1. Williamson Ether Synthesis9-6 Ethers are prepared by S N 2 reactions. Ethers can be prepared by the reaction of an alkoxide with a primary haloalkane or sulfonate ester under S N 2 conditions. The parent alcohol of the alkoxide can be used as the solvent, however other polar solvents are often better, such as DMSO (dimethyl sulfoxide) or HMPA (hexamethylphosphoric triamide). 34

2. Cyclic ethers: intramolecular Williamson synthesis. Haloalcohols serve as the starting point for the Williamson synthesis of cyclic ethers. The intramolecular reaction is usually much faster than the intermolecular reaction. If necessary, the intermolecular reaction can be suppressed by using a high dilution of the haloalcohol. Use of alkoxides in ether synthesis is limited to primary unhindered alkylating agents, otherwise E2 products are formed in major.

3. Cyclic ethers of even small rings can be prepared using the Williamson synthesis. 36

4. Ring size controls the speed of cyclic ether formation. The rate of ring closure is based on both enthalpic and entropic contributions. These rate differences can be explained based on the interplay between strain, entropy, and proximity. Entropy reduction (due to ring closure) increases with increasing ring size. (Reaction rate decrease with increasing ring size.) Ring strain decreases with increasing ring size. (Reaction rate increase with increasing ring size.) Transition-state strain is reduced in the 2-haloalkoxides because the 2-haloalkoxide is already strained by the proximity of the halide and hydroxyl. (Reaction rate increase for the 2-haloalkoxides.)

5. The intramolecular Williamson synthesis is stereospecific Since the Williamson synthesis is a S N 2 substitution reaction, an inversion of configuration occurs at the carbon bearing the leaving group. The leaving group must be on the opposite side of the molecule from the attacking nucleophile in order for the reaction to occur. 38

6. Synthesis of Ethers: Alcohols and Mineral Acid9-7 Alcohols give ethers by both S N 2 and S N 1 mechanisms. Strong nucleophilic acids (HBr, HI) yield haloalkanes when reacted with alcohols. Strong non-nucleophilic acids yields ethers when reacted with alcohols.

7. At higher temperatures, an E2 elimination of water occurs with the subsequent production of alkenes. Secondary / tertiary alcohols form ethers via an S N 1 reaction with a second molecule of the alcohol trapping the carbocation. The E1 pathway becomes dominate at higher temperatures. 40

8. Mixed ethers containing one tertiary and one primary or secondary alcohol can be prepared in the presence of dilute acid. The tertiary carbocation is trapped by the less hindered alcohol. Ethers also form by alcoholysis This occurs by simply dissolving a tertiary or secondary haloalkane in an alcohol and waiting until the S N 1 process is complete.

9. Reactions of Ethers9-8 Ethers are usually inert, however, they do react slowly with oxygen to form hydroperoxides and peroxides which can decompose explosively. 42

10. The ether oxygen atom can be protonated to generate alkyloxonium ions. With primary groups and strong nucleophilic acids (HBr), S N 2 displacement takes place.

11. Oxonium ions from secondary ethers may transform by either S N 2 or S N 1 reactions, depending upon conditions. 44

12. Tertiary ethers are protecting groups for alcohols. Esters containing tertiary alkyl groups react in dilute acid to give carbocations which are either trapped (S N 1) by good nucleophiles or deprotonated in the absence of good nucleophiles. Because they are readily formed (and equally readily hydrolyzed), tertiary ethers are commonly used as protecting groups during chemical reactions which might otherwise interact with the unprotected alcohol.

13. Reactions of Oxacyclopropanes9-9 Nucleophilic ring opening of oxacyclopropanes by S N 2 is regioselective and stereospecific. Oxacyclopropane can be ring-opened by anionic nucleophiles. Because the molecule is symmetric, nucleophilic attack can be at either carbon atom. The driving force for this reaction is the release of ring strain. 46

14. With unsymmetric epoxides, attack is at the less substituted carbon center. This selectivity is referred to as “regioselectivity” If the ring opens at a stereocenter, inversion is observed.

15. Hydride and organometallic reagents convert strained ethers into alcohols. LiAlH 4 can open the rings of oxacyclopropanes to yield alcohols. (Ordinary ethers do not react) Asymmetrical systems: hydride attacks less substituted side. 48

16. If the reacting carbon is a stereocenter, inversion is observed. Oxacyclopropanes are sufficiently reactive electrophiles to be attacked by organometallic compounds.

17. Acids catalyze oxacyclopropane ring opening. Ring opening of oxacyclopropane by acid catalysis proceeds through an initial cyclic alkyloxonium ion. This acid catalyzed ring opening is both regioselective and stereospecific. 50

18. The acid catalyzed methanolysis of 2,2-dimethyloxacyclopropane is ring-opened at the more hindered carbon.

19. In the alkyloxonium ion, more positive charge is located on the tertiary carbon than on the primary carbon. This effect counteracts the effect of steric hindrance and the alcohol attacks the tertiary carbon. Because inversion of configuration occurs during ring opening, free carbocations cannot be involved in the reaction mechanism. 52

20. Sulfur Analogs of Alcohols and Ethers9-10 Sulfur analogs of alcohols and ethers: thiols and sulfides. The IUPAC system calls the sulfur analogs of alcohols, R-SH, “thiols.” The –SH group in more complicated compounds is referred to as “mercapto”

21. The sulfur analogs of ethers are called “sulfides” (common name, thioethers). The RS group is called “alkylthio” and the RS - group is called “alkanethiolate” 54

22. Thiols are less H-bonded and more acidic than alcohols The boiling points of thiols are similar to those of the analogous haloalkanes. Compared to oxygen, sulfur has a large size, diffuse orbitals and a relatively nonpolarized S-H bond. Thiols are more acidic than water and can therefore be easily deprotonated by hydroxide and alkoxide ions:

23. Thiols and sulfides react much like alcohols and ethers The sulfur in thiols and sulfides is more nucleophilic than the oxygen in the analogous compounds. Thiols and sulfides are readily made through nucleophilic attack by RS - or HS - on haloalkanes: A large excess of HS - is used to prevent the reaction of the product with the starting halide. 56

24. Sulfides are prepared by the alkylation of thiols in the presence of a base, such as hydroxide. The nucleophilicity of the generated thiolates is much greater than that of hydroxide which eliminates the competing S N 2 substitution by hydroxide ion.

25. Sulfides can attack haloalkanes to form sulfonium ions. Sulfonium ions are subject to nucleophilic attack, the leaving group being a sulfide. 58

26. Valence-shell expansion of sulfur accounts for the special reactivity of thiols and sulfides. Sulfur can expand its valence shell from 8 to 10 or 12 electrons using its available 3d orbitals, allowing oxidation states not available to its oxygen analogs. Oxidation of thiols with strong oxidizing agents (H 2 O 2, KMnO 4 ) gives the corresponding sulfonic acids:

27. Milder oxidizing agents (I 2 ) yield disulfides. These can be reduced back to thiols by alkali metals. Reversible disulfide formation is important in stabilizing the folding of biological enzymes: 60

28. Sulfides can also be oxidized to sulfoxides and then sulfones:

29. Physiological Properties and Uses of Alcohols and Ethers 9-11 Methanol: Formed by catalytic reduction of CO and H 2 at high temperatures and pressure. Used as a solvent, a fuel for camp stoves and soldering torches, and as a synthetic intermediate. Highly poisonous. May lead to blindness or death. A possible precursor of gasoline. 62

30. Ethanol: Alcohol in alcoholic beverages General depressant High in calories, little nutritional value Metabolically degraded linearly with time Poisonous (lethal concentration ~ 0.4%) Near toxic dose used to treat methanol poisoning Produced by fermentation of sugars and starch Commercially produced by the hydration of ethylene. Used as a solvent, a synthetic intermediate, and as a gasoline additive (gasahol)

31. 2-Propanol: Toxic, but not absorbed through the skin Used as a rubbing alcohol, a solvent, and as a cleaning agent 64 1,2-Ethanediol (ethylene glycol): Used as an antifreeze (completely miscible with water) Produced from ethene:

32. 1,2,3-Propanetriol (glycerol, glycerine): Non-toxic Major component of fatty tissue Liberated by the action of alkali on fats to form soaps: Phosphoric esters of glycerols are major cell membrane components. Used in lotions, cosmetics, and medicinal preparations.

33. Forms nitroglycerine upon treatment with nitric acid. Cholesterol: An important steroid alcohol Ethoxyethane (diethyl ether): Formally used as an anesthetic Explosive when mixed with air 66

34. Oxacyclopropane (oxirane, ethylene oxide) Industrial chemical intermediate Fumigating agent for seeds and grains Oxacyclopropane derivatives control insect metamorphosis and are formed during enzyme-catalyzed oxidations of aromatic hydrocarbons (highly carcinogenic). Alcohol and ether groups are found in natural products such as morphine and tetrahydrocannabinol:

35. Lower MW thiols and sulfides are notorious for their foul smells. The odor of the skunk’s defensive spray are thiols and a sulfide: When highly diluted, thiols and sulfides have a pleasant odor: freshly chopped onion or garlic, black tea, grapefruit. The compound responsible for the taste of grapefruit can be tasted in concentrations in the ppb range: 68

36. Drugs such as the sulfonamides (sulfa drugs) contain sulfur in their molecular framework:

37. Important Concepts9 1.Reactivity of ROH With Alkali Metals – R = CH 3 > primary > secondary > tertiary 2.Reactions with Acid and a Nucleophilic Counterion – Primary Alcohols – S N 2 reactions Secondary and Tertiary Alcohols – Form carbocations capable of E1 and S N 1 reactions, before and after rearrangement 3.Carbocation Rearrangements – Hydride and alkyl group shifts Result in interconversion of secondary carbocations or conversion of secondary to tertiary carbocation Primary alkyloxonium can rearrange to secondary or tertiary carbocations

38. Important Concepts9 4.Haloalkane Synthesis – Methods using inorganic esters yield primary and secondary haloalkanes with less chance of rearrangement. 5.Ether Preparation – Williamson ether synthesis – Best when S N 2 reactivity is high Reaction of alcohols with strong non-nucleophilic acids – elimination completes at higher temperatures 6.Crown Ethers and Cryptands – Examples of ionophores which solubilize metal ions in hydrophobic media.

39. Important Concepts9 7.Ring Opening of Oxacyclopropanes – Nucleophilic attack at the less substituted ring carbon Acid-catalyzed attack favors the more substituted ring carbon 8.Sulfur – More diffuse orbitals than oxygen The thiol S-H bond is less polarized than the O-H bond in alcohols (less hydrogen bonding) Acidity of S-H is greater than O-H