Nitriles acid-base chemistry

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

There are several areas of uncertainty regarding the literature classification of phosgene chemistry. The most common classification is based on the nature of the reaction center and usually lists the reagents, or the products of reaction (isocyanates, carbonates, carbamates, ureas, chloroformates, acid chlorides, isonitrUes, nitriles, carbodiimides, etc.) [1, 2]. 

The gas-phase ion chemistry of HCN, MeCN and various alkyl nitriles has previously been investigated111 using ion cyclotron resonance techniques (ICR)112-115. The developments in such techniques have made it possible to quantify base strengths relative to a variety of cationic reference acids in the gas phase116-130. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

In a recent pubhcation the nitrile (EWG = CN) variant [ 126] of this chemistry was performed in water by applying N,N-diethylaminopropylated sihca gel as heterogeneous catalyst [ 128]. Another variant of this reaction sequence, leading to chiral sulfinylated enones, has been developed by Llera [ 129] employing the enantiomerically pure geminal bis(sulfoxide) 208 (Scheme 54). This bis(sulfoxide) was prepared from (-)-p-toluenesulfinic acid menthyl ester [100], as described by Kunieda [130]. Later this procedure was improved to increase the yield from 35 to 91% [13,131]. Treatment of 208 with enolizable aldehydes or ketones, in the presence of piperidine as a base and thiophile, initiated a reaction cascade involving a condensation step (to 210), a proton shift to allylic sulfoxide 211, and a [2,3]-0-shift followed by a piperidine-mediated desulfuration delivering the alcohols 212 as isomeric mixtures. Oxidation of the latter compounds (one of the R = H) led to enantiomerically pure E-y-oxo vinyl sulfoxides 213. 

Activation with sulfonic acid chlorides is more general, rendering amides with the possible participation of symmetric anhydrides after disproportionation. This method has also found use in the synthesis of modem 3-lactam antibiotics. However, in peptide chemistry this activation method leads to unwanted side reactions, like formation of nitriles in the cases of glutamine and asparagine, and racemization. In a convenient one-pot procedure, the carboxylic acids are activated by sulfonyl chlorides under solid-liquid phase transfer conditions using solid potassium carbonate as base and a lipophilic ammonium salt as catalyst. ... 

Three additional approaches to the synthesis of CNT are shown in Fig. 9. The first [77, 78] involves transformation of 3 -ketonucleoside 44 into cyanohydrin 45, followed by deoxygenation at 3 and then at 2 to afford 47, which is easily epimerized to 31 by treatment with base (pH = 9). Treatment of 2 -0-acyl derivatives of 46 with bases produced elimination to give the 2, 3 -unsaturated nucleoside 48. An important factor in the chemistry of these cyanonucleosides is the acidity of the H-3 hydrogen atom in a-position to the nitrile group. This acidity is responsible for the facile epimerization 47 31 and for the elimination... 

Michael Addition. The Michael reaction is a typical base-catalyzed reaction used in organic chemistry to form a C—C bond. It is usually a consecutive side reaction accompanying the base-catalyzed synthesis of a, -unsaturated ketones, aldehydes, nitriles, or carbo lic acid derivatives. The reaction between an Q ,)S-unsaturated compoimd and an activated methylene compoimd is known as the Michael addition Scheme 9. The reaction is the nucleophilic addition of a car-banion intermediate to the ft carbon of the C—C double bond in the conjugated system (49) without releasing a water molecule. The carbanion is provided by the activated methylene compoimd, and contrarily to the Knoevenagel condensation the product retains the substituents of both reactant molecules. 

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