1. Substitution Reactions of Alcohols We have looked at substitution reactions that take place via two mechanisms: S N 1 - works for substrates that can form relatively stable carbocations... S N 2 - works best for substrates where the carbon that bears the leaving group is sterically uncluttered. Both mechanisms involve loss of the leaving group in the rate-determining step. Good leaving groups are... So, if we want to use alcohols as substrates in these reactions, we must do something to make the –OH group a better leaving group. The problem with alcohols... 1

2. Substitution Reactions of Alcohols 3° alkyl halides via S N 1 Propose a mechanism for this reaction: 2

3. 1° alcohols are converted into alkyl halides via S N 2 Propose a mechanism for this reaction: Substitution Reactions of Alcohols 3

4. Consider the following reaction. We doesn’t it proceed to products? OK, so what if we use HCN instead? The reaction still doesn’t proceed. Why? Substitution Reactions of Alcohols 4

5. If we want to make nitriles, we will have to use a different approach. One method is to convert the alcohol into a sulfonate ester. To make a sulfonate ester, you react an alcohol with an appropriate sulfonyl chloride in the presence of an amine (usually pyridine): Substitution Reactions of Alcohols 5

6. Some common Sulfonate Esters: 6

7. Sulfonate Esters An alternative approach would be to deprotonate the alcohol first, then react it with the sulfonyl chloride: The alkoxides can be made by reacting an alcohol with NaH or with an alkali metal (Na or K): 7

8. Sulfonate Esters Once the alcohols have been converted to the sulfonate ester, it can then be used in an S N 2 reaction: 8

9. Sulfonate esters make good leaving groups because the pKa of their conjugate acids is ~-6.5, roughly the same as that for Cl -. As such, another strategy for making alcohols a better leaving group is to convert them into a halide! Substitution Reactions of Alcohols – Converting Alcohols to Alkyl Halides 9

10. Converting Alcohols to Alkyl Halides Propose a mechanism for the following reaction: P=O bonds are very strong, making this process favourable. 10

11. Converting Alcohols to Alkyl Halides Propose a mechanism for the following reaction: 11

12. Converting Alcohols to Alkyl Halides – The Mitsunobu Reaction A Mitsonobu reaction involves four main reactants: The alcohol to be substituted The conjugate acid of the desired nucleophile (e.g. HCl for Cl - ) Triphenylphosphine (Ph 3 P = (C 6 H 5 ) 3 P) Diethyl azodicarboxylate (DEAD = CH 3 CH 2 OC(O)NNC(O)OCH 2 CH 3 ) 12

13. Converting Alcohols to Alkyl Halides – The Mitsunobu Reaction Propose a mechanism for the Mitsunobu reaction: 13

14. HX can be a weak acid...HCN, RCO 2 H, HN 3, ArOH, ArSH This is a very convenient technique for doing SN2 reactions with alcohols without requiring the alkyl halide. The Mitsunobu Reaction 14

15. Converting Alcohols to Ethers If you wanted to make an ether, you could imagine an alcohol reacting with itself. What are the two main reasons why this reaction does not work? X The Williamson ether synthesis is a versatile method for making ethers. What kind of mechanism does this reaction follow? 15

16. Converting Alcohols to Ethers It is also possible to prepare ethers via S N 1 processes. Keep in mind that the nucleophilic site and electrophile site don’t necessarily have to be in different molecules. Propose a mechanism for the following reactions: 16

17. Cleavage of Ethers The cleavage of ethers also occurs via substitution reactions. Propose a mechanism for the following reaction: 17

18. Cleavage of Ethers The cleavage of ethers can also be done using trimethylsilyl iodide (TMSI): 18

19. Epoxides – S N 2 substrates With good nucleophiles and under neutral or basic conditions, epoxides are excellent substrates for S N 2 reactions. This type of reaction does not proceed with other ethers. Why? no reaction 19

20. Like all S N 2 reactions, epoxides react with inversion of stereochemistry at the least hindered electrophilic carbon atom. Epoxides – S N 2 substrates 20

21. Under acidic conditions, epoxides are good S N 1 substrates. Epoxides – S N 1 substrates 21

22. To understand the reactivity of epoxides under acidic conditions, we have to consider the intermediate that is formed: Epoxides – S N 1 substrates 22

23. So what does this mean in terms of product distribution? Epoxides – S N 1 substrates 23

24. Common Leaving Groups 24

25. 25