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  2. 2. Neighboring Group Participation (Anchimeric asssitance)Hydrolysis of EtS–CH2CH2 – Cl is 104 times faster than that ofCH3–CH2CH2–Cl. Why? .. slow fast ..EtS EtS EtS Cl Cl OH .. OH2
  3. 3. Stereochemistry
  4. 4. Neighboring Group Participation : Retention of configuration Et2Et2(HO)C C NaOH HO Cl OH Retention Me Me H H Et2 C - OH -O OH Et2 Et2 Me C C - OH H Inversion 1 Inversion 2 O - Cl O OH Me Me H H
  5. 5. Different types of NG
  6. 6. NGP by a cyclopropane, cyclobutane or a homoallyl group
  8. 8. INTERMEDIATE ION CH3 CH3 Bridged ion,O OAc attacks O + O O equally on + either side, but always anti - O-Ac trans diacetate
  9. 9. Neighboring group participationQ. H HNO2 H O S S O CO2H O CO2H OH H2N H R HO O O H O S H H O C OH N2 O O
  10. 10. Q. Which one will undergo SN1 solvolysis faster? Exaplain? CH3 H3C C CH2Cl H3C C C Cl I H H H2 II phenonium ion δ H H + Cl H H H H Cl H H3C Cl H3C H TS H3C H Sol OH Solvolysis products
  11. 11. Q. Which compound solvolyses faster in HOAc? (I or II). Give the structure of the product from I. OTs OTs I II δ OTs OAc δ HOAc I III Participation of the π electrons of the double bond gives the ion III, which would be stabilized by delocalization of the positive charge. I undergoes 1011 times greater rate than II
  12. 12. Neighboring group participation: Summary• Retention of configuration• Enhanced rate of reaction
  13. 13. α-Bromopropionate Ion H3C conc. [OH-] CH3 H C Br 4M HO C H C O O C O- 0.1M O (R)-config(S)-config - inversion dilute [OH-] H3C H C OH SN 2 C O O- (S)-config retention Two different results! neither SN1 or SN2
  14. 14. REACTION IN CONCENTRATED BASE straightforward SN2 displacement -H O H3C CH3 H C Br conc [OH-] HO C H C O S N2 O C inversion O O (S)-config (R)-config SN2 ( rate = k[RBr] [OH] ) is favored by high [OH]
  15. 15. REACTION IN DILUTE BASE neighboring group participation H3C inversion-1 CH3 H C Br dilute [OH-] O C H S N2 O H C O C O O(S)-config inversion-2 SN2In dilute base H3C C OHthe internaldisplacement Hhas a competing C O Two inversionsrate. O give a product with retention. (S)-config
  16. 16. Important name reactions based on Nucleophilic substitution
  17. 17. Appel Reaction
  18. 18. A modern SN2 reaction: Mitsunobu reaction
  19. 19. O PhCOOH O O N Et Et N O DEAD +Ph3P O R O Ph R OH Diethyl azo dicarboxylate (DEAD) 100% inversionMechanism: First step involves neither the Nu nor the alcoholPh3P: Ph3P Ph3P N CO2Et N CO2Et EtO2C N EtO2C N N CO2Et + O R EtO2C N H H Stable anion O R Ph3P=O H Nu + Nu H 100% Ph3P N CO2Et N CO2Et R Nu O R + EtO2C N EtO2C N H H SN2
  20. 20. Nitrogen nucleophile; Gabriel procedure of amine synthesis
  21. 21. Problems
  22. 22. State with reasons whether these reactions will be either S N1 or SN2. O O (a) Br N3 N3 O OSN2 due to carbonyl O O n-PrOH (b) OH H _ (+)SN1 _ (+)Acid catalysis makes better LG, inversion unusual, but due to OH group hindrance OH O n-PrO (c) OPr SN2 _ (+) _ (+) base catalysis makes better Nu, inversion usual
  23. 23. How to choose between SN1 and SN2 when the choice is more subtleQ. The chemistry shown here is the first step in the manufacture ofPfizer’s doxasolin (Cardura), a drug for hypertension. Draw themechanism of the reaction involved and comment on the bases used OH O CO2Me + Br K2CO3, acetone A OH Br O CO2Me O KOH A H2O O CO2H Carbonate is good enough to remove H+ from ArOH 1°, C=O adjacent, both go by SN2 Ester hydrolysis
  24. 24. Problems : 1) S N 2 reaction by EtO - in EtOH: CH3CH2 Br CH3CH2CH2 Br Me2HCCH2 Br Me3CCH2 Br Explain ?relative rate 1 2.8X10-1 3.0X10-2 24.2X10-6 2) Rate of solvolysis in EtOH : Br Br Explain? A) Br cc at bridge head, less stable, difficult to attain planarity due to rigidity 1 10-6 10-14 Br Br B) Explain ? A) Rigid structure, cation empty p-orbitals are at right angles to π orbitals of Ph 1 10-23 1-bromotriptycene
  25. 25. Q. Which compound solvolyses faster in HOAc containing NaOAc (I or II)?The product is the same from either I or II. What is the structureof the product? S S H Cl Cl H II I S H OAc
  26. 26. OTs OTs CH3 CH3Q. O O I II O O• Which compound solvolyses in HOAc faster ?• Predict the stereochemistry in each case• If I is optically active, is the product is also optically active? OTs O OAc O HOAc O O OAc AcOH .. (+) OAc s OAc R O s OAc O R OAc (+) AcOH
  27. 27. Q. Suggest a mechanism for the following reaction O O H2O O Ph Ph Cl N Ph N CH3CN, heat H Ph O O O O O ClPh N Ph N Ph N O O Ph O Ph Ph OH O O Ph Ph N H O
  28. 28. Phase- transfer catalysis of the SN2 reaction between NaCN and an alkyl halide aq. phase (H2O) aq. phase (H2O) Na CN + - Na+ CN - Na+ X- + + + - Q X Q CN - + organic phase (CH2Cl2) Q+X- Q + CN - RX QX = R4N + X - + + such as (CH3CH2CH2 CH2)4 N+ X- RCN RX organic phase Here no reaction takes Here the PTC transports place as CN- can’t enter the CN- ion (Q CN-) into the org. phase to into the org. phase react with RX CN - + RX RCN + X - takes place rapidly
  29. 29. Nucleophilic NGP Case IIConsider the following: HClCH3 CH2 S CH CH2 OH CH3 CH2 S CH CH2 Cl + CH3 CH CH2 S CH2 CH3 CH3 CH3 Cl "normal" product "rearranged" productRationale: - - H Cl H Cl H OH2 H3 C C H3 C H CH2 + C C products NGP + S S CH2 CH3 CH2 CH3 episulfonium ionAn S N 1 pathway leading to a primary carbocationic intermediate is not as favorable asa neighboring group participation (internal displacement) pathway leading to anepisulfonium ion intermediate.
  30. 30. Mechanism of Gabriel amine synthesis
  31. 31. Arbuzov ReactionMichaelis-Arbuzov Reaction; Phosphorous nucleophiles