Water, acyl addition mechanism

Anhydrides may be prepared by coupling two carboxylic acids under acidic conditions. If ethanoic acid (acetic acid, 21) is heated with HCl, protonation to give an oxocarbenium ion is followed by reaction with a second equivalent of acetic acid to give a tetrahedral intermediate. This reaction is the usual acid-catalyzed acyl addition mechanism. Protonation of the OH unit leads to loss of water and formation of the anhydride. Each step in this process is reversible and steps must be taken to drive the equilibrium (see Chapter 7, Section 7.10, for a discussion of equilibria) toward the anhydride product by removing the water by-product (see Chapter 18, Section 18.6.3). Remember that such techniques are an application of Le Chatelier s principle (discussed in Section 18.3). Even when this is done, isolation of pure anhydrides by this method can be difficult. Unreacted acid may contaminate the product and atternpts to remove the acid with aqueous base may induce hydrolysis of the anhydride. 

The second example involves an acyl transfer from chloride to water. The addition and elimination reactions are combined into one step. Although the arrows do keep track of the electrons involved in the reaction, such steps are known not to occur simultaneously, and thus the electron-pushing notation does not reflect what is known about the mechanism. 

The reaction of 1,2,4-triazine 4-oxides 55 with water in the presence of benzoyl chloride affords 3-hydroxy-1,2,4-triazines 78. The mechanism suggested for this reaction includes acylation of the substrate at the oxygen of the iV-oxide group, followed by the addition of water to the 1,2,4-tiiazinium cation and the autoaromatization of the (T -adducts with the elimination of benzoic acid. 

A reasonable mechanism for their formation starts with the primary adduct 339, which is capable of ring-opening to the ketene 340 this can either be trapped by addition of water (337) or undergo intramolecular acylation followed by dehydrogenation (338). 

Mechanism of esterification of carboxylic acids The esterification of carboxylic acids with alcohols is a kind of nncleophilic acyl snbstitntion. Protonation of the carbonyl ojq gen activates the carbonyl gronp towards nncleophilic addition of the alcohol. Proton transfer in the tetrahedral intermediate converts the hydrojq l group into - 0H2 group, which, being a better leaving group, is eliminated as neutml water molecule. The protonated ester so formed finally loses a proton to give the ester. 

Yang et al reeently reported on the meehanism of 4-chlorobenzoyl eoenzyme A dehalogenase, an enzyme that catalyzes the hydrolytic dehalogenation of 4-chlo-robenzoyl coenzyme A (4-CBA-CoA) to form 4-hydro-xybenzoyl coenzyme A (4-HBA-CoA). The mechanism involves attack of an active site carboxylate at C4 of the substrate benzoyl ring to form a Meisenheimer complex (shown above). Loss of chloride ion from this intermediate then forms an arylated enzyme intermediate that is hydrolyzed to free enzyme plus 4-HBA-CoA by the addition of water at the acyl carbon. In later work, Taylor et al examined the activation of the 4-CB A-CoA toward nucleophilic attack by the active site carboxylate group. 

The reaction is also called hydrocarboxylation. According to a later modification, the alkene first reacts with carbon monoxide in the presence of the acid to form an acyl cation, which then is hydrolyzed with water to give the carboxylic acid.97 The advantage of this two-step synthesis is that it requires only medium pressure (100 atm). Aqueous HF (85-95%) gave good results in the carboxylation of alkenes and cycloalkenes.98 Phosphoric acid is also effective in the carboxylation of terminal alkenes and isobutylene, but it causes substantial oligomerization as well.99 100 Neocarboxylic acids are manufactured industrially with this process (see Section 7.2.4). The addition may also be performed with formic acid as the source of CO (Koch-Haaf reaction).101 102 The mechanism involves carbocation formation via protonation of the alkene97 103 [Eq. (7.10)]. It then reacts with carbon monoxide... 

Stoichiometry (28) is followed under neutral or in alkaline aqueous conditions and (29) in concentrated mineral acids. In acid solution reaction (28) is powerfully inhibited and in the absence of general acids or bases the rate of hydrolysis is a function of pH. At pH >5.0 the reaction is first-order in OH but below this value there is a region where the rate of hydrolysis is largely independent of pH followed by a region where the rate falls as [H30+] increases. The kinetic data at various temperatures both with pure water and buffer solutions, the solvent isotope effect and the rate increase of the 4-chloro derivative ( 2-fold) are compatible with the interpretation of the hydrolysis in terms of two mechanisms. These are a dominant bimolecular reaction between hydroxide ion and acyl cyanide at pH >5.0 and a dominant water reaction at lower pH, the latter susceptible to general base catalysis and inhibition by acids. The data at pH <5.0 can be rationalised by a carbonyl addition intermediate and are compatible with a two-step, but not one-step, cyclic mechanism for hydration. Benzoyl cyanide is more reactive towards water than benzoyl fluoride, but less reactive than benzoyl chloride and anhydride, an unexpected result since HCN has a smaller dissociation constant than HF or RC02H. There are no grounds, however, to suspect that an ionisation mechanism is involved. 

The isocyanate can he isolated if the Curtius degradation is carried out in an inert solvent. The isocyanate also can be reacted with a heteroatom-nucleophile either subsequently or in situ. The heteroatom nucleophile adds to the C=N double bond of the isocyanate via the mechanism of Figure 8.12. In this way, the addition of water initially results in a carbamic acid. However, all carbamic acids are unstable and immediately decarboxylate to give amines (see Figure 8.5). Because of this consecutive reaction, the Curtius rearrangement represents a valuable amine synthesis. The amines formed contain one C atom less than the acyl azide substrates. It is due to this feature that one almost often refers to this reaction as Curtius degradation, not as Curtius rearrangement. 

A. N-Phenylhydroxylamine. Het, 5% rhodium on carbon (1.1 g) (Note 1), tetrahydrofuran (200 nt) (Note 2) and nitrobenzene (41.0 g) (Note 3) are Introduced Into a 500-mL, three-necked, round-bottomed flask fitted with a mechanical stirrer, thermometer and condenser. The mixture Is cooled to 15°C and hydrazine hydrate (17.0 g) (Note 4) is introduced Into the reaction mixture from a pressure-equalized addition funnel over 30 min. The temperature of the mixture 1s maintained at 25-30°C throughout the addition by means of an ice-water bath. After the mixture is stirred for a further 2 hr at 25-30 C, the reaction is complete (Note 5), The mixture Is filtered and the catalyst washed with a little tetrahydrofuran. The solution Is used immediately In the acylation step (Note 6). 

The mechanism of alcohol oxidation with NAD has several analogies in laboratory chemistry. A base removes the 0-H proton from the alcohol and generates an alkoxide ion, which expels a hydride ion leaving group as in the Cannizzaro reaction (Section 19.13). The nucleophilic hydride ion then adds to the C=C-C=N part of NAD in a conjugate addition reaction, much the same as water adds to the C=C-O=0 part of the ,j8 unsaturated acyl CoA in step 2. 

The second example in this chapter is the carboxypeptidase A (CPA) [42, 43]. CPA is an exo-peptidase which can hydrolyze the C terminal amino acid from the peptide or ester substrates, whose X-ray structures have been reported for its native form [44, 45] or enzyme-inhibitor complex [46-51]. In addition, an X-ray stmc-mre of enzyme complexed with the proteolysis product was also reported [52]. No matter accumulation of experimental data, its reaction mechanisms still remain incompletely understood [53]. In particular, two major mechanisms, promoted-water pathway and nucleophilic pathway (traditionally it was named as anhydride pathway), using a peptide as the model substrate are depicted in Fig. 9.4. The nucleophilic pathway envisages an acyl-enzyme (AE) intermediate resulting from direct... 

Small molecule-small molecule reactions. These reactions are almost non-existent in the mechanism except for the addition of oxygen to small radical fragments such as the acyl radical from type I cleavage of methyl ketones. The relatively high solubility of oxygen and the mobility of these small molecules in a medium that is essentially equivalent to a very viscous liquid in local regions, minimizes any special "polymer effect". The other stable small molecule product is water which may have effects on electrical properties but does not participate in the photooxidation sequence per se. 

Hydrolyses of acyl halides are sometimes described in terms of the Sn1-Sn2 duality of the mechanism, or variants of it (56, 57), but these descriptions are unsatisfactory because they neglect the possibility of rehybridization of the carbonyl group in the course of reaction. Strongly electron withdrawing substituents favor nucleophilic addition by water to acyl centers, with assistance by a second water molecule acting as a general base (56-60), and good evidence for this mechanism exists in hydrolyses of carboxylic anhydrides and diaryl carbonates. This addition step should be followed by very rapid conversion of an anionic covalent intermediate into products, and the intermediate should have only a transient existence, at most, in polar, nucleophilic solvents. 

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