Chapter 4 Electrophilic Addition to Carbon Carbon Multiple Bonds 1. Addition of H X 2. Addition of H OH and addition of Y X 3. Addition to allene and

Transcription

1 Chapter 4 Electrophilic Addition to Carbon Carbon Multiple Bonds 1. Addition of X 2. Addition of and addition of Y X 3. Addition to allene and alkyne 4. Substitution at α-carbon 5. eactions via organoborane intermediates 1

2 To break a π-bond requires 60 kcal/mol that cannot occur at room temperature. Acid catalysis or photochemical activation can be applied to the isomerization of C=C double bond. 2

3 Alteration of Double Bond Configuration Photochemical isomerization Ph Ph hν, Benzil Ph cis (91%) Ph trans (9%) Corey Winter reaction (Et) 3 P S C 2 m-clc 6 4 C 3 S (Et) 3 P Syn elimination 3 + N N N N S 3

4 N C Electron-rich species (pair-electron donors): 1. Bases (Bronsted and Lewis definitions) 2. Nucleophiles (targeting electron-deficient carbon center) Electron-poor species (pair-electron acceptors): 1. Acids (Bronsted and Lewis definitions) 2. Electrophiles (targeting electron-deficient carbon center) 4

5 eaction chanism and Active Species Carbocation C 6e Carbon adical C Electron deficient species 7e Carbanion C 8e Electron rich species + Br Br Br 5

6 Electrophilic addition Addition eaction of Alkene with Br Why the reaction does not proceed with nucleophilic addition? 6

7 Addition eaction of Alkene with Br 7

8 eaction Diagram ate-limiting step Negative Δ Negative ΔS = Δ -ΤΔS 8

9 Stability of Carbocations 9

10 The carbocation is stabilized by the interaction of the vacant p-orbital with the adjacent parallel C σ-bond 10

11 Stabilization of Allylic and Benzylic Cations 11

12 Markovnikov s rule: egioselectivity in the addition reaction of unsymmetric alkene Faster pathway More stable intermediate 12

13 Selectivity in rganic Synthesis 1. Chemoselectivity 2. egioselectivity 3. Stereoselectivity (diastereoselectivity) 4. Enantioselectivity 13

14 Chemoselectivity 2,Pd/C NaB 4 NaB 4 B 3 14

15 egioselectivity + ArC 3 67% 33% t-bu, V(acac) 2 0% 100% 15

16 Addition eactions of Conjugated Dienes Conjugation: delocalization of π-electrons in alternative single and multiple bonds, contributing to molecular stability. 1,3-butadiene Br Br secondary allylic cation more stable resonance Br primary allylic cation less stable Br 3-bromo-1-butene Br 1-bromo-2-butene 1,2-addition (71%) 1,4-addition (29%) Allylic cation (1 o ) is as stable as isopropyl cation (2 o ) 3 C C 3 16

17 Addition eactions of Conjugated Diene Conjugation: delocalization of π-electrons in alternative single and multiple bonds 17

18 Stereoselectivity (Diastereoselectivity) + Li, 2 CuLi Li, (Ar) 2 Al 94% 6% 0.5% 99.5% N N S LDA, TF; 2 S 4 N N S N N S 100% de S 100% 0% 18

19 Enantioselectivity + Al Li Et 97.5% 2.5% 95% ee (S) (S)-BINAL- Al Li Et 2.5% 97.5% 95% ee () ()-BINAL- 19

20 Enantioselectivity Ph PhI, catalyst Ph + Ph cat. Ph Ph N Mn Cl N 92% (1,2S) 8% (1S,2) 84% ee t Bu t Bu t Bu N Mn Cl N t Bu 4% (1,2S) 96% (1S,2) 92% ee t Bu t Bu 20

21 Asymmetric Catalysis Preparation of (+)-Naproxen C 2 2 C 3 3 C C mol % chiral catalyst C 3 (+)-naproxen C 3 ( )-naproxen 止痛退燒藥 無效的鏡像體 Chiral catalyst 21

22 ydration: Acid Catalyzed Addition of 2 to Alkene Markovnikov s rule 22

23 ydration of Alkene via xymercuration Demercuration 23

24 ydroboration of Alkene Syn addition of B 3 24

25 ydration of Alkene via ydroboration xidation Anti-Markovnikov s orientation C 3 C 3 25

26 alogenation of Alkene: Anti Addition of alogen This carbocation intermediate cannot explain the selectivity of anti addition 26

27 Br Anti addition 27

28 Addition of alohydrin X to Alkene eaction of halogen in (alkaline) water 28

29 Cis-Dihydroxylation xidation of Alkenes KMn 4, Na, 2 C 3 or s 4 C 3 Mn Mn C C 3 zonation C 3 + C 3 C 3 Zn, Ac C 3 2 2, Na C 3 29

30 Initiation step: adical eaction Cl Cl heat or light Cl Cl Propagation step: C + Cl C + Cl C + Cl Cl C Cl + Cl Termination step C + C C C 30

31 31 adical Polymerization of Alkenes n adical initiator polymerization Ethene Ethylene Polyethylene (PE)

32 Addition of 2, X 2, X, and 2 to Alkyne 2 2, Pd/C 9 C 4 C C 4 C 2 C 2 C decyne decane 9 C 4 C 4 9 2, CaC 3, Pb(Ac) 2 9 C 4 C 4 9 (Lindlar catalyst) (Z)-2-decene 1-hexyne C 4 9 Br C 4 9 Br 2-bromo-1-hexene Br Br 3 C C 4 9 Br 2,2-dibromohexane 1-hexyne C 4 9 Br 2 Br C 4 9 Br 2 Br Br C 4 9 Br Br Br (E)-1,2-dibromo-1-hexene 1,1,2,2-tetrabromohexane 1-hexyne C cat. + C 4 9 enol form C 4 9 keto form 2-hexanone 32

33 Alkenes from Alkynes ydrogenation C 3 C 2 C 2 2, Pd-BaS 4 C 3 Si 2 t Bu tal ammonia reduction N 83%, Si 2 t Bu n C 3 7 C C n Na, N n 3 (l) C 3 7 C 3 7 C C n C 3 7 Na N 3 n C 3 Na + 7 C C n C 3 7 N 3 n C 3 7 C C n C 3 7 Na n C 3 7 C C n C 3 7 Na + 33

34 ydration of Alkyne to thyl Ketone (or + catalysis) Vinylic carbocation Enol Ketone 34

35 eduction of Alkyne to (E)-Alkene with Li tal in liquid N 3 35

36 Keto Enol Tautomerism 3 C C 3 3 C C 2 > 99.9% > 0.01% Acetone Intramolecular hydrogen bonding 3 C C 3 3 C 8% in hexane 92% 2,4-Pentadione C 3 Acidity of α- (pka): 3 C C 3 3 C C 3 3 C C 3 Acetone, pk a = 20 Acetate, pk a = 25 Malonate, pk a = 10 36

37 Keto Enol Tautomerism Acid catalyzed enol formation 37

38 Keto Enol Tautomerism Base catalyzed enol formation 38

39 Formation and Configuration of Enolates Na, (i-pr) 2 NLi and ( 3 Si) 2 NLi are generally used as the bases M Base Base M kinetic enolate thermodynamic enolate BuLi and EtMgI may add onto carbonyl group, instead of deprotonation Using 1.1 equiv LDA gives kinetic enolate, but using 0.9 equiv LDA gives thermodynamic enolate 39

40 Acid-Catalyzed Electrophilic Substitution at α-carbon catalyst Electrophile 40

41 Bidentate Property of Enolate Ion eaction at α-carbon eaction at oxygen α-ketocarbanion Vinylic alkoxide C 3 I Ac 2 α 41

42 Alkylation of Enolates Stabilizing Substituent: PhS, C 2 Et, CN C 2 Et Na Na C 2 Et I C 2 Et NaCl, 2 S or 3 +, Δ i) Na i) i-pri Na +, Li + ii) BuLi ii) 3 + SPh 1) LDA Li, N 3 Li Br 2) I SPh 42

43 Formation of Conjugated Carbonyls C 3 1) LDA, (PhS) 2 2) LDA, C 3 I C 3 PhS C 3 C 3 1) m-cpba 2) Δ C 2 C 3 C 3 1) LDA, C 3 I 2) LDA, (PhS) 2 C 3 PhS C 3 1) m-cpba 2) Δ + C 3 C 2 C 3 1) LDA SePh 2 2 2) PhSeBr 25 o C 43

44 Synthetic Applications of B, Si, P and S Contents 1. Use of Boron eagents 2. Use of Silicon eagents 3. Use of Phosphorus eagents 4. Use of Sulfur eagents 44

45 General Properties of B, Si, P and S eagents B empty p orbital Nu: stabilized C α strong B Si empty d orbital Nu: stabilized C α and C α C β + strong Si and Si F S lone electon-pairs empty d orbital E + stabilized C α P lone electon-pairs empty d orbital E + stabilized C α strong P= 45

46 Preparation of rganoborons ydroboration of Alkenes B 2 6 B α-pinene B 3 B B 2 2 ydroboration follows syn addition and anti-markovnikov orientation. This method is not applicable to preparation of C 3 B 2 or PhB 2. 46

47 Preparation of rganoborons Substitution of rganoborons with Nucleophiles B 2 1) 1 2CuLi 2) 2 2CuLi B 1 2 MgBr Cl B BCl B 2 Et B 2 2 ' ( 2 2 ) ' B ' Boronate ester B() 3 (1) 1 equiv PhC 2 MgCl (2) (+)-Pinanediol, rt PhC 2 B 47

48 eactions of rganoborons B to and : eactions with + and Ac or Cl + B X B B X B B 2 2 2, aq. Na + retention of configurations 48

49 eactions of rganoborons 3 Bto 2 C: eactions with C or CN B C 2 C B C B 2 2 C 2 C B B C N B C N (CF 3 C) 2 B C N CF C 49

50 eactions of rganoborons 1,4-Pentadiene to Cyclohexanone C 3 C 3 B 2 B C, 2 = 2 CC 2 B C 3 2 2, Na C 3 50

51 eactions of rganoborons eactions of Allylboranes C 2 B (E)-crotylborane C Y B Y anti-adduct C 2 B (Z)-crotylborane C Y B Y syn-adduct 51

52 eactions of rganoborons eactions of Alkenylboranes B C C C 2 Et B C Na C C 2 Et C B() 2 C 2 C 2 Et C C 2 C 2 Et B Br C C Bu Na B C C C C () Bu Br Bu 2 B via addition elimination Ac C C Bu B C Br C Bu Br C B C Bu 52