Heteroatomic nucleophiles mechanisms

Alkenylations of heteroatom nucleophiles with alkenyl(aryl)iodonium salts occur by a variety of mechanisms, including SN1, SN2, alkylidenecarbene, and addition-elimination pathways [ 126,127]. Reactions that occur with retention of configuration at vinylic carbon are sometimes attributed to a ligand-coupling... 

Carboxylic amides, carboxylic esters, and carboxylic acids react with acid-stable heteroatom nucleophiles in a neutral solution much more slowly via the mechanism of Figure 6.2 than in an acidic solution via the mechanism of Figure 6.5. In an acidic solution, their car-boxonium ion derivatives, which result from the reversible protonation of the carboxyl oxygen, act as precursors of the tetrahedral intermediate. According to the discussion earlier in... 

Quite a few substitution reactions of heteroatom nucleophiles at the carboxyl carbon as well as their mechanisms are discussed in introductory organic chemistry courses. The left and the center columns of Table 6.3 summarize these reactions. Accordingly, we will save ourselves a detailed repetition of all these reactions and only consider ester hydrolysis once more. Section 6.4.1 will not only revisit the acidic and basic ester hydrolysis but will go into much more detail. Beyond that, SN reactions of this type will only be discussed using representative examples, namely ... 

Fig. 8.12. Mechanism of the uncatalyzed addition (starting top left and proceeding clockwise) and the acid-catalyzed addition (starting top left and then proceeding counterclockwise) of heteroatom nucleophiles to heterocumulenes.

Ketenes are extremely powerful acylating agents for heteroatom nucleophiles. They react in each case according to the uncatalyzed mechanism of Figure 8.12. In this manner, ketenes can add... 

The isocyanate can he isolated if the Curtius degradation is carried out in an inert solvent. The isocyanate also can be reacted with a heteroatom-nucleophile either subsequently or in situ. The heteroatom nucleophile adds to the C=N double bond of the isocyanate via the mechanism of Figure 8.12. In this way, the addition of water initially results in a carbamic acid. However, all carbamic acids are unstable and immediately decarboxylate to give amines (see Figure 8.5). Because of this consecutive reaction, the Curtius rearrangement represents a valuable amine synthesis. The amines formed contain one C atom less than the acyl azide substrates. It is due to this feature that one almost often refers to this reaction as Curtius degradation, not as Curtius rearrangement. 

Carbodiimides are diaza derivatives of C02. It is also possible to add heteroatom nucleophiles to them. The addition of carboxylic adds to dicyclohexyl carbodiimide was mentioned in the context of Figures 6.15 and 6.26, but there we looked at it only from the point of view of activating a carboxylic add. This addition follows the proton-catalyzed mechanism of Figure 7.1. 

Urea A is the starting material for preparing the carbodiimide C, which activates carboxylic acids according to the same mechanism and for the same reason as DCC, with which you are already familiar (Figures 6.15 and 6.26). If the carbodiimide C from Figure 7.5 were not so much more expensive than DCC, everybody would use the former instead of the latter for carboxylic acid activation. There is a practical reason for this. When a heteroatom nucleophile is acylated with the DCC adduct of a carboxylic acid, besides the desired carboxylic acid derivative one obtains dicyclohexyl urea (formula B in Figure 7.5). This (stoichiometric) by-product must be separated from the acylation product, which is relatively laborious when realized by chromatography or by crystallization. When a carboxylic add has been activated with the carbodiimide C and the subsequent acylation of a heteroatom nucleophile has been effected, one also obtains a urea as a stoichiometric by-product. It has the structure D and is therefore... 

Nucleophilic ring opening of epoxides with heteroatom nucleophiles is another valuable method for the synthesis of many heteroatom-modified carbohydrate derivatives. The cyclic nature of epoxides renders the competing elimination process stereoelectronically unfavorable. Analogous to the above-discussed Sn2 nucleophilic mechanism, nucleophiles can open epoxide rings, and give rise to Walden inversion at the attacked carbon, furnishing a-hydroxy derivatives as illustrated in O Scheme 10. 

The positively charged sulfonium ion in SAM makes the three carbon atoms that are bonded to the sulfur atom prone to attack by nucleophiles. When the alkyl acceptor is a heteroatom (most commonly O, N), the methyl- or the acp-transfer reactions occur via simple nucleophilic mechanism (Sn2) 0-methyl or 0-acp and N-methyl or A-acp linkages may be generated using hydroxyl and amino functions as nucleophiles (Figure 1.4). Some examples of 0-methylation in the presence of SAM as the donor methyl group are depicted in Figure 1.5. 

Scheme 1.58 Proposed mechanism for the Cu-catalyzed coupling of aryl halides with heteroatom nucleophiles.

Prins cyclizations, which proceed by intramolecular addition of alkenes to oxocarbenium ions, provide a simple, efficient method for the stereoselective synthesis of carbocycles and cyclic ethers [77]. Halosilanes and (la) have been used for Prins cyclizations not only as Lewis acids but also as heteroatom nucleophiles. For instance, in the presence of MesSil or MesSiBr, and lutidine, mixed acetals (26) are efficiently cyclized to 4-halotetrahydropyrans (27) with high diastereoselectivity [78]. The halide is introduced into the axial site of the C(4) position. The proposed mechanism for the MesSiBr-promoted reaction involves the initial formation of a-bromoethers (28) from (26). Solvolysis of (28) provides the intimate ion pair (29). Cyclization to the chair transition structure (30) and proximal addition of the bromide produces the observed axial adduct (27). The role of lutidine is to suppress a less selective HBr-promoted cyclization (Scheme 9.23). Acetals bearing an alkyne or allene moiety also undergo the halosilane-promoted cyclization to form haloalkenes [79, 80]. 

Scheme 4 shows in a general manner cyclocondensations considered to involve reaction mechanisms in which nucleophilic heteroatoms condense with electrophilic carbonyl groups in a 1,3-relationship to each other. The standard method of preparation of pyrazoles involves such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity in the condensation does not occur. However, with a monosubstituted hydrazine such as methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained the 1,3-dimethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 represents this type of reaction as a relatively straightforward process, it is considerably more complex and an appreciable effort has been expended on its study (77BSF1163). Details of these reactions and the possible variations of the procedure may be found in Chapter 4.04. 

Allylic nitro groups are readily displaced by nucleophiles via an SNl-type mechanism. Thus, nitro groups with heteroatoms at the OC- or P-positions (for example, a- or P-nitrosulfides) are expected to be cleaved in a similar way. In fact, the nitro group in a-nitrosulfides is replaced by nucleophiles in the presence of a Lewis acid31 or acetic acid.32 The nitro groups in the reaction of Eqs. 7.27 and 7.28 are cleanly replaced by CN, allyl, or PhS group on treatment with MejSiY (Y = CN, allyl) in the presence of SnCl4 or simple treatment with PhSH in AcOH. 

Relatively soon after the discovery that aqueous solutions containing PtCl - and PtClg- can functionalize methane to form chloromethane and methanol, a mechanistic scheme for this conversion was proposed (16,17). As shown in Scheme 4, a methylplatinum(II) intermediate is formed (step I), and this intermediate is oxidized to a methylplatinum(IV) complex (step II). Either reductive elimination involving the Pt(IV) methyl group and coordinated water or chloride or, alternatively, nucleophilic attack at the carbon by an external nucleophile (H20 or Cl-) was proposed to generate the functionalized product and reduce the Pt center back to Pt(II) (step III) (17). This general mechanism has received convincing support over the last two decades (comprehensive reviews can be found in Refs. (2,14,15)). Carbon-heteroatom bond formation from Pt(IV) (step III) has been shown to occur via nucleophilic attack at a Pt-bonded methyl, as discussed in detail below (Section V. A). 

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