Other Acid Derivatives

Mucic acid reacted with triethyl phosphite to give the bis(cyclic phosphite) 

---

Acid derivatives are made directly from acids or by conversion from other acid derivatives depending on their stabihty. The most important are esters (RCOiEt), amides (RCO2NR2), anhydrides (RCOO COR) and add clilorides (RCOCI). Arrange these in an order of stabilily, the most reactive at the top of the list, the most stable at the bottom. 

Reaction between acyl halides and organometallic compounds 10-115 Reaction between other acid derivatives and organometallic compounds... 

For conversion of amide to other acid derivatives, a novel synthesis of urea glycosides in aqueous media has been reported via the reaction of Steyermark s glucosyl carbamate with amines in good yields (Eq. 9.17).38 This method was successfully applied to develop a new route to the synthesis of urea-tethered neo-glycoconjugates and pseudooligosaccharides. 

The common methods of esterification utilize an acid chloride or an acid anhydride as the reagent, but other acid derivatives often show different selectivities, and these are also considered here. In view of the extensive articles on sulfonic esters of carbohydrates,2 4... 

II c., Cl 0 M L- X c Reaction of acyl halides or other acid derivatives with organometallic compounds... 

Parent ions of esters resemble those of other acid derivatives and carboxylic acids in that they cleave into an acylium ion. 

One can also compare faces of a molecule in the same way as groups, since the comparison actually applies to environments. Thus, the two faces of the carbonyl groups of aldehydes, unsymmetrical ketones, esters, and other acid derivatives are enantiotopic. Reaction at the two faces by a chiral nucleophile will take place at different rates, resulting in asymmetric induction. 

Reaction of halo ketones or diazo ketones with boranes 0-102 Carbonylation of alkyl halides 0-104 Reaction between acyl halides and organometallic compounds 0-105 Reaction between other acid derivatives and organometallic compounds... 

Enzymatic Hydrolysis Reactions of Esters. Xenobiotic compounds containing esters or other acid derivatives in their structures (e.g., amides, carbamates, ureas, etc., see Table 17.3) are often readily hydrolyzed by microorganisms. To understand how enzymatic steps can be used to transform these substances, it is instructive to consider the hydrolases (i.e., enzymes that catalyze hydrolysis reactions) used by organisms to split naturally occurring analogs (e.g., fatty acid esters in lipids or amides in proteins). The same chemical processes, and possibly even some of the same enzymes themselves, are involved in the hydrolysis of xenobiotic substrates. 

Lithium aluminum hydride usually reduces carbonyl groups without affecting carbon-carbon double bonds. It is, in addition, a good reducing agent for carbonyl groups of carboxylic acids, esters, and other acid derivatives, as will be described in Chapter 18. 

Amides can be prepared from ammonia and other acid derivatives. They can also be prepared by heating ammonium salts. They are named by replacing the -ic or -oic acid ending with amide. 

Acid chlorides can be converted to acid anhydrides, esters, or amides. These reactions are possible because acid chlorides are the most reactive of the four carboxylic acid derivatives. Nucleophilic substitutions of the other acid derivatives are more limited because they are less reactive. For example, acid anhydrides can be used to synthesise esters and amides, but cannot be used to synthesise acid chlorides. 

The possible nucleophilic reactions for each carboxylic acid derivative depends on its reactivity with respect to the other acid derivatives (Following fig.). Reactive acid derivatives can be converted to less reactive (more stable) acid derivatives, but not the other way round. For example, an ester can be converted to an amide, but not to an acid anhydride. 

Amides differ from carboxylic acids and other acid derivatives in their reaction with Li A1H4 Instead of forming primary alcohols, amides are reduced to amines (Fig.P). The mechanism (Fig.Q) involves addition of the hydride ion to form an intermediate that is converted to an organoaluminium intermediate. The difference in this mechanism is the intervention of the nitrogen s lone pair of electrons. These are fed into the electrophilic centre to eliminate the oxygen that is then followed by the second hydride addition. 

Carboxylic acids commonly are used as the starting materials for the preparation of the other acid derivatives. However, any of the acid derivatives can be hydrolyzed to the carboxylic acid by reaction with water under the appropriate conditions. Acid or base catalysis is necessary for the less reactive derivatives. 

Lithium aluminum hydride (LiAlH4, abbreviated LAH) is a much stronger reagent than sodium borohydride. It easily reduces ketones and aldehydes and also the less-reactive carbonyl groups those in acids, esters, and other acid derivatives (see Chapter 21). LAH reduces ketones to secondary alcohols, and it reduces aldehydes, acids, and esters to primary alcohols. The lithium salt of the alkoxide ion is initially formed, then the (cautious ) addition of dilute acid protonates the alkoxide. For example, LAH reduces both functional groups of the keto ester in the previous example. 

Acid chlorides are the most reactive acid derivatives, so they are easily converted to any of the other acid derivatives. Acid chlorides are often used to synthesize anhydrides, esters, and amides. Acid chlorides react with carboxylic acids (or their carboxylate salts) to form anhydrides. Either oxygen atom of the acid can attack the strongly electrophilic carbonyl group of the acid chloride to form a tetrahedral intermediate. Loss of chloride ion and a proton gives the anhydride. 

Lithium aluminum hydride reduces acids, acid chlorides, anhydrides, and esters to primary alcohols. (The reduction of acids was covered in Section 20-13.) Acid chlorides are more reactive than the other acid derivatives. Either lithium aluminum hydride or sodium borohydride converts acid chlorides to primary alcohols. 

Acid chlorides are more reactive than other acid derivatives, and they are reduced to aldehydes by mild reducing agents such as lithium tri-ferf-butoxyaluminum hydride. Diisobutylaluminum hydride (DIBAL-H) reduces esters to aldehydes at low temperatures, and it also reduces nitriles to aldehydes. These reductions were covered in Sections 18-9,18-10, and 20-13. 

Reactions of Acid Chlorides Acid chlorides react quickly with water and other nucleophiles and are therefore not found in nature. Because they are the most reactive acid derivatives, acid chlorides are easily converted to other acid derivatives. Often, the best synthetic route to an ester, anhydride, or amide may involve using the acyl chloride as an intermediate. 

Show how acid derivatives are easily interconverted by nucleophilic acyl substitution from more reactive derivatives to less reactive derivatives under acidic or basic conditions. Show how acid chlorides serve as activated intermediates to convert acids to other acid derivatives. 

Carboxylic acids and esters (and other acid derivatives) are generally inert to Sm. However, in strongly basic or acidic conditions, reduction occurs Carboxylic acids and amides are reduced to primary alcohols (amides afford some amine as secondary... 

Several other transannular lactonizations and reductions have been reported to proceed in high overall yields. Also other acid derivatives, such as amides and esters, cyclize to form lactones. Alkynoic acids have been lactonized to y-alkylidene-y-lactones in good yield, e.g. the conversion of (31) to (32 equation 29). Unfortunately the vinyl selenide product can isomerize from ( ) to (Z) in a secondary process. Analogous lactam formation is also known. Unsaturated amides, when cyclized with benzenese-lenenyl halides, produce good yields of lactams or iminolactones depending upon the alkene utilized. The amide (33) cyclizes to the iminolactone (34), producing a mixture of stereoisomers (65 35 Scheme 5). The amide (35) is cyclized to lactam (36) in moderate yield. 

The acid-catalyzed hydrolysis continues to be used as a highly satisfactory method for the synthesis of quinaldic acids. The reaction of Reissert compound (7) with hydrobromic acid in acetic acid gave near quantitative yields of quinaldic acid hydrobromide with no contamination from other acid derivatives and would appear to be the method of choice for this conversion. This method has subsequently been used to produce high yields of benzo(/)quinoline-3-carboxylic acid and phthalazine-1-carboxylic acid. ... 

Esters, Acid Chlorides, Acid Amides.—Just as oxalic acid, because of its di-basic character, forms two series of salts, it also forms two series of the other acid derivatives, viz., estersy acid chlorides and acid amides. 

Enolate anions are an important class of carbanions that appear in a variety of important reactions, including alkylation a- to a carbonyl group and the aldol (reaction 16-34) and Claisen condensation (reaction 16-85) reactions. Metal enolate anions of aldehydes, ketones, esters, and other acid derivatives exist as aggregates in ether solvents, and there is evidence that the hthium enolate of... 

In the presence of a strong base, the a carbon of a carboxylic ester or other acid derivative can condense with the carbonyl carbon of an aldehyde or ketone to give a p-hydroxy ester, ° amide, and so on., which may or may not be dehydrated to the a,p-unsaturated derivative. This reaction is sometimes called the Claisen reaction an rmfortunate usage since that name is more firmly connected to 16-85. Early reactions used hydroxide or an alkoxide base in water or alcohol solvents, where self-condensation was the major process. Under such conditions, the aldehyde or ketone was usually chosen for its lack of an a-proton. Much better control of the reaction was achieved when amide bases in aprotic solvents, such as ether or THE, were used. The reaction of tert-butyl acetate and in hexane... 

Acylation of Amines by Other Acid Derivatives Acylamino-de-halogenation or dealkoxiaton... 

For a review, see Tsuji, J. Ohno, K. Synthesis 1969, 157. For extensions to certain other acid derivatives, see Minami, L Nisar, M. Yuhara, M. Shimizu, 1. Tsuji, J. Synthesis 1987, 992. 

Like other acid derivatives, acid chlorides typically undergo nucleophilic substitution. Chlorine is expelled as chloride ion or hydrogen chloride, and its place is taken by some other basic group. Because of the carbonyl group these reactions take place much more rapidly than the corresponding nucleophilic substitution reactions of the alkyl halides. Acid chlorides are the most reactive of the derivatives of carboxylic acids. 

Addition of sulfides and sulfones to acid derivatives has been investigated by Agawa. Phenyl and methyl (trimethylsilyl)methyl sulfides and sulfones added to amides (323) to produce the aminovinyl sulfides (324 equation 74) and sulfone (326 equation 7S). The reactions proceeded in good yield with some examples of stereocontrolled synthesis of the ( )-isomer. Other acid derivatives such as esters, carbonates and ureas were investigated, but gave inconsistent results. 

---