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Phản ứng hóa học của ankyl halogenua: Phản ứng thế nucleophil và tách loại - TS. Trần Thượng Quảng

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  1. Phản ứng hóa học của ankyl halogenua: Phản ứng thế nucleophil và tách loại TS. Trần Thượng Quảng Bộ Môn Hóa Hữu cơ Viện Kỹ Thuật Hóa học HUST
  2. Ankyl halogenua phản ứng với tác nhân nucleophil và bazơ ◼ Liên kết C-X phân cực ◼ Tác nhân nucleophil sẽ thay thế nguyên tử halogen trong liên kết C-X 2
  3. Ankyl halogenua phản ứng với tác nhân nucleophil và bazơ ◼ Các nucleophil có tính bazơ mạnh theo Brønsted gây ra phản ứng tách loại 3
  4. Phản ứng thế vs. Phản ứng tách loại 4
  5. 8.11The Nature of Substitution ◼ Substitution requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule. ◼ A nucleophile is a reactant that can be expected to participate as a Lewis base in a substitution reaction. 5
  6. Substitution Mechanisms ◼ SN1 Two steps with carbocation intermediate Occurs in 3°, allyl, benzyl ◼ SN2 Concerted mechanism - without intermediate Occurs in primary, secondary 6
  7. Kinetics of Nucleophilic Substitution ◼ Rate is the change in concentration with time ◼ Depends on concentration(s), temperature, inherent nature of reaction (energy of activation) ◼ A rate law describes the relationship between the concentration of reactants and the overall rate of the reaction ◼ A rate constant (k) is the proportionality factor between concentration and rate 7
  8. Kinetics of Nucleophilic Substitution -1 Rate = d[CH3Br]/dt = k[CH3Br][OH ] This reaction is second order: two concentrations appear in the rate law nd SN2: Substitution Nucleophilic 2 order 8
  9. 8.12 The SN2 Reaction ◼ Reaction occurs with inversion at reacting center ◼ Follows second order reaction kinetics ◼ Ingold nomenclature to describe rate- determining step: S=substitution N (subscript) = nucleophilic 2 = both nucleophile and substrate in rate-determining step (bimolecular) 9
  10. SN2 Process 10
  11. SN2 Transition State ◼ The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups ◼ Hybridization is sp2 11
  12. 8.13 Characteristics of the SN2 Reaction ◼ Sensitive to steric effects ◼ Methyl halides are most reactive ◼ Primary are next most reactive ◼ Unhindered secondary halides react under some conditions ◼ Tertiary are unreactive by this path ◼ No reaction at C=C (vinyl or aryl halides) 14
  13. Steric Effects on SN2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast SN2 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 SN2 reactions. 15
  14. Steric Effect in SN2 16
  15. Steric Hindrance Raises Transition State Energy Very hindered ◼ Steric effects destabilize transition states ◼ Severe steric effects can also destabilize ground state 17
  16. Order of Reactivity in SN2 ◼ The more alkyl groups connected to the reacting carbon, the slower the reaction 18
  17. Vinyl and Aryl Halides: 19
  18. Order of Reactivity in SN2 DMF R Br + Cl-1 R Cl + Br-1 Br Br Br Br ethyl propyl isobutyl neopentyl 1.0 0.69 0.33 0.000006 20
  19. The Nucleophile ◼ Neutral or negatively charged Lewis base ◼ Reaction increases coordination (adds a new bond) at the nucleophile Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral See Table 8.2 for an illustrative list 21
  20. For example: Br C N -1 + CN-1 + Br -1 CH2 Cl + H2O CH2 OH2 + Cl 22
  21. Relative Reactivity of Nucleophiles ◼ Depends on reaction and conditions ◼ More basic nucleophiles react faster (for similar structures. See Table 8.3) ◼ Better nucleophiles are lower in a column of the periodic table ◼ Anions are usually more reactive than neutrals 24
  22. The Leaving Group ◼ A good leaving group reduces the energy of activation of a reaction ◼ Stable anions that are weak bases (conjugate bases of strong acids) are usually excellent leaving groups ◼ Stronger bases (conjugate bases of weaker acids) are usually poorer leaving groups 26
  23. The Leaving Group 27
  24. Poor Leaving Groups ◼ If a group is very basic or very small, it does not undergo nucleophilic substitution. 28
  25. Converting a poor LG to a good LG: 29
  26. The Solvent ◼ Protic solvents (which can donate hydrogen bonds; -OH or –NH) slow SN2 reactions by associating with reactants (anions). ◼ Energy is required to break interactions between reactant and solvent ◼ Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction 30
  27. Some Polar Aprotic Solvents O H3C CH3 H C S N 3 CH3 CH3 O P N dimethylsulfoxide CH3 (DMSO) CH3 N H3C CH3 O N hexamethylphosphoramide C CH3 H (HMPT) dimethylformamide (DMF) 31
  28. Summary of SN2 Characteristics: o o o ◼ Substrate: CH3->1 >2 >>3 (Steric effect) ◼ Nucleophile: Strong, basic nucleophiles favor the reaction ◼ Leaving Groups: Good leaving groups (weak bases) favor the reaction ◼ Solvent: Aprotic solvents favor the reaction; protic reactions slow it down by solvating the nucleophile ◼ Stereochemistry: 100% inversion 33
  29. Prob. 8.8 Arrange in order of SN2 reactivity 34
  30. 8.14 The SN1 Reaction ◼ Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to the addition of the nucleophile. ◼ Reaction occurs in two distinct steps, while SN2 occurs in one step (concerted). ◼ Rate-determining step is formation of carbocation: 35
  31. SN1 Reactivity: 36
  32. SN1 Energy Diagram 37
  33. Rate-Limiting Step ◼ The overall rate of a reaction is controlled by the rate of the slowest step ◼ The rate depends on the concentration of the species and the rate constant of the step ◼ The step with the largest energy of activation is the rate-limiting or rate-determining step. ◼ See Figure 11.9 – the same step is rate- determining in both directions) 38
  34. SN1 Energy Diagram 39
  35. Stereochemistry of SN1 Reaction ◼ The planar carbocation intermediate leads to loss of chirality ◼ Product is racemic or has some inversion 41
  36. Stereochemistry of SN1 Reaction •Carbocation is usually biased to react on side opposite leaving group because it is unsymmetrically solvated •The second step may occur with the carbocation loosely associated with leaving group. •The result is racemization with some inversion: 43
  37. Effects of Ion Pair Formation 44
  38. 8.15 Characteristics of the SN1 Reaction ◼ Tertiary alkyl halides are the most reactive simple halides by this mechanism Controlled by stability of carbocation 45
  39. Relative Reactivity of Halides: 46
  40. Delocalized Carbocations ◼ Delocalization of cationic charge enhances stability ◼ Primary allyl is more stable than primary alkyl ◼ Primary benzyl is more stable than allyl 47
  41. Allylic and Benzylic Halides ◼ Allylic and benzylic intermediates stabilized by delocalization of charge (See Figure 11-13)  Primary allylic and benzylic are also more reactive in the SN2 mechanism 48
  42. Relative SN1 rates (formolysis): RCl + HCOO-1 Cl Cl 1.0 3550 Cl Cl 0.5 5670 50
  43. Formation of the allylic cation: Cl Cl 51
  44. Effect of Leaving Group on SN1 ◼ Critically dependent on leaving group  Reactivity: the larger halides ions are better leaving groups ◼ In acid, OH of an alcohol is protonated and leaving group is H2O, which is still less reactive than halide ◼ p-Toluensulfonate (TosO-) is an excellent leaving group 52
  45. Nucleophiles in SN1 ◼ Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile 53
  46. Solvent Is Critical in SN1 ◼ The solvent stabilizes the carbocation, and also stabilizes the associated transition state. This controls the rate of the reaction. Solvation of a carbocation by water 55
  47. Polar Solvents Promote Ionization ◼ Polar, protic and unreactive Lewis base solvents facilitate formation of R+ ◼ Solvent polarity is measured as dielectric polarization (P) (Table 11-3) 56
  48. Effect of Solvent 57
  49. Solvent Polarity 58
  50. Effects of Solvent on Energies ◼ Polar solvent stabilizes transition state and intermediate more than reactant and product 59
  51. Summary of SN1 Characteristics: ◼ Substrate: Benzylic~allylic>3o >2o ◼ Nucleophile: Does not affect reaction (although strong bases promote elimination) ◼ Leaving Groups: Good leaving groups (weak bases) favor the reaction ◼ Solvent: Polar solvents favor the reaction by stabilizing the carbocation. ◼ Stereochemistry: racemization (with some inversion) 60
  52. Prob. 8.9 Arrange in order of SN1 reactivity 61
  53. Problem 8.10: SN1 or SN2? 62
  54. Problem 8.11: SN1 or SN2? 63
  55. Biological Substitution Reactions 64
  56. Biological Substitution Reactions 65
  57. Biological Substitution Reactions 66
  58. 8.16 Alkyl Halides: Elimination ◼ Elimination is an alternative pathway to substitution ◼ Elimination is formally the opposite of addition, and generates an alkene ◼ It can compete with substitution and decrease yield, especially for SN1 processes 67
  59. Zaitsev’s Rule for Elimination Reactions (1875) ◼ In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates 68
  60. Mechanisms of Elimination Reactions ◼ Ingold nomenclature: E – “elimination” ◼ E1 (1st order): X- leaves first to generate a carbocation  a base abstracts a proton from the carbocation ◼ E2 (2nd order): Concerted transfer of a proton to a base and departure of leaving group ◼ E1cb : Carbanion intermediate is formed in the rate-determining step 69
  61. E1 mechanism: starts out like SN1 70
  62. E2 mechanism: concerted 71
  63. E1cb: common in biochemical reactions 72
  64. 8.17 The E2 Reaction Mechanism ◼ A proton is transferred to base as leaving group begins to depart ◼ Transition state combines leaving of X and transfer of H ◼ Product alkene forms stereospecifically 73
  65. E2 Reaction Kinetics ◼ One step (concerted): rate law dependent on base and alkyl halide ◼ Rate = k[R-X][B] ◼ Reaction goes faster with stronger base, better leaving group 75
  66. Kinetic Isotope Effect ◼ Substitute deuterium for hydrogen at position ◼ Effect on rate is kinetic isotope effect (kH/kD = deuterium isotope effect) ◼ Rate is reduced in E2 reaction Heavier isotope bond is slower to break Shows C-H bond is broken in or before rate- limiting step 76
  67. kH/kD 77
  68. Geometry of Elimination – E2 ◼ Antiperiplanar allows orbital overlap and minimizes steric interactions 78
  69. E2 Stereochemistry 79
  70. Comparison of SN2 and E2: 80
  71. Predicting Product ◼ E2 is stereospecific ◼ Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2- diphenyl-1-bromoethene ◼ RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl- 1-bromoethene 81
  72. Anti periplanar geometry 82
  73. 8.18 Elimination From Cyclohexanes ◼ Abstracted proton and leaving group should align trans-diaxial to be anti periplanar (app) in approaching transition state (see Figures 11-19 and 11-20) ◼ Equatorial groups are cannot be in proper alignment 83
  74. Elimination From Cyclohexanes 84
  75. Axial vs. Equatorial Leaving Groups 85
  76. 8.19 The E1 Reaction ◼ Competes with SN1 and E2 at 3° centers ◼ Rate = k [RX] 87
  77. Stereochemistry of E1 Reactions ◼ E1 is not stereospecific and there is no requirement for alignment ◼ Product has Zaitsev orientation because the step that controls product formation is loss of proton after formation of carbocation 89
  78. Comparing E1 and E2 ◼ Strong base is needed for E2 but not for E1 ◼ E2 is stereospecifc, E1 is not ◼ E1 gives Zaitsev orientation; E2 may not due to stereospecificity ◼ E1 is favored in protic solvents; competes with SN1 90
  79. Comparing E1 and E2 91
  80. E1cb: 92
  81. A biochemical example (from fat biosynthesis): 93
  82. Reactivity Summary: SN1, SN2, E1, E2 94
  83. General Pattern by Substrate 95
  84. Primary alkyl halides (SN2 vs E2) 96
  85. Secondary alkyl halides (SN2 vs E2) 97
  86. Tertiary alkyl halides (SN1/E1 vs E2) 98
  87. Prac. Problem 99
  88. Answers 100
  89. Problem 8.12 101
  90. Problem 8.13: This halide does not undergo SN1 or SN2 reactions. Why? 102
  91. It also fails to eliminate HBr under basic conditions. Why? 103