Substitution reactions carboxylic acids

This hydrolysis reaction can V I be considered the reverse of the carbonyl substitution reaction carboxylic acid + alcohol —> ester + water. 

At the present time, most of the positive photoresists used in the manufacture of microcircuits consist of a low molecular weight phenolic resin and a photoactive dissolution inhibitor. This composite system is not readily soluble in aqueous base but becomes so upon irradiation with ultraviolet light. When this resist is exposed, the dissolution inhibitor, a diazoketone, undergoes a Wolff rearrangement followed by reaction with ambient water to produce a substituted indene carboxylic acid. This photoinduced transformation of the photoactive compound from a hydrophobic molecule to a hydrophillic carboxylic acid allows the resin to be rapidly dissolved by the developer. (L2,3)... 

Rate of reaction of trans-4-substituted cyclohexane carboxylic acids with diazodiphenylmethane EtOH 30 C02Me 0.320... 

A major factor dictating the product distribution of singlet oxygen ene reactions of a substituted alkene carboxylic acid salt (7) in water has been determined to be hydrogen bonding interactions between the solvent and substrate.6... 

The nucleophilic substitution of carboxylic acids is complicated due to the fact that an acidic proton is present. Since most nucleophiles can act as bases, the reaction of a carboxylic acid with a nucleophile results in an acid-base reaction rather than nucleophilic substitution. 

It is often very useful to be able to alkylate a readily available chiral a-hetero-substitut-ed carboxylic acid in an enantiospecific manner, as a means of using the chiral center and at the same time building-up the rest of the target carbon skeleton. Such a reaction has been devised by Seebach and coworkers524. In this process a-hydroxy- and a-mercaptocar-boxylic acids were first reacted with pivaldehyde, to produce a 1,3-dioxolanone or 1,3-oxathiolanone. This was followed by reaction with base and alkylation by an alkyl halide and subsequent hydrolysis to regenerate the hydroxyl or mercapto group (equation 70). The product was obtained in greater than 95% ee. Similar reactions with other electrophiles were also successful. 

Step 1 Reaction of the diphosphate oxygen of GDP with the phosphorus of the acyl phosphate to produce an intermediate similar to the intermediates formed in nucleophilic acyl substitutions of carboxylic acid derivatives. 

Reactions between A -tosylpyrroles 394 and a-substituted unsaturated carboxylic acids in the presence of TFAA result in smooth 2-acylation of the pyrrole, followed by Nazarov cyclization to give 50-80% yields of 4,5-dihydrocy-clopenta[3]pyrrol-6(lf/)-ones 395 (Equation 93) <20060L163>. The presence of an a-substituent in the unsaturated acid appears to be mandatory. 

Yamamoto and Maruoka investigated the reaction of chiral acetals with organoaluminum reagents. Unprecedented regio- and stereochemical control was observed in the addition of trialkylaluminums to chiral a,/3-unsaturated acetals derived from optically pure tartaric acid diamide [83]. The course of the reaction seemed to be highly influenced by the nature of substrates, solvents, and temperature. These findings provide easy access to optically active a-substituted aldehydes (84), /3-substituted aldehydes (85), a-substituted carboxylic acids (86), or allylic alcohols (87). Because optically pure RJi)- and (5,5)-tartaric acid diamides are both readily available, this method enables the predictable synthesis of both enantiomers of substituted aldehydes, carboxylic acids, and allylic alcohols from a,/3-unsaturated aldehydes (Sch. 54). 

The 8( 2 reaction rarely occurs with poor leaving groups. However, in other reactions, such as the nucleophilic substitution of carboxylic acid... 

Let us now examine how substituent effects in reactants influence the rates of nucleophilic additions to carbonyl groups. The most common mechanism for substitution reactions at carbon centers is by an addition-elimination mechanism. The adduct formed by the nucleophilic addition step is tetrahedral and has sp hybridization. This adduct may be the product (as in hydride reduction) or an intermediate (as in nucleophilic substitution). For carboxylic acid derivatives, all of the steps can be reversible, but often one direction will be strongly favored by product stability. The addition step can be acid-catalyzed or base-catalyzed or can occur without specific catalysis. In protic solvents, proton transfer reactions can be an integral part of the mechanism. Solvent molecules, the nucleophile, and the carbonyl compound can interact in a concerted addition reaction that includes proton transfer. The overall rate of reaction depends on the reactivity of the nucleophile and the position of the equilibria involving intermediates. We therefore have to consider how the substituent might affect the energy of the tetrahedral intermediate. 

A useful method of a-substitution in carboxylic acids is via the a-bromo derivative, synthesized using the Hell-Volhard-Zelinsky reaction. Decarboxylation... 

The first-order kinetics of this unusual substitution reaction is here to illustrate a point, but it should not distract you from the fact that most nucleophilic substitutions of carboxylic acid derivatives (the reactions you met in Chapter 10) are bimolecular reactions with ratedetermining formation of the tetrahedral intermediate. 

Homogeneous blends of PVA with 5-15 per cent of a KL modified by reaction with a maleimide-substituted aromatic carboxylic acid provided a means to improve the thermal and photochemical stability of the vinyl polymer [34]. Thus, the thermal resistance of the PVA-modified lignin blends increased, as illustrated in Rg. 11.8 [34]. Spectroscopic... 

When acid derivative 2 reacts with sulfuric acid, the oxygen atom is the base and the conjugate acid product of this acid-base reaction is oxocarbenium ion 3, which is resonance stabilized. When 2 is an acid chloride, anhydride, ester, or amide, a heteroatom is attached to the positive carbon in 3. As in Chapter 18 (Section 18.1), the acid-base reaction of the carbonyl unit in 2 to give 3 facilitates reactions with nucleophiles. The reaction of intermediate 3 with a nucleophile ( Y) gives tetrahedral intermediate 4 contrary to acyl addition, reaction 4 contains an X group that can function as a leaving group. Loss of X leads to the final product of this reaction 5. If the nucleophile ( Y) is hydroxide, compormd 5 is the carboxylic acid (X = OH). If the nucleophile Y is an alcohol, the product 5 is an ester, and if Y is an amine, the product 5 is an amide. This first reaction is therefore the acid-catalyzed acyl substitution reaction of acid derivatives. 

Rh-Catalyzed Reactions Zhao and coworkers have shown that the reaction of ortho-substituted arene carboxylic acids with electron-deficient olefins in the presence of ahydrorhodium(I) complex as the catalyst gave the Mizoroki-Heck products (8) and the conjugate addition products (9) with high selectivity (Scheme 22.18a) [13, 26]. The selectivity depends on the content of water in the reaction mixture higher water content favored the hydrolysis of the enolato intermediate 10, while lower water content favored P-H elimination. This reaction works only for ortho-suhstituted arene carboxylic acids and with electron-deficient olefins (Scheme 22.18h). 

The monoalkylated biaryl compound (S)-l formed in this coupling reaction can be used as a useful chiral building block, as the triflate group can be readily substituted with carboxylic acid functions or diphenylphosphane groups. 

The Faworski-rearrangement of a-halocyclobutanones provides a very attractive and in practice, often particularly useful method [488-491], since it usually utilizes readily available acid chlorides and olefins as precursors. Not only the commercially important (fenpropathrin) tetramethyl cyclopropane carboxylic acid 247 as in Reaction scheme 169, but many others, particularly higher alkyl-substituted cyclopropane carboxylic acids are preferentially prepared in this way (Reaction scheme 170). 

In numerous [4-1-2] cycloaddition reactions the diene, such as an a-oxoketene, is generated in situ and trapped by the carbodiimide. The functional ketenes are generated from diketene or from masked heterocyclic precursors. Also, o-substituted aromatic carboxylic acids are used as precursors for the functional ketenes. 

The cyclopropenium activation approach has been employed in a number of elimination reactions, such as nucleophilic substitution of alcohol, nucleophilic acyl substitution of carboxylic acid, cyclodehydration of diol, and the Beckmann rearrangement (Scheme 6.17) [45]. 

The transfonnation is called nucleophilic aromatic substitution. The key to its success is the presence of one or more strongly electron-withdrawing groups on the benzene ring located ortho or para to the leaving group. Such substituents stabilize an intermediate anion by resonance. In contrast with the Sn2 reaction of haloalkanes, substitution in these reactions takes place by a two-step mechanism, an addition-elimination sequence similar to the mechanism of substitution of carboxylic acid derivatives (Sections 19-7 and 20-2). 

A Pt-catalyzed C(sp )-H functionalization with ort/zo-alkyl-substituted aromatic carboxylic acids 12 for the synthesis of aryl lactones 13 was explored by Chang and coworkers in 2006 (Scheme 12.6) [10]. Kinetic isotope studies reveal that the reaction takes place presumably by the chelation assistance of metal catalyst to the carboxylic group followed by the C-H bond activation. 

Condensed 1,3f4-Thiadiazoles. - Triazolof3,4-b][1,3,4Jthiadiazoles and thiadiazolines are prepared by cyclisation of 3-mercapto-4-amino-1,2,3-triazoles with substituted alkyl carboxylic acids or treatment with HCl followed by reflux with aldehydes. Thiazolo[4,3-b]M,3,4Ithiadiazoles (368 R=Me,Ph,H,R =Ar) result from treatment of acyl rhodanines (367) with PCl. Further reactions of the former have been reported. Imidazo [2,3-b][1,3,4]-... 

A further example is given below illustrating the use of a dibasic anhydride (succinic anhydride) the succinoylation reaction is a valuable one since it leads to aroyl carboxylic acids and ultimately to polynuclear hydrocarbons. This general scheme of synthesis of substituted hydrocarbons through the use of succinic anhydride is sometimes called the Haworth reaction. Thus a-tetralone (see below) may be reduced by the Clemmensen method to tetralin (tetrahydronaphthalene) and the latter converted into naphthalene either catal3d.ically or by means of sulphur or selenium (compare Section, VI,33). 

Maleic anhydride condenses with 2-aminothiazole-4-carboxylic acid giving the raaleimide 107 (269) another report claims, however, that the reaction of 2-amino-4-methylthiazole with this anhydride gives the N-substituted maleamic acid (108) (Scheme 73) (270). 

Solvent Effects on the Rate of Substitution by the S 2 Mechanism Polar solvents are required m typical bimolecular substitutions because ionic substances such as the sodium and potassium salts cited earlier m Table 8 1 are not sufficiently soluble m nonpolar solvents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate Other than the requirement that the solvent be polar enough to dis solve ionic compounds however the effect of solvent polarity on the rate of 8 2 reactions IS small What is most important is whether or not the polar solvent is protic or aprotic Water (HOH) alcohols (ROH) and carboxylic acids (RCO2H) are classified as polar protic solvents they all have OH groups that allow them to form hydrogen bonds... 

Friedel-Crafts acylation of aromatic compounds (Section 12 7) Acyl chlorides and carboxylic acid anhydrides acylate aromatic rings in the presence of alumi num chloride The reaction is electrophil ic aromatic substitution in which acylium ions are generated and attack the ring... 

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