Acyl derivatives reaction mechanism

Only in 1961 did Woodward and Olofson succeed in elucidating the true mechanism of this interesting reaction by making an extensive use of spectroscopic methods. The difficulty was that the reaction proceeds in many stages. The isomeric compounds formed thereby are extremely labile, readily interconvertible, and can be identified only spectroscopically. The authors found that the attack by the anion eliminates the proton at C-3 (147) subsequent cleavage of the N—0 bond yields a -oxoketene imine (148) whose formation was established for the first time. The oxoketene imine spontaneously adds acetic acid and is converted via two intermediates (149, 150) to an enol acetate (151) whose structure was determined by UV spectra. Finally the enol acetate readily yields the W-acyl derivative (152). 

In the following the reaction is outlined for an a-bromination. The reaction mechanism involves formation of the corresponding acyl bromide 3 by reaction of carboxylic acid 1 with phosphorus tribromide PBr3. The acyl bromide 3 is in equilibrium with the enol derivative 4, which further reacts with bromine to give the a -bromoacyl bromide 5 ... 

The 0-acyl derivatives of hydroxamic acids give isocyanates when treated with bases or sometimes even just on heating, in a reaction known as the Lossen rearrangement. The mechanism is similar to that of 18-13 and 18-14 ... 

The conclusions derived from the preceding experiments may be summarized with the aid of the reaction mechanism illustrated in Scheme II. The ester undergoes a rapid, reversible association with the cycloamylose, C—OH. An alkoxide ion derived from a secondary hydroxyl group of the cycloamylose may then react with an included ester molecule to liberate a phenolate ion and produce an acylated cycloamylose. This reaction is characterized by a rate constant, jfc2(lim), the maximal rate constant for the appearance of the phenolate ion from the fully complexed ester in the pH range where the cycloamylose is completely ionized. Limiting rates are seldom achieved, however, because of the high pK of cycloamylose. 

Although kinetic evidence for prior equilibrium inclusion was not obtained, competitive inhibition by cyclohexanol and apparent substrate specificity once again provide strong support for this mechanism. Since the rate of the catalytic reaction is strictly proportional to the concentration of the ionized hydroxamate function (kinetic and spectrophotometric p/Cas are identical within experimental error and are equal to 8.5), the reaction probably proceeds by a nucleophilic mechanism to produce an acyl intermediate. Although acyl derivatives of N-alkylhydroxamic acids are exceptionally labile in aqueous solution, deacylation is nevertheless the ratedetermining step of the overall hydrolysis (Gruhn and Bender, 1969). 

It therefore appeared that a general mechanism for enzymatic esterification of phenolic acids with glucose was operative, whereas the reaction with other alcoholic moieties proceeded via carboxyl-activated acyl derivatives. [In this context it should be emphasized that glucose esters must not be confused with glucosides different enzymes are involved in the biosynthesis of these two types of phenolic glucose derivatives (36)]. 

The mechanism for bacterial synthesis of PHA is not the simple dehydration reaction between alcohol and carboxyl groups. It is more complicated and involves the coenzyme A thioester derivative of the hydroxyalkanoic acid monomer (produced from the organic feedstock available to the bacteria) [Kamachi et al., 2001], Growth involves an acyl transfer reaction catalyzed by the enzyme PHA synthase (also called a polymerase) [Blei and Odian,... 

Nucleophilic attack at sulfur is implicated in many reactions of 1,2,4-thiadiazoles <84CHEC-I(6)463> and in general soft nucleophiles attack at sulfur. For example, reaction of 3-hydroxy-5-phenyl-1,2,4-thiadiazole (23) with acetic anhydride in the presence of dbu at 130°C gives the thiazoles (31) and (32) <85JHC1497>. These products may be reasonably explained by the mechanism outlined in Scheme 9 in which the thiadiazole ring is opened by the acetic anhydride carbanion. There is some evidence that (32) may arise from attack of the carbanion on the A-acylated derivative (30a) (Scheme 9) <85JHC1497>. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

A treatment of the many types of replacement reaction which have received study by carbohydrate chemists would of necessity be superficial and thus defeat the present purpose. Instead, an attempt will be made to gather all information which sheds light on the mechanisms of a few types of reaction. The reactions of 0-acyl derivatives of sugars, glycosides, and glycosyl halides were chosen because of the central role these substances play in carbohydrate chemistry. 

The 2-hydroxyglycals provide additional source material for the study of dismutation reactions, the reaction of the acyl derivatives of the hexoses climaxing in di-O-acetylkojic acid or di-O-benzoylkojic acid through loss of acetic or benzoic acid and of the O-methyl derivatives in 5-(methoxymethyl)-2-furaldehyde through loss of methanol. The formation of the 2-hydroxyglycals as intermediates in the reaction of some alkalis on sugars has been proposed by Kusin8 in an effort to explain the cationic dependence exhibited by the products. His mechanism has not, however, been established. 

As we study these conversions of acid derivatives, it may seem that many individual mechanisms are involved. But all these mechanisms are variations on a single theme the addition-elimination mechanism of nucleophilic acyl substitution (Key Mechanism 21-1). These reactions differ only in the nature of the nucleophile, the leaving group, and proton transfers needed before or after the actual substitution. As we study these mechanisms, watch for these differences and don t feel that you must learn each specific mechanism. 

The reason these reactions occur can be found in the relative stabilities of the anions involved. This approach could be of general use for the synthesis of inherently chiral calix[4]arenes. The stabilization of the monoanion of a mono-0-alkyl/-acyl calix[4]arene by two intramolecular hydrogen bonds explains the usually easy access to 1,3-derivatives. However, upon further deprotonation the monoanion of a 1,2-O-alkyl (1,2-O-acyl) derivative is stabilized by an intramolecular hydrogen bond (unlike the analogous 1,3-derivative) and rearrangement occurs if there is a reaction pathway available. For the phosphorotropic rearrangement the authors assume a cyclic intermediate with five-coordinated phosphorus, which is not unreasonable although an intermolecular mechanism is not strictly ruled out. 

Summary In recent years trimethylsilylphosphanes proved to be versatile starting compounds in the syntheses of phosphaalkenes and phosphaalkynes. The tris(trimethylsilyl) derivative, for example, reacts with acyl chlorides in a molar ratio of 1 1 give the corresponding [l-(trimethylsiloxy)-alkylidene]trimethylsilylphosphanes first. From a subsequent hexamethyldisiloxane elimination catalyzed by solid sodium hydroxide at 110-120 C many phosphaalkynes have been obtained so far. In order to understand the underlying reaction mechanism, studies on the chemical behavior of [l-bis(l,2-dimethoxy-ethane-0,0 )fithoxy-2,2-dimethylpropylidene]trimethylsilylphosphan prepared by lithiation of the related trimethylsiloxy derivative are being started. 

This reaction converts a less reactive acyl derivative (a carboxylic acid) into a more reactive one (an acid chloride). This is possible because thionyl chloride converts the OH group of the acid into a better leaving group, and because it provides the nucleophile (Cl ) to displace the leaving group. The steps in the process are illustrated in Mechanism 22.5. 

The mid-chain dehydrogenation of saturated fatty acyl derivatives is carried out by a large family of 02-dependent, nonheme diiron-containing enzymes known as desaturases. Both soluble and membrane-bound desaturases have been characterized. The mechanism of desaturation is thought to involve the stepwise syn removal of vicinal hydrogen atoms via a short-lived carbon-centered radical intermediate. The most common desaturase inserts a (Z)-double bond between the C-9,10 carbons of a stearoyl thioester however, many variations of this prototypical reaction have been discovered. Accounting for this diversity in terms of subtle alterations in active-site architecture constitutes a new frontier for research in this area. 

First, we will discuss reactions in which hydrogen or a metallic ion (or in one case phosphorus or sulfur) adds to the heteroatom and second reactions in which carbon adds to the heteroatom. Within each group, the reactions are classified by the nature of the nucleophile. Additions to isocyanides, which are different in character, follow. Acyl substitution reactions that proceed by the tetrahedral mechanism, which mostly involve derivatives of carboxylic acids, are treated at the end. 

Scheme 4. Reaction of [Rh(p-pz)(L)2]2, 72 (L = /-BuNC) with MeCCI, and proposed mechanism for the formation of the acyl derivative 74 (see text). [Adapted from (94).]...

Although cephalosporin C is divisable into a-aminoadipic acid, cysteine, and valine, the actual mechanism whereby Cephalosporium sp. incorporates the three amino acids into cephalosporin C has not been established, Arnstein and Morris isolated 8 (a-aminoadipyl) cysteinyl valine from mycelia of Penicillium chrysogenum and suggested that the tripeptide is a precursor in all penicillin biosynthesis.. This same tripeptide also appears to be found in the intracellular pool of Cephalosporium sp.- The final postulated step in the biosynthesis of penicillin is an acyl transfer reaction, or the production of 6-aminopeni-cillanic acid if precursor is not added. Cephalosporium sp. apparently do not produce sidechain amidases or acyl transferases, and no 7-ACA has been reported found in the fermentation. Thus, to obtain clinically useful antibiotics, chemical manipulation of cephalosporin C is necessary. Synthesis of many 7-acyl derivatives was possible once a practical cleavage reaction made available large amounts of 7-ACA from cephalosporin C. of these derivatives, sodium cephalothin was the first... 

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