Cyanides electrophilic additions

It is important to be able to look at a molecular structure and deduce the possible reactions it can undergo. Take an alkene, for example. It has a 7t bond that makes it electron-rich and able to attack electrophiles such as water, halogens and hydrogen halides in electrophilic addition reactions. Haloalkanes, on the other hand, contain polar carbon-halogen bonds because the halogen is more electronegative than carbon. This makes them susceptible to attack by nucleophiles, such as hydroxide, cyanide and alkoxide ions, in nucleophilic substitution reactions. 

Linkers that enable the preparation of y-lactones by cleavage of hydroxy esters from insoluble supports are discussed in Section 3.5.2. Resin-bound y-lactones have been prepared by Baeyer-Villiger oxidation of cyclobutanones [39], by intramolecular addition of alkyl radicals to oximes [48], by electrophilic addition of resin-bound sele-nenyl cyanide or bromide to 3,y-unsaturated acids (Figure 9.2 [100]), and by palladium-mediated coupling of resin-bound aryl iodides with allenyl carboxylic acids (Entry 10, Table 5.7 [101]). 

The addition reactions we have met so far have involved electrophilic addition across the C = C bond in alkene molecules (see page 209). Aldehydes and ketones both undergo addition reactions with hydrogen cyanide, HCN. In this case, addition of HCN takes place across the C=0 bond. However, the attack is by a nucleophile, not an electrophile. We can show this using the nucleophilic addition reaction of propanal with HCN. The HCN is generated in situ (in the reaction vessel) by the reaction of sodium cyanide, NaCN, and dilute sulfuric acid. 

Addition (Sections 14.2, 19.13) Addition of a reactant to the ends of a conjugated tt system. Conjugated dienes yield 1,4 adducts when treated with electrophiles such as MCI. Conjugated enones yield 1,4 adducts when treated with nucleophiles such as cyanide ion. 

Alternatively, unreactive heterocyclic N-oxides might also be readily converted into their a-cyano heterocycles on reaction with the strongly electrophilic Cl3SiCN, Cl2Si(CN)2, or ClSi(CN)3, which should be formed in situ on addition of SiCl4 to a solution or suspension of sodium or potassium cyanide in acetonitrile or DMF (cf the analogous formation of ClSi(N3)3 708 in Scheme 5.70). 

Arenes, on complexation with Cr, Fe, Mn, and so forth, acquire strongly electrophilic character such complexes in reactions with nucleophiles behave as electrophilic nitroarenes.71 Synthesis of aromatic nitriles via the temporary complexation of nitroarenes to the cationic cyclopentadienyliron moiety, cyanide addition, and oxidative demetalation with DDQ has been reported (Eq. 9.43).72... 

Despite intense study of the chemical reactivity of the inorganic NO donor SNP with a number of electrophiles and nucleophiles (in particular thiols), the mechanism of NO release from this drug also remains incompletely understood. In biological systems, both enzymatic and non-enzymatic pathways appear to be involved [28]. Nitric oxide release is thought to be preceded by a one-electron reduction step followed by release of cyanide, and an inner-sphere charge transfer reaction between the ni-trosonium ion (NO+) and the ferrous iron (Fe2+). Upon addition of SNP to tissues, formation of iron nitrosyl complexes, which are in equilibrium with S-nitrosothiols, has been observed. A membrane-bound enzyme may be involved in the generation of NO from SNP in vascular tissue [35], but the exact nature of this reducing activity is unknown. 

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

Addition of an alkyl nucleophile leads, due to the loss of one double bond, to a decrease of electron affinity and a concomitant negative shift of the reduction potential of about 100 to 150 mV per lost double bond. One possibility to compensate for this negative shift is the introduction of an electron-withdrawing substituent such as cyanide. Reaction of liCN or NaCN with Cjq at room temperature generates the monoadduct anion that can be quenched with various electrophiles [6]. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

Epoxynitrone (742) can be transformed to a positively charged heterodiene (743) using CF3S03SiMe3 or CF3S03Si(Bu )Me2 as electrophilic reagents (79HCA205). The diene adds to isolated double bonds to afford oxazines such as (744) via an inverse electron demand Diels-Alder pathway. Subsequent addition of cyanide to the iminium salt leads to a stable derivative (745) which can be converted through its mesylate (746) to an a-methylene y-lactone (747) on base treatment followed by acid hydrolysis (Scheme 171). 

The bifunctional mechanism proposed for the Ti-catalyzed Strecker suggests that electrophiles other than amines can be induced to undergo catalytic asymmetric additions with cyanide. The details of the optimal conditions (exactly what ligand structure, metal salt, solvent, and any needed additives) would however have to be identified through screening of parallel libraries as mentioned above. In this fashion, we have been able to develop an Al-catalyzed asymmetric... 

Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation A thiazolium salt may also be used as the catalyst in this reaction. 

Nucleophilic addition of the metal-stabilized pyrrolium complexes is readily achieved with borohydride and cyanide ion. The scope of this reactivity is bracketed by the diminished electrophilicity of the iminium carbons and the acidity of the ammine ligands, which prevents the use of strongly basic nucleophiles. Competing deprotonation of the acidic pyrrolium ring protons is observed primarily only with 3//-pyrrolium complexes or when bulky nucleophiles are used. 

Addition of the cyanide anion (which is isoelectronic with carbon monoxide) to alkylboranes produces stable organoborates. Treatment of these with electrophiles such as trifluoroacetic anhydride induces alkyl-group migration. 

The nucleophilic addition involves the addition of a nucleophilic to a molecule. This is a distinctive reaction for ketones and aldehydes and the nucleophile will add to electrophilic carbon atom of the carbonyl group. The nucleophile can be a negatively charged ion like cyanide or hydride, or it can be a neutral molecule like water or alcohol. 

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