space due to restricted rotation of a double bond (C=C) or by a cyclic structure. Cis –trans isomers ( geometric isomers ) result from restricted rotation. For example: An alkene such as 2-pentene can exist as cis and trans isomers.

12. GEOMETRIC ISOMERISM The cis isomer has the hydrogens on the same side of the double bond, whereas the trans isomer has the hydrogens on opposite sides of the double bond. CIS Groups/atoms are on the SAME SIDE of the double bond TRANS Groups/atoms are on OPPOSITE SIDES across the double bond

13. 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

14. RESTRICTED ROTATION OF C=C BONDS The carbon - car bon double bonds consist of σ bond and π bond . The presence of π bond locks the molecule in one posi tion, therefore rotation around the C=C bond is not possible .

15. 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 . RESTRICTED ROTATION OF C=C BONDS This produces two possibilities . The two structures cannot interchange easily so the atoms in the two molecules occupy different positions in space .

16. ISOMERISM IN BUTENE (Ball and stick model) There are 3 structural isomers of C 4 H 8 that are alkenes. Of these ONLY ONE exhibits geometrical isomerism . BUT-1-ENE 2-METHYLPROPENE trans BUT-2-ENE cis BUT-2-ENE

17. Diastereomers of butene Cis -trans isomers are not mirror images (non- superimpossible ) , so these are diastereomers . Diastereomers are stereoisomers that are not mirror images of each other – they are stereoisomers that are not enantiomers Molecules with 2 or more chiral carbons.

18. Properties of Geometric Isomers Geometric isomers have similar chemical properties but some different physical properties . Symmetrical alkenes have the same groups or atoms attached to one of the carbon atoms in the C=C bond.

19. Cis isomer is less stable than T rans isomer • In cis isomer, two large groups on the separate carbons are always on the same side. Thus, these two groups are closer to each other and repel each other. This is called steric strain. • On the other hand, in trans isomer the two large groups are on the opposite sides. So they are far apart. Hence they don’t repel each other. So, the steric strain is far less.

20. Determination of configuration of geometrical isomerism Dipole Moment Cis isomer have higher dipole moment than trans-isomer. In cis , polar C- Cl bond dipole moments combine to give an overall molecular dipole, creating intermolecular dipole forces I n trans-isomer two bond moments are opposed, because trans-isomer being non-symmetrica l. b ond moments cancel and molecule has a net zero dipole moment .

21. 2. Melting/ Boiling Point T rans isomer have higher Melting and Boiling than cis -isomer. Trans-isomers are more symmetrical and hence fit more closely in the crystal lattice as compared to the molecules of cis isomer. Intermolecular forces work well in trans-isomer and U shape of cis isomer can not firmly perfectly in crystal lattice. Poor packing leads to poor intermolecular attraction forces. So they require less energy to break.

22. 3. Solubility. C is isomer are more soluble than trans isomer . T rans isomers pack tightly over each other in crystal lattice . But molecules of a cis isomer are less tightly held. The poor packing leads to weak force of attraction of molecules in the crystal lattice, thus easily broken by the dielectric constant of the solvent hence greater solubility.

23. 4 . Stability The trans isomer is more stable than cis isomer due to steric hindrance . Intramolecular rxns occur easily when reacting groups are close to each other. Hence , the cis isomer will form cyclic derivatives more readily from open chain molecule, as against trans derivatives . But this rxn will take place in only those cis isomers in which carry substituent groups on C=C atoms that are capable of reacting with each other, forming intramolecular rxns

24. Q.N Why trans is more stable than cis ? Because in trans the large substituents (methyl groups, etc.) are farther apart and therefore have less steric strain. Explanations:- In cis alkyl group present on the same side of double bond repulsive force occur. but in trans alkyl group present on opposite side while repulsive force dose not occur.

25. STEREOISOMERISM IN CYCLIC COMPOUNDS Stereoisomers are molecules that have molecular formula, same connectivity of atom along carbon chain, but differ in spatial arrangement of their atoms in space

26. 1.Geometrical Isomerism : Cyclic cpds also have cis and trans isomers The cis isomer has the hydrogens on the same side of the ring, whereas the trans isomer has the hydrogens on opposite sides of the ring.

27. CONTN: Orientation of atoms in cis and trans diastereomers

28. 2. OPTICAL ISOMERISM IN C YCLIC COMPOUNDS

29. APPLICATION; OPTICAL ISOME RISM IN NATURE Stereochemistry plays an important role in determining the properties and reactions of organic compounds : The (+)- limonene has the od or of oranges while (-)-limonene has the odor of lemons

30. APPLICATION ; R - fluoxetine is an effective antidepressant but it h as no activity against migraine . Th e pure S - enantiomer , however, works remarkably well in preventing m igraine

31. QN. Why do different stereoisomers have different biological activity??? To exert its biological action , a chiral molecul e must fit into a c hiral receptor at a target site, much as a hand fits into a glove . But just as a right hand can fit only into a right - hand glove , so a particul ar stereoisomer can fit only into a receptor having the proper complementary shape . Any other stereoisomer will be a misfit like a rig ht hand in a left - handed glove .

32. Enzymes like (Catechol O - methyltransferase and Monoamine oxidase) are capable of distinguishing between epinephrine stereoisomers :

33. 3. Conformational Isomerism in C yclo Hexane All C in Cyclohexane is SP 3 Hybridized, So they will attached to each other with bond angle 109° not by 120° as in planner structure. So they will appear as Two different confirmation in 3D- Chair and Boat. As Cyclohexane ring is free of Angle Strain and Torsional Strain.

34. ENERGY LEVEL DIAGRAM FOR Relative Stability o f confirmers of Cyclohexane Ring Flipping or Ring Inversion

35. 4. Atropisomerism Biphenyl compounds

36. Atropisomerism Biphenyls: are compounds whereby a phenyl ring is connected to another through a central σ bond . Exist in a kind of confirmation isomerism. Atropisomers : are stereoisomers resulting from restricted rotation about one or more single bonds . where the energy barrier to rotation is high enough to allow for the isolation of the conformers, Kind of enantiomer and non- superimpossible . (From Greek, a =not and tropos = turn ).

37. Conditions for Atropisomerism Two necessary preconditions for axial chirality are: a rotationally stable axis Presence of different substituents on both sides of the axis Atropisomers are recognised as physically separable species when, at a given temperature, they have a half life of at least 1000s. The minimum required free energy barriers at different temperatures are as below .

38. BIPHENYL DERIVATIVES Substituted biphenyls show optical isomerism when substituents in the 2-positions are large enough to prevent rotation about the bond joining the two benzene rings . Atropisomerism is also called axial chirality. The chirality is not simply a center or a plane but an axis.

39. For example: Biphenyl-2,2’-disulphonic acid exist in two forms. Rings do not interconvert at room temperature because the energy required to twist one ring through 180 angle relative to the other is too high. In twisting process : T he two bulky - SO 3 H groups on ortho positions of biphenyl come into very - close proximit y. T he two benzene rings become coplanar and strong repulsive forces are in troduced resulting into a strained ring structure.

40. Bond Rotation Chirality

41. APPLICATION USE OF BIPHENYL COMPOUNDS AS PRECURSORS

42. ROLE OF BIPHENYL CHIRALITY IN DRUG - RECEPTOR INTERACTION

43. APPLICATION: POLYCHLORINATED BIPHENYL COMPONDS ( T4 ANALOGES) IN HYPERHYROIDSM

44. Examples of Natural Bridged Atropisomers (phytochemicals)

45. ALLENE ISOMERISM

46. Allenes A re alkene compounds, in which one carbon double bonds with each of its two adjuscent carbon atoms. Allenes are classified to as cumulated dienes i.e CH3-CH=C=CH-CH3 OPTICAL ACTIVIT Y WITHOUT ASYMMETRIC CARBON Compounds containing a chiral carbon are optically acti ve. However , there exist some compounds which do not possess a c hiral atom but are optically active provided that the molecule is dissymmetric.

47. NOMECLACURE ( Propadiene ) C₃H ₄ : H ₂C=C=CH₂ The simplest allene , consisting of three carbon atoms with two double bonds. It serves as the parent compound for the class of allenes . 3-methyl 1, 2, butadiene C₅ H₈ : H₂C=C=C(CH₃)-CH₃ This allene has two double bonds and is chiral due to the presence of different substituents at the ends, making it a good example of a substituted allene . 1,2-3-Butatriene C ₄H ₄ : H ₂C=C=C=CH₂ A compound with four carbon atoms and three consecutive double bonds, making it a cumulene rather than a typical allene . Allene

48. ALLENE DERIVATIVES Some derivatives of allenes ( CH 2 =C= CH 2 ) exhibit optical isomerism . Example is I,3-diphenylpropadiene . In allenes , the central carbon forms two sp - sp 2 sigma bonds . The central carbon has also two p- orbitals which are m utually perpendicular. These form pi-bonds with the p - orbitals on the other carbon atoms . As a result , the substituents at one end of the molecule are in plan e which is perpendicular to that of the substituents at the other end, so that the compound exists in two forms which are non - superimpo sable mirror images and are optically acti ve .

49. Allene Isomerism Allenes of the type are chiral molecules and can exist in two stereoisomeric forms, 1. Optical Isomerism one being the mirror image of the other and non-superimposable (i.e., enantiomers).

50. Chirality of Allenes : The chirality observed in substituted allene is a consequence of dissymmetry resulting from restricted rotation about the double bonds, not because of a tetrahedral atom carrying four different groups. Restricted rotation also occurs in cpds which includes, trans- cycloalkenes , spiranes and ortho -substituted biphenyl cpds . To have enantiomers, the structure must not have a plane or center of symmetry .

51. 2. Cis -Trans Isomerism (Geometric isomerism) In a cumulated triene , or any cumulated polyene with an odd number of double bonds, the atoms connected to the terminal carbons lie in the same plane, just as they do in an ordinary alkene. substituted cumulated polyenes of this type should then have cis and trans forms: Cis -trans Diastereoisomers

52. There are relatively few cis -trans forms of 1,2,3-alkatrienes known. They appear to interconvert readily on mild heating , which suggests that one of the double bonds has a lower rotational barrier than is normal for an alkene double bond CHEMICAL PROPERTIES OF ALLENES

53. Chemistry of Allenes The properties of allenes are similar to those of alkenes, Thou pure compounds are not indefinitely stable. Allenes under go hydrogenation, bromination and oxidation with KMnO4 solution. H ydration of allenes resembles, the hydration of alkynes in giving initially an unstable enol , that rapidly rearranges to form a ketone:

54. Stability & functional isomerization Allenes are not as stable as dienes with conjugated or isolated double bonds. The relative instability of allenes probably reflects extra strain as the result of one carbon atom forming two double bonds. 1,2-Propadiene is slightly more strained than that of propyne . It is not surprising then that 1,2-propadiene isomerizes to propyne . This isomerization occurs under the influence of strongly basic substances such as sodium amide in liquid ammonia or potassium hydroxide in ethyl alcohol:

55. Isomerisation of allenes to form functional isomers

56. Difficulties associated with synthesis of allenes and alkynes In the presence of strong bases, results to concurrent formation of isomerization products Major pdt in excess Less minor pdt

57. Application of chiral allenes U sed as building blocks in construction of organic, materials with exception of chiroptical properties Example; Mycomycin an antibiotic with tuberculostatic properties (by inhibiting bacterial division and growth). It exhibits enatiomerism , due to allene system.

58. 1.How does Walden inversion affects the solubility and bioavailability of a drug. 2.How does Walden inversion affects the development of a drug especially the synthesis of chiral active drugs. 3.How does geometric isomerism ( cis -trans) isomers) affects the pharmacokinetic and pharmacodynamic properties of a drug. 4.How does stereoisomerism of cyclic compounds such a ring conformations and stereo-centers influence the pharmacological activity and specifity of a drug. 5.How does the unique structure and electronic properties of allenes be employed in formulation of drugs with improved pharmacokinetics and pharmacodynamic properties DISCUSION QUESTIONS

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