Intermediates cationic

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

By using an aromatic aldehyde carrying an electron-releasing group the intermediate cation can be stabilized. This is the basis of the widely-used Ehrlich colour reaction for pyrroles, indoles and furans which have a free reactive nuclear position (Scheme 21). 

Oxidation of A-aminoazetidines (19), deoxygenation of A-nitrosoazetidines (20) and direct deamination of azetidines (21) with difluoroamine leads to cyclopropanes (23) by extrusion of nitrogen from a diazine intermediate (22) (63JA97). A further interesting ring contraction occurs in the Ag" catalysed solvolysis of the A-chloroazetidine (24), which appears to involve the intermediate cation (2S) (7ITLI09). 

Data on the intermediate cations are available 4-aminobiphenyl+Br+, 4-amino-2 -methylbiphenyl+Br+, 4-amino-3 -methylbiphenyl+Br+). Which reaction is most selective Least selective Why Hint Consider the torsion angle about the bond connecting the two phenyl rings. 

It is apparent from simple valence bond considerations as well as from calculations of rr-electron density, " that isoindoles should be most susceptible to electrophilic attack at carbon 1. This preference is most clearly evident when the intermediate cations (85-87) from electrophilic attack (by A+) at positions 1, 4, and 5 are considered. The benzenoid resonance of 85 is the decisive factor in favoring this intermediate over its competitors. 

When 1-hydroxymelatonin (19) is treated with acid, removal of its 1-hydroxy group leaves an indolyl cation (a hybrid of resonance structures 254,168, and so on) as shown in Scheme 37. If there is a subsequent intramolecular nucleophilic attack by the Ab-nitrogen atom on the side chain or if an intermolecular attack by suitable nucleophiles occurs on this intermediate cation, the birth of a new type of product can be expected. 

The mechanism of the alkoxymercuration reaction is similar to that described in Section 7.4 for hvdroxymercuration. The reaction is initiated by electrophilic addition of Iig2+ to the alkene, followed by reaction of the intermediate cation with alcohol and reduction of the C-Hg bond by NaBH4. A variety of alcohols and alkenes can be used in the alkoxymercuration reaction. Primary, secondary, and even tertiary alcohols react well, but ditertiary ethers can t be prepared because of steric hindrance to reaction. 

Keto-enol tautomerism of carbon) ] compounds is catalyzed by both acids and bases. Acid catalysis occurs by protonation of the carbonyl oxygen atom to give an intermediate cation that Joses H+ from its a carbon to yield a neutral enol (Figure 22.1). This proton loss from the cation intermediate is similar to what occurs during an El reaction when a carbocation loses H+ to form an alkene (Section 11.10). 

When an alkene reacts with an electrophile, such as HC1, initial addition of H+ gives an intermediate cation and subsequent reaction with Cl" yields an addition product (Section 6.7). When an enol reacts with an electrophile, however, only the initial addition step is the same. Instead of reading with Cl- to give an addition product, the intermediate cation loses the -OH proton to give an cr-substituted carbonyl compound. The general mechanism is showm in Figure 22.3. 

Electrophilic substitutions normally occur at C2, the position next to the nitrogen, because reaction at this position leads to a more stable intermediate cation having three resonance forms, whereas reaction at C3 gives a less stable cation with only two resonance forms (Figure 24.6). 

Problem 24.24 Indole reacts with electrophiles at C3 rather than at C2. Draw resonance forms of the intermediate cations resulting from reaction at C2 and C3, and explain the observed results. 

Interconversion occurs by S l dissociation to a common intermediate cation. 

Finally, intermediate cationic allyl complexes of palladium15,16 and ruthenium17, produced from allylic esters by the action of substoichiometric amounts of the metal catalyst, have been electronically inverted by reduction to become nucleophilic anion equivalents, which are capable of carbonyl addition. 

Observations of reactivity are concerned with rate determining processes and require the knowledge of the structure and energy of the activated complexes. Up to now, the Hammond principle has been employed (see part 3.2) and reactive intermediates (cationic chain ends) have been used as models for the activated complexes. This was not successful in every case, therefore models of activated complexes related to the matter at hand were constructed, calculated and compared. For example, such models were used to explain the high reactivity of the vinyl ethers19 80). These types of obser-... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Added KI (.1 M) was observed to cause a 40% rate depression in the solvolysis of 2,2-diphenyl-1-anisyliodoethylene, 146, Y = OCH3, X = H. Such common-ion rate depressions are indicative of relatively stable and selective intermediate cations (133). 

The stabilisation of the intermediate cation explains why the activation energy of the reaction is reduced this will increase its speed considerably. The transition state resembles the cation. There are numerous consequences so far as risk is concerned the speed at which heat evolves increases due to the exothermicity of the reaction and there is an easy polysubstitution, which leads to trisubstitutions that can give rise to very unstable compounds. 

As discussed previously, West and coworkers developed a two-step domino process, which is initiated by a Nazarov reaction. This can be extended by an electrophilic substitution. Thus, reaction of 1-179 with TiCl4 led to 1-182 via the intermediate cations 1-180 and 1-181. The final product 1-183 is obtained after aqueous workup in 99% yield (Scheme 1.43) [23]. It is important to mention here that all six stereocenters were built up in a single process with complete diastereoselectivity hence, the procedure was highly efficient. 

Reaction of 2-amino-benzyl alcohol and 2-chloroH-phcnylaminopyrimidinc forms the intermediate cation 204, which contains ene and iminium functionalities and undergoes electrocyclic rearrangement to the 2-phenylamino-6//-pynmido[2,l-2 ]quinazoline 205 (Scheme 32). The cation 204 is stabilized by the aryl groups. The 2-NHPh stmcture of the product was confirmed by 111 NMR spectroscopy <2002TL1303>. 

It is necessary for the intermediate cation or complex to bear considerable car-bocationic character at the carbon center in order for effective hydride transfer to be possible. By carbocationic character it is meant that there must be a substantial deficiency of electron density at carbon or reduction will not occur. For example, the sesquixanthydryl cation l,26 dioxolenium ion 2,27 boron-complexed imines 3, and O-alkylated amide 4,28 are apparently all too stable to receive hydride from organosilicon hydrides and are reportedly not reduced (although the behavior of 1 is in dispute29). This lack of reactivity by very stable cations toward organosilicon hydrides can enhance selectivity in ionic reductions. 

The cycloaddition of allenyl cations with 1,3-dienes results in a number of intermediate cations from which different products result. The allenyl cations 38 are generated first by the reaction of propargyl chlorides with zinc chloride and are then allowed to react with cyclopentadiene or other 1,3-dienes. The products of cycloaddition depend on the substituents on the allenyl cations32,35. The products formed with cyclopentadiene are given in equation 14. 

If one compares the solvolyses of 2-bromo-l,l-diphenyl-4-(p-methoxyphenyl)-but-l-en-3-yne (57) and 4.4-diphenyl-1 -bromo-1 -(/ -mcthoxyphcny l)-buta-1,2,3-tricncs (58, X = Br) in aqueous ethanol (equation 21), the destabilization of the intermediate cation 59 by the large inductive effect of the triple bond as compared to its conjugative effect is evident42. Only in the case of 58 could the substitution product butatrienyl enol ether 60 be isolated in 40% yield, while it was only detected by UV and IR spectroscopy in the solvolysis product of 57. The faster observed reaction rate of 58 as compared to 57 was ascribed to a difference in their ground-state energies42. 

An unusual approach toward the preparation of a-bisphospho-nates began by treatment of an oxime with a phosphorus nucleophile (trialkyl or dialkyl phosphite) and phosphorus oxychloride (as promoter).354 The oxime undergoes a Beckman rearrangement the phosphorus nucleophile attacks the intermediate cation leading to an imine, which is then further attacked by the phosphorus nucleophile to give the a-bisphosphonate (Equation 3.21). 

For silylation of six-membered cyclic nitronates (342), the influence of the nature of base on the regioselectivity of the synthesis of nitrosals (343) was studied in sufficient detail. Intermediate cations A can be deprotonated at the a-C atom of the substituent at C-3 as well as the C-4 atom (see Scheme 3.202 and Table 3.20) (264, 474). 

It should be noted that specially purified individual stereoisomers of six-membered cyclic nitronates were used in coupling with silyl ketene acetal. Hence, the mechanistic model of the C,C-coupling reaction can be discussed on the basis of the configurations of the stereocenters of the starting nitronates of intermediate cations (357) (see Section 3.5.2.1), and the resulting tetrahydro-oxazines (358) (for more details, see below). It should be noted that most of C,C-coupling reactions of six-membered cyclic nitronates with silyl ketene acetal are characterized by a very high diastereoselectivity. 

It is very likely, that this reaction occurs due to the equilibrium between trimethylsilyl halide and a nitrogen-containing nucleophile, which increases the electrophilicity of silyl Lewis acids. It should be noted that the configuration of stereocenters at the carbon atoms of the oxazine ring is partially distorted. Hence, it is assumed that the reaction proceeds through the intermediate cation B, which is partially isomerized into the stereoisomeric cation B through the open chain cation B". 

Detailed aspects of the catalytic mechanism remain unclear. However, influence of basic additives on the partitioning of the conventional hydrogenation and reductive cyclization manifolds coupled with the requirement of cationic rhodium pre-catalysts suggests deprotonation of a cationic rhodium(m) dihydride intermediate. Cationic rhodium hydrides are more acidic than their neutral counterparts and, in the context of hydrogenation, their deprotonation is believed to give rise to monohydride-based catalytic cycles.98,98a,98b Predicated on this... 

Adsorption at high cationicity is low and relatively independent of molecular weight because the polyelectrolyte is adsorbed in a relatively flat conformation. Adsorption at low to intermediate cationicities is higher and also tends to be dependent upon molecular weight. This is because the polyelectrolyte is adsorbed in a much less compressed conformation. This is represented pictorially in Figure 6.9. 

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