The Effect of Substituents on Orientation

List the compounds in each set from most reactive to least reactive toward electrophilic aromatic substitution  

Explain why the halo-substituted benzenes have the relative reactivities shown in Table 19.1. 

When a substituted benzene undergoes an electrophilic aromatic substitution reaction, where does the new substituent attach itself In other words, is the product of the reaction the ortho isomer, the meta isomer, or the para isomer  

The substituent already attached to the benzene ring determines the location of the new substituent. The attached substituent will have one of two effects it will direct an incoming substituent to the ortho and para positions, or it will direct an incoming substituent to the meta position. 

All activating substituents and the weakly deactivating halogens are ortho-para directors, and all substituents that are more deactivating than the halogens are meta directors. Thus, the substituents can be divided into three groups  

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We have also examined the effect of substituents on orientation in the addition of BH3 to the carbon-carbon double bond. Consider the substituted ethylene XCH=CH2. The boron may become bonded either to carbon 1 or to carbon 2. The overall rate constant for the reaction is given by... 

The effect of substituents on the orientation of the lithiation has been critically examined (790R(26)l), and the following generalizations arrived at. 

Also the mononitration of methylbenzene does not lead to equal amounts of the three possible products. The methyl substituent apparently orients the entering substituent preferentially to the 2 and 4 positions. This aspect of aromatic substitution will be discussed in Section 22-5 in conjunction with the effect of substituents on the reactivity of aromatic compounds. 

On the whole the effect of substituents on the relative stability of isomeric arenium ions (for details see Sect. IV, 1) is described in the same terms as those used to explain the influence of substituents on the orientation and relative rates of electrophilic aromatic substitution. However, the isomeric composition of electrophilic substitution products is often controlled by kinetic factors while the equilibrium composition of isomeric arenium ions formed in aromatic compound protonation is determined by thermodynamic equilibrium. Therefore, no quantitative agreement may be observed between the relative hydrogen substitution rates at different positions of this compound and the ratio of equilibrium concentrations of the respective arenium ions formed in protonating the same compound even under identical conditions (cf. Sect. IV, 7). 

The effect of substituents on the regiochemistry of the reaction was also studied. While the phenyl group (styrene) oriented the C02Me attack on the /S-position, the regioselectivity was lost with alkyl groups. A satisfactory enantiomeric excess was obtained. 

Even in simple cases, the structure determination may present unexpected pitfalls for the unwary, and several methods of determining stereochemistry have failed when applied to limonoids. The molecular conformation is not always readily predictable, and in n.m.r. spectroscopy of limonoids use of the Karplus equation and of solvent shift methods has led to mistaken conclusions 98, 152). More reliable has been the effect of substituents on the chemical shift of nearby methyl groups 105,151). It has been shown that the presence of a hydroxy substituent causes a considerable downfield shift of methyl substituents in a 1,3 diaxial relationship, while an acetoxy or other carbonyl containing substituent may or may not produce a similar shift depending on orientation effects. This can produce good evidence of the stereochemistry, and in suitable cases, of the position of a substituent 98, 152). 

The effect of conformation on reactivity is intimately associated with the details of the mechanism of a reaction. The examples of Scheme 3.2 illustrate some of the w s in which substituent orientation can affect reactivity. It has been shown that oxidation of cis-A-t-butylcyclohexanol is faster than oxidation of the trans isomer, but the rates of acetylation are in the opposite order. Let us consider the acetylation first. The rate of the reaction will depend on the fiee energy of activation for the rate-determining step. For acetylation, this step involves nucleophilic attack by the hydroxyl group on the acetic anhydride carbonyl... 

The structural theory of organic chemistry was developed in the last half of the nineteenth century. It led to the concept that chemical, physical and biological properties of all kinds must be a function of structural change. The earliest structure-property relationships (SPR) were qualitative. Examples are the directional effect of substituents on the benzene ring with respect to electrophilic aromatic substitution and orientation in... 

When substituted benzene undergoes electrophilic attack, groups already on the ring affect the reactivity of the benzene ring as weU as the orientation of the reachon. A summary of these effects of substituents on reachvity and orienta-hon of electrophihc substituhon of substituted benzene is presented below. 

Understand the activating and directing effects of substituents on aromatic rings, and use inductive and resonance arguments to predict orientation and reactivity. 

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