Preparation of carboxylic acids

The pifa of j -(trifIuoromethyl)benzoic acid is 3.6. Would you expect the tri-fluoromethyl substituent to be an activating or deactivating group in the Friedel-Crafts reaction  

Decide whether p-(trifluorotnethyl)benzoic acid is stronger or weaker than benzoic acid. A substituent that strengthens the acid is a deactivating group because it withdraws electrons, and a substituent that weakens the acid is an activating group because it donates electrons. 

A pAa of 3.6 means that p- trifluoromethyl)benzoic acid is stronger than benzoic acid, whose is 4.19. Thus, the trifluoromethyl substituent favors dissociation by helping to stabilize the negative charge. Trifluoromethyl must therefore be an electron-withdrawing, deactivating group. 

Probiem 20.7 The p a ofp-cyciopropylbenzoic acid is 4.45. Is cyclopropylbenzene likely to be more reactive or less reactive than benzene toward electrophilic bromination Explain. 

Probiem 20.8 Rank the following compounds in order of increasing acidity. Don t look at a table of pK data to help with your answer. 

Carboxylic acids commonly are used as the starting materials for the preparation of the other acid derivatives. However, any of the acid derivatives can be hydrolyzed to the carboxylic acid by reaction with water under the appropriate conditions. Acid or base catalysis is necessary for the less reactive derivatives. 

Acyl chlorides and anhydrides must be protected from water because they react readily, often vigorously, with water to produce carboxylic acids. This reaction is not of much synthetic usefulness because the acyl chloride or anhydride is usually prepared from the acid. However, the hydrolysis reaction is occasionally used for the preparation of a carboxylic acid if the acyl chloride or anhydride is available from some other source. The following equation provides an example  

0 Next, the leaving group, ethoxide ion, departs as an electron pair from the negative oxygen reforms the double bond of the carbonyl group. 

Mechanism of the base-catalyzed hydrolysis (saponification) of an ester. 

Click Mechonisms in Motion to view the Mechanism of Hydrolysis of an Ester by Base. 

2 PREPARATION OF CARBOXYLIC ACIDS 1. Oxidation of 1° Alcohols, Aldehydes, and Arenes 

Problem 16.7 Account for the fact that on oxidative cleavage all substituted alkynes give carboxylic acids, whereas some alkenes give ketones.  

Imagine that the net effect of the oxidation is replacement of each bond and H on the multiple-bonded C by OH. Intermediates with several OH s on C are unstable and lose HjO, leaving 0=0. 

Alkenes with the structural unit RjC=C— would give (R2C(OH)2]- 

Multiple-bonded Cs bonded only to H s would form [C(OH)4], which loses two molecules of H O to give COj. 

Aspirin is the most widely used pain reliever and antiinflammatory agent in the world, yet its mechanism of action remained unknown until the 1970s. John Vane, Bengt Samuelsson, and Sune Bergstrom shared the 1982 Nobel Prize in Physiology or Medicine for unraveling the details of its mechanism. 

Unlike hormones, which are transported in the bloodstream to their sites of 

Both salicylic acid and sodium salicylate (its sodium salt) were widely used analgesics in the nineteenth century, but both had undesirable side effects. Salicylic acid irritated the mucous membranes of the mouth and stomach, and sodium salicylate was too sweet for most patients. Aspirin, a synthetic compound, was first sold in 1899 after Felix Hoffman, a German chemist at Bayer Company, developed a feasible commercial synthesis. Hoffman s work was motivated by personal reasons his father suffered from rheumatoid arthritis and was unable to tolerate the sweet taste of sodium salicylate. 

How does aspirin relieve pain and reduce inflammation Aspirin blocks the synthesis of prostaglandins, 20-carbon fatty acids with a five-membered ring that are responsible for pain, inflammation, and a wide variety of other biological functions. PGF2 , the chapter-opening molecule, contains the typical carbon skeleton of a prostaglandin. 

How many tetrahedral stereogenic centers does PGF20 contain Draw its enantiomer. How many of its double bonds can exhibit cis-trans isomerism Considering both its double bonds and its tetrahedral stereogenic centers, how many stereoisomers are possible for PGF2a  

Our discussion of the reactions involving carboxylic acids begins with a brief list of reactions that synthesize them. This list serves as a reminder of where you have seen this functional group before, hi these reactions, the carboxy group is formed in the product, and many different functional groups serve as starting materials. Reactions that produce a particular functional group are called preparations. 

In the remainder of Chapter 19 (and Chapters 20 and 22) we discuss reactions in which a carboxylic acid is a starting material that may be converted to a variety of different products. Keep in mind that reactions of a particular functional group follow a conunon theme. For example, alkenes undergo addition reactions. As a result, these reactions are easier to learn than the list of preparations, in which vastly different functional groups undergo a wide variety of reactions to form the same kind of product. 

The carbon atoms of the alkyl groups of carboxylic acids and Iheir derivatives have chemical shifts much further upheld. The chemical shifts for each carbon of pentanoic acid 

Most of the methods for the preparation of carboxylic acids have been presented previously  

By oxidation of alkenes. We learned in Section 8.17A that alkenes can be oxidized to carboxylic acids with hot alkaline KMn04  

Alternatively, ozonides (Section 8.17B) can be subjected to an oxidative workup that yields carboxylic acids  

By oxidation of aldehydes and primary alcohols. Aldehydes can be oxidized to carboxylic acids with mild oxidizing agents such as Ag(NH3)2 OH (Section 16.12B). Primary alcohols can be oxidized with KMn04. Aldehydes and primary alcohols are oxidized to carboxylic acids with chromic acid (H2Cr04) in aqueous acetone (the Jones oxidation Section 12.4C). 

Although this reaction is used mainly for structure elucidation, it has synthetic utility when methyl ketones are readily prepared and halides are not. 

Problem 16.8 (a) Why isn t 2-naphthoic acid made from 2-chloronaphthalene (b) How is 2-naphthoic acid prepared in a haloform reaction -4 

Interactive to use your problemsolving skills to design syntheses of carboxylic acids. 

Let s review briefly some of the methods for preparing carboxylic acids that we ve seen in past chapters. 

I Oxidation t)f a substituted alkylbenzene with KMnO or Ka2Cr207 gives a substituted benzoic acid (Section 16.9). Both primal) and secondary alkyl groups can be oxidized, but tertiary groups are not affected. 

I Oxidative cleavage of an alkene with KMn04 gives a carboxylic acid if the alkene has at least one vinylic hydrogen (Section 7.9). 

I Oxidation of a j)rimary alcohol or an aldehyde yields a carboxylic acid (Sections 17.7 and 19.3). Primary alcohols are often oxidized with Cr03 in aqueous acid, and aldehydes are oxidized with either acidic CrO or basic silver oxide (Tollens reagent). 

In previous chapters, we studied a variety of methods for preparing carboxyhc acids (T able 21.1). In addition to the methods we have already seen, there are many other ways of preparing carboxylic acids. We will examine two of them. 

TABLE 21.1 A REVIEW OF METHODS FOR PREPARING CARBOXYLIC ACIDS 

Oxidative cleavage will break a C=C triple bond forming two carboxylic acids. 

A variety of strong oxidizing agents can be used to oxidize primary alcohols and produce carboxylic acids. 

Any alkyl group on an aromatic ring will be completely oxidized to give benzoic acid, provided that the benzylic position has at least one hydrogen atom. 

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The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

Although these humble origins make interesting historical notes m most cases the large scale preparation of carboxylic acids relies on chemical synthesis Virtually none of the 3 X 10 lb of acetic acid produced m the United States each year is obtained from vinegar Instead most industrial acetic acid comes from the reaction of methanol with carbon monoxide... 

Malonic ester synthesis (Section 21 7) Synthetic method for the preparation of carboxylic acids involving alkylation of the enolate of diethyl malonate... 

The classification is unaffected by allylic, vinylic, or acetylenic unsaturation appearing in both starting material and product, or by increases or decreases in the length of carbon chains for example, the reactions f-BuOH f-BuCOOH, PhCHgOH - PhCOOH, and PhCH=CHCH20H -PhCH=CHCOOH would all be considered as preparations of carboxylic acids from alcohols. Conjugate reduction and alkylation of unsaturated... 

Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

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... 

The development of diversification linkers allows introduction of an additional element of diversity. Upon completion of the synthesis sequence, the linker is activated facilitating nucleophilic release of the library members from support In the ideal case, as implemented with the acylsulfonamide linker (Scheme 4a), the activated linker is sufficiently reactive that limiting amounts of nucleophile may be added to provide pure product after resin filtration.181 Diversification linkers have been developed for the preparation of carboxylic acid derivatives (Scheme 4a), amines (Scheme 4b),191 aromatic (Scheme 4c) and even heteroaromatic compounds (Scheme 4d).1101... 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

Some Important methods of preparation of carboxylic acids are as foUows. 

Detellurative carbonylation of organotellurium compounds preparation of carboxylic acids... 

Zammatteo et al. (2000) Preparation of carboxylic acid and aldehyde slides... 

Fig. 2. Preparation of carboxylic acid 3 and methyl ester 4 from 4-bromobenzocyclobutene 2...

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