Carboxylic derivs., reactions base hydrolysis

Carboxylic derivs., reaction, 230-244 acid hydrolysis, 240, base hydrolysis, 238 electronic effects in, 237 Grignard reagents, 238... 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

The S5mthetic approach of in situ activation of carboxylic acids is based on the preliminary reaction of the carboxylic acid with a specific reagent to give an intermediate reactive daivative which can be prepared prior to the reaction with cellulose or converted directly in a one-pot process. This approach opens the way to a broad variety of new esters, because for numwous acids, for example unsaturated or hydrolytically unstable ones, reactive derivatives such as anhydrides or chlorides simply cannot he synthesized. The mild reaction conditions apphed for the in situ activation prevent common side reactions hke pericychc reactions, hydrolysis, and oxidation. Moreover, due to their hydrophobic charactCT, numa-ous anhydrides are not soluble in organic media used for cellulose modification, resulting in unsatisfactory yields and insoluble products. In addition, the conversion of an anhydride is combined with the loss of half of the acid during the reaction. Consequently, in situ activation is much more efficient. 

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

All acid derivatives react with water in the presence of an acid catalyst to generate the parent carboxylic acid used to prepare that derivative. In other words, the product is the carboxylic acid used to generate the acid derivative. This reaction is known as acid hydrolysis. The reaction of an acid derivative with aqueous hydroxide also generates the parent carboxylic acid, but the basic conditions convert the acid to its carboxylate salt, as described before. Therefore, a second reaction with aqueous acid is required to convert the carboxylate salt to the carboxylic acid. This reaction is known as base hydrolysis. Both reactions are discussed in this section. 

This section discussed the acid and base hydrolysis of the derivatives of carboxylic acids. The mechanisms for all of these reactions are essentially identical, with the only real mechanistic difference being the leaving group. There is an order of reactivity for acid derivatives ... 

Sulfonyl diisocyanates, such as m-phenylenedisulfonyl diisocyanate, are used as monomers for base-soluble polymers (15). 4-Isocyanatobenzenesulfonyl isocyanate can also be used as a monomer for base-soluble polymers. Reaction of p-toluenesulfonyl isocyanate with polymers having amide units in the backbone structure affords sulfonyl urea derivatives, which on hydrolysis with 1 N NaOH degrade the polymer to carboxylic acids (16). Likewise, polymerization of the monomer derived from acrylamide and p-toluenesulfonyl isocyanate affords a homopolymer, which on hydrolysis with 1 N NaOH affords polyCacrylic acid) (17). 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

Amides are the least reactive carboxylic acid derivative, and the only nucleophilic acyl substitution reaction they undergo is hydrolysis. Amides are fairly stable in water, but the amide bond is cleaved on heating in the presence of strong acids or bases. Nominally, this cleavage produces an amine and a car boxylic acid. 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

As far as propargyl thioethers are concerned, the substrates in this section follow all the principles discussed for propargyl ethers and propargylamines in the two preceding sections. For alkyl propargyl thioethers typical bases used are sodium amide in liquid ammonia, alcoholate or alkali metal hydroxide [178, 186-189, 191, 287-291], and again some derivatives of carbohydrates have been used successfully [292, 293], If an ester group is also present in the molecule, the reaction can be accompanied by a hydrolysis to the carboxylate [294]. 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

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