Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14.1 Introduction to Ethers An ether group is an oxygen atom that is bonded to two carbons. The ether carbons can be part of alkyl, aryl, or vinyl groups. 14.2 omenclature of Ethers 1. ame each group of the ether 2. Arrange them alphabetically 3. add ether to the name three separate words -or- 1. Make the larger of the groups the parent chain 2. ame the smaller of the groups as an alkoxy substituent C 3 C 2 C 2 C 2 C 2 C 3 butyl ethyl ether (1-ethoxybutane 1-methylethyl 2-methylpropyl ether (isobutyl isopropyl ether) (1-isopropoxy-2-methylpropane) 279 14.3 Structure and Properties of Ethers The -atom of ethers is sp 3 hydrbidized water methanol dimethyl ether Ether can only act as a hydrogen bond acceptor δ + -bond acceptor δ -bond donor δ + δ δ δ + -bond acceptor δ δ + δ + δ δ M + δ C 3 C 2 C 2 C 2 C 3 C 3 C 2 C 2 C 2 C 3 C 2 C 2 C 3 MW = 72 MW = 74 MW = 74 bp = 36 C bp = 116 C bp = 35 C In general, the C- bonds of ethers have low reactivity this makes then good solvents for other reactions. diethylether tetrahydrofuran 1,4-dioxane 280 140
14.4 Crown Ethers (please read) Polyethers Polyethylene glycol (PEG) n Monensin ionophore antibiotic 281 16.5: Preparation of Ethers a. Addition of alcohols to alkenes (recall hydration of alkenes in and oxymercuration from Chapter 9) b. Condensation of alcohols (not very useful) 282 141
c. The Williamson Ether Synthesis (the workhorse of ether syntheses) - eaction of an alkoxide with an alkyl halide or tosylate to give an ether. Alkoxides are prepared by the reaction of an alcohol with a strong base such as sodium hydride (a). The Williamson ether synthesis is an S 2 reaction. 283 The Williamson Ether Synthesis: Few restrictions regarding the nature of the the alkoxide Works best for methyl- and 1 -halides or tosylates. E2 elimination is a competing reaction with 2 -halides or tosylates 3 -halides undergo E2 elimination Vinyl and aryl halides do not react 284 142
14.6 eactions of Ethers typical ethers are not very reactive Acid Cleavage of Ethers recall the reaction of an alcohol with X to give a halide C 2 - + -X C 2 -X + 2 The mechanism for the acid cleavage of ethers is similar C 2 --C 2 + -X C 2 -X + C 2 - (X) 285 Autoxidation (please read) 14.7 omenclature of Epoxides a reactive cyclic ether oxirane oxetane oxolane oxane (epoxide) (furan) (pyran) a. The ether oxygen is treated as a substituent, and two numbers are given as designate its location; or b. xirane is used as the parent name 286 143
14.8 Preparation of Epoxides a. eaction of alkenes with a peroxyacid (Chapter 9.9) b. Base promoted ring closure of a vicinal halohydrin this is an intramolecular Williamson ether synthesis. 287 14.9 Enantioselective Epoxidation (please read) the previous are stereospecific but not enantiospecific, and give racemic products. Epoxidations useing a chiral catalysts can give epoxides in high enantiomeric excess. 14.10 ing-opening of Epoxides epoxides are more reactive than a typical ether do to the strain of the three-membered ring. Epoxides undergo ring-opening reaction with nucleophiles. + u: u then 2 u: = (hydroxide) (alkoxides) S (thiolates) C (cyanide) MgBr (Grignard reagents) (LA) 288 144
egio- and stereochemistry of epoxide opening Epoxides react with anionic nucleophiles (under basic conditions) through an S 2. The nucleophile adds to the less hindered (substituted) carbon of unsymmetrical epoxides and there is inversion of stereochemistry at the carbon undergoing substitution. 289 The regiochemistry of epoxide opening under acidic conditions is dependent on the substitution of the epoxide. ucleophiles will preferentially add to a tertiary carbon over primary of secondary under acidic conditions (S 1 like regiochemistry). The ring opening proceeds with inversion of stereochemistry. ucleophiles will preferentially add to a primary carbon over a secondary (S 2 like regiochemistry). 290 145
14.11 Thiols and Sulfides Thiols (mercaptans) are sulfur analogues of alcohols. Thiols have a pk a ~ 10 and are stronger acids than alcohols. S- + S + - (pk a ~10) (pk a ~15.7) S and S are weakly basic and strong nucleophiles. Thiolates react with 1 and 2 alkyl halides to yield sulfides (S 2). C 3 C 2 -S a, TF _ C 3 C 2 -S a + Br S 2 C 3 C 2 -S-C 2 C 2 C 2 C 3 _ S a + + TF Br-C 2 C 2 C 2 C 3 S 2 S-C 2 C 2 C 2 C 3 S a + + Ts TF S 291 xidation States of organosulfur compounds Thiols can be oxidized to disulfides 2 3 2 C 2 -S S glutathione thiols C 2 [] [] -2e -, -2 + +2e -, +2 + xidation of thiols to sulfonic acids S [] S [] 3 2 C -S-S- disulfide 2 C S S S [] C 2 C 2 3 2 S Thiol sulfenic acid sulfinic acid sulfonic acid xidation of thioethers S ' [] S ' [] +2 S ' Thioether Sulfoxide Sulfone 292 292 146
Bioactivation and detoxication of benzo[a]pyrene diol epoxide: P450 2 benzo[a]pyrene P450 2 DA DA 2 glutathione transferase G-S DA SG 3 2 C S C 2 Glutathione (G-S) 293 Sulfides (thioethers) sulfur analogs of ethers. eaction of a thiolate anions with 1 and 2 alkyl halides and tosylates (analogous to the Williamson ether synthesis) alcohol or -C 2 X -S + a water solvent -S - a + -S-C 2 pk a ~ 11 pk a ~ 16-18 Thiolates are more reactive nucleophiles and less basic than alkoxides 294 147
Alkylation of Sulfides to Sulfonium Salts The sulfur atom of sulfides is much more nucleophilic than the oxygen atom of ethers, and will react with alkyl halides to give stable sulfonium salts. S 3 C I 3 C C 3 dimethyl sulfide S C 3 3 C C 3 trimethyl sulfonium iodide I 2 C 3 C S 3 + 2 S-adenosylmethionine (SAM) 14.12 Synthesis Strategies Involving Epoxides Epoxide ring opening by a nucleophile installs two functional groups on adjacent positions ac then 2 or extend a carbon chain by 2 (or more) C Br Mg(0), TF MgBr then 2 295 148