Basicity carboxylic acid derivatives

Acidic and basic hydrolysis of ethyl 4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-carboxylates gave 3-carboxylic acid derivatives (OlMIPl). Stirring rerr-butyl ( )-3-(2-hydroxy-8-[2-(4-isopropyl-l, 3-thiazol-2-yl)-l-ethenyl]-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenoate in CF3CO2H at room temperature yielded ( )-3-substituted 2-propenoic acid. 

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. 

This is a consequence of delocalization, with resonance stabilization being possible when the carbonyl oxygen is protonated, but not possible should the OR oxygen become protonated. This additional resonance stabilization is not pertinent to aldehydes and ketones, which are thus less basic than the carboxylic acid derivatives. However, these oxygen derivatives are still very weak bases, and are only protonated in the presence of strong acids. 

Dihalogenocycloproparenes, particularly the chloro-derivatives such as 22, are sol volyzed very readily with ring-opening to carboxylic acid derivatives. Under acidic conditions, esters or carboxylic acids 342 are produced, while basic condi-... 

Carboxylic acid derivatives are compounds that possess an acyl group (R—C=0) linked to an electronegative atom, e.g. —Cl, —CO2 R, —OR or —NH2. They can be converted to carboxylic acids via simple acidic or basic hydrolysis. The important acid derivatives are acid chlorides, acid anhydrides, esters and amides. Usually nitriles are also considered as carboxylic acid derivatives. Although nitriles are not directly carboxylic acid derivatives, they are conveniently hydrolysed to carboxylic acids by acid or base catalysts. Moreover, nitriles can be easily prepared through dehydration of amides, which are carboxylic acid derivatives. 

The reactivity of carboxyhc acid derivatives depends on the basicity of the substituent attached to the acyl group. Therefore, the less basic the substituent, the more reactive is the derivative. In other words, strong bases make poor leaving groups. Carboxylic acid derivatives undergo a variety of reactions under both acidic and basic conditions, and almost aU involve the nucleophilic acyl substitution mechanism (see Section 5.5.5). 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

Amides, azides and nitriles are reduced to amines by catalytic hydrogenation (H2/Pd—C or H2/Pt—C) as well as metal hydride reduction (LiAlH4). They are less reactive towards the metal hydride reduction, and cannot be reduced by NaBITj. Unlike the LiAlIU reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlIU reduction of amides, azides and nitriles yields amines. Acid is not used in the work-up step, since amines are basic. Thus, hydrolytic work-up is employed to afford amines. When the nitrile group is reduced, an NH2 and an extra CH2 are introduced into the molecule. 

The standard notation for successive acid dissociation constants of a polyprotic acid is Kt, K2, K2, and so on, with the subscript a usually omitted. We retain or omit the subscript as dictated by clarity. For successive base hydrolysis constants, we retain the subscript b. The preceding examples illustrate that Kal (or K ) refers to the acidic species with the most protons, and Kbl refers to the basic species with the least number of protons. Carbonic acid, a very important diprotic carboxylic acid derived from COz, is described in Box 6-4. 

Ketenimines are usually prepared from carboxylic acid derivatives such as amides and imino chlorides via elimination and from nitriles via alkylation with alkyl halides under strong basic conditions (21,64). 

All carboxylic acid derivatives hydrolyze to give the carboxylic add. Typically, hydrolysis can occur under either acidic or basic conditions. 

Simultaneous treatment of a carbonyl compound with a Lewis acid and a tertiary amine or another weak base ( soft enolization ) can sometimes be used to generate enolates of sensitive substrates which would have decomposed under strongly basic reaction conditions [434]. Boron enolates, which readily react with aldehydes at low temperatures, can also be prepared in situ from sensitive, base-labile ketones or carboxylic acid derivatives [293, 295, 299]. Unwanted decomposition of a carbanion may also be prevented by generating it in the presence of an electrophile which will not react with the base (e.g. silyl halides or silyl cyanides [435]). 

Figure 6.2 shows the standard mechanism of substitution reactions carried out on carboxylic acid derivatives in neutral or basic solutions. The tetrahedral intermediate—formed in the rate-determining step—can be converted to the substitution product via two different routes. The shorter route consists of a single step the leaving group X is eliminated with a rate constant Ad. In this way the substitution product is formed in a total of two steps. The longer route to the same substitution product is realized when the tetrahedral intermediate is proto-nated. To what extent this occurs depends, according to Equation 6.1, on the pH value and on the equilibrium constant Kcq defined in the middle of Figure 6.2 ...

Equation 6.4 shows the following in strongly basic solutions, SN products can be produced from carboxylic acid derivatives in two steps. An example of such a reaction is the saponification PhC(=0)0Et + KOH —> PhC(=0)0 K + EtOH. However, in approximately neutral solutions the four-step path to the SN product should predominate. An example of this type of reaction is the amino lysis PhC(=0)0Et + HNMe2 —> PhC(=0)NMe2 + EtOH. 

For this mechanism to occur for an aldehyde or ketone, hydride ion or a carbanion would have to act as the leaving group. These species are much too basic to leave under normal circumstances. In the case of carboxylic acid derivatives the leaving group is one of the following less basic species ... 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts 1n group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2 6 a-hydroxycarboxylic acid esters,7 and even very acid labile... 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

Acid derivatives differ in the nature of the nucleophile bonded to the acyl carbon —OH in the acid, —Cl in the acid chloride, —OR in the ester, and —NH2 (or an amine) in the amide. Nucleophilic acyl substitution is the most common method for interconverting these derivatives. We will see many examples of nucleophilic acyl substitution in this chapter and in Chapter 21 ( Carboxylic Acid Derivatives ). The specific mechanisms depend on the reagents and conditions, but we can group them generally according to whether they take place under acidic or basic conditions. 

Heating of 7-nitro-l,2,4-benzoxadiazine-3-carboxylic acid or basic hydrolysis of its ethyl ester results in 2-amino-6-nitrobenzoxazole [495, 496]. Earlier this compound was wrongly ascribed the structure of 7-nitro-l,2,4-benzoxadiazine [497], Nitrated 2-aminobenzoxazoles are obtained in good yield in the reaction of o/t/zo-aminophenols with cyanogen bromide [498-500] or with S-methylisothiourea derivatives (Scheme 2.77) [501],... 

A15.1.2.3 Nitriles. Nitriles are classihed as carboxylic acid derivatives because they are converted to carboxylic acids on hydrolysis. Like the hydrolysis of amides, nitrile hydrolysis is irreversible in the presence of acids or bases. Acid hydrolysis yields an ammonium ion and a carboxylic acid, e.g., cimeti-dine [15]. Nitriles are also susceptible to oxidation by peroxides under mildly basic conditions (e.g., pH 7.5 to 8). 

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