Direct carboxylic acid

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 conversion of primary alcohols and aldehydes into carboxylic acids is generally possible with all strong oxidants. Silver(II) oxide in THF/water is particularly useful as a neutral oxidant (E.J. Corey, 1968 A). The direct conversion of primary alcohols into carboxylic esters is achieved with MnOj in the presence of hydrogen cyanide and alcohols (E.J. Corey, 1968 A,D). The remarkably smooth oxidation of ethers to esters by ruthenium tetroxide has been employed quite often (D.G. Lee, 1973). Dibutyl ether affords butyl butanoate, and tetra-hydrofuran yields butyrolactone almost quantitatively. More complex educts also give acceptable yields (M.E. Wolff, 1963). 

Let s first consider how to prepare an aldehyde from a carboxylic acid There are no good methods for going from RCO2H to RCHO directly Instead we do it indirectly... 

The methyl ketone shown in the example can enohze in only one direction and typifies the kind of reactant that can be converted to a carboxylic acid in synthetically accept able yield by the haloform reaction When C 3 of a methyl ketone bears enolizable hydro O... 

Most methods for their preparation convert one class of carboxylic acid derivative to another and the order of carbonyl group stabilization given m Figure 20 1 bears directly on the means by which these transformations may be achieved A reaction that converts one carboxylic acid derivative to another that lies below it m the figure is pracfical a reacfion fhaf converts if fo one fhaf lies above if is nol This is anofher way of saying fhaf one carboxylic acid derivative can be converted to another if the reaction leads to a more stabilized carbonyl group Numerous examples of reacfions of fhis fype will be pre senfed m fhe secfions fhaf follow... 

Amides are sometimes prepared directly from carboxylic acids and amines by a two step process The first step is an acid-base reaction m which the acid and the amine combine to form an ammonium carboxylate salt On heating the ammonium carboxy late salt loses water to form an amide... 

Prostaglandins arise from unsaturated C20 carboxylic acids such as arachidonic acid (see Table 26 1) Mammals cannot biosynthesize arachidonic acid directly They obtain Imoleic acid (Table 26 1) from vegetable oils m their diet and extend the car bon chain of Imoleic acid from 18 to 20 carbons while introducing two more double bonds Lmoleic acid is said to be an essential fatty acid, forming part of the dietary requirement of mammals Animals fed on diets that are deficient m Imoleic acid grow poorly and suffer a number of other disorders some of which are reversed on feed mg them vegetable oils rich m Imoleic acid and other polyunsaturated fatty acids One function of these substances is to provide the raw materials for prostaglandin biosynthesis... 

Phthalocyanine sulfonic acids, which can be used as direct cotton dyes (1), are obtained by heating the metal phthalocyanines in oleum. One to four sulfo groups can be introduced in the 4-position by varying concentration, temperature, and reaction time (103). Sulfonyl chlorides, which are important intermediates, can be prepared from chlorosulfonic acid and phthalocyanines (104). The positions of the sulfonyl chloride groups are the same as those of the sulfonic acids (103). Other derivatives, eg, chlormethylphthalocyanines (105—107), / /f-butyl (108—111), amino (112), ethers (109,110,113—116), thioethers (117,118), carboxyl acids (119—122), esters (123), cyanides (112,124—127), and nitrocompounds (126), can be synthesized. 

Primary synthesis has limited application in making pyrimidine-carboxylic acids or even their esters. However, some pyrimidine-4(and 5)-carboxylic acids can be effectively so made. For example, bromomucic acid (785) reacts as an aidehydo ketone with S-methyl-thiourea to give 5-bromo-2-methylthiopyrimidine-4-carboxylic acid (786) directly (53JCS3129) while the Whitehead synthesis (Section 2.13.3.1.2<7) can give, for instance, 3-methylcytosine-5-carboxylic acid (787) (55MI21300). 

Orotic acid (971) has a chequered history. It was isolated in 1905 from the whey of cows milk in Italy and it was subsequently synthesized in the United States in 1907. However, the workers involved were discouraged by some difference in melting points and no direct comparison of specimens was ever made. To make matters worse, the same laboratories prepared the isomeric 5-hydroxy-2-oxo-l,2-dihydropyrimidine-4-carboxylic acid and announced it as orotic acid, again without any direct comparison. Only in 1930 did a German worker actually compare directly natural and the original synthetic orotic acid, thereby showing them to be identical (30CB1000). 

There are at least eight syntheses of orotic acid in the literature. The most practical in the laboratory is that involving the condensation of diethyl oxalacetate (972) with S-methylthiourea to give 2-methylthio-6-oxo-l,6-dihydropyrimidine-4-carboxylic acid (973) which undergoes either direct acidic hydrolysis or a less smelly oxidative hydrolysis, via the unisolated sulfone (974), to afford orotic acid (971) (B-68MI21303). 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

Avery direct synthesis of certain lactones can be achieved by heating an alkene, a carboxylic acid, and the Mn(III) salt of the acid. Suggest a mechanism by which this reaction might proceed. 

Nickel peroxide is a solid, insoluble oxidant prepared by reaction of nickel (II) salts with hypochlorite or ozone in aqueous alkaline solution. This reagent when used in nonpolar medium is similar to, but more reactive than, activated manganese dioxide in selectively oxidizing allylic or acetylenic alcohols. It also reacts rapidly with amines, phenols, hydrazones and sulfides so that selective oxidation of allylic alcohols in the presence of these functionalities may not be possible. In basic media the oxidizing power of nickel peroxide is increased and saturated primary alcohols can be oxidized directly to carboxylic acids. In the presence of ammonia at —20°, primary allylic alcohols give amides while at elevated temperatures nitriles are formed. At elevated temperatures efficient cleavage of a-glycols, a-ketols... 

Participation of fluorocarbocations, derived from carboxylic acids and from halo acetones, in reactions of carbonyl compounds with sulfur tetrafluoride has been directly evidenced by trapping them with aromatic hydrocarbons [207, 20S],... 

An interesting class ot covalent Inflates are vin l and ar>/ or heteroaryl Inflates Vinyl inflates are used for the direct solvolytic generation of vinyl cations and for the generation of unsaturated carbenes via the a-elimination process [66] A triflate ester of 2-hydroxypyridine can be used as a catalyst for the acylation of aromatic compounds with carboxylic acids [109] (equation 55)... 

FIGURE 20.1 Structure, reactivity, and carbonyl-group stabilization in carboxylic acid derivatives. Acyl chlorides are the most reactive, amides the least reactive. Acyl chlorides have the least stabilized carbonyl group, amides the most. Conversion of one class of compounds to another is feasible only in the direction that leads to a more stabilized carbonyl group that is, from more reactive to less reactive. 

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