Electrophilic substitution intramolecular

Low-density lipoprotein Tosylate (y>-toluenesulfonate) Unimolecular electrophilic substitution Bimolecular electrophilic substitution Aromatic electrophilic substitution Intramolecular electrophilic substitution... 

The selectivity relationship merely expresses the proportionality between intermolecular and intramolecular selectivities in electrophilic substitution, and it is not surprising that these quantities should be related. There are examples of related reactions in which connections between selectivity and reactivity have been demonstrated. For example, the ratio of the rates of reaction with the azide anion and water of the triphenylmethyl, diphenylmethyl and tert-butyl carbonium ions were 2-8x10 , 2-4x10 and 3-9 respectively the selectivities of the ions decrease as the reactivities increase. The existence, under very restricted and closely related conditions, of a relationship between reactivity and selectivity in the reactions mentioned above, does not permit the assumption that a similar relationship holds over the wide range of different electrophilic aromatic substitutions. In these substitution reactions a difficulty arises in defining the concept of reactivity it is not sufficient to assume that the reactivity of an electrophile is related... 

Evidently S, is a measure of intramolecular selectivity because it involves a ratio, the contribution of the benzene substitution rate disappears, and the selectivity factor expresses the selectivity of the reagent X in Eq. (7-83) for the para position relative to the meta position. Each individual partial rate factor, on the other hand, is expressive of an inteimolecular selectivity thus p is a measure of the selectivity of the reagent for the para position in CgHsY relative to benzene. It was observed that Eq. (7-85), where Cmc is a constant, is satisfied for a large number of electrophilic substitutions of toluene. 

The mechanism for the conversion of the A -oxide (94) to the o-methylaminophenylquinoxaline (96) involves an initial protonation of the A -oxide function. This enhances the electrophilic reactivity of the a-carbon atom which then effects an intramolecular electrophilic substitution at an ortho position of the anilide ring to give the spiro-lactam (98). Hydrolytic ring cleavage of (98) gives the acid (99), which undergoes ready dehydration and decarboxylation to (96), the availability of the cyclic transition state facilitating these processes. ... 

Benzo-fused pyridopyrrolizines can be prepared by an acid-induced cyclodehydration of the appropriately substituted hydroxypyrrolopyridines. In the case of 124 (Equation 7), this is best rationalized as an intramolecular electrophilic substitution at the o-carbon of the benzyl substituent <1988CC623, 1990J(P1)1757, 2001J(P1)1446>. 

The intramolecular arylation of sp3 C-H bonds is observed in the reaction of l-/ r/-butyl-2-iodobenzene under palladium catalysis (Equation (71)) 94 94a 94b The oxidative addition of Arl to Pd(0) gives an ArPdl species, which undergoes the electrophilic substitution at the tert-butyl group to afford the palladacycle. To this palladacycle, another molecule of Arl oxidatively adds, giving the Pd(iv) complex. 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

Electrophilic substitution reactions on alkynylsilanes are also known. In 1978 K. Ultimootd, M. Tanaka and coworkers by an intramolecular reaction carried out the synthesis of a macrocyclic ketone. 

Perhaps, many of the intramolecular C-H activations that are known for metal ligand complexes are actually best described as electrophilic substitutions rather than oxidative additions. A very large number of palladium(II) complexes are known to react intramolecularly to the metallated species. 

On the other hand, we also planned alternative completely new approach (Route B) to Nakadomarin A, which involves the spirolactam followed by coupling reaction with furan derivative and subsequent intramolecular electrophilic substitution reaction of an iminium cation generated from an aminal to give highly functionalized tetracyclic core system (Scheme 10.3). 

Cyclic epoxides such as 124 can react in two ways with strong bases (a) via abstraction of a /3-proton to form allylic alcoholates 125 or (b) by deprotonation at the epoxide carbon atom forming the intermediate 126 and, after electrophilic substitution, the epoxides 128. If there is a suitable C—H bond in the vicinity of the C-Li moiety, intramolecular carbenoid insertion reactions to 127 may take place (equation 27) ° . ... 

Isothiocyanate 23 (X = CO), when treated with AICI3 in nitromethane undergoes ring closure by an intramolecular electrophilic substitution between C3 of the pyrrole ring and the isothiocyanate group to afford pyrrolo[3,2-c][l]benzazepine-10(lH)-one-4(5H)-thione 24 (Scheme 2 (2005BMCL3220, 1998MI197)). 

Few examples of the intramolecular electrophilic substitution on a C2py oie site have been reported for benzo[/]pyrrolo[l,2-a]azepinones. Thus, treatment of acid 62 with phosphorous pentachloride results in Friedel-Crafts product 63 (Scheme 13 (2000T9351)). 

Intramolecular ene reactions can also be carried out with Lewis acid catalysts. Several examples are included in Scheme 6.15. Mechanistic analysis of Lewis acid-catalyzed reactions indicates they may more closely resemble an electrophilic substitution process related to reactions which will be discussed in Section 10.1.1.210... 

Heating dicarboxylic acids, HOOC(CH,) COOH n = 2 or 3), forms cyclic anhydrides by intramolecular dehydration [Problem 16.22(a), (6)]. Anhydrides resemble acid halides in their reactions. Because acetic anhydride reacts less violently, it is often used in place of acetyl chloride. Acid anhydrides can also be used to acylate aromatic rings in electrophilic substitutions. 

The isomerization of 4-benzyl-4//-thiopyran (22) with hydrogen chloride to 496 proceeds by an intramolecular electrophilic substitution of the benzyl group (Eq. 31).54... 

The title derivatives with strong acids generate heterocyclic carbocations that may lead to intramolecular electrophilic substitution in ortho sites of 4-benzyl or 4-benzyl-like substituents. 

Electrophilic substitution hexahydrophenanthrenes. Electrophilic attack could occur at three sites in 1, but no products of a-substitution have been reported. Benzyl bromide reacts exclusively by y-attack. Aldehydes and ketones react usually by e- and/or y-attack, but with variahlc regioselectivity. c-Attack is useful because products can be obtained that undergo an intramolecular Diels-Alder reaction. An example is the synthesis of the two isomeric hexahydrophenanthrenes (3, equation... 

An electrophilic substitution at the pyrroloid five-membered ring of 5-methyl-2-phenyI-indolizine with ethoxalyl chloride gave a 1,3-disubstituted derivative (2). This was converted into a mixture of the [2.2.3] cyclazine (3) and the [2.3.3]cyclazine (4) by an intramolecular condensation occurring at the activated 5-methvl group of the pyridinoid six-membered ring (see Sections 3.08.2.5 and 3.08.4 for other examples.)... 

The electrophilic substitution of P-diketonate complexes appears to occur as for arenes, and a process involving initial coordination of the electrophile, followed by an intramolecular group transfer, has not been observed, although it has been postulated for the reaction of copper(II) acetylacetonate with thioacetals (equation 14).31... 

The overall mechanistic picture of these reactions is poorly understood, and it is conceivable that more than one pathway may be involved. It is generally considered that cycloheptatrienes are generated from an initially formed norcaradiene, as shown in Scheme 30. Equilibration between the cycloheptatriene and norcaradiene is quite facile and under acidic conditions the cycloheptatriene may readily rearrange to give a substitution product, presumably via a norcaradiene intermediate (Schemes 32 and 34). When alkylated products are directly formed from the intermolecular reaction of carbenoids with benzenes (Scheme 33 and equation 36) a norcaradiene considered as an intermediate alternatively, a mechanism may be related to an electrophilic substitution may be involved leading to a zwitterionic intermediate. A similar intermediate has been proposed143 in the intramolecular reactions of carbenoids with benzenes, which result in substitution products (equations 37-40). It has been reported,144 however, that a considerable kinetic deuterium isotope effect was observed in some of these systems. Unless the electrophilic attack is reversible, this would indicate that a C—H insertion mechanism is involved in the rate-determining step. 

The 2-chloro compound may be formed via an intramolecular process, whereas an intermolecular route may be operative in the formation of the 4-chloro compound.73 The 3-chloro isomer, however, could be formed through a modified electrophilic substitution process. 

Syntheses of 3- and 4-benzothienyl propionic acids were carried out by various routes. Schemes 3 and 4 introduce some of them and describe the formation of two representatives of 4-benzothienyl propionic acids (66AJC1909 77LA904). Intramolecular electrophilic substitution with the goal of attaching a carbocycle was applied also to the syntheses of some polynuclear compounds 101 (83JHC1149, 83JHC1453) and 102 (81JHC977). 

The intramolecular C-acylation into position 4 becomes possible after hydrogenation of the C2—C3 bond in the indole nucleus. Thus, by the action of aluminum chloride, l-benzoyI-2,3-dihydroindo ylpropionyl chloride 197 is converted into pentahydrobenzo[crf]indolone 198 (54J A5256 56JA3087). Intramolecular electrophilic substitution is favored also by conjugation between a carbonyl or a nitrile group at the /3-substituent containing three carbon atoms and the indole nucleus. 

The 3-methyl group of nitrile 2b selectively activates C-2 for intramolecular electrophilic substitution so that only one isomer [3b (30%)]18 is formed. Cydization of nitrile esters 4 in the presence of hydrogen chloride did not lead to the expected ketenimmonium chlorides, l-amino-3//-pyrrolizines (5) being formed instead. This may be caused by conjugation of the 1-amino and the 2-alkoxycarbonyl groups on the 1,2-double bond. The dihydropyrrolizinone (6a) could be obtained from compound 5 (R = Me)19 only under drastic conditions.20... 

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