Reactivity, patterns

Pyridines are less reactive toward electrophilic substitution than are the corresponding benzenoid compounds because of the electron-withdrawing inductive (-/) and mesomeric (-M) effects of the ring nitrogen. These effects place substantial positive charge on the 2- and 4-carbon atoms (9.14), which are therefore considerably less reactive than the car- 

Moreover, as has been recognized, pyridine is strongly hydrogen bonded in protolytic media (hence, for example, its high water solubility). Such hydrogen bonding substantially reduces the reactivity toward electrophiles, and as a consequence reactivity parameters determined for the free base in solution in H-donor solvents differ markedly from those determined in the gas phase. This difference is —0.3 ct units at each position. 

The positive charge on nitrogen withdraws electrons by an inductive (or field) effect more strongly from all positions than in unprotonated pyri- 

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Reagents with carbonyl type groupings exhibit a or (if n. S-unsaturated) a properties. In the presence of acidic or basic catalysts they may react as enol type electron donors (d or d reagents). This reactivity pattern is considered as normal . It allows, for example, syntheses of 1,3- and 1,5-difunctionaI systems via aldol type (a -H d or Michael type (a + d additions. 

This reactivity pattern underlies a group of important synthetic methods in which an a-substituent is displaced by a nucleophile by an elimination-addition mechanism. Even substituents which are normally poor leaving groups, such as alkoxy and dialkylamino, are readily displaced in the indole series. 

The preparation and spectroscopic properties (infrared, ultraviolet, NMR) of iV-alkoxycarbonyl-N -(2-thiazolyl)thioureas (268) have been studied by the Nagano group (78, 264). These compounds react with bromine in acetic acid or chloroform to give 2--alkoxycarbonylimino-thiazolo[3,2-h]thiadiazolines (Scheme 162), whose structures were established by mass spectroscopy, infrared, NMR, and reactivity patterns (481). 

The sonochemistry of solutes dissolved in organic Hquids also remains largely unexplored. The sonochemistry of metal carbonyl compounds is an exception (57). Detailed studies of these systems led to important mechanistic understandings of the nature of sonochemistry. A variety of unusual reactivity patterns have been observed during ultrasonic irradiation, including multiple ligand dissociation, novel metal cluster formation, and the initiation of homogeneous catalysis at low ambient temperature (57). 

Indole is a heterocycHc analogue of naphthalene. The basic reactivity patterns of indole can be understood as resulting from the fusion of an electron-rich pyrrole ring with a ben2ene ring. 

Electrophilic Aromatic Substitution. The Tt-excessive character of the pyrrole ring makes the indole ring susceptible to electrophilic attack. The reactivity is greater at the 3-position than at the 2-position. This reactivity pattern is suggested both by electron density distributions calculated by molecular orbital methods and by the relative energies of the intermediates for electrophilic substitution, as represented by the protonated stmctures (7a) and (7b). Stmcture (7b) is more favorable than (7a) because it retains the ben2enoid character of the carbocycHc ring (12). 

This basic reactivity pattern is not greatiy affected by the presence of a 1- or 2- substituent, although electron-attracting substituents do diminish the reactivity. The pattern for substitution in 3-substituted indoles can be compHcated by the fact that the electrophile may preferentially attack the 3-position, even when it is already substituted. When this is the case, migration of either the new or the original substituent to C-2 may occur. 

Oxidation. As a 7t-excessive heterocycle, indole is susceptible to oxidation a variety of oxidation intermediates and products have been observed. With oxygen as the oxidant, the key intermediate is normally a 3-hydroperoxy-3ff-indole. These intermediates ate observable for 2,3-disubstituted indoles but are unstable for less substituted derivatives. Figure 1 indicates typical reactivity patterns toward oxygen. 

The same reactivity pattern is observed with i9-methy1 anilides in which a carhanion-stahili ing substituent is attached to the methyl group. For Z = trimethylsilyl or triphenylphosphonio, elimination occurs with cyclization. 

A great variety of differently substituted pteridine derivatives have been synthesized starting from (109) or the 2,4,6,7-tetrabromo compound (60USP2940972), which shows a corresponding reactivity pattern. Amines at low temperature substitute only the 6- and... 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

In order to understand the physical properties and reactivity patterns of S-N compounds it is particularly instructive to compare their electronic structures with those of the analogous organic systems.On a qualitative level, the simplest comparison is that between the hypothetical HSNH radical and the ethylene molecule each of these units can be considered as the building blocks from which conjugated -S=N- or -CH=CH-systems can be constructed. To a first approximation the (j-framework of... 

Reactivity Patterns The Role of Frontier Orbital Theory... 

Experimental reactivity patterns are based on solution behavior which are influenced by interactions between solvent and reacting molecules (especially ions). Compare electrostatic potential maps of 2-methyl-2-propyl cation and dimethylhydroxy cation. Identify sites that might form strong hydrogen bonds with water. Which ion will be better stabilized by its interaction with water ... 

Examine the geometries (in particular, CN bond distances) of methyl diazonium, tert-butyl diazonium and phenyl diazonium ions. Which, if any, of these ions is best described as a weak complex between a cation and N2 Which is furthest away from this description Is your result consistent with the observed reactivity patterns Explain. 

Examine atomic charges and electrostatic potential maps of these ions. Which ion has the most electron-poor electrophilic carbon Which has the least electrophilic carbon Is the variation in charge consistent with the observed reactivity patterns Explain. 

Specific alterations of the relative reactivity due to hydrogen bonding in the transition state or to a cyclic transition state or to electrostatic attraction in quaternary compounds or protonated azines are included below (cf. also Sections II, B, 3 II, B, 5 II, C and II, F). A-Protonation is often reflected in an increase in JS and therefore the relative reactivity can vary with the significance of JS in controlling the reaction rate. Variation can also result from rate determination by the second stage of the SjjAr2 mechanism or from the intervention of thermodynamic control of product formation. Variation in the rate and in the reactivity pattern of polyazanaph-thalenes will result when nucleophilic substitution [Eq. (10)] occurs only on a covalent adduct (408) of the substrate rather than on its aromatic form (400). This covalent addition is prevented by any 4-... 

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