Reactions carboxylic acids with water

Figure 7-9. Activation of carboxylic acids with water-soluble carbodiimide and subsequent reaction of the O-acylisourea formed with a primary amine.

An acid anhydride reacts with an alcohol to form an ester and a carboxylic acid, with water to form two equivalents of a carboxylic acid, and with an amine to form an amide and a carboxylate ion. In each case, the incoming nucleophile—after it loses a proton—is a stronger base than the departing carboxylate ion. In the reaction of an amine with an anhydride, two equivalents of the amine or one equivalent of the amine plus one equivalent of a tertiary amine such as pyridine must be used so that sufficient amine is present to react with the proton produced in the reaction. 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

The next major obstacle is the successful deprotection of the fully protected palytoxin carboxylic acid. With 42 protected functional groups and eight different protecting devices, this task is by no means trivial. After much experimentation, the following sequence and conditions proved successful in liberating palytoxin carboxylic acid 32 from its progenitor 31 (see Scheme 10) (a) treatment with excess 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in ie/t-butanol/methylene chloride/phosphate buffer pH 7.0 (1 8 1) under sonication conditions, followed by peracetylation (for convenience of isolation) (b) exposure to perchloric acid in aqueous tetrahydrofuran for eight days (c) reaction with dilute lithium hydroxide in H20-MeOH-THF (1 2 8) (d) treatment with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran first, and then in THF-DMF and (e) exposure to dilute acetic acid in water (1 350) at 22 °C. The overall yield for the deprotection sequence (31 —>32) is ca. 35 %. 

Reaction of Isocyanates with Water and Carboxylic Acids... 

Scheme 4.13 Reaction of isocyanates with water and carboxylic acids.

Highly concentrated ether carboxylic acids with a low degree of ethoxylation even at room temperature can give an esterification reaction with the non-converted nonionic, especially with the fatty alcohol, to several percentage points. The result may be that a too low value is found for the ether carboxylate content. This mistake in analysis can be avoided by saponification of the formed ester [238]. Two hundred to 300 mg matter and ca 100 mg NaOH were weighed in a 50-ml Erlenmeyer glass, heated with 20 ml ethanol under reflux, and after cooling supplied with water to 100 ml. Afterward a two-phase titration was carried out. 

From the previous discussion, in which it was pointed out that both a and P must be functions of Y, we see that pR, which is a function of a and p, must also be a function of Y. It will therefore be convenient to compare the composition of the electrical effect transmitted by various groups G with Y and the reaction conditions held constant. Again, the most useful reaction for this purpose is the ionization of carboxylic acids in water at 25°. Not only are there more sets of data available for this reaction than for any other, but the sets studied for this reaction generally include more substituents than do sets for other reactions or under other reaction conditions. 

Oxidative addition of the O-H bond to transition metal complexes gives hydrido(hy-droxo), hydrido(alkoxo) or hydrido(carboxylato) complexes (Eq. 6.1), but web-characterized complexes obtained as primary products from the reaction of the compound, XO-H (XO-H = water, alcohol, and carboxylic acid) with late transition metals are quite rare [1]. Furthermore, the crystal stractures of very few complexes of this type have been reported. In this section we will survey late transition metal complexes resulting from activation of water, alcohol, and carboxylic acid. 

Such esterifications and acetal formations are achieved through enzyme catalyses. However, such reactions are relatively rare in aqueous conditions chemically. This is because the reversed reactions, hydrolysis, are much more favorable entropically. Kobayashi and co-workers found that the same surfactant (DBSA) that can catalyze the ether formation in water (5.2 above) can also catalyze the esterification and acetal formations reactions in water.52 Thus, various alkanecarboxylic acids can be converted to the esters with alcohols under the DBSA-catalyzed conditions in water (Eq. 5.6). Carboxylic acid with a longer alkyl chain afforded the corresponding ester better than one with a shorter chain at equilibrium. Selective esterification between two carboxylic acids with different alkyl chain lengths is therefore possible. 

The decarboxylation of carboxylic acid in the presence of a nucleophile is a classical reaction known as the Hunsdiecker reaction. Such reactions can be carried out sometimes in aqueous conditions. Man-ganese(II) acetate catalyzed the reaction of a, 3-unsaturated aromatic carboxylic acids with NBS (1 and 2 equiv) in MeCN/water to afford haloalkenes and a-(dibromomethyl)benzenemethanols, respectively (Eq. 9.15).32 Decarboxylation of free carboxylic acids catalyzed by Pd/C under hydrothermal water (250° C/4 MPa) gave the corresponding hydrocarbons (Eq. 9.16).33 Under the hydrothermal conditions of deuterium oxide, decarbonylative deuteration was observed to give fully deuterated hydrocarbons from carboxylic acids or aldehydes. 

Although the ability of microwaves (MW) to heat water and other polar materials has been known for half a century or more, it was not until 1986 that two groups of researchers independently reported the application of MW heating to organic synthesis. Gedye et al. [1] found that several organic reactions in polar solvents could be performed rapidly and conveniently in closed Teflon vessels in a domestic MW oven. These reactions included the hydrolysis of amides and esters to carboxylic acids, esterification of carboxylic acids with alcohols, oxidation of alkyl benzenes to aromatic carboxylic acids and the conversion of alkyl halides to ethers. 

The hydrolysis of an ester to alcohol and acid (1) and the esterification of a carboxylic acid with an alcohol (2) are shown here as an example of the Sn2 mechanism. Both reactions are made easier by the marked polarity of the C=0 double bond. In the form of ester hydrolysis shown here, a proton is removed from a water molecule by the catalytic effect of the base B. The resulting strongly nucleophilic OH ion attacks the positively charged carbonyl C of the ester (la), and an unstable sp -hybridized transition state is produced. From this, either water is eliminated (2b) and the ester re-forms, or the alcohol ROH is eliminated (1b) and the free acid results. In esterification (2), the same steps take place in reverse. 

The reaction of a carboxylic acid with sodium hydroxide (NaOH) produces the sodium salt of the carboxylic acid. The sodium salt then reacts with an acid chloride to form the anhydride. Figure 12-16 illustrates the final step in this process. In this reaction, the carboxylate ion behaves as a nucleophile and attacks the carbonyl Ccirbon atom of the acid chloride. The reaction of a carboxylic acid with sodium hydroxide also generates water, which, if not removed, reacts with the acid chloride and lowers the yield of the reaction. 

The conceptually simple cyclodehydration of a carboxylic acid and a (3-amino alcohol to an oxazoline requires harsh conditions of high temperature with azeotropic water removal (e.g., boric acid in refluxing xylene). Nonetheless, good yields of the oxazoline can be obtained if sensitive functionalities are absent. " A much milder approach has been developed by Vorbriiggen where the reaction of carboxylic acids with (3-amino alcohols is carried out in the... 

The oxidation of carboxylic acids with H202 and an acid catalyst is the best general method for the preparation of peroxy acids.450 The most common catalyst for aliphatic R is concentrated sulfuric acid. The reaction is an equilibrium and is driven to the right by removal of water or by the use of excess reagents. For aromatic R the best catalyst is methanesulfonic acid, which is also used as the solvent. 

Alkenes may also react with certain oxidizing agents to result in anti hydroxyla-tion. Treatment with peroxycarboxylic acids435 leads initially to an epoxide. Ring scission of the latter via an SN2 reaction in an anti manner with the corresponding carboxylic acid or water gives the trans monoester or tram diol, respectively. Complete anti stereoselectivity and high yields in the oxidation of cycloalkenes are... 

One of the most characteristic types of ground-state reaction for alkenes is electrophilic addition, often involving a proton acid as addend or catalyst. In the excited state similar reactions can occur, with water, alcohols or carboxylic acids as commonly encountered addends. However, there is a variety of photochemical mechanisms according to the conditions or substrate used. In a few instances it is proposed that the electronically excited state is attacked directly by a proton from aqueous acid, for example when styrenes are converted to l-arylethanols (2.47 the rate constant for such attack is estimated to be eleven to fourteen orders of magnitude greater than that for attack on the ground state, and the orientation of addition is that expected on the basis of relativecarbonium ion stabilities (Markowni-kov addition). 

The reaction of chromone-2-carboxylic acid with thionyl chloride or phosphorus halides gives the trihalide (400). This compound readily loses one of its geminal chlorine atoms and with water, for example, affords 4-chlorocoumarin through the simultaneous loss of carbon monoxide (Scheme 131) (63JGU1806). 

The reaction of a carboxylic acid with an alcohol yields an ester plus water, and the reaction of an amide with water yields a carboxylic acid and an amine (or ammonia). Write the reagents to show how H2O is removed, and then connect the remaining fragments to complete the substitution reaction. 

A recent procedure for the preparation of methyl esters involves refluxing the carboxylic acid with methanol and 2,2-dimethoxypropane in the presence of toluene-p-sulphonic acid as the catalyst (Expt 5.146). The water produced in the esterification process is effectively removed by acid-catalysed reaction with the ketal to give acetone and methanol. 

The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines. 

To a solution of 5-methoxymethoxy-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid methyl ester (4.9 g, 22.9 mmol) in 8/l-Me0H/H20 (175 ml, v/v) was added sodium azide (7.44 g, 114.5 mmol) and ammonium chloride (2.69 g, 50.4 mmol) and the mixture was refluxed for 15 h. The reaction was diluted with water (75 ml) to dissolve precipitated salts and the solution was concentrated to remove methanol. The resulting aqueous phase containing a precipitated oily residue was diluted to a volume of 200 ml with water and was extracted with ethyl acetate (3 times 100 ml). The combined organic extracts were washed with saturated NaCI (100 ml), dried (MgS04), filtered and evaporated. The crude was purified on silica gel (1/1-hexane/ethyl acetate) to afford 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-l-ene-l-carboxylic acid methyl ester (5.09 g, 86%) as a pale yellow oil. Subsequent preparations of 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-l-ene-l-carboxylic acid methyl ester provided material which was of sufficient purity to use in the next step without further purification. 

Any carboxylic acid derivative can be converted to any other using one or more of the reactions discussed in the previous sections. If the conversion requires going from a less reactive derivative to a more reactive one, then an indirect route may be necessary. Remember that any derivative can be hydrolyzed to a carboxylic acid using water and acid or base. Also remember that the carboxylic acid can be converted to the acyl chloride with thionyl chloride, providing access to the other derivatives. 

The first authentic synthesis of a bisphosphonic acid, l-hydroxyethane-l,l-bisphos-phonic acid (etidronic acid), was published by von Baeyer and Hofmann in 1897 [1], although it is possible that the same compound had already been obtained in 1865 by Menschutkin [2], The synthetic approach to BPs employed today differs only little from that used over a hundred years ago, and it is still based on the reaction of a carboxylic acid with phosphorus trichloride with the addition of some water [3], (Note BPs are usually represented as the free bisphosphonic acids the generic names given refer, however, to their salt forms.)... 

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