Carboxylic Acids and their Derivatives

The taste of vinegar, the sting of an ant, the rancid smell of butter, and the relief derived from aspirin or ibuprofen—all of 

In this chapter, we will describe the structures, properties, preparation, and reactions of carboxylic acids and will also discuss some common carboxylic acid derivatives, in which the hydroxyl group of an acid is replaced by other functional groups. 

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5 Effect of Structure on Acidity the Inductive Effect Revisited 

11 The Mechanism of Acid-Catalyzed Esterification Nucleophilic Acyl Substitution 

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A number of mechanistic pathways exist for nucleophilic acyl substitution. In the simplest of these, a negatively charged nucleophile, Nu , attacks the electrophilic acyl carbon atom of 3 to give the tetrahedral intermediate 4. This then collapses to regenerate the carbon-oxygen double bond with loss of the leaving group, Z, to provide a substitution product 5, which is also a carboxylic acid derivative (Eq. 20.2). The first step in this reaction may be considered to be a Lewis acid-Lewis base reaction in which the acyl carbon atom is the Lewis acid and the nucleophile is the Lewis base. 

The experiments described in this chapter illustrate some of the representative reactions of carboxylic acids and their derivatives. For example, you will perform a Fischer esterification, one of the classic reactions in organic chemistry that was discovered by the Nobel laureate Emil Fischer (see the Historical Highlight at the end of Chapter 23 for an account of the life of this famous chemist), to prepare the anesthetic agent benzocaine from p-aminobenzoic acid (Sec. 20.2). In another experiment, you will synthesize the mosquito repellent N,N-diethyl-7n-toluamide (DEET) by a two-step process that involves the conversion of a carboxylic acid into an acid chloride and subsequent reaction with an amine to produce the desired amide (Sec. 20.3). 

Finally, you will prepare a hydrazide, a close relative of an amide, and study its chemical decomposition in a process that produces visible light. 

See Who was Le Chatelier See more on Molecular Sieves See more on Azeotropes See more on Benzocalne 

Fill in the blanks below. To verify that your answers are correct, look in your textbook at the end of Chapter 21. Each of the sentences below appears verbatim in the section entitled Review of Concepts and Vocabulary. 

Treatment of a carboxyhc acid with a strong base yields a The pkTa of most carboxylic acids is between and  

Using the Henderson-Hasselbalch equation, it can be shown that carboxyhc acids exist primarily as at physiological pH. 

Electron- substituents can increase the acidify of a carboxyhc acid. 

When treated with aqueous acid, a nitrile wUl undergo, yielding a carboxyhc acid. 

3 equiv Et2N 3 equiv pCICtH-iOAc CH2C12 60 °C, 43 h 

PS-C (type II) from Amano is Pseudomonas cepacia lipase 

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The recent discovery of a convenient synthesis of sulfur tetrafluoride from sulfur dichloride and sodium fluoride in acetonitrile invited the application of this reagent in fluorination reactions. Hasek, Smith and Engelhardt showed that carboxylic acids and their derivatives can be converted into trifluoromethyl derivatives and that aldehydes and ketones are converted into 5 em-difluoro compounds. They also observed that the reaction was acid... 

The discussion of acylation reactions in this chapter is focused on fluonnated carboxylic acid derivatives and their use to build up new fluorine-containing molecules of a general preparative interest Fifteen years ago, fluonnated carboxylic acids and their derivatives were used mainly for technical applications [/] Since then, an ever growing interest for selectively fluonnated molecules for biological applications [2, 3, 4, 5] has challenged many chemists to use bulk chemicals such as tnfluoroacetic acid and chlorodifluoroacetic acid as starting materials for the solution of the inherent synthetic problems [d, 7,, 9]... 

Differences in solubility of the reactants may for example be utilized as follows. Sodium iodide is much more soluble in acetone than are sodium chloride or sodium bromide. Upon treatment of an alkyl chloride or bromide with sodium iodide in acetone, the newly formed sodium chloride or bromide precipitates from the solution and is thus removed from equilibrium. Alkyl iodides can be conveniently prepared in good yields by this route. Alkyl bromides are more reactive as the corresponding chlorides. Of high reactivity are a-halogen ketones, a-halogen carboxylic acids and their derivatives, as well as allyl and benzyl halides. 

We ve already seen in Sections 20.7 and 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of 5 2 displacement with C followed by reduction thus converts an alkyl halide into a primary alkylamine having one more carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. 

Conversion of Alkyl Halides, Alcohols, or Alkanes to Carboxylic Acids and Their Derivatives... 

Esters of [1-(diethoxyphosphinyloxy)perfluoro-l-alkene]-phosphonic acid appear to be effective reagents for the synthesis of perfluoro-a,B-unsaturated carboxylic acids and their derivatives presumably an initially-generated perfluoroketene (166 ) is acted upon by a nucleophile (NuH=RNH2, I NH, or ROH). The ( E) / (Z) ratio of the product components increases with increasing length of R. 2 ... 

Compared with aldehydes and ketones, carboxylic acids and their derivatives are less reactive toward reduction. Nevertheless, it is still possible to reduce various acid derivatives in aqueous conditions. Aromatic carboxylic acids, esters, amides, nitriles, and chlorides (and ketones and nitro compounds) were rapidly reduced by the Sml2-H20 system to the corresponding products at room temperature in good yields... 

The condensation reactions described above are unique in yet another sense. The conversion of an amine, a basic residue, to a neutral imide occurs with the simultaneous creation of a carboxylic acid nearby. In one synthetic event, an amine acts as the template and is converted into a structure that is the complement of an amine in size, shape and functionality. In this manner the triacid 15 shows high selectivity toward the parent triamine in binding experiments. Complementarity in binding is self-evident. Cyclodextrins for example, provide a hydrophobic inner surface complementary to structures such as benzenes, adamantanes and ferrocenes having appropriate shapes and sizes 12) (cf. 1). Complementary functionality has been harder to arrange in macrocycles the lone pairs of the oxygens of crown ethers and the 7t-surfaces of the cyclo-phanes are relatively inert13). Catalytically useful functionality such as carboxylic acids and their derivatives are available for the first time within these new molecular clefts. 

The thioester hypothesis can be summed up as follows the formation of thiols was possible, for example, in volcanic environments (either above ground or submarine). Carboxylic acids and their derivatives were either formed in abiotic syntheses or arrived on Earth from outer space. The carboxylic acids reacted under favourable conditions with thiols (i.e., Fe redox processes due to the sun s influence, at optimal temperatures and pH values) to give energy-rich thioesters, from which polymers were formed these in turn (in part) formed membranes. Some of the thioesters then reacted with inorganic phosphate (Pi) to give diphosphate (PPi). Transphosphorylations led to various phosphate esters. AMP and other nucleoside monophosphates reacted with diphosphate to give the nucleoside triphosphates, and thus the RNA world (de Duve, 1998). In contrast to Gilbert s RNA world, the de Duve model represents an RNA world which was either supported by the thioester world, or even only made possible by it. 

Cyano-substituted selenophenes are valuable precursors of formyl derivatives.89 They are also used as starting materials for the preparation of carboxylic acids and their derivatives.128 By treating the cyano compounds with hydrogen selenide, selenoloamides (101) were obtained. As shown in... 

Ring syntheses of 1,2,4-oxadiazoles from a one-atom component and a four-atom component 5.04.9.1,2(i) Syntheses from amidoximes and carboxylic acids and their derivatives... 

Furazan- and furoxan-carboxylic acids and their derivatives 341... 

Monothiodiacylhydrazines 127, derived from the acylation of thiosemicarbazides or as intermediates in the reactions of (1) thiohydrazides with carboxylic acids and their derivatives (see Section 5.10.9.2.2(i)) or (2) hydrazides with thiocarbonyl compounds (see Section 5.10.9.2.3(i)), cyclize in the presence of an acid catalyst to give 1,3,4-thiadiazoles 128 (Equation 39, Table 4). 

The processes classified in the third group are of primary importance in elucidating the significance of electric variables in electrosorption and in the double layer structure at solid electrodes. These processes encompass interactions of ionic components of supporting electrolytes with electrode surfaces and adsorption of some organic molecules such as saturated carboxylic acids and their derivatives (except for formic acid). The species that are concerned here are weakly adsorbed on platinum and rhodium electrodes and their heat of adsorption is well below 20 kcal/mole (25). Due to the reversibility and significant mobility of such weakly adsorbed ions or molecules, the application of the i n situ methods for the surface concentration measurements is more appropriate than that of the vacuum... 

Several papers have been devoted to the subject of reactions of phosphoranes with carboxylic acids and their derivatives. Thus triphenylphosphine dibromide (111) in acetonitrile cleaves lactones,93 while the corresponding dichloride (112) converts esters into acid chlorides.94 The reactions of esters with phosphorus pentachloride (101) have been studied further,95 and the influence of structural changes on the yields of products (113) and (114) has resulted in minor modifications to the mechanism previously96 outlined. 

Carbonylation is one of the most important reactions leading to C-C bond formation. Direct synthesis of carbonyl compounds with CO gives rise to carboxylic acids and their derivatives, such as esters, amides, lactones, lactams etc. The process can be represented by the simple reactions of Scheme 5.1. 

Very important compounds are the carboxylic acids and their derivatives, which can be formally obtained by exchanging the OH group for another group. In fact, derivatives of this type are formed by nucleophilic substitutions of activated intermediate compounds and the release of water (see p. 14). Carboxylic acid esters (R-O-CO-R ) arise from carboxylic acids and alcohols. This group includes the fats, for example (see p.48). Similarly, a carboxylic acid and a thiol yield a thioester (R-S-CO-R ). Thioesters play an extremely important role in carboxylic acid metabolism. The best-known compound of this type is acetyl-coenzyme A (see p. 12). 

REDUCTION OF CARBONYL COMPOUNDS, CARBOXYLIC ACIDS AND THEIR DERIVATIVES... 

Chapter 10 - Reduction of Carbonyi Compounds, Carboxylic Acids and Their Derivatives, Pages 330-370... 

Organocatalysed carbonylations of arylhalogenides are an interesting way of synthesizing carboxylic acids and their derivatives. They are usually carried out with the use of pressurized CO at elevated temperatures [27-29]. 

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the... 

In Part 111 we cover that broad category of organic compounds called the carbonyls. First we give you an overview of Ccirbonyl basics, including structure, reactivity, and spectroscopy. Then we go into more detail on aldehydes and ketones, enols and enolates, and carboxylic acids and their derivatives. 

Carboxylic acids and their derivatives are also an important part of Organic 11. We spend quite a few pages looking at the structure, nomenclature, synthesis, reactions, and spectroscopy of carboxylic acids. While on this topic in Chapter 12, we use a lot of acid-base chemistry, most of which you were exposed to in your introductory chemistry course. (For a quick review, look over a copy of Chemistry For Dummies or Chemistry Essentials For Dummies, both written by John T. Moore and published by Wiley.)... 

Tackling the names and forms of carboxylic acids and their derivatives Analyzing the physical properties of these compounds Assessing how they are synthesized Looking at their reactions... 

You see in Chapter 10 that aldehydes and ketones contain a carbonyl group attached to carbon or hydrogen atoms. In the case of carboxylic acids and their derivatives, a carbonyl group is attached to an electronegative element such as oxygen, chlorine, or nitrogen. The presence of these elements tends to increase the 5+ charge on the carbonyl carbon, which makes the carbon atom more susceptible to nucleophilic attack. 

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