Acids and Their Derivatives

Carboxylic Acids and their Derivatives.—2,3-Seco-A -unsaturated dicarboxylic acids (443), obtained by ozonolysis of 2-hydroxymethylene-4-en-3-ones, have been considered rather resistant to cyclisation to form the A-nor-3-en-2-one system (444). Two convenient methods for achieving such a reaction are now described. Dieckmann condensation of the dimethyl ester (445) was successful with sodium hydride, in toluene containing a little methanol. The 5-methoxy-carbanion (446), resulting from conjugate addition of methoxide ion, is suggested as a possible activated intermediate. Alternatively, the diacid (in the B-nor-series) 

Very smooth conversion of the keto-acid (447) into the enol-lactone (448) was recently reported, using acetic anhydride and perchloric acid in ethyl acetate as 

Reduction of the lactone (453) can be controlled to give any one of the three products illustrated. Brief reaction (0.5 hr) with one mole of borane-tetra-hydrofuran gives the lactol (455), which slowly (4 days) undergoes elimination 

Bromine reacts with the keto-acid (459) to give the 5)8,19-lactone (460), possibly by intramolecular displacement of a 5a-bromo-substituent by the carboxy-group. The )S-lactam (460) readily loses carbon dioxide on pyrolysis or alkaline 

The maleic anhydride adduct (465) of a 5,7-diene is reduced selectively by complex hydrides to give the lactone (466).  

PART II. CARBOXYLIC ACIDS AND THEIR DERIVATIVES A. GENERAL INTRODUCTION 

While it is possible to divide this material on oxidation, reduction, addition, substitution, elimination, and rearrangement of carboxylic acids (RCO2H) into sections corresponding to carboxylic acids themselves and then, further, to consider in the 

Throughout the chapter it is important to keep in mind that carboxylic acids are, clearly, acidic. Generally, carboxyhc acids are weak acids in that proton donation to water is incomplete and thus carboxylic acids are not completely ionized. So, as pointed out earlier (Chapter 5), the add strength or addity is referred to as the position of equilibrium in the reaction of the acid with a base. Thus, for the generalized acid RCO2H ionizing in water (H2O), Equation 9.75 can be written  

We may then write that the equilibrium constant, K is a measure of the acid 

as is fully anticipated, and as shown in Table 9.11, carboxylic acids enjoy a wide range of acidities since their relative ability to ionize must clearly be a function of substituents in the ubiquitious R group. That is, those R groups that increase the positive nature of the carbon of the carbonyl through, for example, electron withdrawal, will increase the ability of the proton to ionize those in which the positive nature of the carbonyl is diminished will produce the opposite effect. 

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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. 

Many chiral phosphorus ligands have shown excellent reactivities and enantio-selectivities in the Rh-catalyzed hydrogenation of itaconic acids or esters. Some successful ( 95% ee) hydrogenations of itaconic acid or its dimethyl ester with different chiral phosphorus ligands are listed in Table 26.7. High reactivity is observed with electron-rich phosphane ligands such as BICHEP [7c[. 

In contrast to the many successful examples of hydrogenation of the parent itaconic acid or its dimethyl ester, only a few ligands have been reported to be 

Ligand R SCR Reaction conditions % ee of product (config.) Reference 

The carboxyl group is polar and readily forms hydrogen bonds. A carboxylic acid dissociates to a carboxylate anion and a proton. In the carboxylate anion, the negative charge is delocalized equally over both oxygens. The pKas of simple carboxylic acids are about 4-5, but the acidity can be increased by electron-withdrawing substituents (such as chlorine) close to the carboxyl group. 

Carboxylic acids react with bases to give salts. These are named by naming the cation first and then the carboxylate anion. The name of the anion is obtained by changing the -ic ending of the acid name to -ate (acetic becomes acetate). 

Carboxylic acids are prepared by at least four methods (1) by oxidation of primary alcohols or aldehydes, (2) by oxidation of an aromatic side chain, (3) from a Grignard reagent and carbon dioxide, or (4) by hydrolysis of a nitrile, RC=N. 

Carboxylic acid derivatives are compounds in which the carboxyl -OH group is replaced by other groups. Examples include esters, acyl halides, anhydrides, and amides. 

Esters, RC02R, are named as salts are the R group is named first, followed by the name of the carboxylate group (for example, CH3CO2CH2CH3 is ethyl acetate). Esters can be prepared from an acid and an alcohol, with a mineral acid catalyst (Fischer esterification). The key step of the mechanism is nucleophilic attack by the alcohol on the protonated carbonyl group of the acid. Many esters are used as flavors and perfumes. 

You find them in citrus fruits (citric acid), vinegar (acetic acid), aspirin (acetylsalicylic acid), and numerous other natural and synthetic compounds, as well on numerous organic exams. In this chapter you explore the structure, synthesis, and reactions of these acids and acids like them. 

Seeing the Structure and Nomenclature of Carboxylic Acids and Derivatives 

In Chapter 9 you see the basic structure of each of the carboxylic acids and carboxylic acid derivatives. In this chapter we focus on the carboxylic acids and related compounds, such as esters, acyl chlorides, and acid anhydrides, and we also include some information on amides (see Chapter 13 for an additional examination of amides). Before you can get into synthesis and reactions, though, you need to understand the structure and nomenclature of these compounds. 

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 8+ charge on the carbonyl carbon, which makes the carbon atom more susceptible to nucleophilic attack. 

The general formula for a carboxylic acid is RCOOH, where R may be hydrogen or any alkyl or aryl group. The derivatives vary slightly from that formula  

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TABl.E 11-10. THIAZOt E CARBOXYLIC. THIAZOLE ALKANOIC ACIDS, AND THEIR DERIVATIVES (10)... 

As mentioned previously, aldehydes can be prepared by Stephen s method of reduction of nitriles by stannous chloride (37, 91). Polaro-graphic reduction of thiazolecarboxylic acids and their derivatives gives lower yields of aldehydes (58). Ozonolysis of styrylthiazoles, for example, 2-styryl-4-methylthiazole, followed by catalytic reduction gives aldehyde with 47% yield of crude product (30). 

The ketones can be obtained by addition of organometallic reagents to acids and their derivatives. 

Fluorinated diacids offer a convenient method for introducing a perfluoro moiety into organic molecules. They are of potential interest in the preparation of polyamides and other fluorinated polymers. A detailed description of the perfluorocarboxyUc acids and their derivatives has been pubflshed (1), and a review article on polyfluorinated linear biflmctional compounds has appeared (35). 

Sulfur Tetrafluoride and Aromatic Carboxylic Acids. Ben2otrifluorides also are prepared from aromatic carboxyhc acids and their derivatives with sulfur tetrafluoride (SF (106,107). Hydrogen fluoride is frequently used as a catalyst. Two equivalents of sulfur tetrafluoride are required ... 

A. W. Ralston, Eatty Acids and Their Derivatives,]ohn Wiley Sons, Inc., New York, 1948, p. 582. 

In Cosmetics. Amino acids and their derivatives occur in skin protein, and they exhibit a controlling or buffering effect of pH variation in skin and a bactericidal effect (216). Serine is one component of skin care cream or lotion. Ai-Acylglutamic acid triethanolamine monosalt is used for shampoo. Glucose glutamate is a moisturizing compound for hair and skin (234). 

The long-chain alkanoic acids and their derivatives are polymorphic with the unit cell containing dimers formed by hydrogen bonding between carboxyl groups. 

Organic Acids and Their Derivatives (Anhydrides, Nitriles, Ureas). Alkyleneamines react with acids, esters, acid anhydrides or acyl hahdes to form amidoamines and polyamides. Various diamides of EDA are prepared from the appropriate methyl ester or acid at moderate temperatures (25,26). 

Anthraquinone-a,a -disulfonic acids and Related Compounds. Anthraquinone-a,a -disulfonic acids and their derivatives are important intermediates for manufacturing disperse blue dyes (via 1,5-, or 1,8-dihydroxyanthraquinone, or 1,5-dichloroanthraquinone) and vat dyes (via... 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

The second type, dihydro-bases (II), hydrolyses with alkali or with hydrazine to (+)-dihydro-d-wolysergic acid (II), which is probably identical with the y-dihydrolysergic acid of Jacobs and Craig. The principal characters of the dihydro-lysergic and isolysergic acids and their derivatives are summarised in the following table —... 

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... 

Perfluoroalkanesulfomc Acids and Their Derivatives (Russ ) Huang, W, Chen Q Chern Sulphonic Acids, Esters, Their Derivatives 903-946 157... 

Esters of penta- and trivalentphosphorus acids and their derivatives readily undergo cleavage of the phosphorus-oxygen bond under extremely mild conditions with formation of the phosphorus-fluorine bond Phosphates and phosphi-... 

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]... 

Section 19.14 The mechanism of acid-catalyzed esterification involves some key features that are fundamental to the chemistry of car boxylic acids and their-derivatives. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Synthesis of acylpyridines, pyridinecarboxylic acids and their derivatives 98KGS1013. 

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. 

Natural PPARy Ligands. Endogenous ligands demonstrated to bind and activate PPARy in vitro include unsaturated fatty acids and their derivatives such as prostaglandin J2 (15-deoxy-A12,l4-PGJ2). Consistent... 

Sulfinyl chlorides may be prepared from the corresponding thiols or disulfides by oxidative reactions rather than by reductions of sulfonyl compounds. A recent example, which improves the earlier procedure of Douglass, is given by equation (3)50. The chemistry of sulfinic acids and their derivatives has been reviewed51 52,53. 

There are several methods for preparing surface-active phosphonic acids and their derivatives. 

The most widely studied interactions between biologically active ligands and organotin(lV) cations relate to the amino acids and their derivatives (N- or S-protected amino acids and peptides), though new data on several of the most commonly occurring amino acids are still being published. This is specially true for aqueous speciation studies. Nice and very detailed reviews were published in this area by Molloy and Nath. ... 

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

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