Chapter 8 Nucleophilic Substitution

1. Chapter 8Nucleophilic Substitution

2. 8.1Functional Group Transformation By Nucleophilic Substitution

3. – – : X Y : Nucleophilic Substitution + + R Y R X • nucleophile is a Lewis base (electron-pair donor) • often negatively charged and used as Na+ or K+ salt • Substrate is usually an alkyl halide

4. X C C Nucleophilic Substitution Substrate cannot be an a vinylic halide or an aryl halide, except under certain conditions to be discussed in Chapter 23. X

5. – .. R X R' O: .. gives an ether – + R : X O .. .. R' Table 8.1 Examples of Nucleophilic Substitution Alkoxide ion as the nucleophile +

6. (CH3)2CHCH2OCH2CH3 + NaBr Ethyl isobutyl ether (66%) Example (CH3)2CHCH2ONa + CH3CH2Br Isobutyl alcohol

7. O R X gives an ester .. – O + R'C R : X O .. Table 8.1 Examples of Nucleophilic Substitution Carboxylate ion as the nucleophile – .. + R'C O: ..

8. O O + CH3(CH2)16C KI O CH2CH3 Ethyl octadecanoate (95%) Example + CH3(CH2)16C OK CH3CH2I acetone, water

9. – .. R X H S: .. gives a thiol .. – + H R : X S .. Table 8.1 Examples of Nucleophilic Substitution Hydrogen sulfide ion as the nucleophile +

10. + KBr CH3CH(CH2)6CH3 SH 2-Nonanethiol (74%) Example KSH + CH3CH(CH2)6CH3 Br ethanol, water

11. : : N R X C gives a nitrile – + : N C R : X Table 8.1 Examples of Nucleophilic Substitution Cyanide ion as the nucleophile – +

12. Br + NaBr CN Cyclopentyl cyanide (70%) Example NaCN + DMSO

13. + – – : : N N N + R X .. .. gives an alkyl azide + – – : + N N N R : X .. .. Table 8.1 Examples of Nucleophilic Substitution Azide ion as the nucleophile

14. CH3CH2CH2CH2CH2N3 + NaI Pentyl azide (52%) Example NaN3 + CH3CH2CH2CH2CH2I 2-Propanol-water

15. .. : : I R X .. gives an alkyl iodide .. – + : I R : X .. Table 8.1 Examples of Nucleophilic Substitution Iodide ion as the nucleophile – +

16. + NaI CH3CHCH3 Br + NaBr CH3CHCH3 I 63% Example acetone NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.

17. 8.2Relative Reactivity of Halide Leaving Groups

18. most reactive RI RBr RCl RF least reactive Generalization • Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination.

19. Problem 8.2 A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? • Br is a better leaving group than Cl BrCH2CH2CH2Cl + NaCN

20. : N C CH2CH2CH2Cl + NaBr Problem 8.2 A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? BrCH2CH2CH2Cl + NaCN

21. 8.3The SN2 Mechanism of Nucleophilic Substitution

22. Kinetics • Many nucleophilic substitutions follow asecond-order rate law. CH3Br + HO – CH3OH + Br – • rate = k[CH3Br][HO – ] • inference: rate-determining step is bimolecular

23.   HO CH3 Br transition state HO – CH3Br + HOCH3 + Br – Bimolecular Mechanism • one step

24. Stereochemistry • Nucleophilic substitutions that exhibitsecond-order kinetic behavior are stereospecific and proceed withinversion of configuration.

25. Nucleophile attacks carbonfrom side opposite bondto the leaving group. Three-dimensionalarrangement of bonds inproduct is opposite to that of reactant. Inversion of Configuration

26. Stereospecific Reaction • A stereospecific reaction is one in whichstereoisomeric starting materials givestereoisomeric products. • The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. • (+)-2-Bromooctane  (–)-2-Octanol • (–)-2-Bromooctane  (+)-2-Octanol

27. H H CH3(CH2)5 (CH2)5CH3 C HO Br C CH3 CH3 (R)-(–)-2-Octanol Stereospecific Reaction NaOH (S)-(+)-2-Bromooctane

28. Problem 8.4 • The Fischer projection formula for (+)-2-bromooctaneis shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration.

29. CH3 CH3 Br H HO H CH2(CH2)4CH3 CH2(CH2)4CH3 Problem 8.4 • The Fischer projection formula for (+)-2-bromooctaneis shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration.

30. 8.4Steric Effects and SN2 Reaction Rates

31. Crowding at the Reaction Site The rate of nucleophilic substitutionby the SN2 mechanism is governedby steric effects. Crowding at the carbon that bears the leaving group slows the rate ofbimolecular nucleophilic substitution.

32. Table 8.2 Reactivity Toward Substitution by the SN2 Mechanism RBr + LiI  RI + LiBr • Alkyl Class Relativebromide rate • CH3Br Methyl 221,000 • CH3CH2Br Primary 1,350 • (CH3)2CHBr Secondary 1 • (CH3)3CBr Tertiary too small to measure

33. Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr

34. Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr

35. Crowding Adjacent to the Reaction Site The rate of nucleophilic substitutionby the SN2 mechanism is governedby steric effects. Crowding at the carbon adjacentto the one that bears the leaving groupalso slows the rate of bimolecularnucleophilic substitution, but the effect is smaller.

36. Table 8.3 Effect of Chain Branching on Rate of SN2 Substitution RBr + LiI  RI + LiBr • Alkyl Structure Relativebromide rate • Ethyl CH3CH2Br 1.0 • Propyl CH3CH2CH2Br 0.8 • Isobutyl (CH3)2CHCH2Br 0.036 • Neopentyl (CH3)3CCH2Br 0.00002

37. 8.5Nucleophiles and Nucleophilicity

38. The nucleophiles described in Sections 8.1-8.6have been anions. – – – .. – .. .. : etc. : : : : N C HS HO CH3O .. .. .. Not all nucleophiles are anions. Many are neutral. .. .. : for example NH3 CH3OH HOH .. .. Nucleophiles All nucleophiles, however, are Lewis bases.

39. .. CH3OH HOH .. .. Nucleophiles Many of the solvents in which nucleophilic substitutions are carried out are themselvesnucleophiles. .. for example

40. Solvolysis The term solvolysis refers to a nucleophilic substitution in which the nucleophile is the solvent.

41. solvolysis + R—Nu—H + :X— R—X + :Nu—H step in which nucleophilicsubstitution occurs Solvolysis substitution by an anionic nucleophile • R—X + :Nu— • R—Nu + :X—

42. Solvolysis substitution by an anionic nucleophile • R—X + :Nu— • R—Nu + :X— solvolysis + R—Nu—H + :X— R—X + :Nu—H products of overall reaction R—Nu + HX

43. CH3 CH3 CH3 + –H+ : : R : R : O O O .. H H The product is a methyl ether. Example: Methanolysis Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent andthe nucleophile. + R—X

44. O O O O Typical solvents in solvolysis solvent product from RX water (HOH) ROH methanol (CH3OH) ROCH3 ethanol (CH3CH2OH) ROCH2CH3 formic acid (HCOH) acetic acid (CH3COH) ROCH ROCCH3

45. Nucleophilicity is a measure of the reactivity of a nucleophile • Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relativerate of 1.0.

46. Table 8.4 Nucleophilicity • Rank Nucleophile Relative rate • strong I-, HS-, RS- >105 • good Br-, HO-, 104 • RO-, CN-, N3- • fair NH3, Cl-, F-, RCO2- 103 • weak H2O, ROH 1 • very weak RCO2H 10-2

47. Major factors that control nucleophilicity • basicity • solvation • small negative ions are highly solvated in protic solvents • large negative ions are less solvated

48. Table 8.4 Nucleophilicity • Rank Nucleophile Relative rate • good HO–, RO– 104 • fair RCO2– 103 • weak H2O, ROH 1 When the attacking atom is the same (oxygenin this case), nucleophilicity increases with increasing basicity.

49. Major factors that control nucleophilicity • basicity • solvation • small negative ions are highly solvated in protic solvents • large negative ions are less solvated

50. Figure 8.3 Solvation of a chloride ion by ion-dipole attractiveforces with water. The negatively charged chlorideion interacts with the positively polarized hydrogensof water.