Amides from nitriles hydration

Amides from nitriles. This hydration is catalyzed by KF on natural phosphate and... 

Despite the great advances reached in the catalytic nitrile hydration, reactions to form A-substituted amides from nitriles have few precedents. In this context, although little studied, the catalytic amidatimi of nitriles with amines in the presence of water has emerged in recent years as a useful tool for the straightforward generation of secondary and tertiary amides (Scheme 10) [71-77]. 

It has been noted already that reports can be found in the literature, as far back as the 1960s, of modest amounts of amides being formed in the presence of nitrilases [20-22]. This side activity (see Figure 16.7) could not be accounted for by the commonly accepted nitrilase mechanism [21] and was largely neglected until quite recently. It was then shown, for example, that nitrile hydration in the presence of recombrnantly expressed and purified nitrilases from Arahidopsis thali-ana was a major pathway with some nitriles, in particular electron-deficient ones [23-25]. 

We found that nitrile hydration in the presence of PfNLase is Hkewise subject to electronic effects. Hardly any amide was formed from 2-phenylpropionitrile (Id) in the presence of this latter enzyme but the hydration pathway predominated, in contrast, with the electron-deficient 2-chloro-2-phenylacetonitrile (le) the extent... 

Wang N, Zou X, Li F et al (2014) The direct synthesis of A -alkylated amides via a tandem hydration/A/-alkylation reaction from nitriles, aldoximes and alcohols. Chem Commun 50(61) 8303 305... 

Nitrile hydratases (EC 4.2.1.84) are metallo-enzymes that catalyze the hydration of nitriles to their corresponding amides. From a structural viewpoint, nitrile hydratases consist of two non-identical subunits (a and P), with similar molecular masses of approximately 23kDa. Nitrile hydratases exist as ap dimers or 0i2 2 tetramers, with each ap dimer binding a single metal atom. The amino acid sequence of each subunit is unrelated, with the structural genes normally adjacent to each other on the same operon [49]. Nitrile hydratases are classified into two groups on the basis of their catalytic metal ion center a nonheme iron atom [50] or a noncorrinoid cobalt atom [51]. 

There are two pathways for the degradation of nitriles (a) direct formation of carboxylic acids by the activity of a nitrilase, for example, in Bacillus sp. strain OxB-1 and P. syringae B728a (b) hydration to amides followed by hydrolysis, for example, in P. chlororaphis (Oinuma et al. 2003). The monomer acrylonitrile occurs in wastewater from the production of polyacrylonitrile (PAN), and is hydrolyzed by bacteria to acrylate by the combined activity of a nitrilase (hydratase) and an amidase. Acrylate is then degraded by hydration to either lactate or P-hydroxypropionate. The nitrilase or amidase is also capable of hydrolyzing the nitrile group in a number of other nitriles (Robertson et al. 2004) including PAN (Tauber et al. 2000). 

Hydration of nitriles providing carboxamides is usually carried out m strongly basic or acidic aqueous media - these reactions require rather bars conditions and suffer from incomplete selectivity to the desired amide product. A few papers in the literature deal with the possibihty of transition metal catalysis of this reaction [28-30]. According to a recent report [30], acetonitrile can be hydrated into acetamide with water-soluble rhodium(I) complexes (such as the one obtained from [ RhCl(COD) 2] and TPPTS) under reasonably mild conditions with unprecedently high rate... 

A suspension of potassium amide (0.23 mole) in liquid ammonia is prepared in a 1-1. three-necked flask equipped with an air condenser (without drying tube), a ball-sealed mechanical stirrer, and a dropping funnel. Commercial anhydrous liquid ammonia (500 ml.) is introduced into the flask from a cylinder through an inlet tube. To the stirred ammonia is added a small piece of potassium metal. After the appearance of a blue color, a few crystals (about 0.25 g.) of ferric nitrate hydrate are added, followed by small pieces of potassium (Note 1) until 9.0 g. (0.39 g.-atom) has been added. After all the potassium has been converted to the amide (Note 2), 44.6 g. (0.23 mole) of diphenyl-acetonitrile (Note 3) is added and the resulting greenish-brown solution is stirred for 5 minutes. To this is added, over 10 minutes, 30.5 g. (0.24 mole) of benzyl chloride (Note 4) in 100 ml. of anhydrous ether. The orange solution is stirred for 1 hour, and the ammonia is then evaporated on a steam bath as 300 ml. of anhydrous ether is being added. To the ether solution is added 300 ml. of water, whereupon the crude nitrile precipitates. riie ether is then removed by distillation and the crude... 

In general, dehydration means loss of water molecules from chemical substances, irrespective of their structure. Even if all cases where water is bonded in hydrate form are excluded, a number of reactions remain which also include formation of nitriles from amides, lactones from hydroxy acids etc. However, the present treatment will concentrate on the heterogeneous catalytic decomposition of alcohols in the vapour phase, which can be either olefin-forming or ether-forming reactions, and on the related dehydration of ethers to olefins. 

It must be stated that the use of ethanol as solvent in the nitrile reaction makes it difficult to understand the mechanism. At this stage of our present results, it is particularly not possible to determine if the ester is formed from a direct addition of ethanol on the starting nitrile or from the amide as intermediate. As shown in Table 1, the less acidic HY zeolite favours ester formation while in the case of the HMg zeolites the amide is preferably formed. Such results seem to indicate that the ester formation occurs over weak acidic sites whereas the hydration reaction needs stronger acidic sites. 

In addition to OH , other nucleophiles such as BH4 ,318 CN-319,320 and N3-321 also add at the nitrile carbon of cobalt(III)-nitrile complexes at rates which are = 104 times those of the corresponding reactions of the free ligands. Catalysis by C032 in the hydration of [(NH3)5RuNCMe]3+,316 and of the acrylonitrile complex [(NH3)5CoNCCH=CH2]3+,322 has been observed. In the latter complex, a direct nucleophilic pathway results in the incorporation of oxygen from C032 into the amide product with elimination of C02. 

The most effective commercially available form of this desiccant is the monohydrate a cheaper grade contains from 30 to 40 per cent of water but this retains useful desiccating action (the fully hydrated form is the heptahydrate). It is an excellent neutral desiccant, rapid in its action, chemically inert and fairly efficient, and can be employed for most compounds including those (e.g. esters, aldehydes, ketones, nitriles, amides) to which calcium chloride is not applicable. 

Hydration of nitriles. The hydration of nitriles to amides is commonly carried out under acid or basic catalysis. The reaction can be carried under neutral conditions by catalysis with a black powder consisting essentially of Cu(0), obtained by reduction of CuS04 with NaBH4 in aqueous NaOH. The method is applicable even to sparingly water-soluble nitriles, and yields range from 50-95% (crude). ... 

The hydration of nitriles to form amides is promoted by metallic catalysts such as nickel and copper,9 and the copper catalyzed hydration has been utilized in an industrial process for the production of acrylamide from acrylonitrile.10 The hydration of... 

In the aromatic series the direct conversion of acid amides into acid nitriles does not take place readily but the acid itself is made from the acid amide by the reverse process as indicated above, viz., by hydration to the ammonium salt of the acid, which then yields the acid. A related method, however, is used for preparing acids from anilides of formic acid. Aniline being an ammonia compound yields acid-amidelike products with aliphatic acids, e.g. acet anilide, CH3—CO—NH— CeHs (p. 556). Such a compound can not, however, lose water in the same way as the acid amide in the above reaction for the ammonia residue in an anilide contains only one hydrogen. Nevertheless anilides lose water but in a different way. In the case of the anilide of formic acid, i.e. formanilide, H—CO—NH—CeHs, the loss of water results in a compound in which the carbon and nitrogen remain linked to the benzene ring and an iso-cyanide or iso-nitrile is formed. The isonitrile is readily converted into the nitrile and the acid may then be obtained from that. 

The preparation of amide hydrazones is quite simple, by mixing corresponding nitriles (or dinitriles) and hydrazine (1 1.5 molar ratio) in ethanol at room temperature and then allowing the mixture to stand overnight. This is called the direct method. The yield by this method is normally good (>90%). If this method does not work, the so-called indirect method can be used, in which a nitrile, e.g., malononitrile, is converted into its imidate then reacted with hydrazine. In early references (e.g., Case, 1965150), anhydrous or 95% hydrazine was employed. We have found that 85% hydrazine hydrate still works without any difference in yield. Common recrystallization solvents are benzene or toluene. The amide hydrazones are stable to moisture, and so some amide hydrazones can be recrystallized from water, but they are sensitive to light and heat. As an example, we observed that picolinamide hydrazone (white crystals) partially turns into an orange compound, which has been identified as 3,6-picolin-(2H)-tetrazine. 

A Hofmann degradation is used to synthesize pyrido[3,4-t/]pyrimidines starting from 3-cyano-6-methylpyridine-4-carboxamidc.478 By heating the amide in aqueous potassium hydroxide/ sodium hypochlorite at 80 JC, a 70% yield of 6-methylpyrido[3,4-tf]pyrimidine-2,4(1 7/,3/f)-dione (17) is obtained, together with a minor amount of 2-methylpyridine-4,5-diamine. It is concluded that, under alkaline conditions, hydration of the nitrile to the amide apparently proceeds even faster than hydrolysis of the amide in the 4-position. 

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