Nitriles basic hydrolysis

The preparation of y-phenoxybutyric acid (61%) by acid hydrolysis of the phenoxycyanide is a typical example of the formation of an ether acid by this method. Nine alkoxypropionic acids, ROCH CHjCOjH, have been made in 4S> 86% yields by acid hydrolysis of the alkoxy nitriles. Basic hydrolysis gives readily polymerizable material propably because of partial decomposition of the alkoxy nitrile into the alcohol and acrylonitrile. ... 

We aheady discussed both the acidic and basic hydrolysis of fflnides (see Section 20.17). All that remains to complete the mechanistic picture of nitrile hydrolysis is to examine the conversion of the nitrile to the conesponding amide. 

Basic hydrolysis serves to convert the nitrile to the acid... 

Active Figure 20.4 MECHANISM Mechanism of the basic hydrolysis of a nitrile to yield an amide, which is subsequently... 

Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-t-butylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>. 

In a similar closure onto a nitrile, activation of the cyano functionality of intermediates 16 with TMSC1 (17) resulted in ring closure of the urea nitrogen to the nitrile carbon to form pyrimidones 18 following basic hydrolysis <00H347>. 

The basic hydrolysis (reaction with water) of a nitrile (R-CN) followed by acidification yields a carboxylic acid. In general, an reaction (nucleophilic substitution) of an alkyl halide is used to generate the nitrile before hydrolysis. Figure 12-12 illustrates the formation of a carboxylic acid beginning with an alkyl halide. 

An unusual rearrangement provides the key to the preparation of a highly substituted pyrrolidone, doxapram (26-7), that is used as a respiratory stimulant. The synthesis starts with the displacement of chlorine on pyrrolidine (26-1) by the carbanion from diphenylacetonitrile (26-2) to give (26-3) as the product. The quite hindered nitrile is then hydrolyzed to the corresponding carboxylic acid (26-4) by basic hydrolysis. The reaction of acid with thionyl chloride presumably proceeds initially to form the corresponding acid chloride. The close proximity of that group to basic... 

Carboxylic acid derivatives are compounds that possess an acyl group (R—C=0) linked to an electronegative atom, e.g. —Cl, —CO2 R, —OR or —NH2. They can be converted to carboxylic acids via simple acidic or basic hydrolysis. The important acid derivatives are acid chlorides, acid anhydrides, esters and amides. Usually nitriles are also considered as carboxylic acid derivatives. Although nitriles are not directly carboxylic acid derivatives, they are conveniently hydrolysed to carboxylic acids by acid or base catalysts. Moreover, nitriles can be easily prepared through dehydration of amides, which are carboxylic acid derivatives. 

The conservation of charge is a fundamental law for all processes, such as the addition of nucleophiles to it systems or acid-base reactions. The first step of die basic hydrolysis of nitriles has die hydroxide ion adding to the it bond of die nitrile. For the purposes of mechanistic discussion, the hydroxide is shown widiout its counterion and die net charge on the reactant side of the equation is — 1. Consequently, the product of diis first step (and each subsequent step) must also have a net negative charge. 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

Another way to convert an alkyl halide (or tosylate) to a carboxylic acid with an additional carbon atom is to displace the halide with sodium cyanide. The product is a nitrile with one additional carbon atom. Acidic or basic hydrolysis of the nitrile gives a carboxylic acid by a mechanism discussed in Chapter 21. This method is limited to halides and tosylates that are good SN2 electrophiles usually primary and unhindered. 

The mechanism for acidic hydrolysis of a nitrile resembles the basic hydrolysis, except that the nitrile is first protonated, activating it toward attack by a weak nucleophile (water). Under acidic conditions, the proton transfer (tautomerism) involves protonation on nitrogen followed by deprotonation on oxygen. Propose a mechanism for the acid-catalyzed hydrolysis of benzonitrile to benzamide. 

Reactions of Nitriles Nitriles undergo acidic or basic hydrolysis to amides, which may be further hydrolyzed to carboxylic acids. Reduction of a nitrile by lithium aluminum hydride gives a primary amine, and the reaction with a Grignard reagent gives an imine that hydrolyzes to a ketone. 

Nagata s method. Reduction of the ketone with sodium borohydride stereoselec-tively led to the alcohol, which on repeated chromatography on basic alumina cyclized to the iminoether, 165. Its conversion into 14-oxodendrobine (97) was achieved by tosylation to the tosylamide and subsequent basic hydrolysis. The authors developed an alternative route from cyanoketone 164 to 14-oxodendrobine (97) by hydrolyzing the nitrile under acidic conditions. The acid formed was esterified with diazomethane and the ketone 166 was reduced stereoselectively with sodium borohydride. Subsequent saponification and acidic lactonization led to 14-oxodendrobine (97). Inubushi et al. also used Borch s method to convert 14-oxodendrobine (97) into dendrobine (82) via the lactimether 167 and reduction. 

The alkaline hydrolysis of the nitrile is accelerated by 7 powers of ten if catalyzed by Ni2+, or by 9 powers of ten if catalyzed by Cu2+. The mechanism of the metal ion catalyzed reaction probably involves external attack of hydroxide ion at the nitrile carbon. It is unlikely that the strong acceleration caused by the metal ion is solely due to the field effect of the positive charge. The metal ion probably interacts (weakly) with the Tf-electrons of the CN multiple bond. The basic hydrolysis of the amide is also catalyzed by transition metal ions, but the acceleration of the reaction rate is much smaller. 

In a similar way, transition metal ions catalyze the basic hydrolysis of esters of a-amino acids [271]. The rate law [272, 273] is analogous to that observed in the hydration of phenanthroline-nitrile, viz. 

Active Figure 20.4 MECHANISM Mechanism of the basic hydrolysis of a nitrile to yield an amide, which is subsequently hydrolyzed further to a carboxylic acid anion. Sign in at www.thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

The mechanism of nitrile hydrolysis in both acid and base consists of three parts [1] nucleophilic addition of H2O or OH to form the imidic acid tautomer [2] tautomerization to form the amide, and [3] hydrolysis of the amide to form RCOOH or RCOO. The mechanism is shown for the basic hydrolysis of RCN to RCOO (Mechanism 22.11). 

Various substituents at the 3-position of benzisoselenazoles were transformed into other functional groups by standard methods (Scheme 17) thus, oxidation of the aldehyde 55 or basic hydrolysis of the amide 56 gave 3-benzisoselenazolecarboxylic acid 57, which was converted into the ester 58 and then by Curtius degradation to 3-aminobenzisoselenazole 60. The amide 56 was dehydrated to the nitrile 59 <1975JHC1091>. 

Hydrolysis with powdered potassium hydroxide or potassium fluoride on alumina in r-butyl alcohol converts nitriles to amides without further hydrolysis to carboxlic acids. Under similar conditions, addition of alkyl halides gives iV-alkylcarboxyamides. Less drastic acidic or basic hydrolysis conditions involve disproportionation of alkaline hydrogen peroxide with concomitant hydration of the nitrile (equation 21). 

The first stereoselective total synthesis of AI-77B, a gastroprotective substance, was accomplished by Y. Hamada and co-workers. In the final stages of the synthetic effort, the intramolecular Pinner reaction was utilized to convert the cyano group into the corresponding carboxylic acid. The nitrile substrate was dissolved in 5% HCI in methanol, and excess trimethyl orthoformate was added at 5 °C and the reaction mixture was stirred at this temperature for almost two days. Next, the cyclic imino ether hydrochloride salt was treated with water at room temperature followed by basic hydrolysis. Finally, the pH was adjusted with HCI to obtain the natural product. 

The easily available naphthalene acetonitriles are suitable starting components for the benzannelation of naphthalene32,34,44). The naphthalene-l-acetonitrile (64) produces phenanthrene-4-carbonitriles (66). The direction of cyclization in (55) is structurally fixed. It turns out the nitrile group in (66) to be sterically strongly screened. Basic hydrolysis under very hard conditions succeeds only to the stage of the corresponding amide. 

The basic hydrolysis of nitrile 50 with aqneons NaOH in ethanol was examined, which proceeded throngh intermediate amides 57, and reached 98% conversion to acid 3 within 4 hr with <1% of amides remaining. Both cis- and trani-amides were observed by liqnid chromatogra-phy/mass spectrometry (LC/MS) during reaction, and the strnctnre of trans-amide Sit was confirmed by LC/MS and independent synthesis (by treatment of trani-pyrrolidine acid with CDI and ammoninm hydroxide). It is reasonable to postnlate that the hydrolysis of both di-nitrile 50 and di-amide Sic to the corresponding di-acids was slow relative to epimerization, which provided a mechanism for complete conversion of di-nitrile 50 to trani-acid 3. 

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