Hydrolysis, of nitriles

Three proposals for the mechanism of metal-depending nitrile hydratases have been suggested, the most plausible assumes direct corrdination of the nitrile to the metal, which (by acting as Lewis-acid) increases the electrophilicity of the carbon atom to allow attack of a water-molecule. The hydroxy-imino-species thus formed tautomerizes to form the carboxamide [638-640]. 

Enzymatic hydrolysis of nitriles is not only interesting from an academic standpoint, but also from a biotechnological point of view [645-652]. Cyanide 

Another important aspect is the enzymatic hydrolysis of cyanide for the detoxification of industrial effluents [653-656]. 

Acrylamide is one of the most important commodity chemicals for the synthesis of various polymers and is produced in an amount of about 200,000 t/year worldwide. In its conventional synthesis, the hydration of acrylonitrile is performed with copper catalysts. However, the preparative procedure for the catalyst, difficulties in its regeneration, problems associated with separation and purification of the formed acrylamide, undesired polymerization and over-hydrolysis are serious drawbacks. Using whole cells of Brevibacterium sp. [658, 659], Pseudomonas chlororapis [660, 661] or Rhodococcus rhodochrous [662] acrylonitrile can be converted into 

Even more important from a commercial standpoint was that o-, m-, and p-substituted cyanopyridines were accepted as substrates [664, 665] to give picolinamide (a pharmaceutical), nicotinamide (a vitamin), and isonicotinamide 

Enantioselective transformations of several cyclopropane or oxirane-containing nitriles were studied using nitrile-transforming enzymes [78]. Microbial Rhodococcus sp. whole cells containing a nitrile hydratase/amidase system hydrolyzed a number 

2 Emntioselective Biotransformations of Carboxylic Acid Derivatives 145 Rhodococcus sp 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile 

An important nitrile is acrylonitrile, CH2=CHCN. It is prepared industrially from propene, ammonia, and oxygen in the presence of a special catalyst. Polymers of acrylonitrile have many applications, the most prominent being their use in the preparation of acrylic fibers. 

Nitriles are classified as carboxylic acid derivatives because they are converted to carboxylic acids on hydrolysis. The conditions required are similar to those for the hydrolysis of amides, namely, heating in aqueous acid or base for several hours. Like the hydrolysis of amides, nitrile hydrolysis is irreversible in the presence of acids or bases. Acid hydrolysis yields ammonium ion and a carboxylic acid. 

In aqueous base, hydroxide ion abstracts a proton from the carboxylic acid. In order to isolate the acid a subsequent acidification step is required. 

Nitriles are susceptible to nucleophilic addition. In their hydrolysis, water adds across the carbon-nitrogen triple bond. In a series of proton-transfer steps, an amide is produced  

We already discussed both the acidic and basic hydrolysis of amides (see Section 20.16). All that remains to complete the mechanistic picture of nitrile hydrolysis is to examine the conversion of the nitrile to the corresponding amide. 

Carboxylic acids are produced by the hydrolysis of nitrile compounds. In the hydrolysis the —CN group is converted to the —COOH group. Nitriles can be prepared by substitution reactions of alkyl halides with KCN or NaCN. 

Nucleophiiic substitution by cyanide ion (Sections 8.1,8.11) Cyanide ion is a good nucleophile and reacts with alkyl halides to give nitriles. The reaction is of the n2 type and is limited to primary and secondary alkyl halides. Tertiary alkyl halides undergo elimination aryl and vinyl halides do not react. 

Cyanohydrin formation (Section 17.7) Hydrogen cyanide adds to the carbonyl group of aldehydes and ketones. 0 II RCR + HCN - OH 1 RCR 1 C=N 

Show how ethyl alcohol could be used to prepare (a) CH3CN and (b) CH3CH2CN. Along with ethyl alcohol you may use any necessary inorganic reagents. 

Chapter 19 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution 

Alkyl and aryl nitriles readily hydrolyze when submitted to NCW conditions. The hydrolysis is a multistep sequence as shown in Fig. 9.26. For instance, Katritzky et al. have reported that benzonitrile is converted to benzamide and benzoic acid at 250°C over a period of 5 days, and they conclude that the amide and the acid were in equilibrium. Under these conditions some decarboxylation can also occur. An et al. have reported the product distribution for the hydrolysis of benzonitrile as a function of time and temperature. Specifically, the ratio of benzamide to benzoic acid varied as follows after 1 h at 250°C, the distribution was 5 4. However, at 280°C after 1 h, the ratio was 1 1, and became 1 25 when the reaction time was extended to 6 h. Alkylnitriles exhibit similar behaviors Siskin et ah reported that at 250°C for 2.5 days decanonitrile quantitatively yields two major products, decanoic acid and decanoamide. When octanenitrile was hydrolyzed to octanoic acid amide and octanoic acid, the reaction was slightly slower than that ofbenzonitrile. Only 29% conversion took place in 1 h at 290°C. The limited solubility of octanenitrile in water, even in NCW conditions, was suggested as a possible factor for the slow reaction. Again the product distribution was dependent on the residence time and the temperature. 

They report activation volumes for ki and k2 at a pressure of 128.5 bar of-362 and -231 cm /mol, respectively. The activation volume is a useful mechanistic probe for reactions in liquids however, in compressible fluids the mechanistic contribution is far overshadowed by that of solvation. The values of NCW reported are intermediate between the corresponding values in normal liquid solvents and about an order of magnitude lower than those observed in supercritical solvents. At higher pressures, where water is less compressible, the activation volumes varied between -19.3 and -12 cm /mol, values comparable in magnitude to those in liquid solvents. 

200° C despite 98% conversion of starting material. Additionally, separation is easy as the products are insoluble in water at ambient temperature. The separation of nicotinic acid from nicotinamide will also be facile by fractional crystallization, as the melting points differ by 100°C. 

The reaction of pinene to form or-terpineol has been known since the late nineteenth century. Pinene is relatively abundant in nature, with the major source being pine trees, a- and pinene (1) will hydrolyze in aqueous add to form a tertiary carbocation, as shown in Fig. 9.30, followed by a series of carbonium ion rearrangements, which results in a multitude of products. The major product of the reaction is or-terpineol (2) however, as a consequence of carbonium ion rearrangements, terpinen-4-ol (3) and y-terpineol (4,5) are also produced. These monocyclic alcohols are collectively known as terpineol. Smaller amounts of the bicyclic alcohols fenchol (6) and borneol (7) are also formed. Undesirable side reactions 

Chamblee et al. have reported the reaction of /3-pinene with water at 200 and 250 C. The distribution of products obtained was identical to those obtained under aqueous acid-catalyzed conditions (Fig. 9.30). As a consequence, it is assumed that the reaction in hot water proceeded via carbonium ion intermediates. The reaction with j8-pinene in water at 200°C is relatively fast with 90% conversion in 20 min. However, the yield of terpineol is small (10%) vs the formation of hydrocarbons, which are the major products formed under these conditions. Reactions run at 250°C show even greater hydrocarbon formation. 

The aqueous sodium hydroxide soiution is caustic. Wear iatex gioves when handling it. Shouid it contact the skin, immediateiy flood the area with water. 

Preparation Sign in at www.cengage.coin/login to read the MSDSs for the chemicals used or produced in this procedure. 

Basic Hydrolysis. In a small Erlenmeyer flask, mix 10 mL of 3 M sodium hydroxide solution and 1 g of the nitrile. Heat the mixture to boiling and note either the odor of ammonia or the color change that occurs when a piece of moist pHydrion paper is held over the flask. After the mixture is homogeneous, cool and then acidify it. If the acid solidifies, collect the crystals by vacuum filtration. If it is a liquid. extract the acidic solution with small portions of diethyl ether, dry and decant the ethereal solution, and then remove the solvent by one of the techniques described in Section 2.29. The residue is the acid. Prepare a suitable derivative of the acid (Sec. 25.13). 

Neutralize all aqueous solutions before flushing them down the drain. Pour any diethyl ether isolated into the container for nonhalogenated organic liquids. 

Concentrated sulfuric and nitric acids may produce severe chemical burns. Wear latex gloves when handling these reagents. Should these acids contact your skin, 

The first four steps of the mechanism for hydrolysis of nitriles in basic solution are given in Mechanism 19.6. These steps convert the nitrile to an amide, which then proceeds to the hydrolysis products according to the mechanism of amide hydrolysis in Mechanism 19.5. 

The acid-catalyzed mechanism for nitrile hydrolysis also goes through the amide as an intermediate. Problem 19.25 encourages you to propose a mechanism for that process. 

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Hydrolysis of p-tolunitrile to p-toluic acid. Boil a mixture of 5 g. of p-tolunitrile, 80 ml. of 10 per cent, aqueous sodium hydroxide solution and 15 ml. of alcohol under a reflux condenser. (The alcohol is added to prevent the nitrile, which volatUises in the steam, from crystalhsing in the condenser it also increases the speed of hydrolysis. The alcohol may be omitted in the hydrolysis of nitriles which are hquid at the ordinary temperature, e.g., benzo-nitrUe.) The solution becomes clear after heating for about 1 hour, but continue the boiling for a total period of 1 - 5 hours to ensure complete hydrolysis. Detach the condenser and boil the solution for a few minutes in the open flask to remove dissolved ammonia and incidentally some of the alcohol CAUTION /). Cool, and add concentrated hydrochloric acid until precipitation of the p-toluic acid is complete. When cold, filter off the p-toluic acid with suction and wash with a little cold water. Recrystallise from a mixture of equal volumes of water and alcohol (methylated spirit) or from benzene. The yield of p-toluic acid, m.p. 178°, is 5-5 g. 

By the hydrolysis of nitriles. The nitriles may be easily prepared either from amines by the Sandmeyer reaction (Section IV,66) or by the action of cuprous cyanide upon aryl halides (compare Section IV,163). Benzyl cyanide... 

SYNTHESIS OF CARBOXYLIC ACIDS BY THE PREPARATION AND HYDROLYSIS OF NITRILES... 

Primary and secondary alkyl halides may be converted to the next higher carboxylic acid by a two step synthetic sequence involving the preparation and hydrolysis of nitriles Nitnles also known as alkyl cyanides are prepared by nucleophilic substitution... 

Section 20 19 The hydrolysis of nitriles to carboxylic acids is irreversible m both acidic and basic solution... 

Aldehydes, Ketones, ndAcids. As with many aromatic compouads, the oxidatioa of methyl groups is an attractive synthetic route to both aldehydes and carboxyUc acids ia the quiaoliaes. The hydrolysis of dibromomethyl groups has also beea used for aldehydes and the hydrolysis of nitriles for carboxyhc acids. Detailed reviews of the synthesis of these compounds have appeared (4). 

Hydrolysis of Nitriles. The chemical hydrolysis of nitriles to acids takes place only under strong acidic or basic conditions and may be accompanied by formation of unwanted and sometimes toxic by-products. Enzymatic hydrolysis of nitriles by nitrile hydratases, nittilases, and amidases is often advantageous since amides or acids can be produced under very mild conditions and in a stereo- or regioselective manner (114,115). 

The hydrolysis of nitriles can be carried out with either isolated enzymes or immobilized cells. Eor example, resting cells of P. chlororaphis can accumulate up to 400 g/L of acrylamide in 8 h, provided acrylonitrile is added gradually to avoid nitrile hydratase inhibition (116). The degree of acrylonitrile conversion to acrylamide is 99% without any formation of acryUc acid. Because of its high efficiency the process has been commercialized and currentiy is used by Nitto Chemical Industry Co. on a multithousand ton scale. 

A second practical route to AT-unsubstituted amides is by the controlled hydrolysis of nitriles, which can often be made (in the 5-position) by primary synthesis or (elsewhere) by displacement of an ammonio grouping. Thus 4,6-dimethylpyrimidine-2-carbonitrile (798 R = CN) in warm aqueous ammonia gives the amide (798 R = CONH2) in good yield... 

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

An interesting observation was reported concerning the hydrolysis of nitrile 253 with barium hydroxide (Scheme 166). It was stated that 3-hydroxyfurazancarbox-ylic acid was formed, although an adequate proof of the structure was not given (12LA196, 30LA43). 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

The hydrolysis of nitriles catalyzed by boron trifluoride is a reliable and high yield process for conversion to the corresponding amide. Other methods give variable yields and may result in a significant quantity of acid being formed, whereas the procedure given below frequently results in yields above 90%. 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

The reaction proceeds via die hydrolysis of nitrile groups to an amide. The amides may also be A-formyl amines, which react with acid groups whereby volatile formic acid is shipped10 ... 

Hydrolysis of nitriles normally requires quite harsh conditions and long reaction times [101,102]. Applying microwave irradiation for this type of re-... 

Scheme 18 Hydrolysis of nitriles to carboxylic acids under microwave irradiation...

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids [4]. Scientists at Diversa expanded the collection of nitrilases by metagenome panning [56]. Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity, limited activity (substrate acceptance), and/or product inhibition. Diversa also reported the first example of the directed evolution of an enantioselective nitrilase [20]. An additional limitation had to be overcome, which is sometimes ignored, when enzymes are used as catalysts in synthetic organic chemistry product inhibition and/or decreased enantioselectivity at high substrate concentrations [20]. 

Upon screening genomic libraries obtained from environmental samples, more than 200 new nitrilases that allow mild and selective hydrolysis of nitriles were discovered [56]. One of them catalyzes the (R)-selective hydrolysis of (16) with a value... 

The hydrolysis of nitriles to carboxylic acids is one of the best methods for the preparation of these compounds. Nearly all nitriles give the reaction, with either acidic or basic catalysts. Hydrolysis of cyanohydrins, RCH(OH)CN, is usually carried out under acidic conditions, because basic solutions cause competing reversion of the cyanohydrin to the aldehyde and CN . However, cyanohydrins have been hydrolyzed under basic conditions with borax or alkaline borates. ... 

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