Nitriles to Carboxylic Acids

Nitriles are considered carboxylic acid derivatives because they are often prepared from acids through the primary amides. Show how you would convert the following carboxylic acids to nitriles. 

The in situ generation of carbon nucleophiles via extrusion of CO2 from benzoates cannot only be combined with cross-coupling processes but also with 1,2- and 1,4-addition reactions. An example is the rhodium-catalyzed decarboxylative conjugate addition of activated benzoic acids to acrylic esters or amides developed by Zhao et al. (Scheme 19, right side) [65]. A nice application is the decarboxylative addition of aromatic carboxylic acids to nitriles in the presence of... 

Hydrolysis Conversion of Nitriles into Carboxylic Acids A nitrile is hydrolyzed in either basic or acidic aqueous solution to yield a carboxylic acid plus ammonia or an amine. 

Interactive to use a web-based palette to predict products from a variety of reactions involving carboxylic acids and nitriles. 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

The compound NaBH4 in the presence of Me2N=CHCl" Cl" reduces carboxylic acids to primary alcohols chemoselectively in the presence of halide, ester, and nitrile groups Fujisawa, T. Mori, T. Sato, T. Chem. Lett., 1983, 835. 

Acyl nitronates (63) derived from primary AN are characterized by two types of such transformations the rearrangement into a-acetoxy aldoximes (219) and elimination of the corresponding carboxylic acids to form nitrile oxides (Scheme 3.63). 

Bacterial enzymes have been reported to catalyze the hydrolysis of nitriles [118][121], A nitrilase (EC 3.5.5.1) acts to hydrolyze aromatic nitriles directly to the carboxylic acid. A nitrile hydratase (a lyase, EC 4.2. E84) acts on short-chain aliphatic nitriles to form the amide. As discussed below, the hydrolysis of nitriles to amides is also documented in mammals, but little appears known about the enzymes involved. 

As indicated in Section ni.B, deprotonation of a carbamate affords a dipole-stabilized a-amino-organolithium that can be transmetalated with copper salts to form cuprates, thereby expanding the versatility of the organolithium. Suitable electrophiles include enones, alkenyl, alkynyl, allenyl and dienyl carboxylic acid derivatives, nitriles and sulfoxides. Dieter and coworkers have shown that the same process can be accomplished via transmetalation of a stannane (Scheme 36). The procedure is particularly... 

Notably, nitrile-degrading enzymes (e.g. nitrilase that converts the CN group to carboxylic acid, and nitrile hydratase that produces an amide function) have been described, and they co-exist with aldoxime-degrading enzymes in bacteria (Reference 111 and references cited therein). Smdies in this area led to the proposal that the aldoxime-nitrile pathway, which is implemented in synthesis of drugs and fine chemicals, occurs as a natural enzymic pathway. It is of interest that the enzyme responsible for bacterial conversion of Af-hydroxy-L-phenylalanine to phenacetylaldoxime, an oxidative decarboxylation reaction, lacks heme or flavin groups which are found in plant or human enzymes that catalyze the same reaction. Its dependency on pyridoxal phosphate raised the possibility that similar systems may also be present in plants . 

Nitriles are most commonly prepared via the conversion of carboxylic acids to primary amides, followed by dehydration with boiling acetic anhydride, or other commonly employed dehydration reagents, e.g. SOCI2 or POCI3. This is a useful synthesis for amide, because it is not limited by steric hindrance. Alkyl nitriles can be prepared by the action of metal cyanides on alkyl halides (see Section 5.5.2). 

Solid heteropoly compounds are suitable oxidation catalysts for various reactions such as dehydrogenation of O- and N-containing compounds (aldehydes, carboxylic acids, ketones, nitriles, and alcohols) as well as oxidation of aldehydes. Heteropoly catalysts are inferior to Mo-Bi oxide-based catalysts for the allylic oxidation of olefins, but they are much better than these for oxidation of methacrolein (5). Mo-V mixed-oxide catalysts used commercially for the oxidation of acrolein are not good catalysts for methacrolein oxidation. The presence of an a-methyl group in methacrolein makes the oxidation difficult (12). The oxidation of lower paraffins such as propane, butanes, and pentanes has been attempted (324). Typical oxidation reactions are listed in Table XXXI and described in more detail in the following sections. 

Amides and Nitriles. Primary amines or ammonia, from the thermal decomposition of amino acids, can be acylated by carboxylic acids to produce amides (30). 

According to Appendix 1, the pK value for a carboxylic acid is approximately 4.75. Furthermore, if we imagine converting the carboxylic acid to an ester, we recognize that protons adjacent to esters have pATa values of approximately 25-30. Finally, the pKa value for a proton adjacent to a nitrile is approximately 20-25. Using the formula described in Problem 7, we calculate a pKa value of approximately 11.25-13.75 for the protons between the two functional groups. Therefore, the order of deprotonation is as follows ... 

It reduces esters or lactones selectively in the presence of several other functional groups such as carboxylic acids, amides, nitriles, and h.iiidcs. Simple amides are not reduced, but tertiary amides are reduced to the correspond,ng tertiary amines. LiB(C H,),H or 9-BBN reduces tertiary amides to the corresponding alcohols. 

Like the carboxylic acid derivatives, nitriles contain an electrophilic carbon atom, making them susceptible to nucleophilic attack. 

In contrast to the carboxylic acid derivatives, nitriles are named as alkane derivatives. To name a nitrile using lUPAC rules ... 

Alane (AIH3) and its derivatives have also been utilized in the reduction of carboxylic acids to primary alcohols. It rapidly reduces aldehydes, ketones, acid chlorides, lactones, esters, carboxylic acids and salts, tertiary amides, nitriles and epoxides. In contrast, nitro compounds and alkenes are slow to react. AIH3 is particularly useful for the chemoselective reduction of carboxylic acids containing halogen or nitro substituents, to produce the corresponding primary alcohols. DIBAL-H reduces aliphatic or aromatic carboxylic acids to produce either aldehydes (-75 °C) or primary alcohols (25 C) Aminoalu-minum hydrides are less reactive reagents and are superior for aldehyde synthesis. ... 

Dihalomethyleneiminium salts undeigo condensation reactions with CH-acidic compounds such as ketones, carboxylic acid chlorides, nitriles and amides, to give amide halides, e.g. (51 equation... 

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