This chapter illustrates the formation of silyl ethers. It gives attention to the trimethylsilyl group which has been used extensively for the protection of alcohols. One of the many methods which have been used for protecting a hydroxy group as its trimethylsilyl ether involves adding trimethylsilyl chloride (trimethylchlorosilane, TMCS) to the alcohol in the presence of a weak base. The chapter then argues that silyl ethers are cleaved to their parent alcohols by nucleophiles (often alcohols) under a range of acidic or basic conditions. Finally, the chapter shows some examples of protection of hydroxy groups as silyl ethers emphasizing the synthesis of (R)-isoproterenol and the synthesis of gephyrotoxin.
Chapter
Protection of hydroxy groups as silyl ethers
Chapter
Reactions of Alcohols, Ethers, Thiols, Sulfides, and Amines
This chapter examines the principal methods of preparation of alcohols. It emphasizes that the characteristic properties of alcohols originate in the hydroxy group. Protonation of the O in alcohols and ethers converts poor leaving groups, HO− and RO−, into good ones, H2O and ROH. The chapter then reveals that this enhancement of reactivity by protonation is another example of acid catalysis. The chapter also covers other examples such as acid-catalysed nucleophilic substitution and elimination reactions. In these reactions, R–OH2+ and R–O(H)R+ are comparable with haloalkanes. The chapter also explores the ring-opening reactions of epoxides (oxiranes). It then shifts to discuss the reactions of the sulfur analogues of alcohols (thiols, RSH) and of ethers (sulfides, RSR'), which may be regarded as derivatives of hydrogen sulfide, H2S. It concludes by explaining the reactions of amines.
Chapter
Using organometallic reagents to make C–C bonds
This chapter addresses one of the most important ways of making carbon–carbon (C–C) bonds: using organometallics, such as organolithiums and Grignard reagents, in combination with carbonyl compounds. Carbon dioxide reacts with organolithiums and Grignard reagents to give carboxylate salts. Protonating the salt with acid gives a carboxylic acid with one more carbon atom than the starting organometallic. Meanwhile, aldehydes and ketones react with organometallic reagents to form secondary and tertiary alcohols, respectively. The chapter then looks at the oxidation of alcohols. Oxidation of primary alcohols gives aldehydes and then carboxylic acids, while oxidation of secondary alcohols gives ketones. It is important to note that we cannot oxidize tertiary alcohols without breaking a C–C bond.
Chapter
Acetals and ketals
This chapter examines acetals and ketals. Aldehydes and ketones react reversibly 1:1 with alcohols under general acid or general base catalysis, to give hemiacetals and hemiketals, respectively. With excess alcohol and a catalytic amount of a strong acid, further reversible reaction takes place to replace the OH group and give an acetal (from an aldehyde) or ketal (from a ketone). If arrangements are made to remove the water from the continuously equilibrating mixture, by distillation or other means, then the aldehyde or ketone is quantitatively converted to an acetal or ketal, as the case may be. The reaction proceeds more easily with aldehydes than with ketones, and is practically limited to primary alcohols. The chapter then looks at dithioacetals, dithioketals, and orthoesters. It also considers the protecting group principle.
Chapter
Silyl protecting groups
This chapter evaluates silyl protecting groups. To categorise silicon protecting groups as either acid or base-labile is impractical because both types of cleavage are possible and find routine use. Organosilicon chemistry is characterised by a high affinity for oxygen, which has led to the widespread use of silyl ethers for the protection of alcohols, and higher affinity for fluorine, which provides a very selective deprotection pathway. The chapter then looks at alcohols, diols, aldehydes and ketones, and amines. Deprotection of silyl protecting groups with F-ion is normally highly selective but the basic properties of the hydrated ion in solution can interfere with functionality not containing silicon and can lead to unexpected reactions.
Chapter
Alcohols
This chapter focuses on alcohols (ROH) which have at least one hydroxyl group bonded to a carbon atom. Alcohols are known to undergo two reactions similar to the reactions of halogenoalkanes. Additionally, esters are formed through an alcohol's reaction to carboxylic acids. Alcohols also undergo oxidation reactions. The chapter explores the main manufacturing processes for ethanol which are fermentation and the direct hydration of ethene. It also considers the nucleophilic substitution and oxidation reactions of alcohols. The elimination reactions coincide with alcohol being dehydrated through heating with acid. However, conditions depend on the specific alcohol involved in the process as some of the alcohols could produce more than a single product.
Chapter
Aldehydes and Ketones
This chapter describes aldehydes and ketones. Aldehydes have one alkyl group and one hydrogen atom attached to the carbonyl carbon. Ketones have two alkyl groups and resist oxidation. Both aldehydes and ketones contain the carbonyl group which has a carbon atom doubly bonded to an oxygen atom. Fehling's solution and Tollens' reagent can also help determine the differences between aldehydes and ketones. Oxidation can also help the reduction of aldehydes and ketones to primary and secondary alcohols respectively. The chapter also explains nucleophilic addition, condensation reactions, and alpha carbon reaction of aldehydes and ketones.
Chapter
Suggested solutions for Chapter 9
This chapter provides solutions to the problems posed in Chapter 9 of Clayden, Greeves & Warren Organic Chemistry, second edition, on using organometallic reagents to make C−C bonds.
