Phenyl acetate, reaction

Fries rearrangement and phenol acetylation The Fries rearrangement is the acid catalysed transformation of aryl esters into hydroxyarylketones. Both this rearrangement and the two-step transformation (esterification, Fries rearrangement) in one-pot operation of phenols with carboxylic acid or anhydrides will be examined hereafter. Most studies in which acid zeolites were used as catalysts (Tables 3.6 and 3.7) deal with the synthesis of o- and p-hydroxyacetophenones (o- and p-HAP) either by the Fries rearrangement of phenyl acetate [Reaction (3.5)] ... 

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

To hydrolyse an ester of a phenol (e.g., phenyl acetate), proceed as above but cool the alkaline reaction mixture and treat it with carbon dioxide until saturated (sohd carbon dioxide may also be used). Whether a solid phenol separates or not, remove it by extraction with ether. Acidify the aqueous bicarbonate solution with dilute sulphuric acid and isolate the acid as detailed for the ester of an alcohol. An alternative method, which is not so time-consuming, may be employed. Cool the alkaline reaction mixture in ice water, and add dilute sulphuric acid with stirring until the solution is acidic to Congo red paper and the acid, if aromatic or otherwise insoluble in the medium, commences to separate as a faint but permanent precipitate. Now add 5 per cent, sodium carbonate solution with vigorous stirring until the solution is alkaline to litmus paper and the precipitate redissolves completely. Remove the phenol by extraction with ether. Acidify the residual aqueous solution and investigate the organic acid as above. 

Ingold and his co-workers used the competitive method in their experiments, in which nitration was brought about in acetic anhydride. Typically, the reaction solutions in these experiments contained o-8-I 4 mol of nitric acid, and the reaction time, depending on the reactivities of the compounds and the temperature, was 0-5-10 h. Results were obtained for the reactivities of toluene, > ethyl benzoate, the halogenobenzenes, ethyl phenyl acetate and benzyl chloride. Some of these and some later results are summarized in table 5.2. Results for the halogenobenzenes and nitrobiphenyls are discussed later ( 9.1.4, lo.i), and those for a series of benzylic compounds in 5,3.4. 

However, this method is appHed only when esterification cannot be effected by the usual acid—alcohol reaction because of the higher cost of the anhydrides. The production of cellulose acetate (see Fibers, cellulose esters), phenyl acetate (used in acetaminophen production), and aspirin (acetylsahcyhc acid) (see Salicylic acid) are examples of the large-scale use of acetic anhydride. The speed of acylation is greatiy increased by the use of catalysts (68) such as sulfuric acid, perchloric acid, trifluoroacetic acid, phosphoms pentoxide, 2inc chloride, ferric chloride, sodium acetate, and tertiary amines, eg, 4-dimethylaminopyridine. 

We should distinguish between the phrases nucleophilic attack and nucleophilic catalysis. Nucleophilic attack means the bond-forming approach by an electron pair of the nucleophile to an electron-deficient site on the substrate. In nucleophilic catalysis this results in an increase in the rate of reaction relative to the rate in the absence of the catalyst. However, nucleophilic attack may not result in catalysis. Thus, if methylamine is reacted with a phenyl acetate, the reaction observed is amide formation, not hydrolysis, because the product of the nucleophilic attack is more stable than is the ester to hydrolysis. 

To a solution of 4 g of sodium in 200 ml of n-propanol is added 39 g of homovanillic acid-n-propyl ester (boiling point 160°C to 162°C/4 mm Hg) and the mixture is concentrated by evaporation under vacuum. After dissolving the residue in 200 ml of dimethylformamide and the addition of 0.5 gof sodium iodide, 26.2 g of chloracetic acid-N,N-diethylamide are added drop-wise with stirring at an internal temperature of 130°C, and the mixture is further heated at 130°C for three hours. From the cooled reaction mixture the precipitated salts are removed by filtering off with suction. After driving off the dimethylformamide under vacuum, the product is fractionated under vacuum, and 44.3 g of 3-methoxy-4-N,N-diethylcarbamido-methoxy phenyl acetic acid-n-propyl ester are obtained as a yellowish oil of boiling point 210°C to 212°C/0,7 mm Hg,... 

Only the hydrophobic and steric terms were involved in these equations. There are a few differences between these equations and the corresponding equations for cyclo-dextrin-substituted phenol systems. However, it is not necessarily required that the mechanism for complexation between cyclodextrin and phenyl acetates be the same as that for cyclodextrin-phenol systems. The kinetically determined Kj values are concerned only with productive forms of inclusion complexes. The productive forms may be similar in structure to the tetrahedral intermediates of the reactions. To attain such geometry, the penetration of substituents of phenyl acetates into the cyclodextrin cavity must be shallow, compared with the cases of the corresponding phenol systems, so that the hydrogen bonding between the substituents of phenyl acetates and the C-6 hydroxyl groups of cyclodextrin may be impossible. 

Quantitative structure-reactivity analysis is one of the most powerful tools for elucidating the mechanisms of organic reactions. In the earliest study, Van Etten et al. 71) analyzed the pseudo-first-order rate constants for the alkaline hydrolysis of a variety of substituted phenyl acetates in the absence and in the presence of cyclodextrin. The... 

The chiral acetate reagent is readily prepared from methyl mandelate [methyl (A)-hydroxy-phenyl acetate] which is first converted by treatment with phcnylmagnesium bromide into the triphenylglycol783, c (see Section 1.3.4.2.2.2.) and subsequently transformed into the acetate by reaction with acetyl chloride in the presence of pyridine. Thereby, the secondary hydroxyl group of the glycol is esterified exclusively. Both enantiomers of the reagent are readily accessible since both (R)- and (5)-hydroxyphenylacelic acid (mandelic acids) arc industrial products. 

The phenol ArOH is always a side product, resulting from some ArO that leaks from the solvent cage and abstracts a hydrogen atom from a neighboring molecule. When the reaction was performed on phenyl acetate in the gas phase, where there are no solvent molecules to form a cage (but in the presence of isobutane as a source of abstractable hydrogens), phenol was the chief product and virtually no o- or p-hydroxyacetophenone was found." Other evidence" for the mechanism is that... 

The availability of Nafion on silica has not only lowered the cost of the resin but also has made it versatile (Sun et al., 1997 Harmer et al., 1998). A number of industrially important reactions have been attempted, with considerable success, with these catalysts. Consider the Fries rearrangement of phenyl acetate to p-acetyl phenol (/t-hydroxy acetophenone). This has been accomplished by Hoelderich and co-workers (Heidekum, 1998). In the ca.se of alkylation of benzene with benzyl alcohol, Amberlyst-15 and p-toluene sulphonic acid are ineffective and Nafion on silica works well at 80 °C. 

If one of the species is anionic and we need to transport it to the organic phase, then a phase-transfer catalyst may be employed. Consider the example of benzyl penicillin where the reaction between phenyl acetic acid and the penicillin carboxylate ion, with penicillin amidase as a catalyst, is relevant, and which at pH 4.5 - 5.0 is shifted in the desired direction. Here a catalyst like tetrabutylammonium halide works, and with chloroform as a solvent 60% yield can be realized in contrast to a yield of only 5 - 10 % in water. 

The reactivity of hydrido(ethoxo) complex 4 was examined (Scheme 6-15) [8]. Metatheses similar to those postulated for alcohol exchange (Eq. 6.5) occurred between HCl, LiCl, phenyl acetate or primary amines and yielded complexes 94. The reaction of 4 with cyclic anhydrides proceeded similarly to give iridium-assisted ring opening products 95. Heterocumulenes afforded the inserhon products 96 into the Ir-O bond. 

Values of /c2 and Kd for the reactions of the cycloamyloses with a variety of phenyl acetates are presented in Table IV. The rate constants are normalized in the fourth column of this table to show the maximum accelerations imposed by the cycloamyloses. These accelerations vary from 10% for p-f-butylphenyl acetate to 260-fold for m-f-butylphenyl acetate, again showing the clear specificity of the cycloamyloses for meta-substituted esters. Moreover, these data reveal that the rate accelerations and consequent specificity are unrelated to the strength of binding. For example, although p-nitrophenyl acetate forms a more stable complex with cyclohexa-amylose than does m-nitrophenyl acetate, the maximal rate acceleration, h/kan, is much greater for the meta isomer. 

As a simple model for the enzyme penicillinase, Tutt and Schwartz (1970, 1971) investigated the effect of cycloheptaamylose on the hydrolysis of a series of penicillins. As illustrated in Scheme III, the alkaline hydrolysis of penicillins is first-order in both substrate and hydroxide ion and proceeds with cleavage of the /3-lactam ring to produce penicilloic acid. In the presence of an excess of cycloheptaamylose, the rate of disappearance of penicillin follows saturation kinetics as the cycloheptaamylose concentration is varied. By analogy to the hydrolysis of the phenyl acetates, this saturation behavior may be explained by inclusion of the penicillin side chain (the R group) within the cycloheptaamylose cavity prior to nucleophilic attack by a cycloheptaamylose alkoxide ion at the /3-lactam carbonyl. The presence of a covalent intermediate on the reaction pathway, although not isolated, was implicated by the observation that the rate of disappearance of penicillin is always greater than the rate of appearance of free penicilloic acid. 

More recently, Kaiser and coworkers reported enantiomeric specificity in the reaction of cyclohexaamylose with 3-carboxy-2,2,5,5-tetramethyl-pyrrolidin-l-oxy m-nitrophenyl ester (1), a spin label useful for identifying enzyme-substrate interactions (Flohr et al., 1971). In this case, the catalytic mechanism is identical to the scheme derived for the reactions of the cycloamyloses with phenyl acetates. In fact, the covalent intermediate, an acyl-cyclohexaamylose, was isolated. Maximal rate constants for appearance of m-nitrophenol at pH 8.62 (fc2), rate constants for hydrolysis of the covalent intermediate (fc3), and substrate binding constants (Kd) for the two enantiomers are presented in Table VIII. Significantly, specificity appears in the rates of acylation (fc2) rather than in either the strength of binding or the rate of deacylation. 

The reaction of potassium 3-amino-4-oxo-3,4-dihydroquinazoline-2-thiolate 62 with a-bromophenylacetic acid 63 resulted in the formation of (3-amino-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-phenyl-acetic acid methyl ester 64 which on alkali treatment and subsequent acidification resulted in the synthesis of 2-phenyl- 1-thia-4,4a,9-triaza-anthracene-3,10-dione 65 <1999JCR(S)86>. Similarly, the reaction of potassium 3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3- pyrimidine-2-thiolate 66 with a-bromo-ester 67 resulted in the formation of 2-(3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3- / pyrimidin-2-ylsulfanyl)-propionic acid ethyl ester 68. Subsequent treatment with alkali followed by acidification resulted in the formation of 2,3,7-trimethyl-3a,9a-dihydro-l,8-dithia-4a,5,9-triazacyclopenta[ ]naphthalene-4,6-dione 69 <2000JHC1161>... 

An additional example is the observed moderate acceleration in the cleavage of particular phenyl esters in the presence of a cyclodextrin. In such cases, the bound ester is attacked by an hydroxyl group on the cyclodextrin to yield a new ester. There was found to be a significant enhancement of phenol release from meta-substituted phenyl acetate on interaction with cyclodextrin (relative to other esters which do not fit the cavity so well) (Van Etten, Clowes, Sebastian Bender, 1967). During the reaction, the acyl moiety transfers to an hydroxyl group on the... 

Initial theoretical studies focused on steps (1) and (2). Several model systems were examined with ab initio calculations.1191 For the reaction of methyl amine with methyl acetate, it was shown that the addition/elimi-nation (through a neutral tetrahedral intermediate) and the direct displacement (through a transition state similar to that shown in Figure 5a) mechanisms for aminolysis had comparable activation barriers. However, in the case of methyl amine addition to phenyl acetate, it was shown that the direct displacement pathway is favored by approximately 5 kcal/mol.1201 Noncovalent stabilization of the direct displacement transition state was therefore the focus of the subsequent catalyst design process. 

At the start of this section the cleavage of meta- and para-substituted phenyl acetates by a- and )S-CD was discussed in detail and a variety of evidence was cited that is consistent with the mechanisms A and B, in Scheme 2. Further support for the view that para-substituents tend to force the phenyl group out of the cavity (Scheme 2B) comes from the different effects that neutral additives (potential inhibitors) have on the cleavage of m- and p-nitrophenyl acetate (mNPA and pNPA). In brief, species which bind to CDs, and inhibit the reaction of mNPA, do not necessarily inhibit that of pNPA (Tee and Hoeven, 1989 Tee et al., 1993b). 

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