Nucleophiles in addition reactions

The reacuons of electrophihc tnflyl sources with nucleophiles were investi gated The reaction of tnfhc anhydride with an organolithium reagent is not synthetically promising because of ditnflylation and other side reactions [20] When phenyllithium reacts with tnfhc anhydnde, dimerization products and acetylenic Michael diadducts are observed [20] (equation 17), but using the sodium salt of the alkynes instead of the lithium salt provides the alkynyl tnfluoromethyl sulfones [21] (equation 18) (Table 7) Alkynyl tnfluoromethyl sulfones are of synthetic interest, because they show a pronounced reactivity toward nucleophiles in addition reactions and cyclopentadiene in Diels-Alder reactions [21] (Table 7)... 

Ketenes and other C=0-containing heterocumulenes also react with nucleophiles in addition reactions the C=0 double bond, however, is nonetheless retained (Section 8.2) ... 

Alkynylsilanes can function as carbon nucleophiles in addition reactions to electrophilic ir-systems. In principle electrophilic addition reactions to alkynylsilanes can occur to produce a- or P-silyl-substituted vinyl cations, as illustrated in Scheme 37. The a-silyl carbocation is not the most stabilized cation, the reason being that the caibon-silicon bond can achieve coplanarity with the vacant orbital on the -carbo-nium ion, making possible 3-stabilization through hyperconjugation. Depending on the configuration of the carbocation, the developing vacant orbital can exist as a p-orbital, as in structure (75a), or an rp -hy-brid, as in structure (75b). 

Elsewhere, I have proposed the name "Oxidation-Addition-Substitution Reaction" to describe the oxidation of hydroquinones to quinones followed by nucleophilic addition of SH or other groups to the quinone (7). Analogous oxidation-addition-substitution reactions can also take place when porphyrins are first oxidized to dehydroporphyrin intermediates, which can then participate with nucleophiles in addition reactions to form substituted porphyrins (76). 

The chemistry of nitriles is similar to that of carbonyl compounds. The carbon-nitrogen triple bond can act as an acceptor of nucleophiles in addition reactions. 

Although neutral dialkyl ami no radicals generally do not add to simple alkenes it was possible to observe some addition of dimethylamino radicals to styrene and a-methylstyrene (48). Photolysis of tetramethy1-2-tetrazene (TMT) in cyclohexane, at room temperature, in the presence of a-methylstyrene resulted in the formation of small but reproducible yields of addition products. The bulk of the amino radicals were consumed in the formation of tetramethylhydrazine and dimethyl amine. The relative rate of formation of the adducts from substituted a-methylstyrenes were correlated by the Hammett equation yielding a p = +0.69 + 0.03 (corr. coeff.. 99). This result indicates that the dimethylamino radical behaves like a nucleophile in addition reactions i.e. the styrenes substituted by electron attracting substituents reacted more rapidly than the electron rich styrenes. This result is in marked contrast to that obtained for dimethylamino radicals coordinated by zinc chloride (48). These... 

The use of nonstabilized carbon nucleophiles in this reaction has been rare. Recently, however, it was shown that lithium ester enolates participate in Pd-cata-lyzed 1,4-additions to cyclic and acyclic vinyloxiranes, affording the corresponding 6-hydroxy-4-enoates in good yields and with complete regioselectivity [117, 118]. 

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

The role of the DEAD is to activate the triphenylphosphine toward nucleophilic attack by the alcohol. In the course of the reaction the N=N double bond is reduced. As is discussed later, this method is applicable for activation of alcohols to substitution by other nucleophiles in addition to halide ions. The activation of alcohols to nucleophilic attack by the triphenylphosphine-DEAD combination is called the Mitsunobu reaction.76... 

The most significant amino acids for modification and conjugation purposes are the ones containing ionizable side chains aspartic acid, glutamic acid, lysine, arginine, cysteine, histidine, and tyrosine (Figure 1.6). In their unprotonated state, each of these side chains can be potent nucleophiles to engage in addition reactions (see the discussion on nucleophilicity below). 

As discussed in Section 11.15.4 on thermodynamic aspects, dinitrotetrazolo[l,5- ]pyridines 11 are electrophiles and can react with nucleophilic species in addition reactions as shown in Scheme 18 <1994IZV1278, 2003OBC2764>. In the presence of alcohols on addition of the alcoholate anion in position 5 of tetrazolo[l,5-tf]pyridine takes place. The primary addition product 12 formed in an equilibrium was characterized by its H NMR spectrum and can be isolated in the form of potassium salts 62 in good to high yields 53-96% <1994IZV1278>. 

The solvent is the reaction medium and as such, by solvating the ground and activated states, will influence the energetics of the activation process. In addition it acts as a nucleophile in the reaction path represented by Ati. A large value of relative to Atj is observed in solvents capable of coordinating strongly to the metal so that generally the order... 

Friedman, M., Cavins, I.F., and Wall, l.S. Relative nucleophilic reactivities of amino groups and mercaptide ions in addition reactions with a.p-unsaturated compounds, J. Am. Chem. Soc., 87(16) 3672-3682,1965. 

A specific example involving aflatoxins is shown in Box 6.8. We shall see other examples of glutathione reacting as a nucleophile in detoxification reactions, where conjugation is not the result of nucleophilic substitution. For example, it might be nucleophilic addition to an electrophile such as an unsaturated carbonyl compound (see Box 10.20). 

Rovis and Vora sought to expand the utility in alpha redox reactions to include the formation of amides [116]. While aniline was previously demonstrated as an efficient nucleophile in this reaction (Scheme 29), attempts to develop the scope to include non-aryl amines as various primary and secondary amines resulted in low yields. The discovery of a co-catalyst was the key to effecting amide formation (Table 15). Various co-catalysts, including HOBt, HOAt, DMAP, imidazole, and pentafluorophenol, are efficient and result in high yields of a variety of amides including those involving primary and secondary amines with additional functionality. 

Scheme 7.4 illustrates some of the important synthetic reactions in which organo-lithium reagents act as nucleophiles. In addition to this type of reactivity, the lithium reagents have enormous importance in synthesis as bases and as lithiating reagents. The commerically available methyl, w-butyl, 5-butyl, and /-butyl reagents are used most frequently in this context. 

As seen previously, the Cl -C3 bond of bicyclo[1.1.0]butane behaves as a rc-bond in addition reactions. According to SCF MO calculations, the hybridization in the two central carbons is equivalent to 0% p character.19 As a result, this central bond is easily cleaved by a nucleophilic attack when activated by an electron-withdrawing group. The course of the nucleophilic addition of a hydride ion to bicyclofl.l. 0]butane has been studied by ab initio calculations, the results of which suggested that the hydride ion should approach bicyclofl. 1.0]butane from an equatorial direction.20 An example depicting these features is shown by the attack of an alkoxide on bicyclo[1.1.0]butane-l-carbonitrile, giving the isomeric 3-alkoxycyclobutane-l-carbonitriles 10 in 35% yield.21... 

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