1.2- Disubstituted-benzenes

What happens in electrophilic aromatic substitution when a disubstituted benzene ring is used as starting material To predict the products, look at the directing effects of both substituents and then determine the net result, using the following three guidelines. 

Rule [1 ] When the directing effects of two groups reinforce, the new substituent is located on the position directed by both groups. 

For example, the CH3 group in p-nitrotoluene is an ortho, para director and the NO2 group is a meta director. These two effects reinforce each other so that one product is formed on treatment with Bt2 and FeBr3- Notice that the position para to the CH3 group is blocked by a nitro group so no substitution can occur on that carbon. 

Rule [2] If the directing effects of two groups oppose each other, the more powerful activator wins out.  

In compound A, the NHCOCH3 group activates its two ortho positions, and the CH3 group activates its two ortho positions to reaction with electrophiles. Becau.se the NHCOCH3 is a stronger activator, substitution occurs ortho to it. 

---

OH groups are in the para or 1,4 position to each other. This use of the prefix is confined to disubstituted benzene derivatives in such cases as para-hydrogen and paraldehyde the prefix has no uniform structural significance and is always written in full. 

The student when preparing disubstituted benzenes should bear in mind VorlSnder s Rules of aromatic substitution, which form the most convenient modification of Crum Brown s earlier rules. Vorl5nder stated that if a substance... 

A brief account of aromatic substitution may be usefully given here as it will assist the student in predicting the orientation of disubstituted benzene derivatives produced in the different substitution reactions. For the nitration of nitrobenzene the substance must be heated with a mixture of fuming nitric acid and concentrated sulphuric acid the product is largely ni-dinitrobenzene (about 90 per cent.), accompanied by a little o-dinitrobenzene (about 5 per cent.) which is eliminated in the recrystallisation process. On the other hand phenol can be easily nitrated with dilute nitric acid to yield a mixture of ortho and para nitrophenols. It may be said, therefore, that orientation is meta with the... 

The prefix ortho signifies a 1 2 disubstituted benzene ring meta signifies 1 3 disubstitu tion and para signifies 1 4 disubstitution The prefixes o m and p can be used when a substance is named as a benzene derivative or when a specific base name (such as ace tophenone) is used For example... 

Partial rate factors may be used to estimate product distributions in disubstituted benzene derivatives The reactivity of a particular position in o bromotoluene for example is given by the product of the partial rate factors for the corresponding position in toluene and bromobenzene On the basis of the partial rate factor data given here for Fnedel-Crafts acylation predict the major product of the reaction of o bromotoluene with acetyl chlonde and aluminum chloride... 

FrielA,nderSynthesis. The methods cited thus far all suffer from the mixtures which usually result with meta-substituted anilines. The use of an ortho-disubstituted benzene for the subsequent constmction of the quinoline avoids the problem. In the FrieWider synthesis (52) a starting material like 2-aminoben2aldehyde reacts with an CX-methyleneketone ia the presence of base. The difficulty of preparing the required anilines is a limitation ia this approach, but 2-nitrocarbonyl compounds and the subsequent reduction of the nitro group present a usehil modification (53). 

As appropriately substituted o-disubstituted benzene derivatives are feadily available, this procedure has found widespread application in the synthesis of benzo-fused flve-membered heterocycles. Examples abound in the various chapters in these volumes and the following few examples illustrate the general trend. 

Benzisothiazoles are best prepared by oxidative cyclization of o-aminothiobenz-amides (see Section 4.17.9.1.1), reaction of o-toluidines with thionyl chloride (see Section 4.17.9.2.1) or by sulfuration of 2,1-benzisoxazoles (see Section 4.17.10.2). 1,2-Benzisothiazoles can also be prepared from o-disubstituted benzene compounds, cyclodehydration of o-mercaptobenzaldoximes or oxidative cyclization of p-mercaptobenzylamines (see Section 4.17.9.1.1) being the most convenient. Both series of benzo compounds are readily substituted at the 5- and 7-positions by electrophilic reagents. 

Chemical equivalence atomic nuclei in the same chemical environment are chemically equivalent and thus show the same ehemieal shift. The 2,2 - and 3,3 -protons of a 1,4-disubstituted benzene ring, for example, are ehemically equivalent because of molecular symmetry. 

If, for example, four signals are found in regions appropriate for benzene ring protons S =6-9, four protons on the basis of the height of the integrals), then the sample may be a disubstituted benzene (Fig. 2.6). The most effective approach is to analyse a multiplet with a clear fine structure... 

Since two quaternary atoms and four CH atoms appear in the C NMR spectrum, the latter with a benzenoid coupling constant of 7-9 Hz, this is a disubstituted benzene ring, and the C signal with 5c = 162.2 fits a phenoxy C atom. The keto carbonyl (5c = 204.9) and methyl (5c = 26.6) resonances therefore point to an acetyl group as the only meaningful second substituent. Accordingly, it must be either o- or m-hydroxyacetophenone A or B the para isomer would show only four benzenoid C signals because of the molecular symmetry. 

Adding these substituent effects gives the following calculated shift values (as compared with the observed values in parentheses) for C-1 to C-4 of the pura-disubstituted benzene ring in A and B ... 

Open-chained systems containing the disubstituted benzene subunit. . . 321... 

III. In tropeines containing a disubstituted benzene ring, those in which the replacing groups occupy the pam-position have the least mydriatic action thus 0- and m-hydroxybenzoyltropeines are active, but not the p-isomeride. 

The usual syntheses of quinazolines make use of an o-disubstituted benzene structure (46) from which the quinazoline skeleton is completed by adding C-2 and N-3 in various ways. Substituents could either be in (a) the pyrimidine ring or (b) the benzene ring or in both rings. The syntheses will be described in this order and the methods used for (a) apply equally well to quinazolines substituted in both rings. 

Syntheses from Phthalimidines Syntheses from Ortho-Disubstituted Benzenes Condensation of 1,4-Diketones with Amines and Pyrroles Other Reactions and Rearrangements Leading to Isoindoles IV. Properties of the Isoindole System A. Tautomerism... 

Although the application of the Hammett equation to side-chain reactions of disubstituted benzene derivatives (1) is relatively straightforward, the introduction of a heteroatom somewhere in the aromatic... 

Disubstituted benzenes are named using one of the prefixes ortho- (o), meta- (in), or para- (p). An ortho-disubstituted benzene has its two substituents in a 1,2 relationship on the ring, a meta-disubstituted benzene has its two substituents in a 1,3 relationship, and a para-disubstituted benzene has its substituents in a 1,4 relationship. 

The term aromatic is used for historical reasons to refer to the class of compounds related structurally to benzene. Aromatic compounds are systematically named according to TUPAC rules, but many common names are also used. Disubstituted benzenes are named as ortho (1,2 disubstituted), meta (1,3 disub-stituted), or para (1,4 disubstituted) derivatives. The C6H5- unit itself is referred to as a phenyl group, and the Cb f5CH2— unit is a benzyl group. 

Electrophilic substitution of a disubstituted benzene ring is governed by the same resonance and inductive effects that affect monosubstituted rings. The only difference is that it s now necessary to consider the additive effects of two different groups. Tn practice, this isn t as difficult as it sounds three rules are usually sufficient. 

Problems arise in the preparation of substituted l//-azepines with (alkoxycarbonyl)nitrenes as nitrene attack on a mono- or disubstituted benzene ring is not generally regioselective, and with toluene, 04 34-136139 144 o- and p-xy ienes,134-139 p-cresoi,134 chlorobenzene104-134 136 and biphenyl,104 136 mixtures of 1//-azepine-1-carboxylates of undetermined composition are produced. 

Disubstituted benzene derivatives containing electrophilic substituents C6H3... 

The equilibrium concentrations of many disubstituted benzenes (containing alkyl and halogen substituents) show that the meta isomer is in nearly all cases the most thermodynamically stable. It is not obvious why this should be so. Shine182 had discussed this problem in terms of the relative sizes of the standard enthalpy and entropy changes between any pair of isomers. 

The orbital phase theory can be applied to the thermodynamic stability of the disubstituted benzene isomers. The cyclic orbital interaction in the benzene substituted with two EDGs is shown in Scheme 21. The orbital phase is continuous in the meta isomer and discontinuous in the ortho and para isomers (Scheme 22, cf. Scheme 4). 

The first recorded correlation of dipole moments with substituent constants was observed by Taft (3), who reported results for alkyl cyanides, chlorides, iodides, and tertiary amines. Kross and Fassel (31) have reported the correlations of dipole moments for 4-substituted nitrobenzenes with the simple Hammett equation. Rao, Wohl, and Williams (32) have studied the correlation of dipole moments of disubstituted benzenes with eq. (1) and of monosubstituted benzenes with the equation... 

Many disubstituted benzenes are of enormous practical importance, especially those where both substituents are identical. Often two or even all three of the isomers enjoy considerable economic utility. But, in general, the isomers produced either from petroleum or by chemical syntheses are not in balance with the market demand. For... 

---