Mixed anhydride reagent

Tsuji, K., K. Konishi, GC analysis of ester-type surfactants by using mixed anhydride reagent, 7. Am. Oil Chem. Soc., 1975,52, 106-109. 

Solutions of dinitrogen tetroxide (the mixed anhydride of nitric and nitrous acids) in sulphuric acid are nitrating agents ( 4.3.2), and there is no doubt that the effective reagent is the nitronium ion. Its formation has been demonstrated by Raman spectroscopy and by cryoscopy ... 

Fluorosulfuric acid [7789-21-17, HSO F, is a colodess-to-light yellow liquid that fumes strongly in moist air and has a sharp odor. It may be regarded as a mixed anhydride of sulfuric and hydrofluoric acids. Fluorosulfuric acid was first identified and characterized in 1892 (1). It is a strong acid and is employed as a catalyst and chemical reagent in a number of chemical processes, such as alkylation (qv), acylation, polymerization, sulfonation, isomerization, and production of organic fluorosulfates (see Friedel-CRAFTSreactions). 

Few racemic alkyl p-tolyl sulphoxides were prepared in rather low yields (16—40%) by the reaction of Grignard reagents with mixed anhydrides 108, 109 and compound HO formed in situ from p-toluenesulphinic acid and 3-phthalimidoxy-l,2-benzoisothiazole 1, 1-dioxide167 (equation 59). The mixed anhydrides 109 or 110 when reacted with cyclopen-tene and cyclohexene enamines 111 gave the corresponding a-ketocycloalkyl sulphoxides 112 in low yields (10-41%) along with small amounts of several by-products such as disulphides and thiosulphonates167 (equation 60). 

Even though formic anhydride is not a stable compound (see p. 714), amines can be formylated with the mixed anhydride of acetic and formic acids (HCOO-COMe) °°° or with a mixture of formic acid and acetic anhydride. Acetamides are not formed with these reagents. Secondary amines can be acylated in the presence of a primary amine by conversion to their salts and addition of 18-crown-6. ° The crown ether complexes the primary ammonium salt, preventing its acylation, while the secondary ammonium salts, which do not fit easily into the cavity, are free to be acylated. 

When a mixed anhydride RCOOCOR is the reagent, two products are possible ArCOR and ArCOR. Which product predominates depends on two factors. If R contains electron-withdrawing groups, then ArCOR is chiefly formed, but if this factor is approximately constant in R and R, the ketone with the larger R group predominantly forms.This means that formylations of the ring do not occur with mixed anhydrides of formic acid HCOOCOR. 

The phosphinic isocyanates (116) and isothiocyanates (117) react with oxygen, nitrogen, and phosphorus nucleophiles by attack at carbon rather than phosphorus. Phenyl phosphonodichloridate has been recommended as a useful reagent for the activation (presumably by mixed anhydride formation) of carboxylic acids for conversion to amides and hydrazides. ... 

Carboxylic acids can also be activated by the formation of mixed anhydrides with various phosphoric acid derivatives. Diphenyl phosphoryl azide, for example, is an effective reagent for conversion of amines to amides.140 The proposed mechanism involves formation of the acyl azide as a reactive intermediate. 

An additional minor source of urethane can be the reaction of unconsumed reagent with V-nucleophile (path C). Aminolysis of chloroformate occurs if there is an excess of reagent or if the anhydride-forming reaction is incomplete. The latter is more likely when the residues activated are hindered. This side reaction can be avoided by limiting the amount of reagent and extending the time of activation. A third side reaction that is of little consequence is disproportionation of the mixed anhydride to the symmetrical anhydride and dialkyl pyrocarbonate (see Section 7.5). 

Mixed anhydrides (see Section 2.6) The mixed-anhydride method provides efficient coupling of peptides with minimal isomerization if the established protocol is strictly adhered to. This includes a short activation time at low temperature, isopropyl chloroformate as the reagent, and A-methylmorpho-line or /V-mcthylpipcridinc as the tertiary amine (Figure 2.25, path D). In what is an apparent anomaly with respect to conventional wisdom, a polar solvent such as dimethylformamide seems to be preferable to apolar solvents for minimizing isomerization. Aminolysis at the wrong carbonyl of the anhydride of a peptide (path F) is less than that for the anhydride from the corresponding /V-alkoxycarbonylamino acid. 

NL Benoiton, Y Lee, FMF Chen. Isopropyl chloroformate as a superior reagent for mixed anhydride generation and couplings in peptide synthesis. Int J Pept Prot Res 31, 577, 1988. 

Use the mixed-anhydride method in dimethylformamide with isopropyl chloroformate as me reagent and (V-methylmorpholine, A -melhylpiperi-dine, or trimethylpyridine as me base (see Sections 7.4 and 7.5). 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

The major side reaction associated with the use of mixed anhydrides is aminolysis at the carbonyl of the carbonate moiety (Figure 7.4, path B). The product is a urethane that resembles the desired protected peptide in properties, except that the amino-terminal substituent is not cleaved by the usual deprotecting reagents. Hence, its removal from the target product is not straightforward. The problem is serious when the residues activated are hindered (Val, lie, MeXaa), where the amounts can be as high as 10%. Other residues generate much less, but the reaction cannot be avoided completely, with the possible exception of activated proline (see Section 7.22). This is one reason why mixed anhydrides are not employed for solid-phase synthesis. 

FIGURE 7.12 Preparation of activated esters of A-alkoxycarbonylamino acids by reaction of the hydroxy compound with a mixed anhydride (path A), obtained by leaving the three reagents (NMM = A-methylmorpholine) in CH2C12 at 23°C for 2 minutes.35 Mixed carbonate that is formed (path B) is readily eliminated by crystallization of the ester. 

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