Summary

In previous chapters, we focused on developing general ideas of organic reactivity, looking at the chemistry of hydrocarbons and alkyl halides and seeing some of the tools used in structural studies. With that accomplished, we have now begun to study the oxygen-containing functional groups that lie at the heart of organic and biological chemistry.

Alcohols are among the most versatile of all organic compounds. They occur widely in nature, are important industrially, and have an unusually rich chemistry. The most widely used methods of alcohol synthesis start with carbonyl compounds. Aldehydes, esters, and carboxylic acids are reduced by reaction with LiAlH₄ to give primary alcohols (RCH₂OH); ketones are reduced to yield secondary alcohols (R₂CHOH).

Alcohols are also prepared by reaction of carbonyl compounds with Grignard reagents, RMgX. Addition of a Grignard reagent to formaldehyde yields a primary alcohol, addition to an aldehyde yields a secondary alcohol, and addition to a ketone or an ester yields a tertiary alcohol. The Grignard reaction is limited by the fact that Grignard reagents can’t be prepared from alkyl halides that contain reactive functional groups in the same molecule. This problem can sometimes be avoided by protecting the interfering functional group.

Alcohols undergo many reactions and can be converted into many other functional groups. They can  be transformed into alkyl halides by treatment with PBr₃ or SOCl₂. Furthermore, alcohols are weakly acidic (pK_a ≈ 16–18) and react with strong bases and with alkali metals to form alkoxide anions, which are used frequently in organic synthesis. Perhaps the most important reaction of alcohols is their oxidation to carbonyl compounds. Primary alcohols yield either aldehydes or carboxylic acids, secondary alcohols yield ketones, but tertiary alcohols are not normally oxidized.

Phenols are aromatic counterparts of alcohols but are more acidic (pK_a ≈ 10) because their corresponding phenoxide anions are resonance stabilized by delocalization of the negative charge into the aromatic ring. Substitution of the aromatic ring by an electron-withdrawing group increases phenol acidity, and substitution by an electron-donating group decreases acidity.

Figure 9.15 The phenol resveratrol, found in the skin of red grapes, continues to be studied for its potential anti-cancer, antiarthritic, and hypoglycemic properties. (credit: modification of work “Weinreben-Ötlingen” by Pierre Likissas/Wikimedia Commons, CC BY 3.0)

This chapter has finished the coverage of functional groups with C–O and C–S single bonds, including ethers, epoxides, thiols, and sulfides. Ethers are compounds that have two organic groups bonded to the same oxygen atom, ROR′. The organic groups can be alkyl, vinylic, or aryl, and the oxygen atom can be in a ring or in an open chain. Ethers are prepared by either Williamson ether synthesis, which involves S_N2 reaction of an alkoxide ion with a primary alkyl halide.

Ethers are inert to most reagents but react with strong acids to give cleavage products. Both HI and HBr are often used. The cleavage reaction takes place by an S_N2 mechanism at the less highly substituted site if only primary and secondary alkyl groups are bonded to the ether oxygen, but by an S_N1 or E1 mechanism if one of the alkyl groups bonded to oxygen is tertiary.

Epoxides are cyclic ethers with a three-membered, oxygen-containing ring. Because of the strain in the ring, epoxides undergo a cleavage reaction with both acids and bases. Base-catalyzed epoxide ring-opening occurs by S_N2 reaction of a nucleophile at the less hindered epoxide carbon.

Thiols, the sulfur analogs of alcohols, are usually prepared by S_N2 reaction of an alkyl halide with thiourea or via an S_N2 reaction with a hydrogensulfide ion (HS^–). Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide returns the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an S_N2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are more nucleophilic than ethers and can be alkylated by reaction with a primary alkyl halide to yield a sulfonium ion.