Substitution on

Adaptations of this method have been proposed in order to take into account the band displacement due either to substitution on the aromatic ring, or to chains of different lengths. The variations consist, instead of measuring the absorbance at maximum absorption, of an integration of the absorbance curve over a specified range (Oelert s method, 1971). More exact, this method is used less often mainly because the Brandes method is simpler... 

Achiral molecules which can be converted to chiral molecules by the chemical change of one atom — substitution on an sp -atom or addition on an sp -atom — are called prochiral molecules (Y. Izumi, 1977). The atom involved is a prochiral centre. Pairs of atorns or groups... 

Because Pd(II) salts, like Hgtll) salts, can effect electrophilic metallation of the indole ring at C3, it is also possible to carry out vinylation on indoles without 3-substituents. These reactions usually require the use of an equiv. of the Pd(ll) salt and also a Cu(If) or Ag(I) salt to effect reoxidation of the Pd. As in the standard Heck conditions, an EW substitution on the indole nitrogen is usually necessary. Entry 8 of Table 11.3 is an interesting example. The oxidative vinylation was achieved in 87% yield by using one equiv. of PdfOAcfj and one equiv. of chloranil as a co-oxidant. This example is also noteworthy in that the 4-broino substituent was unreactive under these conditions. Part B of Table 11.3 lists some other representative procedures. 

Piperazinothiazoies (2) were obtained by such a replacement reaction, Cu powder being used as catalyst (25. 26). 2-Piperidinothiazoles are obtained in a similar way (Scheme 2) (27). This catalytic reaction has been postulated in the case of benzene derivatives as a nucleophilic substitution on the copper-complexed halide in which the halogen possesses a positive character by coordination (29). For heterocyclic compounds the coordination probably occurs on the ring nitrogen. 

Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

Bromination of 2-dialkylaminothiazoles has been reported to be successful by one author (415) and to fail by others (375. 385). If the mechanism of direct electrophilic substitution is accepted for these compounds, it is difficult to understand why alkyl substitution on such a remote position as exocyclic nitrogen may inhibit this reaction in the C-5 position. 

Reactivity of A-4-thiazoline-2-thiones and derivatives involves four main possibilities nucleophilic reactivity of exocyclic sulfur atom or ring nitrogen, electrophilic reactivity of carbon 2 and electrophilic substitution on carbon 5. 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

The salts of derivatives possessing phenyl substitutents on the selenazole ring are easily hydrolyzed in aqueous solution. 

So far we ve been concerned only with electrophilic substitution of benzene Two impor tant questions arise when we turn to substitution on rings that already bear at least one substituent... 

The critical carbon-carbon bond forming step requires nucleophilic substitution on an alkyl halide by an ester enolate Methyl halides are more reactive than... 

Bromo 1 3 dimethylbenzene is inert to nucleophilic aromatic substitution on treatment with sodium amide in liquid ammonia It is recovered unchanged even after extended contact with the reagent Suggest an explanation for this lack of reactivity... 

Nucleophilic aromatic substitution by the elimination-addition mecha nism can lead to substitution on the same carbon that bore the leaving group or on an adjacent carbon... 

The structure of guanine illustrates an important feature of substituted pyrimidines and purines Oxygen substitution on the ring favors the keto form rather than the enol Ammo substitution does not... 

Ecample Miller and Rich investigated the conformational consequences of substitutions on an amino acid in cyclosporin A, an important immunosuppressive drug. One of the amino acids in this cyclic undecapeptide is (2, 3r, 4r, 6e)-3-Hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (MeBmt). It is essential for biological activity. 

Systematic names should be used in derivatives formed by substitution on a carbon atom. Note The names in parentheses are abandoned but are listed for reference to older literature. 

Simple ABO compounds in addition to BaTiO are cadmium titanate [12014-14-17, CdTiO lead titanate [12060-00-3] PbTiO potassium niobate [12030-85-2] KNbO sodium niobate [12034-09-2], NaNbO silver niobate [12309-96-5], AgNbO potassium iodate [7758-05-6], KIO bismuth ferrate [12010-42-3], BiFeO sodium tantalate, NaTaO and lead zirconate [12060-01 -4], PbZrO. The perovskite stmcture is also tolerant of a very wide range of multiple cation substitution on both A and B sites. Thus many more complex compounds have been found (16,17), eg, (K 2 i/2) 3 ... 

Fig. 4. Effect of isovalent substitutions on crystal stmcture transition temperatures of ceramic BaTiO where ( ) represents Pb (—), Ca and ( ) substitution for Ba and (—) and ( ) substitution for. Transition temperatures for pure BaTiO are 135, 15, and...

All laromatics. The aromatic ring is fairly inert toward attack by oxygen-centered radicals. Aromatic acids consisting of carboxyl groups substituted on aromatic rings are good candidates for production by LPO of alkylaromatics since thek k /k ratios are low. TerephthaUc acid [100-21 -0]... 

However, the vast majority of research has been devoted to synthesis involving electrophilic substitution on the aromatic ring of hydroquinone. Hence, phenylhydroquinone can be obtained by the reaction of phenyl dia onium salts (18) with hydroquinone (82). 

Nucleophilic Ring Opening. Opening of the ethyleneimine ring with acid catalysis can generally be accompHshed by the formation of an iatermediate ayiridinium salt, with subsequent nucleophilic substitution on the carbon atom which loses the amino group. In the foUowiag, R represents a Lewis acid, usually A = the nucleophile. 

Dinitrochlorobenzene can be manufactured by either dinitration of chlorobenzene in filming sulfuric acid or nitration ofy -nitrochlorobenzene with mixed acids. Further substitution on the aromatic ring is difficult because of the deactivating effect of the chlorine atom, but the chlorine is very reactive and is displaced even more readily than in the mononitrochlorobenzenes. 

Increasing attention has been paid to the generation of quantitative stmcture—activity relationships in which the effects of molecular substitution on pharmacologic activity can be interpreted in terms of the physicochemical properties of the substituents. These approaches are based on the extrathermodynamic analysis of substituent effects (36) ... 

These products are useful for modification of alkyd resins (qv), preparation of paint vehicles, and copolymeri2ation with other monomers. Substitution on the amino group occurs readily, giving bases stronger than the parent amines. 

The aminophenols are chemically reactive, undergoing reactions involving both the aromatic amino group and the phenoHc hydroxyl moiety, as weU as substitution on the benzene ring. Oxidation leads to the formation of highly colored polymeric quinoid stmctures. 2-Aminophenol undergoes a variety of cyclization reactions. 

The effects of xanthine alkyl substitution on bronchocHlation have been summarized as foUows (60,61) alkylation is essential for adenosine... 

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

Other Radioprotective Chemicals. The bis-methylthio- and methylthioamino-derivatives of 1-methylquinolinium iodide and l-methylpyridinium-2-dithioacetic acid provide reasonable protection to mice at much lower doses than the aminothiols, which suggests a different mechanism of action (139). One of these compounds, the 2-(methylthio)-2-piperidino derivative of the l-methyl-2-vinyl quinolinium iodide (VQ), interacts with supercoUed plasmic DNA primarily by intercalation. Minor substitutions on the aromatic quinolinium ring system markedly influence this interaction. Like WR-1065, VQ is positively charged at physiological pH, and the DNA-binding affinities of VQ and WR-1065 appear to be similar. 

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