Nucleophilic Substitution

1. Nucleophilic Substitution

2. – – : 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.

3. Halogens connected to sp2 carbons are not reactive under the conditions discussed in this chapter. Effect of Hybridization of the Carbon sp2 carbons not reactive sp3 carbon reactive

4. Nucleophilic Substitution Therefore, substrate cannot be an a vinylic halide or an aryl halide, except under certain conditions to be discussed in Chapter 12.

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. Alkyl iodides are most reactive since:(a) the carbon-iodine bond is weakest for the halogens; (b) iodide is the weakest base of the halides (this implies that iodide is most stable) since HI is the strongest acid. Relative Reactivity of Halide Leaving Group

18. Since the rate of reaction depends on the halide the ratedetermining step must involve breaking of the carbon-halogen bond. SN2 Mechanism of Nucleophilic Substitution Kinetic studies of the above reaction showed that the rate is also dependent on the hydroxide concentration: The rate determining step therefore involves both the nucleophile and the alkyl halide.

19. SN2 Mechanism of Nucleophilic Substitution Overall reaction. The mechanism (one step). The transition state. The configuration at carbon. From

20. Potential Energy Diagram for SN2 Reaction

21. The nucleophile attacks carbon from the side opposite the bond to the leaving group. The SN2 reaction at a chirality center proceeds with inversion of configuration at the carbon bearing the leaving group. Inversion of Stereochemistry with SN2

22. The reaction of (S)-2-bromooctane proceeds with inversion of configuration as shown in the equation: Inversion of Configuration The transition state is:

23. Steric Effects and SN2 Reaction Rates

24. The rate of the reaction: RBr + LiI RI + LiBr Effect of the Alkyl Group on the Rate decreases with increasing steric hindrance.The reaction is fastest with the least hindered methylbromide. The rate of SN2 reactions normally decreases in the order:CH3X > primary > secondary > tertiary

25. Substitution on the b-carbon also slows reaction by adding steric hindrance to the carbon bearing the halogen. Effect of b-Substitution on the Rate Neopentyl bromide (a primaryalkyl halide) is so hindered that it is essentially unreactive.

26. Nucleophiles and Nucleophilicity

27. Not all nucleophiles are negatively charged. Amines (R3N), sulfides (R2S) and phosphines (R3P) are good neutral nucleophiles. Neutral Nucleophiles

28. Solvolysis reactions with water (hydrolysis) and alcoholsalso involve neutral nucleophiles Neutral Nucleophiles SN2 hydrolysis reaction mechanism:

29. Nucleophilicity (nucleophile strength) is a measure of how fast a Lewis base displaces a halogen in a reaction.The table compares rates of reaction with CH3I in CH3OH. Nucleophilic Strength

30. When comparing nucleophiles with the same nucleophilic atom then the stronger base is the stronger nucleophile. Nucleophilicity The stronger base is the conjugate base of the weaker acid. This generalization holds when comparing nucleophilesin the same row of the Periodic table

31. When comparing nucleophiles that have the same nucleophilic atom the charged nucleophile is stronger. Nucleophilic Strength

32. When comparing nucleophiles in the same group of the Periodic Table the most important factor is solvationof the nucleophile. Iodide is the weakest base of the halogens but the best nucleophile. The smaller chloride is a stronger base but is more solvated because it has higher charge density. Nucleophilic Strength

33. The SN1 Mechanism of Nucleophilic Substitution

34. A question... Tertiary alkyl halides are very unreactive in substitutions that proceed by the SN2 mechanism.Do they undergo nucleophilic substitution at all? • Yes. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions.

35. The reaction (CH3)3CBr + 2 H2O  (CH3)3COH + H3O+ + Br- Nucleophilic Substitution of Tertiary Alkyl halides follows a first order rate law: Rate = k[(CH3)3CBr] And the reaction is termed SN1.

36. SN1 Mechanism of Nucleophilic Substitution Step 1: Ionization to form a tertiary cation. Step 2: Addition of a water molecule. Step 3: Deprotonation.

37. Potential Energy Graph of the SN1 Reaction

38. Characteristics of the SN1 mechanism • first order kinetics: rate = k[RX] • unimolecular rate-determining step • carbocation intermediate • rate follows carbocation stability • rearrangements sometimes observed • reaction is not stereospecific • much racemization in reactions of optically active alkyl halides

39. Comparison of a series of alkyl bromides under SN1 reaction conditions (solvolysis) reveals that tertiary alkyl halides react fastest. The Alkyl Halide and the Rate of SN1 Reaction In general, methyl and primary alkyl halides never react by the SN1 mechanism and tertiary alkyl halides never react by SN2.

40. SN1 reactions proceed through the carbocation which isplanar. Stereochemistry of the SN1 Reaction The nucleophile can react from either side however, surprisingly a 1:1 mixture of products is not always formed.

41. The incomplete loss of stereochemistry is explained by a partial shielding of one side of the cation by the halideleaving group. Stereochemistry of the SN1 Reaction

42. Rearrangements are evidence for carbocation intermediates and serve to confirm the SN1 reaction mechanism. Carbocation Rearrangements in SN1 Reactions

43. Mechanism with Rearrangement Step 1: Ionization. Step 2: H-shift (to form a more stable tertiary cation). Step 3: Water addition to the carbocation. Step 4: Deprotonation.

44. Solvent affects the rate of a reaction not the products formed and the questions are: 1. What properties of the solvent influence the rate most? 2. How does the rate-determining step of the mechanismrespond to the properties of the solvent? Effect of Solvent on Substitution

45. Protic solvents are those that are capable of hydrogen bonding. Normally they have an –OH group or an N-H group.Aprotic solvents are not hydrogen bond donors. Polarity of a solvent is related to its dielectric constant (e).Solvents with high dielectric constants are considered polar and those with low dielectric constants are non polar. Classification of Solvents

46. Properties of Solvents

47. Polar protic solvents hydrogen bond to, and solvate, the nucleophile and suppress its nucleophilicity and reduce the rate of reaction. Solvents and SN2 Reactions Polar aprotic solvents cannot solvate the nucleophileand the nucleophile is free to react.

48. The table below shows the effect of solvent on this reaction. Solvents and SN2 Reactions The reaction is much faster in polar aprotic solvents.

49. This reaction was studied under two different conditions. Solvents and SN2 Reactions Reaction of hexyl bromide in a polar protic solvent required heating for 24 hours to form 76% of hexyl cyanide.With a polar aprotic solvent dimethyl sulfoxide and the less reactive hexyl chloride at room temperature for 20 minutes yielded 91 % of hexyl cyanide.

50. Comparison of the rates of solvolysis of (CH3)3CCl and dielectric constant of the solvent shows faster reaction with more polar protic solvent. Solvents and SN1 Reactions The reaction is much faster in more polar protic solvents.