Acylation, quantitative studies

Carbamoyl radicals, like acyl radicals, show a net nucleophilic character which permits the amidation of protonated heteroaromatic bases. Quantitative studies concerning the polar character of the carbamoyl radicals have not yet been published, but the complete selectivity of attack at the a- and /-positions of protonated heteroaromatic bases indicates a definite nucleophilic character and synthetic value. 

The labile character of the Zn11— OR species 8b (although isolable as crystals, 8b is stable only at a limited alkaline pH region in aqueous solution) and the vulnerability of the acyl intermediate 10 in aqueous solution prevented more extensive, quantitative studies about the nature of Znn-bound alkoxide. 

A review of solvent properties of, and organic reactivity in, ionic liquids demonstrates the relatively small number of quantitative studies of electrophilic aromatic substitution in these media.3 Studies mentioned in the review indicate conventional polar mechanisms. 1-Methylpyrrole reacts with acyl chlorides in the ionic liquid 1-butylpyridinium tetrafluoroborate to form the corresponding 2-acylpyrrole in the presence of a catalytic amount of ytterbium(III) trifluoromethanesulfonate.4 The ionic liquid-catalyst system is recyclable. Chloroindate(III) ionic liquids5 are catalytic media for the acylation, using acid chlorides and anhydrides, of naphthalene, benzene, and various substituted benzenes at 80-120 °C. Again the ionic liquid is recyclable. 

A.R. Emery, V. Gold, Quantitative studies of the reactivities of mixed carboxylic anhydrides. Part. I. The composition of the acylation products in the reaction between acetic chloroacetic anhydrides and primary aromatic amines. J. Chem. Soc. 1950 1443-1447... 

AijAT-dicyclohexylcarhodiimide (DCC) also leads to essentially quantitative conversion of amic acids to isoimides, rather than imides (30,31). Combinations of trifluoroacetic anhydride—triethjlarnine and ethyl chi oroform a te—triethyl amine also result in high yields of isoimides (30). A kinetic study on model compounds has revealed that isoimides and imides are formed via a mixed anhydride intermediate (12) that is formed by the acylation of the carboxylic group of amic acid (8). 

Recent progress of basic and application studies in chitin chemistry was reviewed by Kurita (2001) with emphasis on the controlled modification reactions for the preparation of chitin derivatives. The reactions discussed include hydrolysis of main chain, deacetylation, acylation, M-phthaloylation, tosylation, alkylation, Schiff base formation, reductive alkylation, 0-carboxymethylation, N-carboxyalkylation, silylation, and graft copolymerization. For conducting modification reactions in a facile and controlled manner, some soluble chitin derivatives are convenient. Among soluble precursors, N-phthaloyl chitosan is particularly useful and made possible a series of regioselective and quantitative substitutions that was otherwise difficult. One of the important achievements based on this organosoluble precursor is the synthesis of nonnatural branched polysaccharides that have sugar branches at a specific site of the linear chitin or chitosan backbone [89]. 

Since the imidazolide method proceeds almost quantitatively, it has been used for the synthesis of isotopically labeled esters (see also Section 3.2), and it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. This advantage has been utilized in biochemistry for the study of transacylating enzymes. A number of enzymatic transacylations (e.g., those catalyzed by oc-chymo-trypsin) have been shown to proceed in two steps an acyl group is first transferred from the substrate to the enzyme to form an acyl enzyme, which is then deacylated in a second step. In this context it has been shown[21] that oc-chymotrypsin is rapidly and quantitatively acylated by Af-fraw.s-cinnamoylimidazole to give /ra/w-cinnamoyl-a-chymotrypsin, which can be isolated in preparative quantities and retains its enzymatic activity (see also Chapter 6). 

We have studied this reaction in considerable detail (88) and have found that when one uses quinine (eq. [25]) or any one of the chiral bases, a variety of aldehydes react with ketene to form the corresponding p-lactones in excellent chemical and nearly quantitative enantiomeric yields. Equation [25] exemplifies the reaction. Note that mild basic hydrolysis of the lactone furnishes a trichlo-rohydroxy acid that was prepared earlier by McKenzie (89). If one uses quinidine as catalyst, the process furnishes the natural (S)-malic acid. Note that ketene first acylates the free hydroxyl group of quinine, so that the actual catalyst is the alkaloid ester. 

In agreement with these observations, kinetic studies on N O acyl migrations and ring-chain tautomerism have quantitatively confirmed the differences just mentioned. 

The original work by Monsanto identified [Rh(CO)2l2] as the major Rh spedes under their process conditions and reaction of Mel with this complex as rate controlling for the process [3]. However, the proposed primary product of oxidative addition of Mel to [Rh(CO)2l2r, [RhMe(CO)2l3] , was not observed in early work. Forster [10] studied the reaction of Mel with [Rh(CO)2l2] by IR and found that it gave the acyl complex [Rh(C(0)Me)(C0)l3] , which was also isolated and characterized in the solid state as a dimer. The reaction could be followed quantitatively but the observed rate constant would be antidpated to be a composite of the rate constants for the formation of the intermediate [RhMe(CO)2l3r and its further reaction to [Rh(C(0)Me)(C0)l3] (Eq. (15)) and (Eq. (16)). 

Few conformational studies have been carried out on saturated or partially unsaturated C-acyl heterocycles. Quantitative thermodynamic data on conformer stabilities and barriers are seldom available. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

We have now extended these studies to synthetic phospholipids that contain short chain fatty acyl groups and which are water soluble, such as dibutyryl and dihexanoyl phosphatidylcholine (PC). These phospholipids are monomeric below their critical micelle concentration (cmc), yet activate the enzyme. In order to carry out kinetic studies, the long chain phospholipid substrate must generally be solubilized by a detergent such as Triton X-100 which serves as an inert matrix. Further understanding of the mechanism of the activation by short-chain phospholipids requires first a quantitation of the solubilization of these compounds by detergent ... 

Acylation of 2- -octylthiochroman by AczO is quantitative at the 6-position (Equation 23) <2003PS(178)993> and benzoylation of thioxanthene occurs at the 2- and 7-positions and both ketone functions have been converted into the hydrazones and thence the diazo compound 277. The bis-carbene derived from 277 by cryogenic photolysis has been used to study magnetic coupling interactions through the sulfur atom (Scheme 32) <1997JA8058>. 

An additional example for the usefulness of IR spectroscopy in studying drug interactions with phospholipid vesicles is the quantitative determination of acyl chain conformation in gramicidin-DPPC mixtures [63]. The technique provides a quantitative measure of the extent to which membrane-spanning peptides induce disorder of phospholipid gel phases and order in liquid crystalline phases. 

Polymer Photochemistry. The occurrence of these reactions in polymeric ketones was first demonstrated by Guillet and Norrish (6, 7), who studied poly (methyl vinyl ketone) in solution and showed that the main features of the photodegradation could be accounted for quantitatively on the basis of Type I and Type II reactions. The conclusion was later confirmed by Wissbrun (13). Recent studies of the ethylene-carbon monoxide polymer (9) confirm that both Type I and Type II reactions occur. The Type I reaction results in the formation of two polymer radicals, one of which is an acyl radical which may subsequently decarbonyl-ate (Reaction 4). 

Cliffe et al. [212] studied the use of TFA-methyl esters of amino acids for quantitative analysis. The yields of the derivatives depend on the reaction conditions esterification was performed with 4 M methanolic HC1 for 90 min at 65°C and acylation with 20% TFA anhydride in dichloromethane at 120°C for 20 min. Injection into the chromatograph was carried out with the aid of a pre-column and the analysis was accomplished on the above-mentioned mixed stationary phase. Fig. 5.16 shows a typical analysis of a known mixture performed by this procedure. Replicate analysis showed a poor reproducibility for Met, Tyr, Arg and Cys (coefficient of variation 20%) and His was not acylated at all. This result is mainly caused by the strong dependence of the yield on the reaction conditions and the instability and high volatility of the derivatives (XE-60 is present in the stationary phase). 

---