Nucleophilic and Electrophilic Substitutions

The purine ring system undergoes substitution by both nucleophilic and electrophilic reagents, although with the latter the substituted atom is usually nitrogen rather than carbon. Attempts, made by various schools of theoretical chemistry, to predict the relative order 

Ciba Found. Symp. Chem. Biol. Purines, p. 72 (1957). 

If the 7- or 9-methyl derivative of 2,6,8-trichloropurine (13) is treated with a strong base, substitution occurs at the 8- (15) and not the 6-position (14) as above.59 This result is the opposite of what might be expected as the inductive effect of the methyl group should increase the electronegativity of the imidazole ring and direct nucleophilic attack into the pyrimidine ring. This apparently anomalous behavior 

Anomalous behavior is shown by 2,8-dichloropurine which, having no chlorine at the 6-position, might be expected to undergo substitution at the 2-carbon. This is not so, as methylamine and methanethiol give rise to the corresponding 2-chloro-8-methylamino- and 2-chloro-8-methylthiopurine.64 The lack of reactivity shown by the chlorine 

The site of nucleophilic substitution under acid conditions is also decided by the protonated specie formed. It has been proposed that with fairly strong acids the proton is associated with an imidazole nitrogen giving rise to the cationic forms 18 and 1965 in which the 

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In addition to nucleophilic and electrophilic substitution reactions, other reactions have also been used to prepare poly(arylene edier)s, especially those with special structures which otherwise could not be prepared. The following paragraph briefly reviews these reactions. 

Nucleophilic and electrophilic substitutions in anion- and cation-radical, respectively, have been considered throughout the book, including the problem of a choice between addition and electron-transfer reactions. Therefore, only some unusual cases are discussed here. 

A reaction in which one functional group (see p.lO) is replaced by another is termed substitution. Depending on the process involved, a distinction is made between nucleophilic and electrophilic substitution reactions (see chemistry textbooks). Nucleophilic substitutions start with the addition of one molecule to another, followed by elimination of the so-called leaving group. 

Problem 11.25 Compare addition-elimination aromatic nucleophilic and electrophilic substitution reactions with aliphatic 5 2 reactions in terms of (a) number of steps and transition states, (b) character of intermediates. 

The cis- and frans-sulfoxides (551) and (552) have been O-methylated with Meerwein s reagent. Reaction of the methoxy derivative with MeMgBr proceeds with inversion of configuration (Scheme 211) (74JA8026). The stereochemical course of the interconversions of sulfoxide, sulfimide and sulfoximide in the 2,3-dihydrobenzo[6]thiophene series has been investigated (73JA1916). The reaction cycle (Scheme 212) involves both nucleophilic and electrophilic substitution at chiral sulfur. Inversion of configuration takes place in the conversion of (553) to (554) in pyridine. 

If R is an alkyl group, reaction (1) leads to the familiar mechanism of nucleophilic substitution at saturated carbon whilst reaction (2) leads to an electrophilic substitution of saturated carbon. Of course for these mechanisms to be followed it is not necessary for a completely developed carbonium ion or carbanion to be formed, and both nucleophilic and electrophilic substitution at saturated carbon may proceed by mechanisms in which the carbon atom undergoing substitution has a carbonium ion character or a carbanion character respectively. 

It is obvious that the choice between nucleophilic and electrophilic substitution must be mechanistically made but this is generally true of the choice of all disconnections, synthons and reagents. The formation of 31 was easy because the aryl chloride was activated by three groups. In the synthesis of fluoxetine (Prozac), a rather widely taken anti-depressant, aryl ether 34 is an essential intermediate.6 Though disconnection b looks attractive, as a simple Sn2 reaction should work well, disconnection a was preferred because 34 must be a single enantiomer and enantiomerically pure alcohol 36 was available. 

Protein chemical modification is a problem-solving technique in research and technology. Modifications also occur in natural deteriorations. Generally these modifications are with the most reactive side chains and are predominantly oxidations, reductions, and nucleophilic and electrophilic substitutions. Deteriorations include peptide bond scissions, racemizations, fi-eliminations, and formation of products by the reaction of proteins with added chemicals. Proteins are modified intentionally for structure-function relationship studies or for development of new and improved products. Although appearing quite varied, the techniques used in pharmacological, food and feed, or other industrial areas differ more operationally than from major differences in the levels of chemical sophistication that are used. 

Reactions of chloramine include radical, nucleophilic, and electrophilic substitution of chlorine, electrophilic substitution of hydrogen, and oxidative additions, for example ... 

If only the electron density of the highest occupied molecular orbital (HOMO) is taken into account, an electrophilic attack is said to be regulated by the frontier electron density index (54JCP1433 79FCF1). In nucleophilic substitutions, the aromatic substrate tends to accept an electron pair in the transition state, and so the frontier orbital is taken as the lowest unoccupied molecular orbital (LUMO). In this case, the frontier electron density is assumed to be as the electron distribution that would be present in the LUMO if it were occupied by two electrons. In contrast to arguments based on the charge or 7c-electron densities, both nucleophilic and electrophilic substitution occur preferentially at the atom with the highest electron density within the appropriate frontier orbital, i.e., LUMO or HOMO, respectively. 

In the Sections above, various aspects of the electronic structure of the carbonyl halides have been discussed in some detail, and it is now appropriate to consider what insight this knowledge yields concerning their chemical reactivity. In particular, their reactivity towards nucleophilic and electrophilic substitutions will be examined. 

Of course, with charged electrophiles, the Coulombic term of Equation 3.13 will probably be more important than the frontier orbital term. However,the changes in electron distribution which are occasioned by photoexcitation all take place in frontier orbitals. So an argument based on changes in the total electron distribution is very similar to the one just given. Table 8.1 summarises the effect of frontier orbitals on aromatic nucleophilic and electrophilic substitution, both in the ground state and in the excited state. 

Examples of the completely unsaturated 10 -electron hetero-aromatic ring system are known for all the above heterocycles. The chemical reactivity of these heterocyclic systems can be viewed as a microcosm of heterocyclic chemistry. Although little explored, the literature on these compounds is already replete with examples of imaginative synthetic entry, nucleophilic and electrophilic substitution reactions, mechanistically intriguing molecular rearrangements and compilations of spectral data, which now allow structure assignment to new reaction products with relative certainty. 

The process by which bi-or poly-functional reactants are condensed to form polymer chains with the elimination of small molecules in each condensing step, is known as condensation polymerisation. As the polymer chains are grown incrementally, it may also be called step growth polymerisation. Esterification (direct or ester exchange), amidation, nucleophilic and electrophilic substitution are the general reactions for this polymerisation process. The formation of vegetable oil-based polyester is an example of this type of polymerisation (Fig. 1.1). 

The material is presented according to the mechanistic types nucleophilic and electrophilic substitution, addition reactions, radical, pericyclic, proton and electron transfer reactions. Orbital and electrostatic models are used for structural correlations of interacting molecular systems along the reaction paths. Particular attention is focussed on the characteristics of the transition state. The text combines phenomenology with the basic theoretical principles needed to understand and predict chemical reactivity. 

Finally, much of the wealth of information for radical, nucleophilic, and electrophilic substitution results from the exploration of a second (or further) substitution reaction of the aromatic ring. For example, as shown in Equation 6.92, the reaction of some electrophile, ET, with benzene (CefT), where aU six positions are equivalent, can, at some rate under some specified reaction conditions of solvent and temperature, produce a substitution compound, where Ei has replaced (been substituted for) a proton (Ft+). ... 

Nucleophilic and electrophilic substitution reactions can indeed take place in two steps as indicated in equations (5.41)-(5.42) and (5.43)-(5.44). In the Ingold terminology, the former mechanism is designated S l and the latter S l. Such substitution reactions can, however, also occur by single bimolecular processes involving concerted formation of the new RY bond and breaking of the old RX one. These reactions, designated S 2 and 5 2, respectively, can be represented as follows in the curved arrow symbolism ... 

Can nrr be a successful index for nucleophilic and electrophilic substitution if these are observed to occur at different sites ... 

The major area of (arene)Cr(CO)3 chemistry however remains applications to synthetic organic chemistry. A study of nucleophilic and electrophilic substitution reactions of conformationally restricted (arene)Cr(CO)3 complexes has shown that nucleophiles react at carbons eclipsed by Cr-CO bonds and electrophiles at staggered postions.Both the stabilisation of a-carbocations and reactivity of a-hydrogens towards base has been investigated. The substitution of arenes with alkyllithium reagents has been studied and measurements of acidities carrried out. ... 

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