Chapter 11 Outline: Ethers, Epoxides & Sulfides Review Nomenclature & Physical Properties on your own 1. Structure of Ethers & Epoxides 2. Preparation of Ethers & Thioethers 3. Reactions of Ethers 4. Preparation of Epoxides 5. Reactions of Epoxides 6. Practicing problems You should do all the problems in the textbook, but these are some suggested homework problems: 11.10 17, 11.19 11.21, 11.23, 11.30 11.36, 11.38, 11.42 11.44. Brevetoxin B is a naturally occurring polyether exerts its neurotoxic effects by binding to sodium channels on nerve and muscle cell membranes, causing an excessive influx of sodium ions across the membranes, which leads to cell death. o It s synthesis was a 12-year effort by chemistry K. C. Nicolaou s group at Scripps Research Institute, (UC-San Diego J Am. Chem. Soc., 117, 1171 and 1173 (1995). o Structure that includes 11 trans-fused rings and 23 stereocenters. It was synthesized in 83 steps, overall yield of the synthesis was 0.043%; with average yield for each site was about 91%. Page 1 of 27
1. Structure & Physical Properties Which ones are strained? Crown Ethers: a special kind of cyclic ether 18-crown-6 12-crown-4 Page 2 of 27
What s the Utility of Crown Ethers? Page 3 of 27
2. Preparation Ethers & Thioethers a. Nucleophilic attack of RX with NaOR: in which direction does it lie? What mechanism does this undergo above? But how do you make a metal alkoxide like sodium ethoxide? Page 4 of 27
b. Williamson Ether Synthesis (WES) The WES involves a S N 2 reaction of a strong Nu and a suitable small RX. What is MTBE used for? MTBE = methyl tert-butl ether = One method of synthesis undergoes S N 2 (to afford an ether) and the other option will prefer E2 (to afford an alkene). Which synthetic route will provide S N 2? O Page 5 of 27
c. Acid-catalysed Dehydration of Alcohols Page 6 of 27
d. Acid-catalysed Addition of Alcohols to Alkenes Page 7 of 27
3. Reactions of Ethers -- how to make a good leaving group? a. Acid-catalyzed cleavage by concentrated HX (converting a ROR 2 RX) Determine the products for the following reactions: O excess HCl Page 8 of 27
Mechanism? Page 9 of 27
b. Silyl Ethers as Protecting Groups Sometimes one wants to transform one functional group in the presence of another, more acidic, functional group that they want to leave untouched. Who would be deprotonated first? Organic chemists use protecting groups for this purpose. Several reagents exist as protecting groups: Page 10 of 27
Silyl Ethers as Protecting Groups What is the driving force for the last step? Page 11 of 27
The precautionary tale of ethers: Low molecular weight ethers react with molecular oxygen to form peroxides which are explosive (no we will not be doing a demo of this!) If you see the precipitates at the bottom of the bottle, it should be removed by a bomb squad! Page 12 of 27
4. Preparation of Epoxides a. Synthesis of Epoxides Internal Nucleophilic Substitution in Halohydrins o Also thought of as an internal Williamson Ether Synthesis Mechanism? Page 13 of 27
b. Synthesis of Epoxides o Epoxidation occurs via syn (i.e. same side) addition of an O atom to either side of a planar double bond. o A cis alkene gives an epoxide with cis substituents. o A trans alkene gives an epoxide with trans substituents. Page 14 of 27
5. Reactions of Epoxides Due to ring strain, epoxides undergo a large number of ring opening reactions. There are only two reactions we will see: epoxides reacting in the presence of strong acid Since attack at either side occurs with equal probability, an equal amount of the two enantiomers is formed a racemic mixture. Optically inactive starting materials can give optically-active products. epoxides reacting in the presence of a strong Nu (absence of acid) What do you notice about the product stereochemistry? Anti or syn addition? Page 15 of 27
a. Acid-Catalyzed Ring Opening - In the presence of acid, an epoxide opens to form a glycol Reaction gives anti addition of nucleophile (i.e. trans products) Trans product is favored solely due to sterics (nucleophile attacks opposite side of where original epoxide points) Mechanism? Page 16 of 27
b. Acid-Catalyzed Ring Opening with HX- In the presence of HX, an epoxide opens and X - adds to MOST substituted carbon. o Reaction undergoes anti-addition to afford trans product o In the presence of acid, the Nu attacks at the more substituted C Mechanism? Page 17 of 27
c. Nucleophilic Ring Opening attacking an epoxide with a Nu Ethers are not usually susceptible to attack by strong nucleophiles alone (without first being protonated), but the ring strain in epoxides makes it undergo attack via S N 2 reactions more readily. O 1. NaBr 2. H 2 O HO Br o What overall two key features do you notice from above? o Mechanism? Page 18 of 27
6. Practicing Problems: O 1. NaBr 2. H 2 O HBr Mechanism? Mechanism? Page 19 of 27
A B C D E F G H I J K L M N O P Page 20 of 27
Determine the final product from the following steps: Page 21 of 27
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Br 1. NaH 2. Cl 2 /H 2 O 3. NaH 4. HBr Page 24 of 27
Devise a synthesis for the following: Page 25 of 27
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