Acyl transfer reactions, cationic

Acyl-transfer reactions are some of the most important conversions in organic chemistry and biochemistry. Recent work has shown that adjacent cationic groups can also activate amides in acyl-transfer reactions. Friedel-Crafts acylations are known to proceed well with carboxylic acids, acid chlorides (and other halides), and acid anhydrides, but there are virtually no examples of acylations with simple amides.19 During studies related to unsaturated amides, we observed a cyclization reaction that is essentially an intramolecular acyl-transfer reaction involving an amide (eq 15). The indanone product is formed by a cyclization involving the dicationic species (40). To examine this further, the related amides 41 and 42 were studied in superacid promoted conversions (eqs 16-17). It was found that amide 42 leads to the indanone product while 41... 

Allosteric behavior of the heterotropic variety is seen in the interaction between polymer and detergent or polymer and polymer (Shirahama, 1974 Arai et al., 1973 Tsuchida and Osada, 1973). Shinkai et al. (1977b) observed a sigmoid profile of rate constant vs. concentration of cationic detergents in the acyl transfer reaction from p-nitrophenyl acetate (PNPA) to copolymers (7). 

This section describes the nucleophilic reactions—acyl transfer reactions mostly—promoted by micelles and polysoaps. The nucleophiles are imidazoles, oxyanions and thiols, the same catalytic groups found ubiquitously in the enzyme active site. These nucleophiles are remarkably activated in the anionic form in the presence of cationic micelles and cationic polysoaps. These results are explained by the concept of the hydrophobic ion pair (Kunitake et al.,... 

A similar bait and switch approach has been exploited for acyl-transfer reactions (Janda et al., 1990b, 1991c). The design of hapten [10] incorporates both a transition state mimic and the cationic pyridinium moiety, designed to induce the presence of a potential general acid/base or nucleophilic amino acid residue in the combining site, able to assist in catalysis of the hydrolysis of substrate [11] (Appendix entry 2.6). 

Santry and McClelland (1983a) also generated the tetrahedral intermediate of an 0,S-acyl transfer reaction from an orthothiolester precursor [83]. At PH < 3 the cation [84] could be detected by its strong absorption at X = 350 nm and it was concluded from a kinetic analysis that this was in equilibrium with the hemiorthothiolester [85]. 

Enzyme-mimicking systems that contain metal cations have also been designed. A very elegant supramolecular assembly was designed by Sanders et al.I l (see Fig. 7.11). They constructed trimeric porphyrin structures where Zn " " porphyrin moieties function as templates for the organization of substrates into a conformationaUy optimal configuration that undergoes an efficient acyl-transfer reaction or that lead to Diels Alder products. 

The elusive tetrahedral intermediate, long implicated in acyl transfer reactions, has also been isolated. Under the proper conditions, for example, the phthalimidium cation (62) gives the same intermediate (63) that one envisions from hydroxyl group attack on the carbonyl in (64). " ... 

Acylium ion (Section 12 7) The cation R—C=0 Acyl transfer (Section 20 3) A nucleophilic acyl substitution A reaction in which one type of carboxylic acid derivative IS converted to another... 

In the reaction with PNPA, myristoylhistidine [29] in a cationic micelle rapidly forms acetylimidazole as a fairly stable intermediate which is readily observable at 245 nm. On the other hand, a mixed micelle of [29] and N,N-dimethyl-N-2-hydroxyethylstearylammonium bromide [30] leads to the formation and decay of the intermediate, indicating that the acetyl group is transferred from imidazole to hydroxyl groups (Tagaki et al., 1977 Tagaki et al., 1979). This can be a model of cr-chymotrypsin which catalyses hydrolysis of PNPA (non-specific substrate) by initial acylation of the histidyl imidazole followed by acyl transfer to the seryl hydroxyl group (Kirsh and Hubbard, 1972), as indicated schematically in (12). 

Shi and coworkers found that vinyl acetates 68 are viable acceptors in addition reactions of alkylarenes 67 catalyzed by 10 mol% FeCl2 in the presence of di-tert-butyl peroxide (Fig. 15) [124]. (S-Branched ketones 69 were isolated in 13-94% yield. The reaction proceeded with best yields when the vinyl acetate 68 was more electron deficient, but both donor- and acceptor-substituted 1-arylvinyl acetates underwent the addition reaction. These reactivity patterns and the observation of dibenzyls as side products support a radical mechanism, which starts with a Fenton process as described in Fig. 14. Hydrogen abstraction from 67 forms a benzylic radical, which stabilizes by addition to 68. SET oxidation of the resulting electron-rich a-acyloxy radical by the oxidized iron species leads to reduced iron catalyst and a carbocation, which stabilizes to 69 by acyl transfer to ferf-butanol. However, a second SET oxidation of the benzylic radical to a benzylic cation prior to addition followed by a polar addition to 68 cannot be excluded completely for the most electron-rich substrates. 

The transient nature of carbocations arises from their extreme reactivity with nucleophiles. The use of low nucleophilicity gegenions, particularly tetrafluoroborates (BF4 ) enabled Meerwein in the forties to prepare a series of oxonium and carbo-xonium ion salts, such as R30+BF4- and HC(OR)2+ respectively. These Meerwein salts are effective alkylating agents, and transfer alkyl cations in SN2 type reactions. However, simple alkyl cation salts (R+BF4 ) were not obtained in Meerwein s studies. The first acyl tetrafluoroborate, i. e. acetylium tetrafluoroborate was obtained by Seel16 in 1943 by reacting acetyl fluoride with boron trifluoride at low temperature. 

Because of strong transfer reactions, the free radical polymerization of lactones only produces polymers of low molar masses even though the yields are high. High molar masses are achieved by cationic or anionic polymerizations. Both types of polymerization presumably involve an acyl scission, as for example, with 6-caprolactone ... 

The simplest example of a functional micelle is (49), previously demonstrated to be more effective than its trimethylammonium analogue in both esterolysis and bimolecular elimination reactions. It has now been demonstrated that micelles of (49) are more effective catalysts for the hydrolysis of p-nitrobenzoyl phosphate dianion at high pH than non-functional surfactants. " 2,4-Dinitrochloro- and fluoro-benzene react with micelles of (49) at high pH 10" times faster than with hydroxide ion at a comparable external pH. The initial product is (50) and this in turn is hydrolysed in micelles 2.6 x 10 times faster than is 2,4-dinitrophenyl 2-(trimethylammonium)ethyl ether in water at pH 12. Acyl transfer between p-nitrophenyl acetate and (49) gives an intermediate whose hydrolysis is not micelle catalysed. In contrast to the rate acceleration observed in that case, hydrolysis of p-nitrophenyl acetate is inhibited by micelles of (51) since the phenoxide nucleophile is weak and at the reaction pH its micelles are zwitterionic, not cationic. Synthesis of functional choline-type micelles is facilitated by the use of sulphonate (52), which is reactive towards thiophenoxide in aqueous micelles, but its water-insoluble trifluoromethanesulphonate reacts with a range of anions under phase-transfer conditions. " ... 

Staley RH, Wieting RD, Beauchamp JL. Carbenium ion stabilities in the gas phase and solution. An ion cyclotron resonance study of bromide transfer reactions involving alkali ions, alkyl carbenium ions, acyl cations, and cyclic halonium ions. J Am Chem Soc. 1977 99 5964-72. 

If this should be the case, either apparent acyl transfer or amine transfer would be possible by a direct condensation of the preferentially retained product and an acceptor that can readily displace the product that leaves more easily. That such condensation reactions are catalyzed by pepsin in the case of oligopeptides was demonstrated many years ago (54), and is consistent with the neglible free energy decrease in the hydrolysis of interior peptide bonds (55). For transpeptidation reactions in which an apparent E-Tyr amino-enzyme has been postulated, the free energy change in the condensation of an acceptor such as Ac-Phe with tyrosine would be more unfavorable in free solution, but the possibility must be considered that the ammonium pKa of the tyrosine retained at the active site may be lower than that of tyrosine in free solution, perhaps by virtue of the interaction of the carboxylate group of the amino acid with a complementary cationic group of the active site. 

Knowledge of the degree of proton transfer at the transition state of a proton transfer reaction has many useful applications. An especially interesting one, due to Gravitz and Jencks, uses only changes in the Bronsted exponent [60], and is therefore free of any uncertainty produced by lingering doubts that Bronsted exponents do in fact measure transition state structure in a quantitative way. This work deals with the mechanism of formation of the iV,0-trimethylene-phthalimidium cation, 5, from the corresponding iV-acyl ester aminals (equation 15). 

The preparation of amides by reaction of an amine, an acyl chloride, or an acid anhydride in the presence of aqueous alkali is the well-known Schotten-Baumann reaction. Since the rate of reaction of the acyl chloride with amines is greater than the rate of hydrolysis of the acyl chloride, amide formation is favored. In some cases, the stability of acyl chlorides to aqueous caustic solution is surprising. For example, benzoyl chloride may be kept in contact with sodium hydroxide solutions for long periods of time. We presume that a thin layer of sodium benzoate forms rapidly and that this acts as a protective coating unless the benzoyl chloride is stirred or shaken to disturb the protective layer. As a matter of fact, the Schotten-Baumann reaction (and the analogous Hinsberg reaction with aromatic sulfonyl chlorides) appears to be most satisfactory when acyl chlorides are used which are relatively insoluble in water. Many years ago, we noted that the addition of a small percentage of a surfactant (e.g., sodium lauryl sulfate as well as cationic surfactants) assisted in the dispersion of the acyl chloride with an increase in reaction rate. These may have been early examples of phase-transfer reactions. 

The direct reaction of indoles with carbon dioxide at atmospheric pressure to give the 3-carboxylated derivatives has been reported. The reaction occurs in dimethyl for-mamide in the presence of a large excess in lithium t-butoxide whose function is to deprotonate the indole. Although the N-H proton is more acidic, the C(3) anion yields the thermodynamically more stable carboxylated product. Acyl transfer from amides, such as A-(4-nitrophenyl)acetamide to benzene may occur in triflic acid. The mechanism is likely to involve diprotonation of the amide, as shown in (39), and dissociation of the C-N bond to give an acyl cation. The methodology allows the formation of aromatic ketones by inter- or intra-molecular reaction. The acylation of arenes may also be... 

A mild and effective method for obtaining N- acyl- and N- alkyl-pyrroles and -indoles is to carry out these reactions under phase-transfer conditions (80JOC3172). For example, A-benzenesulfonylpyrrole is best prepared from pyrrole under phase-transfer conditions rather than by intermediate generation of the potassium salt (81TL4901). In this case the softer nature of the tetraalkylammonium cation facilitates reaction on nitrogen. The thallium salts of indoles prepared by reaction with thallium(I) ethoxide, a benzene-soluble liquid. 

Unsymmetrical as well as symmetrical anhydrides are often prepared by the treatment of an acyl halide with a carboxylic acid salt. The compound C0CI2 has been used as a catalyst. If a metallic salt is used, Na , K , or Ag are the most common cations, but more often pyridine or another tertiary amine is added to the free acid and the salt thus formed is treated with the acyl halide. Mixed formic anhydrides are prepared from sodium formate and an aryl halide, by use of a solid-phase copolymer of pyridine-l-oxide. Symmetrical anhydrides can be prepared by reaction of the acyl halide with aqueous NaOH or NaHCOa under phase-transfer conditions, or with sodium bicarbonate with ultrasound. 

In qualitative terms, the rearrangement reaction is considerably more efficient for the oxime acetate 107b than for the oxime ether 107a. As a result, the photochemical reactivity of the oxime acetates 109 and 110 was probed. Irradiation of 109 for 3 hr, under the same conditions used for 107, affords the cyclopropane 111 (25%) as a 1 2 mixture of Z.E isomers. Likewise, DCA-sensitized irradiation of 110 for 1 hr yields the cyclopropane derivative 112 (16%) and the dihydroisoxazole 113 (18%). It is unclear at this point how 113 arises in the SET-sensitized reaction of 110. However, this cyclization process is similar to that observed in our studies of the DCA-sensitized reaction of the 7,8-unsaturated oximes 114, which affords the 5,6-dihydro-4//-l,2-oxazines 115 [68]. A possible mechanism to justify the formation of 113 could involve intramolecular electrophilic addition to the alkene unit in 116 of the oxygen from the oxime localized radical-cation, followed by transfer of an acyl cation to any of the radical-anions present in the reaction medium. 

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