Diastreoslectivity,chemoslectivity&;regioslectivity crams rule felkin anh modal

Stereo selectivity
Regio selectivity
Chemo selectivity
Diastereo selectivity
Cram’s Rule
Felkin Anh Model
with examples

1. S. GOVT. COLLEGE OF SCIENCE EDUCATION AND RESEARCH REGIOSELECTIVITY chemoselectivity & DIASTEREO SELECTIVITY MADE BY Rajat ghalta Guided by prof. sumedha syal 4/11/2018 1

2. Stereo selectivity Regio selectivity Chemo selectivity Diastereo selectivity Cram’s Rule Felkin Anh Model CONTENTS BY Rajat ghalta 4/11/2018 2

3. Stereo selective Reaction A reaction where one stereoisomer of a product is formed preferential over another. A stereo selective reaction is one in which the reactant is not necessary chiral . Example   + Br 2 H H   Cyclohexene     H     BY Rajat ghalta 4/11/2018 3

4. Regioselectivity REGIOSELECTIVE REACTIONS : A reaction which predominantly produces one of several possible structural isomers is called regioselective reactions . Example Michel Reaction R R O 1-4 Or Michel Addition 1-2 Or Direct Addition α , β -unsaturated carbonyl compound BY Rajat ghalta 4/11/2018 4

5. 1,2-versus 1,4-addition in α , β -unsaturated carbonyl compounds A no. of factors govern the direction of addition of nucleophiles to α , β -unsaturated aldehydes & ketones. some of them are Reactivity of carbonyl group : Since the aldehyde group are much more reactive than ketone towards nucleophile , so majority of the addition reactions are 1,2-addition reactions. Conversely, since ketones are less reactive than aldehydes, so majority of reactions of ketones are 1,4-addition reactions . BY Rajat ghalta 4/11/2018 5

6. Examples Aldehide CH 2 CH C H + HCN CH2 CH CH CN O OH CH CH C H CH 3 CH 3 Ph 9-10 CH 3 MgBr/Ether H+/H 2 O pent-3en-2ol Acrolein Cynohydrin Acrolein But-2en-1al BY Rajat ghalta 4/11/2018 6

7. Examples ketone (CH 3 ) 2 NH C CH 2 CH CH 3 O O Ph 9-10 H+ CH 3 CH 3 CH 3 CH 3 CN + C CH C CH 3 + HCN Mesityl Oxide 2,2-Dimethyl-4-oxopentanenitrile But-3en-2-one BY Rajat ghalta 4/11/2018 7

8. Reactivity of the reagent : Organolithium compounds being more nucleophilic predominantly undergo 1,2-addition to a α , β -unsaturated ketones whereas Grignard reagents give mainly 1,4-addition products. CH 3 MgBr/Ether CH 3 Li/Hexane H+/H 2 O H+/H 2 O 4/11/2018 8

9. Steric hindrance : Steric hindrance at the carbonyl group favours 1,4-addition whereas steric hindrance at 3-position favour 1,2-addition . For example : 1,4-addition 1,2-addition BY Rajat ghalta 4/11/2018 9

10. 1,4-Addition or conjugate addition of Grignard reagents can be made to predominate if the reaction is carried out in presence of Cu + ions i.e , cuprous chloride , CuCl or cupric acetate, Cu( OAc ) 2. Catalysis by cuprous salts : Cyclohex-2-en-1-one 3-Alkaylcyclohexanone BY Rajat ghalta 4/11/2018 10

11. It is believed that under these conditions , Grignard reagent react with Cu + ion to form alkyl copper reagent which being less reactive than Grignard reagent exclusively gives 1,4-addition products. For similar reasons lithium dialkylcopper reagents, R 2 CuLi add to α , β -unsaturated aldehydes & ketones to give conjugate addition products . Catalysis by cuprous salts : Cyclohex-2-en-1-one 3-Alkaylcyclohexanone BY Rajat ghalta 4/11/2018 11

12. Regioselectivity in addition of unsymmetrical alkene CH 3 CH CH 2 + HCl CH 3 CH CH 3 Cl CH 3 CH 2 CH 2 Cl Markovnikov product Major product Minor product BY Rajat ghalta 4/11/2018 12

13. Markovnikov rule In the ionic addition of unsymmetrical reagent to double bond , the positive part of the adding reagent adds itself to the carbon atom of double bond gives more stable carbocation as an intermediate, Formation of two different carbocation on addition of positive part of reagent CH 3 CH CH 2 + HX CH 3 CH CH 3 CH 3 CH 2 CH 2 + + secondary primary BY Rajat ghalta 4/11/2018 13

14. Secondary carbocation is more stable then primary carbocation due to +I effect . +I effect dispersed the charge on carbocation which stabilizes it Other example CH 3 CH 3 CH 3 I HI I + + Major product Minor product BY Rajat ghalta 4/11/2018 14

15. Anti- Markovnikov Addition Anti- markovnikov addition is observed if alkene bears a powerful electron-withdrawing group attach directly to the double bond carbon. CF3 CH CH 2 + HBr CF 3 CH CH 3 CF 3 CH 2 CH 2 Br Br Major product Minor product BY Rajat ghalta 4/11/2018 15

16. Formation of alkene by dehydration Many alcohols give rise to mixture of isomeric alkenes on dehydration. But one of the alkenes formed in predominantly large amount. CH 3 CH2 CHOH CH3 CH 3 CH2 CH CH2 CH 3 CH CH CH3 H3PO4-AL2O3 -H2O Major Minor BY Rajat ghalta 4/11/2018 16

17. Explanation Saytzeff rule The preferred product is the alkene which is more highly alkylated at the double bond carbon atom. In alkene more the no of alkyl group, grater the stablaty . R 2 C= CR 2 > R 2 C=CHR > R 2 C=CH 2 > RCH=CH 2 > CH 2 =CH 2 The grater the number of alkyl group attached to doubly bounded carbon atom, more the number of  hydrogen and grater possibility of hyperconjugation . BY Rajat ghalta 4/11/2018 17

18. Reduction of alkene Regioselectivity in But-2-yene CH 3 C C CH 3 C C C C CH 3 CH 3 CH 3 CH 3 H H H H H 2 /Linder’s catalyst Na/NH 3 (l) Cis-But-2-ene Trans-But-2-ene BY Rajat ghalta 4/11/2018 18

19. Regioselectivity in cleavage of epoxides CH 3 C CH 2 O CH 3 CH 3 OH + + CH 3 O - CH 3 OH Basic Medium H+ Acidic Medium CH 3 C CH 2 CH 3 OH CH 3 O CH 3 C CH 2 CH 3 OH OCH 3 2,2-Dimethyloxirene 2-Methoxy-2-Dimethylpropan-1-ol 3-Methoxy-2-Dimethylpropan-2-ol BY Rajat ghalta 4/11/2018 19

20. In basic medium Ring opening is an SN2 displacement by the nucleophile on un protonated oxirane . As in other SN2 reaction the attack takes place at the less substituted and less hindered carbon . Explanation CH 3 C CH 2 O CH 3 The less satirically hindered carbon undergoes SN2 attack BY Rajat ghalta 4/11/2018 20

21. In acidic medium first step is protonation of the oxygen atom. Due to electron releasing group attached to the more substituted carbon positively charged oxygen attracts the electron pair of its bond with this carbon to grater extend then the electron pair of the bond with the less substituted carbon. As a result, the more substituted carbon oxygen bond become weaker then the less substituted carbon oxygen bond. Therefore ring opening take place the more substituted carbon oxygen bond. Explanation CH 3 C CH 2 O CH 3 This weaker bond is preferentially attacked by nucleophile H+ CH 3 C CH 2 O CH 3 H : + BY Rajat ghalta 4/11/2018 21

22. CHEMO SELECTIVITY CHEMOSELECTIVITY REACTION: In a bi functional compound , if a reagent reacts with one functional group preferentially, even though the other is apparently susceptible to the reaction conditions, the reaction is called Chemo selective . Example: 1 the reduction of carbonyl group in presence of a cyano , nitro, alkoxycarbonyl group, 2 the acylation of an aromatic amino group in presence of a phenolic group 4/11/2018 22

23. Example 1 Reduction of carbonyl group in presence of nitro group O 2 N COOH COOH O 2 N CH 2 OH CH 2 OH H 3 N H 3 N BY Rajat ghalta 4/11/2018 23

24. Example 2 Acylation of aromatic amino group in presence of phenolic group HO NH 2 HO NHCOCH 3 NH 2 CH 3 COO NHCOCH 3 CH 3 COO BY Rajat ghalta 4/11/2018 24

25. Guideline 1 : when two functional groups of unequal reactivity are present in a molecule, the more reactive can always be made to react alone. For example : let us consider synthesis of acid (1) ; the phenolate ion is more reactive than the carboxylate ion ( pKa difference about 5 ) ,hence only the phenol is alkylated. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY COOH OH COO O - - I COOH O Alkali Medium 1 BY Rajat ghalta 4/11/2018 25

26. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Guideline 2 : When one functional group can react twice , the starting material & the first product will compete for the product. The reaction will be successful only if the first product is less reactive than the starting material. O Cl Ph O OH Ph Cl O Cl First product Starting material 1 BY Rajat ghalta 4/11/2018 26

27. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Is less reactive then Cl O Cl Conjugation with Oxygen Due to : : BY Rajat ghalta 4/11/2018 27

28. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Guideline : 3 Unfavourable cases from guidelines 1 & 2 may be solved by the use of protecting groups. Protecting group : A group whose use makes possible to react a less reactive functional group selectively in the presence of a more reactive group is known as a protecting group. Protecting group blocks the reactivity of a functional group by converting it into a different group which is inert to the conditions of some reaction(s) that is to be carried out as part of a synthetic route. BY Rajat ghalta 4/11/2018 28

29. For example : if we make phenylmagnesium bromide to react with the less reactive ester group rather than the more reactive keto group. OEt OH Ph Ph Desired product Must not react from hare to get desired product Must react from hare to get desired product BY Rajat ghalta 4/11/2018 29

30. For example : As expected ,simply adding PhMgBr to acetoacetic ester , addition to more electrophilic ketone mainly takes place. OEt OEt Ph OH 2PhMgBr H+/H 2 O BY Rajat ghalta 4/11/2018 30

31. For example : One way of preparing the desired alcohal is to protect the ketone as a ketal , i.e , a ketal protecting group is ( dioxolane ) is used in this case. OEt H+ OH Ph Ph O O H+/H 2 O OH Ph Ph BY Rajat ghalta 4/11/2018 31

32. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Guideline 4 : One of two identical groups may react if the product is less reactive than the starting material , For example : partial reduction of m-dinitrobenzene. NO 2 NO 2 NH 2 NO 2 NaHS MeOH BY Rajat ghalta 4/11/2018 32

33. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Guideline 5 : One of two identical functional groups may react with one equivalent of reagent using the statistical effect. This is an unreliable method , but if successful it avoids protecting groups . For example : the diol (1) can be monoalkylated in reasonable yield by using one equivalent of sodium in xylene to generate mostly the monoanion (2) . Na xylene EtBr 1 2 4/11/2018 33

34. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Guideline 6 : A more reliable method with two identical functional groups is to use a derivative which can react only once . The most important example – is a cyclic anhydride. When the anhydride has combined once with a nucleophile , e.g , to give the half ester , the product is no longer reactive. Further reactions can maintain the distinction , e.g , to give half acid chloride . 4/11/2018 34

35. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY COOH COOH COOMe COOH COOMe COCl Ac 2 O MaOH SOCl 2 BY Rajat ghalta 4/11/2018 35

36. GUIDELINES FOR SOLVING THE PROBLEMS OF CHEMO SELECTIVITY Guideline 7: When two groups are nearly but not quite identical , as in (8) & (9) , avoid attemps , to make only one of them react. OH OH OMe OH OH OH OMe OH Bese Bese MeI MeI BY Rajat ghalta 4/11/2018 36

37. DIASTEREOSELECTIVITY Distereomers are the stereoisomers that are not mirror image of each other i.e , diastereomers are stereo isomers that are not enantiomers. Example tartaric acid have two enantiomers and miso tartaric acid is distereomers of both enantiomers 2R,3R 2S,3S 2R,3S Enantiomers Distereomers Distereomers BY Rajat ghalta 4/11/2018 37

38. DIASTEREOSELECTIVITY A Diatereoselective reaction is one in which one diastereomer is formed in preference to another CH 3 C 6 H 5 CH 3 H C * HO CN CH 3 C 6 H 5 CH 3 H OH CN CH 3 C 6 H 5 CH 3 H + HCN Distereomers BY Rajat ghalta 4/11/2018 38

39. DIASTEREOSELECTIVITY Diastereotopic ligands When the replacement of either of the two homomorphic ligands by different test ligand gives diastereomers then such ligands are terms as diastereotopic . Cl H CH 3 Cl H H Cl H CH 3 Cl Z H Cl H CH 3 Cl H Z Distereomers replace BY Rajat ghalta 4/11/2018 39

40. DIASTEREOSELECTIVITY The two faces of carbonyl group close to a stereocenter are diastereotopic . Thus addition of HCN to methyl- - phenethylketone gives diastereomers . CH 3 C 6 H 5 CH 3 H C * HO CN CH 3 C 6 H 5 CH 3 H OH CN CH 3 C 6 H 5 CH 3 H + HCN Distereomers BY Rajat ghalta 4/11/2018 40

41. Similarly achirial 4-t-butylcyclohexanone has diastereotopic faces since addition of hydride occur from axial or equatorial side to give duastereomers . + H- DIASTEREOSELECTIVITY 4-t-butylcyclohexanone (achiral) Trans-4-t-butylcyclohexanol Cis-4-t-butylcyclohexanol BY Rajat ghalta 4/11/2018 41

42. If ligands are interchangeable by symmetry operation like rotational axis or mirror plane they are enantiotopic not diastereotropic example DIASTEREOSELECTIVITY Cl H H b H H a Cl Ha and Hb are enantiotopic because these are interchangeable by operation C2 BY Rajat ghalta 4/11/2018 42

43. On the reduction with lithium aluminum hydride gives exclusively the equatorial alcohol by attack of the reagent from less hindered face of the molecule DIASTEREOSELECTIVITY in reduction of cholestan-3-one H H H H CH 3 CH 3 R H- H- BY Rajat ghalta 4/11/2018 43

44. Nucleophilic attack on acyclic carbonyl compound For certain addition to carbon oxygen double bond of aldehyde and ketone having a chiral--carbon , cram’s rule is useful to product which diastereomers of two will predominate. The molecule is generally knows as diastereotopic aldehyde or ketone in which four group are attach to the stereo center i.e , COR,S,M and L . S is for small , M is for medium, L is for large L M S COR BY Rajat ghalta 4/11/2018 44

45. Carm’s RULE The oxygen of the carbonyl orients itself so as to between the small and the medium sized groups. Thus L Being the largest group is oriented as far as possible from the carbonyl group. In the orientation L is ellipse to the group R . M S L O R BY Rajat ghalta 4/11/2018 45

46. The rule is that the incoming group prefferently attacks on the side of plane containing the small group i.e , LESS HINDRED FACE. Carm’s RULE M S L O R Nu Nu BY Rajat ghalta 4/11/2018 46

47. M S L R Nu M S L OH R O Nu M S L OH R Nu Major product Minor product BY Rajat ghalta 4/11/2018 47

48. H CH 3 C 6 H 5 H O OH H CH 3 C 6 H 5 H CH 3 OH H CH 3 C 6 H 5 H CH 3 CH 3 MgBr Major product Minor product Example Erythro (2R,3S) Threo (2R,3S) BY Rajat ghalta 4/11/2018 48

49. Important to note The preference of the one of the product stereomers over the other depend on the difference in the size of S,M and L group . In case the S and M are very similar , there is likely to be little difference in the interaction with the incoming nucleophile and distereoslectivity of such molecule is very poor . BY Rajat ghalta 4/11/2018 49

50. Stereo selectivity Regio selectivity Chemo selectivity Diastereo selectivity Cram’s Rule Felkin Anh Model CONTENTS BY Rajat ghalta 4/11/2018 50

51. Case of failure of carm’s rule Case 1 Case 2 One of the substituent on the stereo center is complexeing group One of the substituent on the stereo center is highly electronegative CH 3 C 6 H 5 H 3 CO H C * CH 3 C 6 H 5 Cl H C * BY Rajat ghalta 4/11/2018 51

52. Case 1 If one complexing group is present If one substituent on the stereo centre is an alk -oxy ,hydroxyl , or any other complexing agent . Then the cations (lithium cations ) of reagent effectively coordinate with these oxygen atoms. CH 3 Li+ BY Rajat ghalta 4/11/2018 52

53. For example reduction with LiAlH4 The reagent brings about the reduction by first acting as a conformation locker by coordinating by both the methoxy oxygen and ketone oxygen. CH 3 C 6 H 5 p- tolyl H Li+ CH 3 C 6 H 5 p- tolyl H LiAlH 4 H 3 Al-H T.S BY Rajat ghalta 4/11/2018 53

54. H T.S Backside attack which is away from Ph group is preferred Minor product Major product BY Rajat ghalta 4/11/2018 54

55. CASE 2 when one substituent is strongly electronegative (example chlorine) The preferred transition state is The negatively polarized oxygen and chlorine atoms always tends to remain far away from each other . L S Cl O R BY Rajat ghalta 4/11/2018 55

56. L S Cl R Nu L S Cl OH R O Nu L S Cl OH R Nu Major product Minor product BY Rajat ghalta 4/11/2018 56

57. Felkin argued that the cram modal suffered major drawback an eclipsed conformation in the transition state between - carbonyl substituent and β -carbonyl substituent. He demonstrated that by increasing the steric bulk of the  substituent from methyl to ethyl to isopropyl to isobutyl the stereoslectivity also increase which is not predicted by the cram’s rule . C Felkin Anh modal BY Rajat ghalta 4/11/2018 57

58. R Eyrthro Threo Me 74% 26% Et 76% 24% i-Pr 83% 17% t-Bu 98% 2% 4/11/2018 58 BY Rajat ghalta

59. C Felkin Anh modal In the Felkine Anh modal C-L bond is positioned perpendicular to the carbonyl group. This is un like cram’s rule where L is assumed to be antipariplaner to the C=O group. This argument removes unfavorable eclipsing interaction between L and R. There are two such conformation L S R O M L S R O M Interconverted via rotation around central C-C bond BY Rajat ghalta 4/11/2018 59

60. In Falkin-Ahn modification a large group is positioned at right angles to the carbonyl group and not apposite to it. Nucleophile opts to approach from the side remote from large group as given blow. L S R O M L S R O M Interconverted via rotation around central C-C bond Nu Nu L S R OH M Nu CLASH BY Rajat ghalta 4/11/2018 60

61. Example H 2 O+ LiAlH 4 H 2 O+ LiAlH 4 H- H- CLASH BY Rajat ghalta 4/11/2018 61 Threo (2R,3S) Erythro (2S,3S)

62. FACTORS AFFECTING FELKIN AHN MODEL Size of nucleophile greatly effects diastereo selectivity of addition . Larger the nucleophile generally give rise to greater diastereoselectivity . The size of substituent on the substrate will also effect the diastereoselectivity Larger group result in greater selectivity. BY Rajat ghalta 4/11/2018 62

63. Case of failure of falkin anh Case 1 Case 2 One of the substituent on the stereo center is complexeing group One of the substituent on the stereo center is highly electronegative CH 3 C 6 H 5 H 3 CO H C * CH 3 C 6 H 5 Cl H C * BY Rajat ghalta 4/11/2018 63

64. The major difference b/w cram and Felkin Anh as shown as:- Nu Nu T,S by Felkin Anh T,S by Charm BY Rajat ghalta 4/11/2018 64

65. 4/11/2018 65 BY Rajat ghalta 65 No elapsing strain is present between  carbonyl substituent and other substituent Elapsing strain is present between  carbonyl substituent and other substituent Oxygen atom goes perpendicular to large group. Oxygen remain as far as pssible from large group . Diastereoslectivity depend on size  carbonyl substituent . Diastereoslectivity independent of size of  carbonyl substituent . Nucleophile attack from side between small and medium group . Nucleophile attack from side between small and large group . Felkin Anh Carm

66. BY Rajat ghalta Me Et H O Me H Et H OH LiAlH 4 (1) 3R,6S (2) 3S,6S (2) 3R,6R (4) 3S,6R Hint – Use Carm’s rule Q Stereochemistry of product is ? Problem from U.G.C N.E.T dec 2014 4/11/2018 66

67. Stereo selectivity (P.S. Kalsi stereochemistry) Regio selectivity ( B.Sc.Books ) Chemo selectivity ( Jagdamba singh O.S) Diastereo selectivity (P.S. Kalsi stereochemistry) Cram’s Rule (P.S. Kalsi stereochemistry) Felkin Anh Model (P.S. Kalsi stereochemistry) References BY Rajat ghalta 4/11/2018 67

68. Jai hind BY Rajat ghalta 4/11/2018 68