Nucleophilic substitution reactions

Aliphatic nucleophilic substitution reactions

1. Nucleophilic substitution reactions at saturated carbon atom Dr. Sakshi Kabra Malpani 7/23/2018 1

2. Nucleophilic Substitution Nucleophilic substitution is a substitution reaction in which a nucleophile attacks the positive or partially positive charge of an atom referred as an electrophile . The compound on which substitution takes place is called the substrate and the group that is displaced from carbon, taking the electron pair with it, is called leaving group. The leaving group often leaves as an anion but may also be a neutral molecule. For example, reaction of methyl bromide with sodium hydroxide affords methanol and sodium bromide. In this reaction methyl bromide is substrate, bromide is leaving group and hydroxide ion is the nucleophile . 7/23/2018 2

3. Combinations for Nucleophilic Substitution Reactions On the basis of charge on substrate and nucleophile , four combinations are possible - 7/23/2018 3

4. Nucleophilic substitution reactions are of two types: Nucleophilic aliphatic substitution Nucleophilic aromatic substitution General Scheme for the Nucleophilic Aliphatic Substitution: 7/23/2018 4

5. Types of Nucleophilic Substitution S N 1 S N 2 S: Substitution N: Nucleophilic 1: Unimolecular S: Substitution N: Nucleophilic 2: Bimolecular 7/23/2018 5

6. S N 1 REACTION AND MECHANISM KINETICS STEREOCHEMISTRY FACTORS AFFECTING S N 1 REACTIONS 7/23/2018 6

7. S N 1: Reaction and mechanism 7/23/2018 7

8. 8 S N 1 (Substitution Nucleophilic Unimolecular ) S N 1 reaction proceeds in two steps. The first step (slow step) is the rate determining step and involves the ionization of the reactant to form a carbocation intermediate. The breaking of C-X bond in RX takes place in a heterolytic fashion, in which both the bonding electrons go to the leaving group. In the second step (fast step), the intermediate carbocation is attacked by the nucleophile to give the final product. Step 1. Formation of carbocation Step 2. Capture of the carbocation by the nucleophile 7/23/2018

9. A mechanism for S N 1Reaction 7/23/2018 9

10. 10 S N 1 Energy Diagram Rate-determining step is formation of carbocation rate = k[RX ] or substrate 7/23/2018

11. 7/23/2018 11

12. S N 1 reaction : Kinetics 7/23/2018 12

13. Kinetics of a Nucleophilic substitution: an S N 1 reaction 2 step reaction The reactions follows first order( unimolecular ) kinetics Rate of reaction depends the slowest step Hetero-cleavage of halide Rate of reaction = k [alkyl halide/substrate] 7/23/2018 13

14. S N 1 reaction : Stereochemistry 7/23/2018 14

15. 15 Stereochemistry of S N 1 Reaction The planar intermediate leads to loss of chirality A free carbocation is achiral Product is racemic or has some inversion

16. 16 S N 1 in Reality Carbocation is biased to react on side opposite leaving group Reaction occurs with carbocation loosely associated with leaving group during nucleophilic addition (Ion Pair ) 7/23/2018

17. Effects of Ion Pair Formation If leaving group remains associated, then product has more inversion than retention Product is only partially racemic with more inversion than retention Associated carbocation and leaving group is an ion pair 17

18. Nucleophilic substitutions that exhibit first-order kinetic behavior are not stereospecific Generalization 7/23/2018 18

19. Factors influencing the rate of S N 1 reactions 7/23/2018 19

20. S N 1 reaction : Substrate structure 7/23/2018 20

21. 21 Substrate structure for S N 1 Reaction Controlled by stability of carbocation Remember Hammond postulate, “Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate ” 7/23/2018

22. S N 1 reaction : Effect of Nucleophile 7/23/2018 22

23. 23 Nucleophiles in S N 1 Since nucleophilic addition occurs after formation of carbocation , reaction rate is not normally affected by nature or concentration of nucleophile 7/23/2018

24. Effect of the Nucleophile Weak nucleophiles fail to promote the S N 2 reaction; therefore, reactions with weak nucleophiles often go by the S N 1 mechanism if the substrate is secondary or tertiary 7/23/2018 24

25. Relative Reactivity of Nucleophiles Depends on reaction and conditions More basic nucleophiles react faster Anions are usually more reactive than neutrals 7/23/2018 25

26. S N 1 reaction : Effect of leaving group 7/23/2018 26

27. Leaving Group Two factors affect the rate of an reaction: the ease with which the leaving group dissociates from the carbon the stability of the carbocation that is formed. The weaker the base, the less tightly it is bonded to the carbon and the easier it is to break the carbon–halogen bond. As a result, an alkyl iodide is the most reactive and an alkyl fluoride is the least reactive of the alkyl halides 7/23/2018 27

28. Leaving group Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge 7/23/2018 28

29. S N 1 reaction : Effect of Solvent 7/23/2018 29

30. 30 Solvents in S N 1 Protic solvents favoring the S N 1 reaction are due largely to stabilization of the transition state and facilitate formation of R + Stabilizing carbocation also stabilizes associated transition state and controls rate Solvation of a carbocation by water 7/23/2018

31. -Polar protic solvent has a hydrogen atom attached to a strongly electronegative element (e.g. oxygen) that forms hydrogen bonds. -Polar protic solvent solvate cations and anions effectively while aprotic solvents do not solvate anions to any appreciable extend -Polar protic solvents are more suitable for S N 1 reactions while polar aprotic solvents are more suitable for S N 2 reactions Solvent effect on the Nucleophile Examples of polar protic solvents Transfer from polar, protic to polar, aprotic solvents can change the reaction mode from S N 1  S N 2 7/23/2018 31

32. Effects of Solvent on Energies Polar solvent stabilizes transition state and intermediate more than reactant and product 7/23/2018 32

33. Carbocation Rearrangements 7/23/2018 33

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35. First order kinetics: rate = k [RX] unimolecular rate-determining step Carbocation intermediate rate follows carbocation stability rearrangements are observed Reaction is not stereospecific : racemization in reactions of optically active substrates Characteristics of the S N 1 mechanism

36. S N 2 REACTION AND MECHANISM KINETICS STEREOCHEMISTRY FACTORS AFFECTING S N 2 REACTIONS 7/23/2018 36

37. S N 2 : Reaction and mechanism 7/23/2018 37

38. The nucleophile approaches the carbon bearing the leaving group from the back side Directly opposite the leaving group As the reaction progresses, the bond between nucleophile and the carbon strengthens, and the bond between the carbon atom and the leaving group weakens Carbon atom has its configuration turned inside out  inversion Transition state 7/23/2018 38

39. Transition State Arrangement of the atoms in which nucleophile and the leaving group are both partially bonded to the carbon atom undergoing substitution Bond breaking and forming and occurred simultaneously Concerted reaction 7/23/2018 39

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41. S N 2 reaction : Kinetics 7/23/2018 41

42. 42 The Rate Law of an S N 2 Reaction Obtained experimentally: Rate law includes both the alkyl halide and the nucleophile, a second-order process 7/23/2018 42

43. S N 2 reaction : Stereochemistry 7/23/2018 43

44. S N 2 MECHANISM O C R H CH 3 H O : .. .. attacks back lobe nucleophilic attack (R)- config (S)- config C R H CH 3 Br : : .. .. H : .. .. WALDEN INVERSION 7/23/2018 44

45. C R H CH 3 Br : C R H CH 3 HO : C H CH 3 R Br HO H O : .. .. activated complex is trigonal planar (sp 2 ) (R)-configuration (S)-configuration configuration is inverted Ea HO C B partial bonding 2p THE INVERSION PROCESS sp 3 sp 3 sp 2 7/23/2018 45

46. Factors influencing the rate of S N 2 reactions 7/23/2018 46

47. S N 2 reaction : substrate structure 7/23/2018 47

48. Less bulky Should stabilize the transition state 7/23/2018 48

49. 49 Steric Effects on S N 2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast S N 2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower S N 2 reactions. 7/23/2018

50. Methyl and 1° alkyl halides undergo S N 2 reactions with ease. 2° Alkyl halides react more slowly. 3° Alkyl halides do not undergo S N 2 reactions. This order of reactivity can be explained by steric effects. Steric hindrance caused by bulky R groups makes nucleophilic attack from the backside more difficult, slowing the reaction rate. Order of Reactivity in S N 2 7/23/2018 50

51. S N 2 reaction : Effect of Nucleophile 7/23/2018 51

52. Effect of Nucleophile The nucleophilicity may be correlated to its basicity as both involve the availability of the electron pairs and the ease with which it is donated Nucleophilicity order A negatively charged nucleophile is always stronger than its conjugate acid. 7/23/2018 52

53. The stronger bases are the better nucleophiles 7/23/2018 53 Right-to-left-across a row of the periodic table, nucleophilicity increases as basicity increases:

54. S N 2 reaction : Effect of leaving group 7/23/2018 54

55. 55 The Leaving Group The weaker the basicity of a group, the better is its leaving ability Electron-withdrawing Polarizable to stabilize the transition state. 7/23/2018 Leaving groups are the same as in S N 1 reactions A good leaving group needs to be stable anions that are weak bases which can delocalize charge

56. There are periodic trends in leaving group ability: The Leaving Group (a review of basicity ): 7/23/2018 56

57. S N 2 reaction : Effect of Solvent 7/23/2018 57

58. Solvent Effects on S N 2 Reactions: Polar Protic and Aprotic solvent Aprotic solvents are those solvents whose molecules do not have a hydrogen that is attached to an atom of an electronegative element They do the same way as protic solvents solvate cations ; by orienting their negative ends around cation and by donating unshared electron pairs to vacant orbitals of the cation Rate of S N 2 reaction generally increased when they are carried out in a polar aprotic solvent 7/23/2018 58

59. 59 Solvent Effects ( 1/2) Polar protic solvents (O-H or N-H) reduce the strength of the nucleophile . Hydrogen bonds must be broken before nucleophile can attack the carbon. 7/23/2018

60. 60 Solvent Effects ( 2/2) Examples : 7/23/2018 Polar aprotic solvents form weaker interactions with substrate and permit faster reaction

61. 61 Since no free carbocation is generated, therefore, S N 2 displacement afford unrearranged products. However, some times S N 2 reaction, leads to allylic rearrangement. The attack of nucleophile takes place at the end of the π -system i.e. on C-3 of the allylic -system, with simultaneous expulsion of a leaving group. Such reactions are referred to as S N 2', to distinguish them from the normal S N 2 process. 3 2 1 S N 2 ’ S N 2 7/23/2018 Rearrangement in S N 2

62. Kinetics: Rate = k [RX] [Nu: - ]. Both RX and Nu: - are involved in the rate-determining step. Nucleophile : Negatively-charged (strong nucleophile ) work best ; occasionally neutral nucleophiles can be used. Reactivity of alkyl halides : Sensitive to steric effects CH 3 > 1° > 2° due to steric effects that hinder backside attack . 3° halides do not react . 7/23/2018 62 Characteristics of S N 2 Reaction

63. The S N 2 Reaction Solvents : Wide variety can be used, but polar, aprotic solvents are favored and usually cause 2° halides to react by this mechanism. Rearrangements : Do not occur Stereochemistry : Complete inversion of configuration via pentacoordinate carbon Transition State . 7/23/2018 63

64. Summary of S N 1 and S N 2 Reactions Factor S N 1 S N 2 Substrate 3° (requires formation of a relatively stable carbocation ) Methyl > 1 ° > 2 ° (requires unhindered substrate) Nu: Weak Lewis base, neutral molecule Nu: may also assist Strong Lewis Base, rate increased by high concentration of Nu: Solvent Polar Protic ( e.g alcohol, water…) Polar protic ( e.g DMF, DMSO) * Leaving Group: I > Br > Cl > F for both S N 1 and S N 2 (the weaker the base after the group departs the better the leaving group) 7/23/2018 64

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66. 7/23/2018 66 Factors S N 2 Reactions S N 1 Reactions 11. Polarity Favored by solvents of low polarity Favored by solvents of high polarity 12. Reaction rate determining factor By steric hindrance By electronic factor (stability of carbocation ) Table contd.

67. 67 The structure of substrate, the nature of the nucleophilic reagent, polarity of solvent, and other experimental conditions determine whether nucleophilic substitution will take place by S N 1 or by S N 2 mechanism. High concentration of the nucleophile and / or presence of strong nucleophile favors S N 2, while the factors promoting the S N 1 are, lower concentration of nucleophile or the absence of strong nucleophile , solvents of great ionizing power (such as water) and substrate leading to stable carbocations . The reaction rates of both the S N 1 and S N 2 reactions are increased if the leaving group is a stable ion and a weak base. Competition between S N 1 and S N 2 7/23/2018

68. This is how we got down!!! A graph showing the relative reactivities of the different alkyl halides towards S N 1 and S N 2 reactions 7/23/2018 68

69. Special cases, both S N 1 and S N 2 blocked (or exceedingly slow) Carbocation highly unstable, attack from behind blocked Carbocation highly unstable, attack from behind blocked Carbocation would be primary, attack from behind difficult due to steric blockage Carbocation can’t flatten out as required by sp 2 hybridization, attack from behind blocked 7/23/2018 69

70. S N i (Substitution Nucleophilic Internal ) 7/23/2018 70

71. 71 In this process part of leaving group detaches itself from the rest of the leaving group. This is exemplified by the conversion of (R)-2-butanol to (R)-2-chlorobutane with SOCl 2 in nonpolar solvent and absence of base. The product formed is with complete retention of configuration, i.e., in which the starting material and product have the same configuration. The mechanism appears to involve the formation of intermediate chlorosulfite ester, ROSOCl (R = sec-butyl group), which dissociates into an intimate ion pair, R + : - OSOCl as in S N 1 mechanism. The Cl , with pair of electrons, of the anion attacks the R + from the same side of the carbocation from which – OSOCl departed and the product ( RCl ) is formed with complete retention of configuration. S N i (Substitution Nucleophilic internal) 7/23/2018

72. S N i (Substitution Nucleophilic internal) : Summary Retention of configuration Enhanced rate of reaction 7/23/2018 72

73. Neighboring group participation (NGP) 7/23/2018 73

74. Introduction Nucleophilic substitution reaction Unusual behaviour Substrate and reagent are both parts of the same molecule Enhanced rate with an unexpected stereochemistry 7/23/2018 74

75. What is NGP? Definition:- The interaction of a reaction centre with a lone pair of electrons in an atom or the electrons present in a sigma bond or pi bond. Anchimeric assistance. 7/23/2018 75

76. Mechanism Two S N 2 substitutions take place. STEP 1 :- Attack of the internal nucleophile . STEP 2 :- Substitution of external nucleophile . 7/23/2018 76

77. Stereochemistry 7/23/2018 77

78. NaOH Retention - OH - OH - OH Inversion 1 Inversion 2 Neighboring Group Participation : Retention of configuration 7/23/2018 78

79. Different types of NG 7/23/2018 79

80. Mustard gases contain either S-C-C-X or N-C-C-X what is unusual about the mustard gases is that they undergo hydrolysis rapidly in water, a very poor nucleophile Bis(2-chloroethyl)sulfide (a sulfur mustard gas) Bis (2-chloroethyl)methylamine (a nitrogen mustard gas) C l S C l C l N C l 7/23/2018 80

81. the reason is neighboring group participation by the adjacent heteroatom proton transfer to “solvent” completes the reaction Good nucleophile . 7/23/2018 81

82. Other examples 1. NGP BY PI BONDS 2. NGP BY AROMATIC RINGS 7/23/2018 82

83. Points to remember Adjacent carbon atom. S N 2 mechanism. New cyclic reaction intermediate. Nucleophile must be in trans position to the leaving group. 7/23/2018 83

84. Neighboring group participation: Summary Retention of configuration Enhanced rate of reaction 7/23/2018 84

85. Thank you for your attention 7/23/2018 85