Ammonolysis

The lactone 1 was subjected to ammonolysis by treatment at room temperature for 5 hours with ethanol saturated with ammonia in the expectation that simple ring opening would occur. The product was not, however, the expected amide instead, two products were formed, the amide 2 and (7 )-lactamide, in almost quantitative yield. An unstable intermediate could be isolated and was shown to serve as precursor to 2. 

Ammonia is the smallest noncharged nucleophile for peptide liberation from polymer phase. Cleavage of the benzyl ester link to polystyrene by ammonolysis with the formation of peptide amides, however, liberates on the average only 60—80% of the synthetic product from the support. The best conditions for this detachment yielding directly the important class of peptide amides can be seen in the utilization of dimethylformamide/ methanol 4 1 (v v) saturated with ammonia at 0 °C, in which the peptide-on-polymer is suspended and stored for at least 3 days in a pressure bottle at room temperature. 

The alcohol content of the ammonolytic reagent indicates the consequence of several observations that the amide formation seems not to proceed by direct attack of ammonia on the polymer phase ester bond but on the corresponding alkyl esters intermediately released by base-catalyzed transesterification [87]. It has to be realized that this procedure often yields a mixture of peptide amide and methyl esters, the latter of which can be transformed into amides by extended exposure to ammonia. Direct ammonolytic cleavage with liquid ammonia itself, first, is hindered by the poor solvation of the lipophilic matrix in the polar medium. Second, if remaining anchor functions are still present like chloro-methyl- or bromoacetophenyl-sites, on 0.5% divinylbenzene containing supports, liquid 

To date there have been hardly any experiences concerning the efficiency of ammo-nolytic detachment of peptides Unked to the support by phenacyl groupings. For analytical purposes, in our laboratory we detected, by the aid of our photometric synthesis control system, the release of hpophilic peptide amides within 24 hours of ammonolysis. The reagent we are utilizing is 10% (w) ammonia in dioxane/methanol 9 1 (v v), with renewal of the mixture delivered to the centrifugal reactor every 2 hours. It should be recalled, however, that in most of the cases when peptide amides are to be built up, the target sequences are synthesized on a benzhydrylamine support [171], which by HF-cleavage directly releases the entirely deprotected amide (see p. 64). 

Modified links between peptide and polymer support are introduced for selective fission of this anchoring bond at the end of the synthesis by detachment procedures which do not interfere with other functional sites or protective groups of the peptide. 

Though several specialized anchor groups on polymer were designed and synthesized, to date none of those proposals have become generally applied in practice - as we often can observe the fact that there are advantageous reagents or reaction principles, which remain home methods of the inventor s laboratory. 

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Inorganic amides contain the ion NH2". They are formed by the action of ammonia on metals or by the ammonolysis of nitrides. The heavy metal amides are prepared by meta-thetical reactions in liquid ammonia, e.g. 

We shall describe a specific synthetic example for each protective group given above. Regiosdective proteaion is generally only possible if there are hydroxyl groups of different sterical hindrance (prim < sec < tert equatorial < axial). Acetylation has usually been effected with acetic anhydride. The acetylation of less reactive hydroxyl groups is catalyzed by DMAP (see p.l44f.). Acetates are stable toward oxidation with chromium trioxide in pyridine and have been used, for example, for protection of steroids (H.J.E. Loewenthal, 1959), carbohydrates (M.L. Wolfrom, 1963 J.M. Williams, 1967), and nucleosides (A.M. Micbelson, 1963). The most common deacetylation procedures are ammonolysis with NH in CH OH and methanolysis with KjCO, or sodium methoxide. 

Halothiazoles are usually obtained from 2-aminothiazoles through the Sandmeyer reaction. Nevertheless, ammonolysis has sometimes proved useful for the preparation of 2-aminothiazole derivatives. Detweiler et al. (18) obtained 2-(u-pyridinylamino)thiazole (1) from 2-bromothiazole (Scheme 1). The reaction is easier if a nitro group occupies the 5-position of the thiazole ring (19-21). Ethylene diamine derivatives undergo this reaction with 2-haiothiazoles (22-24). 

Besides the classical heterocydization and ammonolysis methods some other syntheses have been developed to prepare secondary and tertiary... 

Tertiary amines may be obtained from alkaline alkylation of secondary amines (46), but mixtures are obtained (see Section III.l.B) hence heterocyclization and ammonolysis of 2-halothiazoles are to be preferred. 

The amide can be prepared classically from the acid chloride or by ammonolysis of the ester, prepared directly by cyclization (15, 75, 78-80). 

Aqueous ammonia and acryUc esters give tertiary amino esters, which form the corresponding amide upon ammonolysis (34). Modem methods of molecular quantum modelling have been appHed to the reaction pathway and energetics for several nucleophiles in these Michael additions (35,36). 

Reduction. Hydrogenation of dimethyl adipate over Raney-promoted copper chromite at 200°C and 10 MPa produces 1,6-hexanediol [629-11-8], an important chemical intermediate (32). Promoted cobalt catalysts (33) and nickel catalysts (34) are examples of other patented processes for this reaction. An eadier process, which is no longer in use, for the manufacture of the 1,6-hexanediamine from adipic acid involved hydrogenation of the acid (as its ester) to the diol, followed by ammonolysis to the diamine (35). 

In general, the reactions of the perfluoro acids are similar to those of the hydrocarbon acids. Salts are formed with the ease expected of strong acids. The metal salts are all water soluble and much more soluble in organic solvents than the salts of the corresponding hydrocarbon acids. Esterification takes place readily with primary and secondary alcohols. Acid anhydrides can be prepared by distillation of the acids from phosphoms pentoxide. The amides are readily prepared by the ammonolysis of the acid haUdes, anhydrides, or esters and can be dehydrated to the corresponding nitriles (31). 

The second and third reactions are economical, but the first is not. The second reaction is used in a process where HCN is oxidized to (CN)2 and hydrolyzed in the presence of a strong acid catalyst to give oxamide. The third reaction is employed in a newly developed process where diaLkyl oxalates are converted to oxamide by the ammonolysis reaction. This reaction easily proceeds without catalysts and quantitatively gives oxamide as a powder. 

Hydrogenolysis is analogous to hydrolysis and ammonolysis, which involve the cleavage of a bond induced by the action of water and ammonia, respectively. Chemical bonds that are broken by hydrogenolysis reactions include carbon—carbon, carbon—oxygen, carbon—sulfur, and carbon—nitrogen bonds. An example of hydrogenolysis is the hydrodealkylation of toluene to form benzene and methane ... 

If adipamide reacts with hexarnethylenediarnine, then nylon-6,6 can be prepared by aminolysis of the adipamide this could also be viewed as reverse ammonolysis. 

Ammonolysis. In a reaction closely related to aminolysis, ammonia [7664 1-7] reacts with polyamides, usually under pressure and at elevated temperatures (62). 

Lewis acids, such as the haUde salts of the alkaline-earth metals, Cu(I), Cu(II), 2inc, Fe(III), aluminum, etc, are effective catalysts for this reaction (63). The ammonolysis of polyamides obtained from post-consumer waste has been used to cleave the polymer chain as the first step in a recycle process in which mixtures of nylon-6,6 and nylon-6 can be reconverted to diamine (64). The advantage of this approach Hes in the fact that both the adipamide [628-94-4] and 6-aminohexanoamide can be converted to hexarnethylenediarnine via their respective nitriles in a conventional two-step process in the presence of the diamine formed in the original ammonolysis reaction, thus avoiding a difficult and cosdy separation process. In addition, the mixture of nylon-6,6 and nylon-6 appears to react faster than does either polyamide alone. 

Aromatic amines can be produced by reduction of the corresponding nitro compound, the ammonolysis of an aromatic haUde or phenol, and by direct amination of the aromatic ring. At present, the catalytic reduction of nitrobenzene is the predominant process for manufacture of aniline. To a smaller extent aniline is also produced by ammonolysis of phenol. 

The ammonolysis of phenol (61—65) is a commercial process in Japan. Aristech Chemical Corporation (formerly USS Chemical Division of USX Corporation) currently operates a plant at Ha verb ill, Ohio to convert phenol to aniline. The plant s design is based on Halcon s process (66). In this process, phenol is vapori2ed, mixed with fresh and recycled ammonia, and fed to a reactor that contains a proprietary Lewis acid catalyst. The gas leaving the reactor is fed to a distillation column to recover ammonia overhead for recycle. Aniline, water, phenol, and a small quantity of by-product dipbenylamines are recovered from the bottom of the column and sent to the drying column, where water is removed. 

Most derivatives of aniline are not obtained from aniline itself, but ate prepared by hydrogenation of their nitroaromatic precursors. The exceptions, for example, /V-a1ky1ani1ines, /V-ary1ani1ines, sulfonated anilines, or the A/-acyl derivatives, can be prepared from aniline and have been discussed. Nitroanilines are usually prepared by ammonolysis of the corresponding chloronitroben2ene. Special isolation methods may be requited for some derivatives if the boiling points are close and separation by distillation is not feasible. Table 6 Hsts some of the derivatives of aniline that are produced commercially. 

This is an example of an ammonolytic reaction ia which a chemical bond is broken by the addition of ammonia. It is analogous to the hydrolysis reactions of water. An impressive number of inorganic and organic compounds undergo ammonolysis. 

Amination. Amyl alcohols can react with ammonia or alkylamines to form primary, secondary, or tertiary-substituted amines. Eor example, 3-methyl-butylamine [107-85-7] is produced by reductive ammonolysis of 3-methyl-1-butanol over a Ni catalyst at 150°C (59). Some diisoamyl- and triisoamyl amines are also formed in this reaction. Good selectivities (88%) of neopentyl amine [5813-64-9] are similarly produced by reductive ammonolysis of neopentyl alcohol (60). 

Amination. Isopropyl alcohol can be aminated by either ammonolysis ia the presence of dehydration catalysts or reductive ammonolysis usiag hydrogeaatioa catalysts. Either method produces two amines isopropylamine [75-31-0] and diisopropylamine [108-18-9]. Virtually no trisubstituted amine, ie, triisopropyl amine [122-20-3], is produced. The ratio of mono- to diisopropylamine produced depends on the molar ratio of isopropyl alcohol and ammonia [7664-41-7] employed. Molar ratios of ammonia and hydrogen to alcohol range from 2 1—5 1 (35,36). 

Direct ammonolysis involving dehydratioa catalysts is geaerahy ma at higher temperatures (300—500°C) and at about the same pressure as reductive ammonolysis. Many catalysts are active, including aluminas, siUca, titanium dioxide [13463-67-7], and aluminum phosphate [7784-30-7] (41—43). Yields are acceptable (>80%), and coking and nitrile formation are negligible. However, Htfle control is possible over the composition of the mixture of primary and secondary amines that can be obtained. 

Using hexamethylphosphoramide as the solvent, only the second reaction occurs. Disilane also reacts with potassium in 1,2-dimethoxyethane to form KS1H3, although S1H4 and nonvolatile polysHanes are also produced (28,31). Pure crystalline KSiH prepared from SiH and potassium in 1,2-dimethoxyethane has been obtained by slow evaporation of the solvent. WhenHquid ammonia is used as the solvent, only a small fraction of SiH is converted into metal salt most of the SiH undergoes ammonolysis (32). 

The analogous reaction with ammonia leads ultimately to sihcon nitride. In the past, hydrocarbon soluble fractions of the ammonolysis were iacorrecdy referred to as sihcon diimide. This improper designation occasionally persists as of the mid-1990s. 

Additional hahdes can be removed from the above insoluble ammonolysis product by reaction with potassium imide to form zircorhum imide [87227-54-1]... 

Ammonolysis or aminolysis of an ester can be used to make the respective amide or N-substituted amide. 

Ammonium acetate and sodium methoxide are effective catalysts for the ammonolysis of soybean oil (49). Polyfunctional amines and amino alcohols such as ethylenediamine, ethanolamine, and diethanolamine react to give useful intermediates. Ethylenediamine can form either a monoamide or a diamide depending on the mole ratio of reactants. With an equimolar ratio of reactants and a temperature of >250° C, a cyclization reaction occurs to give imidazolines with ethylenediamine (48) ... 

Dichloroethane reacts with toluene in the presence of Friedel-Crafts catalysts such as AIBr., AlCl, GaCl, and ZrCl (26). Ammonolysis of... 

Dicyanoacetylene, 2-hiitynedinitri1e, is obtained from dimethyl acetylenedicarboxylate by ammonolysis to the diamide, which is dehydrated with phosphoms pentoxide (44). It bums in oxygen to give a flame with a temperature of 5260 K, the hottest flame temperature known (45). Alcohols and amines add readily to its acetylenic bond (46). It is a powerhil dienophile in the Diels-Alder reaction it adds to many dienes at room temperature, and at 180°C actually adds 1,4- to benzene to give the bicyclo adduct (7) [18341 -68-9] C QHgN2 (47). 

Aminoanthraquinone and Related Compounds. l-Amiuoanthraquiuone [82-45-1] (17) is the most important iatermediate for manufacturiag acid, reactive, disperse, and vat dyes. It has been manufactured from anthraquiaone-l-sulfonic acid [82-49-5] (16) by ammonolysis of the sulfo group with aqueous ammonia ia the presence of an oxidising agent such as nitroben2ene-3-sulfonic acid. 

Ammonolysis and Aminolysis. Esters and ammonia react to form amides and alcohols ... 

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