Electrophilic substitution reaction monosubstituted benzene

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

The most familiar set of organic reactions is perhaps the electrophilic aromatic substitutions. For monosubstituted benzenes the major products from the process are either o- or p-disubstituted benzenes or m-disubstituted analogs. 

Summary of Electrophilic Substitution Reactions of Deactivated Monosubstituted Benzenes... 

The observations for the electrophilic substitution reactions of the monosubstituted benzenes have been examined for adherence to a linear free-energy relationship. As shown, the Selectivity Relationship,... 

Chapter 15 described the use of this transformation in the preparation of monosubstituted benzenes. In this chapter we analyze the effect of such a first substituent on the reactivity and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifically, we shall see that substituents on benzene can be grouped into (1) activators (electron donors), which generally direct a second electrophilic attack to the ortho and para positions, and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such as the analgesics depicted on the previous page. 

We will restrict our consideration to reactions of substituted benzenes and to nitrogen heteroaromatic systems in which the reaction takes place first with the n system. The simplest example of reaction of a monosubstituted benzene with an electrophile (Lewis acid) is shown in Scheme 11.1. The electrophile may attach itself to the n system (step A) in four distinct modes, ipso, ortho, meta, and para. The reactivity of the aromatic ring and the mode of attachment of the electrophile will be influenced by the specific nature of the substituent group, which may be X , Z, or C type. Detachment of the electro-... 

A quantitative description of the reactivity of monosubstituted benzenes to electrophilic substitution based on considerations of inductive effect parameters and con-jugative effect parameters from the 13 C chemical shifts of the aromatic compounds has been proposed.3 MO calculations on the proton migration in the ipso adducts formed in the reaction of CH3+ and SiH3+ with benzene have been described.4 With SiH3+ the ipso adduct is the most stable of possible isomers, whereas for CH3+ the >ara-protonated isomer is the most stable. 

A review of experimental work prompted the suggestion of the importance of dipolar interactions (Hammond and Hawthorne, 1956). de la Mare and Kidd (1959), observing a parallelism in the parajmeta and ortho/meta ratios, predicted the ortho effect to be primarily electronic in origin. Norman and Radda (1961) explored the general significance of this idea. They studied the orthojpara ratios for the substitution of a series of monosubstituted benzenes by two reagents with the same electrophilic properties but different steric requirements. The reactions, nitration by N02+ and chlorination by CI+, fulfill the requirements. The results are summarized in Table 3. 

Regioselectivity in the formation of regioisomers is also observed in electrophilic aromatic substitution reactions. In the case of monosubstituted benzene derivatives, there are three possible regiosomeric products that form at different rates, based on the mechanism of the reaction (see Figure 13). see also Berzelius, Jons Jakob Chirality Dalton, John Davy, Humphry Molecular Structure Scheele, Carl Wohler, Friedrich. 

The isomer distribution for anodic acetoxylation of a number of monosubstituted benzenes has been determined [122]. The reaction closely resembles ordinary electrophilic aromatic substitution processes, perhaps on the side of low-selectivity reactions. The isotope effect, A h//cd, for nuclear acetoxylation in anisole was found to be 1.0, whereas for a-substitution in ethylbenzene a value of 2.6 was observed. The interpretation of these values is not straightforward [126]. 

The substitution of pure benzene by an electrophile will result in the formation of a monosubstituted product, which is capable of undergoing further substitution reactions. When designing the strategy for the synthesis of an aromatic compound, there are two principal points that must be borne in mind, namely first, the reactivity of the monosubstituted product compared with that of the original benzene and second, the position on the aromatic ring where the second substitution reaction will take place. These two issues will now be examined, and it will be seen that they are, at least to some extent, dependent upon each other. 

Aromatic compounds like benzene undergo a highly characteristic reaction called electrophilic substitution. For example, halogens, such as chlorine and bromine, instead of simply adding to the formal double bonds as if it were an olefin (i.e. electrophilic addition in which both halogen atoms add to the double bond), displace one of the hydrogen atoms to give a monosubstituted aryl halide... 

Naphthalene chemistry differs fundamentally from benzene chemistry in that two isomers can be produced by monosubstitution, facilitating the formation of byproducts. Furthermore, in comparison with benzene, naphthalene is more reactive in electrophilic substitution, so that this type of reaction can be carried out under relatively mild conditions. Naphthalene chemistry is therefore characterized by especially-optimized reaction procedures and complex refining processes. Increased reactivity and substitution capacity offer advantages which can be used, for example, in dyestuffs production, where the naphthalene moiety serves as a carrier for a variety of auxochromic groups. 

Lewis had discussed the unequal distribution of electrons in a covalent bond. This effect, it was now realised, could be transmitted some way along a chain of atoms, and was termed the inductive effect. In 1923 Lowry had proposed that concerted movement of electron pairs in a molecule could occur in the course of a chemical reaction. It was realised in 1926 by both Robinson and Ingold that such displacements make a contribution to the normal state of a molecule, and the phenomenon was named the mesomeric effect (Chapter 11). In the same year both Robinson and Ingold started to explain the orientation observed when a monosubstituted benzene was further substituted in terms of the inductive and mesomeric effects. Ingold introduced the terms electrophilic and nucleophilic for reagents which Lapworth had termed cationoid and anionoid. 

To explain electrophilic aromatic substitution of substituted benzene derivatives, a generic benzene derivative, 61, is used in Figure 21.1, with a substituent X. This is used rather than a specific example in order to show the similarities and differences in reactivity for electron-releasing versus electron-withdrawing groups. The carbon of the benzene ring attached to the substituent is defined as the ipso carbon ( ) in Figure 21.1. There are only three possible arenium ion intermediates for the reaction of any monosubstituted benzene derivative 61 with an electrophile such as Br+ 62, 63, and 64. 

Now let s consider electrophilic aromatic substitution reactions with substituted benzene rings. In order to explore this topic, we must first review important terminology that we will use frequently throughout the remainder of this chapter. The various positions on a monosubstituted benzene ring are referred to in the following way ... 

In Section 14-8 we discussed the effect that substituents have on the efficiency of the Diels-Alder reaction Electron donors on the diene and acceptors on the dienophile are beneficial to the outcome of the cycloaddition. Chapter 15 revealed another manifestation of these effects Introduction of electron-withdrawing substituents into the benzene ring (e.g., as in nitration) caused further electrophilic aromatic substitution (EAS) to slow down, whereas the incorporation of donors, as in the Friedel-Crafts alkylation, caused substitution to accelerate. What are the factors that contribute to the activating or deactivating nature of substituents in these processes How do they make a monosubstituted benzene more or less susceptible to further electrophilic attack ... 

A hydroxyl group is a very powerful activating substituent, and electrophilic aromatic substitution in phenols occurs far- faster, and under milder conditions, than in benzene. The first entry in Table 24.4, for exfflnple, shows the monobromination of phenol in high yield at low temperature and in the absence of any catalyst. In this case, the reaction was carried out in the nonpolar- solvent 1,2-dichloroethane. In polar- solvents such as water it is difficult to limit the bromination of phenols to monosubstitution. In the following exfflnple, all three positions that are ortho or para to the hydroxyl undergo rapid substitution ... 

---