Substitution at

3-alkylindoles with electrophiles in the presence of bismuth(III) nitrate preferentially led to the formation of either the A-substituted or C-2-substituted products depending on the choice of solvent 05TL2915 . Aprotic solvents favored A-substitution while protic solvents favored C-2-substitution. 

Another classical approach to 3-carbolines involves Bischler-Napieralski reaction of indoles, the intramolecular cyclization of iminium chlorides derived from tryptamides. Triphenylphosphite proved to be a mild reagent capable of promoting this reaction 05SL661 . The cyclization of ketene iV,S-acetals derived from tryptamine produced push-pull P-carboline enamines 05SL309 . 

A copper-catalyzed coupling reaction between free N-H indole substrates and tetrahydroisoquinolines gave l-(indol-3-yl)isoquinoline derivatives 05JA6968 . 

Metal-mediated C-H activation processes are useful for the annulation of the indole ring. Palladium-mediated intramolecular annulation reactions were utilized in the preparation of 

A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones 05JOC9077 . A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,l-rf][l,5]benzodiazocines 05T941 and indolo[3,2-d][l]benzazepin-6-ones 05T5489 . 3,3- 

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Ingold, C. K. (1959). Substitution at Elements other than Carbon. Jerusalem. The Wiezmann Science Press of Israel. 

If, on the other hand, the encounter pair were an oriented structure, positional selectivity could be retained for a different reason and in a different quantitative sense. Thus, a monosubstituted benzene derivative in which the substituent was sufficiently powerfully activating would react with the electrophile to give three different encounter pairs two of these would more readily proceed to the substitution products than to the starting materials, whilst the third might more readily break up than go to products. In the limit the first two would be giving substitution at the encounter rate and, in the absence of steric effects, products in the statistical ratio whilst the third would not. If we consider particular cases, there is nothing in the rather inadequate data available to discourage the view that, for example, in the cases of toluene or phenol, which in sulphuric acid are nitrated at or near the encounter rate, the... 

The above proportionality can be expressed by the following equation, in which/p Me and/ j jyjg are the partial rate factors for substitution at p- and we-positions respectively. ... 

As has been noted above, there is no gross change in the mechanism of nitration of PhNH3+ down to 82 % sulphuric acid. The increase in o- andp-substitution at lower acidities has been attributed differential salt effects upon nitration at the individual positions. The two sets of partial rate factors quoted for PhNH3+ in table 9.3 show the effect of the substituent on the Gibbs function of activation at the m- and -positions to be roughly equal for reaction in 98 % sulphuric acid, and about 28 % greater at the -position in 82 % sulphuric acid. ... 

These and other studies of the relative substituent effects of X and CH X in nitration were considered in terms of the transmission factor a of the methylene group. To avoid complications from conjugative interactions, attention was focussed mainly on substitution at the meta-position, and ct was defined in terms of partial rate factors by the equation ... 

A) Sn2 substitution at the allylic alcohol with hydrobromic acid followed by reaction with the requisite secondary amine, or... 

The mechanism of the rearrangement catalyzed by Pd(fl), typically by PdCl2(RCN)2, is explained by the oxypalladation of an alkene to form 810 as an intermediate, or cyclization-induced rearrangement. As a limitation, no rearrangement takes place when the allylie ester 812 is substituted at the C-2 position of the allyl group, while a smooth rearrangement of 811 takes place[500]. 

Chapter 9. Synthetic Modification of Indoles by Substitution at Nitrogen. 89... 

Substitution at C-2 may either occur through a cationic species or by... 

Table 1-28 lists the mean vibration frequencies characteristic of CH bonds (t/CH, 5CH, yCH) as a function of the substitution pattern. For the v(CH) vibrations, the highest frequency peak disappears in the spectra of 5-substituted derivatives, whereas it is unchanged by substitution at the 2-or 4-positions. This band has been assigned to the v(CH) vibration connected with the CH bond at the 5-position (173). 

Taking into account the experimental conditions, a fairly large variety of thiazoles, variously substituted at the 2-position can be obtained from a-thiocyanatoketones. This method, more widely known as Tcherniac s synthesis, is a variation of the first synthesis group. 

Halogenation (e.g., bromination) takes place in chloroform for the 2,4-dialkylthiazoles, and the majority of studies have been of 2,4-dimethylthiazole (227, 228). In other cases and in acetic or stronger acids, substitution occurs at the 5-position and is promoted by electronreleasing groups in the 2-position. When the releasing group is in the 4-(or 5-)-position, steric hindrance may decrease the yield of substitution at the 5- (or 4-) position. Nevertheless, the thiazole nucleus is not very reactive since 4-methylthiazole and 2.5-dimethylthiazole are inert in dilute sulfuric acid with bromine (229-231). 

The role of the quaternization of the azasubstituent in the nucleophilic substitution at 2-halogenothiazoles is in fact emphasized by the reactivity of 2-halogenothiazoles with undissociated thiophenol (35), which proceeds faster than the corresponding reaction of 2-halogenothiazoles with thiophenolate anion, through the pathways shown in Scheme 6. Moreover, the 4-halogenothiazoles do not react with undissociated thiophenols, while the 5-halogenothiazoles react well (48). 

Carbocations are classified according to their degree of substitution at the positively charged carbon The positive charge is on a primary carbon m CH3CH2" a secondary car bon m (CH3)2CH" and a tertiary carbon m (CH3)3C Ethyl cahon is a primary carbocation isopropyl cation a secondary carbocation and tert butyl cation a tertiary carbocation... 

To summarize the most important factor to consider m assessing carbocation sta bility IS the degree of substitution at the positively charged carbon... 

Alcohols (X = OH) and alkyl halides (X = F Cl Br or I) are classified as primary secondary or tertiary according to the degree of substitution at the carbon that bears the functional group... 

Among alkyl halides alkyl iodides undergo nucleophilic substitution at the fastest rate alkyl fluorides the slowest... 

Having just learned that tertiary alkyl halides are practically inert to substitution by the Sn2 mechanism because of steric hindrance we might wonder whether they undergo nucleophilic substitution at all We 11 see m this section that they do but by a mecha nism different from 8 2... 

Halogenation (Section 11 12) Free radical halo genation of alkylbenzenes is highly selective for substitution at the benzylic position In the exam pie shown elemental bromine was used Alterna Lively N bromosuccinimide is a convenient re agent for benzylic bromination... 

When a benzene ring bears two or more substituents both its reactivity and the site of further substitution can usually be predicted from the cumulative effects of its substituents In the simplest cases all the available sites are equivalent and substitution at any one of them gives the same product... 

FIGURE 16 7 Nucleophilic substitution at the primary carbon of adenosine triphosphate (ATP) by the sulfur atom of methionine yields S adenosylmethionme (SAM) The reaction is catalyzed by an enzyme... 

The protons attached to C 2 of malonic acid are not directly involved m the process and so may be replaced by other substituents without much effect on the ease of decar boxylation Analogs of malonic acid substituted at C 2 undergo efficient thermal decar boxylation... 

Nucleophilic acyl substitutions at the ester carbonyl group are summarized m Table 20 5 on page 849 Esters are less reactive than acyl chlorides and acid anhydrides Nude ophilic acyl substitution m esters especially ester hydrolysis has been extensively mves tigated from a mechanistic perspective Indeed much of what we know concerning the general topic of nucleophilic acyl substitution comes from studies carried out on esters The following sections describe those mechanistic studies... 

Nucleophilic acyl substitution (Section 20 3) Nucleophilic substitution at the carbon atom of an acyl group... 

Chemical Properties. Its two functional groups permit a wide variety of chemical reactions for lactic acid. The primary classes of these reactions are oxidation, reduction, condensation, and substitution at the alcohol group. 

Substitution at the Alcohol Group. Acylation of the OH group by acylating agents such as acid chlorides or anhydrides is one of the important high yielding substitution reactions at the OH group of lactic acid and its functional derivatives. AUphatic, aromatic, and other substituted derivatives can be produced. 

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