Substitutions electrophilic

Electrophilic Substitution.—Quantitative aspects of the electrophilic substitution of furan, thiophen, pyrrole, and other five-membered heteroaromatic systems are treated in a review by Marino. Gol dfarb and his school are continuing their extensive work on electrophilic substitution in simple thiophens. The action of benzoyl chloride on 2-acetylthiophen in an excess of aluminium chloride at 110—115 °C without solvent gave a complex mixture of 2-benzoylthiophen, 

4- and 2,5-diacetylthiophen, 2-acetyl-4(5)-benzoylthiophen, and 2,4- and 2,5-di-benzoylthiophen, The transacylations of 2-acylthiophens were demonstrated by heating with excess AICI3 in the absence of an acylating agent, which gave 

The bromination of 2-cyanothiophen with one equivalent of bromine in the presence of an excess of AICI3 gives 2-cyano-, 4-bromo-2-cyano-, 5-bromo-2-cyano-, and 4,5-dibromo-2-cyano-thiophen in the proportions 16 70 2 12, from which pure 4-bromo-2-cyanothiophen can easily be obtained. Nitration of 2-cyanothiophen in concentrated sulphuric acid led to mixtures of almost equal amounts of 4- and 5-nitrothiophen-2-carboxylic acid. The chloromethyl-ation of 2-acetylthiophen and 2-formylthiophen with ota -bis(chloromethyl) ether in 60—100% sulphuric acid has been studied. An increase in the acidity of the medium promoted the formation of 4-substituted products. From these products some otherwise difficultly obtainable 2,4-disubstituted thiophens were prepared.  

The acetylation of some alkoxy- and acetoxy-thiophens under Friedel-Crafts conditions has been described. Some of the by-products obtained were isolated and their mode of formation was discussed. Friedel-Crafts acylation on thienyl- 

Further evidence for the mechanism suggested for the iodination of thiophens by iodine and nitric acid has been presented. For 2-phenylthiophen the kinetic 

Many electrophilic substitution reactions of pyridine (such as sulfonation and chlorination) are catalyzed by salts such as mercuric 

The light-catalyzed chlorination of 2-picoline with chlorine water is said to involve substitution of the side-chain first, to give 2-trichloro-methylpyridine (11) which, under more vigorous conditions, gives the 5-chloro (12), the 3,5-dichloro (13), and the 3,4,5-trichloro, derivatives (14).40 The side-chain chlorination may well be a homolytic process, 

Mercuration of 2-picoline with mercuric acetate followed by treatment with sodium chloride gave 5-chloromercuri-2-picoline (17a),47 the ease of substitution being greater than with pyridine itself. 

5- nitro derivatives but in these cases the addition of iron wire was without influence upon the yields of products.49 As previously mentioned, the gas-phase chlorination of 3-chloropyridine at 200° gave 

5-dichloropyridine39 together with some 3,4,5-trichloropyridine.38 Bromination of 3-bromopyridine at 300° gives mainly 3,5-dibromo-pyridine together with very small amounts of 3,4-dibromopyridine (17b) and trace amounts of 2,5- (18) and 2,3-dibromopyridine (19).50,51 

Langford and H. B. Gray, Ligand Substitution Processes, W. A. Benjamin, New York, 1966. 

Basolo and R. G. Pearson, Mechanisms of Inorganic Reactions, 2nd ed., John WUey Sons, New York, 1967, 

Wilkins, The Study of Kinetics and Mechanism of Reactions of Transition Metal Complexes, AUyn and Bacon, Boston, 1974, pp. 193-196. 

Atwood, Inorganic and Organometallic Reaction Mechanisms, Brooks/Cole, Monterey, CA, 1985, pp. 82-83. 

2-Dihydropyridines (510) are susceptible to electrophilic attack. The 5-position is the kinetic site of protonation giving a 2,5-dihydropyridinium cation (511) which slowly rearranges to the thermodynamically more stable 2,3-dihydropyridinium ion (512). Alkylation of a 1,2-dihydropyridine at the 5-position can be carried out under phase-transfer conditions (513 — 514). 

The iV-lithio-2-phenyl- 1,2-dihydro adduct (515) (Section 3.2.1.6.8.i) is a useful synthetic intermediate that reacts with alkyl halides, bromine (70CC478), carbon dioxide (70TL3371) and benzophenone (70CC921) to give 2,5-disubstituted derivatives. 

Another type of intramolecular electrophilic substitution is shown in Equation (1).25 In this case, the reaction sites are located in different substituents on silicon. This reaction mode is useful for highly diastereoselective alkenylation and phenylation of aminoacetals and hemiaminals.26 Intramolecular conjugative arylation of a-enals bearing an aryldimethylsilyl group is effectively promoted by tetrabutylammonium fluoride (TBAF) (Equation (2)).27,27a 

Intermolecular carbon-carbon bond formation of alkenylsilanes by electrophilic substitution is rather limited except for the reaction with acyl chlorides.1. The alkenylations of imines and epoxides are achieved with electronically activated alkenylsilanes (Equation (3)).2 a Alkynylsilanes have frequently been used for intermolecular alkynylation of carbon electrophiles activated by a Lewis acid.30 30a-30d 

The presence of activating substituent on the carbocyclic ring can, of course, affect the position of substitution. For example, Entries 4 and 5 in Table 14.1 reflect such orientational effects. Entry 6 involves using the ipso-directing effect of a trimethylsilyl substituent to achieve 4-acetylation. 

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline 

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2 6-Acctyl-1 -benzoyl-2.3-dimethvl Acetyl chloride, AICI3 70 [2] 

4 2-(Ethoxycarbonyl)-7- methoxy-3-methyl- 4-propanoyl Propanoyl chloride, AICI3 93 L8J 

The chemistry of pyrrole is rich in substitution reactions which can readily be recognized to involve attack by an electrophilic reagent. On the other hand, little is known of the reactions of pyrroles with radicals or with nucleophilic reagents. With regard to the electrophilic substitutions it should be realized that whilst their general character is usually immediately apparent, in hardly any case is anything known about the detailed mechanism. 

For preparative purposes the Gattermann reaction is much more useful. It was first usedS5 to prepare ethyl 2-formyl-3,5-dimethyl- and ethyl 3-formyl-2,5-dimethyl-pyrrole-4-carboxylate, by means of hydrogen cyanide and hydrogen chloride in ether. Later applications sometimes involved minor changes such as the use of chloroform as solvent, or of Adams modification of the reaction . Formylation generally occurs at an a-position, but if none is open there is usually no difficulty in jS-substitution. Pyrrole-2-aldehyde cannot be made this way, for it reacts further to form dyestuffs, but several 1-alkylpyrroles have been satisfactorily formylated . The initial 

Some eliminations have been reported, as of the carboxyl group in the preparation of 4-bromo-2-formyl-3,5-dimethylpyrrole3i. Replacement of a bromine atom by chlorine or by formyl has also been observed . 

The Hoesch ketone synthesis also functions well in the pyrrole series s, 28, 33 ketones resulting from reaction with a variety of reagents R.CN R = Me, CH2GI, G02Et, GN, -GH2GN) in the presence of ethereal hydrogen chloride. Orientation follows the same rules as in the Gattermann reaction. 2,3,4-Trimethylpyrrole is said not to react with acetonitrile in the Hoesch synthesis. 

The great ease of these C-acylations makes it unlikely that in general they proceed by preliminary N-acylation (p. 109). 

Despite its V excessive character (340), thiazole, just as pyridine, is resistant to electrophilic substitution. In both cases the ring nitrogen deactivates the heterocyclic nucleus toward electrophilic attack. Moreover, most electrophilic substitutions, which are performed in acidic medium, involve the protonated form of thiazole or some quaternary thiazolium derivatives, whose reactivity toward electrophiles is still lower than that of the free base. 

No nitration of thiazole occurs with the classical nitration reagents, even in forcing conditions (341-343). In a study concerning the correlation between the ability of thiazole derivatives to be nitrated and the HNMR chemical shifts of their hydrogen atoms, Dou (239) suggested that only those thiazoles that present chemical shifts lower than 476 Hz can be nitrated. From the lowest field signal of thiazole appearing at 497 Hz one can infer that its nitration is quite unlikely. Thiazole sulfonation occurs 

2- isomer undergoes bromination (352). When the 5-position is not free, as in 2,5-dimethyl thiazole, no reaction occurs (350). 2-Hydroxy (348,353) and 2-amino (348,350) groups strongly activate the 5-position. However, bromination of 2-amino (or acetylamino)-4-(2 -furyl)thiazole (104) in mild conditions, occurs successively on the furan 

Thiazole Nitration Sulfonation Brominadon Mercuration Alkylation 

Under appropriate conditions 2-amino-4-alkylthiazoles are alkylated in the 5-position 2-acetylamino-4-methylthiazole reacts with dimethyl-amine and formaldehyde to afford the corresponding Mannich base (113) (372). 2-Amino-4-methyl-thiazole is alkylated in the 5-position by heat- 

The molecular ionization potentials, obtained by amass-spectral technique, of a number of substituted furans, thiophens, selenophens, and pyrroles have been determined. Hammett-type equations were obtained, which indicated that the sensitivity to substituent effects varies in the order furan pyrrole thiophen benzene. The p-values obtained are more negative than those for the most selective electrophilic substitution.  

Isomer distributions have been determined for several electrophilic substitutions of thiophen, such as bromination by Bra and Br+, chlorination by tin tetrachloride, or iodine-catalysed acetylation by acetic anhydride, trifluoroacetylation, and Vilsmeyer formylation. The a. ratios vary from 100 to over 1000, according to the selectivity of the electrophilic agent. The results obtained, together with other data from the literature, permit a test of the applicability of linear free-energy treatments to electrophilic substitution at the a- and j8-positions of thiophen. Plots of log (Xf and log jSf against p for nine reactions were linear, and from the slopes values of = — 0.79 and 0)3+ = — 0.52 were obtained. Serious deviations were observed for mercuration and protodemercuration, while nitration and protodeboronation were not taken into account, as deviation could be expected for various reasons. The linearity was taken as evidence 

The reactivity of thiophen has also been compared with that of seleno-phen and the relative reactivities in five electrophilic substitutions have been determined by kinetic or competitive procedures. The results have been compared with those available in the literature for furan. In all the reactions examined, selenophen exhibited a reactivity intermediate between those of furan and thiophen. p-Constants for electrophilic substitution of substituted thiophens are usually smaller than in the benzene series. A comparison of the trifluoroacetylation of a series of substituted thiophens and furans yielded p-values of — 7.4 and — 10.7 respectively. The observed order of substrate selectivity in the trifluoroacetylation (furan thiophen) thus parallels the positional selectivity in electrophilic substitution, the oi ratio always being larger in furans than in thiophens. The relative importance of primary steric effects in benzene and thiophen has been investigated by determination of the isomer distributions in the acetylations of 2- and 3-methylthiophen, 2- and 3-t-butylthiophen, and toluene and t-butylbenzene. Steric hindrance is less significant in the thiophen series owing to the more favourable geometry. -  

Thallation of thiophens in the 2-position with thallium(m) trifluoro-acetate in trifluoroacetic acid is complete within a few minutes at room temperature. The thallium derivative reacts in situ with aqueous potassium iodide solution to give a convenient and high-yield synthesis of iodo-thiophens. A mixture of thallium(m) acetate has been shown to be a mild and efficient reagent for electrophilic aromatic bromination. Thiophen yields 2-bromothiophen in 82% yield and very little dibromothiophen. 3-Methylthiophen appears to be selectively brominated in the 2-position and 2-methylthiophen in the 5-position in 70—75% yield. The direct thiocyanation of thiophen and some alkylthiophens with thiocyanogen under various conditions using a variety of Friedel-Crafts catalysts has 

Monobromination of (57) in aqueous acetic acid or ether gives mainly the 2- or the 5-bromo-derivative, respectively. The 2-bromo-derivative reacts further with bromine in acetic acid to give the 2,3-dibromo-derivative 

Direct attack at a ring carbon, even C-3, is normally slow (a) because the concentration of free pyridine in equilibrium with the pyridinium salt is extremely low, and (b) attack upon the salt would also require the positive pyridinium cation to bond to a positively charged reactant. 

Pyridinesulfonic acids are strongly acidic, so that the 3-sulfonic acid that forms then protonaies a second molecule of 2.6-fed butylpyridine (/V-protonation is permitted because of the small size of tfie proton). Once protonated. however, further electrophilic attack is strongly disfavoured, and so the overall conversion is limited to 50 , 

Another feature that is clear from the resonance description of the pyri-dinium cation is that attack by nucleophiles is favoured at C-2(6) and C-4. This has importance in some reactions where at first sight it may appear that electrophilic reagents combine quite easily with pyridine. These reactions are more subtle in nature  

Pyridine N-oxides are frequently used in place of pyridines to facilitate electrophilic substitution. In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the opposite direction. Here, the resonance effect is more important, and electrophiles react at C-2(6) and C-4 (the antithesis of the effect of resonance in pyridine itself). 

There is thus a subtlety in the reactions of pyridine A/-oxides with both electrophiles and nucleophiles that is not easily explained 

Of the processes encompassing this general reaction type, chlorination has received by far the most attention because of its widespread, albeit currently diminishing, use in delignifying chemical pulps in multistage bleaching 

Other processes in which the aromatic ring is modified via electrophilic substitution reactions are nitration and ozonation. The electrophilic substitution of nitro groups on the aromatic moiety of lignin and accompanying reactions have been reviewed by Dence (1971). A nitration process consisting of the pretreatment of chemical pulp with nitrogen dioxide followed by treatment 

2 Conversion of Aromatic Rings to Nonaromatic Cyclic Structures 

On treatment with oxidants such as chlorine, hypochlorite anion, chlorine dioxide, oxygen, hydrogen peroxide, and peroxy acids, the aromatic nuclei in lignin typically are converted to o- and p-quinonoid structures and oxirane derivatives of quinols (E, D, C, resp., Fig. 1.4). It should be noted that the conversion of aromatic nuclei to o-quinonoid rings is accompanied by loss of the methoxyl group as methanol and that conversion to p-quinonoid groups in many cases leads to displacement of the side chain. 

Because of their relatively high reactivity, the foregoing structures often appear as transient intermediates in a series of reactions rather than as end products. Several of the documented reactions of these intermediates include rearomatization (e.g., reduction to catechol and hydroquinone derivatives), further oxidation to mono- and dicarboxylic acids (see below), benzylic acid rearrangements (Corbett 1966, Corbett and Fooks 1967), cycloaddition reactions (Teuber et al. 1966), and various condensation reactions (Erdtman and Granath 1954). The last-named processes, which are accelerated in acidic and basic media, often give rise to structurally complex and poorly defined materials. 

Azaindoles are nitrated readily by treatment with fuming nitric acid at 0°. In his early work, Fischer nitrated apoharmine, obtaining a high-melting crystalline compound, which reacted with methyl iodide and alkali, to give, presumedly, 3-nitro-6,7-dimethyl-6fl -6-azaindole. The stepwise decarboxylation of harminic acid gives a monocarboxylic acid, 7-methyl-6-azaindole-2-carboxylic acid, which was also nitrated. The position of nitration was not established in either case. 

Good evidence for nitration at the 3-position was provided by Clayton and Kenyon. l-Benzoyl-2,5-dimethyl-4-azaindole was nitrated in 60 % yield, and followed with potassium permanganate oxidation in aqueous acetone gave 3-benzamido-6-methylpicolinic acid. Alkaline hydrolysis of the nitration product gave 3-nitro-2,5-dimethyl-4-azaindole (85% yield), which was also obtained by direct nitration of 2,5-dimethyl-4-azaindole in low yield. In addition, reduction gave the 3-amino compound, which was identical to that obtained by catalytic reduction of the product formed by coupling the azaindole with benzenediazonium chloride. 

3-Nitro-7-azaindole was obtained in 83% yield at 0°, and was reduced to the 3-amino compound, which is unstable as the free base, 

The series of unsubstituted, 6-chloro-, and 6-methoxy-4-methyl-7-azaindoles were nitrated at —10° to give the corresponding 3-nitro compounds in 56,57, and 60 %yield, respectively. At 0°, the methoxy isomer gave what appeared to be the 1,3-dinitro compound, which decomposed explosively on heating. 

Bromination proceeds readily with azaindoles to give a monobromo compound, whereas pyrrole and indoles react violently to give poly-halogenated products. 

Stoichiometric Reactions of Coordinated Ligands, in Wilkinson, Gillard, and McCleverty, Comprehensive Coordination Chemistry, pp. 155-226. 

The high-spin complex [Cr(H20)5] is labile, but the low-spin complex ion [Cr(CN)f f is inert. Explain. 

Why is the existence of a series of entering groups with different rate constants evidence for an associative mechanism (A or / )  

Predict whether these complexes would be labile or inert and explain your choices. The magnetic moment is given in Bohr magnetons (pg) after each complex. 

Consider the half-lives of substitution reactions of the pairs of complexes  

The hydroxyquinolizinium salts (or quinolizones) have all been shown to react with electrophiles. Fozard and Jones120 have reported that 1-hydroxyquinolizinium salts can be nitrated by hot dilute nitric acid or by a mixture of concentrated nitric acid and acetic anhydride at O C. From 1-hydroxyquinolizinium nitrate the products were the 2-nitro- (126) and the 2,4-dinitroquinolizinium (127) betaines. When the bromide was nitrated a 

Attempts to brominate benzo[h]quinolizinium bromide (3) with liquid bromine gave an addition product (Section II,B). Bromination with bromine and aluminum bromide in dimethylformamide gave 1 l-bromobenzo[b]-quinolizinium bromide (137).71 Sulfuryl chloride and aluminum chloride under similar reaction conditions gave the chlorobenzquinolizinone (139), presumably from the 6,11-dichlorobenzquinolizinium salt (138).71 Without 

A detailed study of the kinetics and mechanism of the nitration of 3-methylindoxazene has been reported.40 Contrary to earlier findings, nitration in cold concentrated mixed acids furnishes only one product, the 5-nitro derivative. Apparently, nitration of the free base occurs in 80-90% sulfuric acid, whereas at higher acidities the conjugate acid is the species undergoing nitration. Formation of the 5-nitro isomer is in conflict with the theoretical predictions based on the 7t-electron densities (see Section II,B). This has led the authors to the conclusion that nitration is subject to frontier orbital control rather than charge control. 

Indoxazene-3-carboxylic acid and methyl 6-nitroindoxazene-3-carbox-ylate in mixed acids are nitrated exclusively at the 5-position.8 

Nitration studies on a series of 3-methyl- and 3-ethylindoxazenes have been recorded.12 3-Methyl- and 3-ethylindoxazene yield a mixture of the 5-nitro and 5,7-dinitro derivatives. If the 5-position is blocked (e.g., by chloro or alkyl groups) then, surprisingly, nitration takes place at the 4-position. As expected, the 7-chloro-3-alkyl and the 3,7-dialkyl derivatives are nitrated exclusively at the 5-position, whereas the 3,6-dialkyl and 3-alkyl-6-chloro derivatives yield a mixture of the 5-nitro and 5,7-dinitro compounds. The structures of the nitro compounds were confirmed by H-NMR spectroscopy and, in some instances by synthesis from the nitro-substituted ketoxime acetates (see Section II,A,2). 

Acylations of indoxazenes are rare events.1 Of interest, therefore, are reports of the acylation (at the 7-position) of 3-alkyl-6-hydroxyindoxazenes 

2-Ethyl-7-hydroxyindoxazenium tetrafluoroborate in boiling sulfuryl chloride yields a monochloro derivative (either the 4- or 6-) in 77% yield.45 Similarly, sulfonation of the tetrafluoroborate in fuming 30% sulfuric acid affords the zwitterionic 4- or 6-sulfonic acid (29) in 90% yield. In contrast, chlorosulfonation of indoxazene at 100°C yields indoxazene-5-sulfonyl chloride (67%).46 

Gol dfarb and co-workers have also carried out investigations on the directing effect of onium groups. Nitration of trimethyl-(2-thienyl)-ammonium salts occurs almost exclusively at position 5. This is considered to be in agreement with MO calculations. Nitration of dimethyl-(2-thienyl)-sulphonium salts occurs at position 4, whereas bromination gives a mixture of the 4- and 5-monobromo-derivatives and the 4,5-dibromo-derivative. Dimethyl-(3-thienyl)sulphonium salts are nitrated at position 5. Chlorination of 2-nitrothiophen in CHCh and AlCl, gives 4,5-dichloro-2-nitrothio-phen.  

The directing effect of activating groups has been studied less extensively during this period. Vilsmeier formylation of 2-alkyl-5-methoxy-thiophens at 

Novikov, L. 1. Khmel nitskii, T. S. Novikova, and O. V. Lebedev, Khim. geterotsikl. Soedinenii, 1970, 590. 

20 C leads, as expected, to the 4-substituted derivative (80). However, at 50—70 C, dealkylation occurs, leading to N-substituted 5-alkyl-3-amino-methylene-A -thiolen-2-ones (81).  

2-Alkylthio-5-alkylthiophens are chloromethylated at position 3 by chloromethyl methyl ether. 3-Methylthiothiophen has been nitrated at position 2. The influence of the reaction conditions on the isomer distribution in the acylation of 2-methoxy-, 2-methylthio-, and 2-dimethyl-amino-thiophen has been studied. Azo-coupling and aminomethylation occur at position 3 of some 4,5-disubstituted 2-acylaminothiophens. 3-Acetylamino-2-benzoylthiophen yields the 4,5-dichloro-derivative with sulphuryl chloride, while 3-acetylamino- or 3-benzoylamino-4-carbonyl-thiophen derivatives are chlorinated at position 2.  

---

The most widely used reactions are those of electrophilic substitution, and under controlled conditions a maximum of three substituting groups, e.g. -NO2 (in the 1,3,5 positions) can be introduced by a nitric acid/sul-phuric acid mixture. Hot cone, sulphuric acid gives sulphonalion whilst halogens and a Lewis acid catalyst allow, e.g., chlorination or brom-ination. Other methods are required for introducing fluorine and iodine atoms. Benzene undergoes the Friedel-Crafts reaction. ... 

Nitration is important for two reasons firstly, because it is the most general process for the preparation of aromatic nitro compounds secondly, because of the part which it has played in the development of theoretical organic chemistry. It is of interest because of its own characteristics as an electrophilic substitution. 

Nitration can be effected under a wide variety of conditions, as already indicated. The characteristics and kinetics exhibited by the reactions depend on the reagents used, but, as the mechanisms have been elucidated, the surprising fact has emerged that the nitronium ion is preeminently effective as the electrophilic species. The evidence for the operation of other electrophiles will be discussed, but it can be said that the supremacy of one electrophile is uncharacteristic of electrophilic substitutions, and bestows on nitration great utility as a model reaction. 

The fact that nitration with acetyl nitrate is sometimes accompanied by acetoxylation has been mentioned ( 5.3.3). In proposing the ion pair ACONO2H+ NOg- as the nitrating agent, Fischer, Read and Vaughan also suggested that it was responsible for the acetoxylation, which was regarded as an electrophilic substitution. 

If acetoxylation were a conventional electrophilic substitution it is hard to understand why it is not more generally observed in nitration in acetic anhydride. The acetoxylating species is supposed to be very much more selective than the nitrating species, and therefore compared with the situation in (say) toluene in which the ratio of acetoxylation to nitration is small, the introduction of activating substituents into the aromatic nucleus should lead to an increase in the importance of acetoxylation relative to nitration. This is, in fact, observed in the limited range of the alkylbenzenes, although the apparently severe steric requirement of the acetoxylation species is a complicating feature. The failure to observe acetoxylation in the reactions of compounds more reactive than 2-xylene has been attributed to the incursion of another mechan-104... 

For electrophilic substitutions in general, and leaving aside theories which have only historical interest, two general processes have to be considered. In the first, the 5 3 process, a transition state is involved which is formed from the aromatic compound, the electrophile (E+), and the base (B) needed to remove the proton ... 

For electrophilic substitutions in general, some form of the S 2 mechanism is now believed to operate. We can now review the evidence concerning the particular case of nitration. 

At one time a form of 8 2 mechanism was favoured for electrophilic substitution in which in the transition state bonding between carbon and the electrophile and severance of the proton had proceeded to the... 

There is evidence for the existence of structures of this kind, and for their importance in electrophilic substitution in general, and in nitration in particular. Because of the way in which the electrophile is attached to the ring they are called cr-complexes. 

The relative basicities of aromatic hydrocarbons, as represented by the equilibrium constants for their protonation in mixtures of hydrogen fluoride and boron trifluoride, have been measured. The effects of substituents upon these basicities resemble their effects upon the rates of electrophilic substitutions a linear relationship exists between the logarithms of the relative basicities and the logarithms of the relative rate constants for various substitutions, such as chlorination and... 

The heats of formation of Tt-complexes are small thus, — A//2soc for complexes of benzene and mesitylene with iodine in carbon tetrachloride are 5-5 and i2-o kj mol , respectively. Although substituent effects which increase the rates of electrophilic substitutions also increase the stabilities of the 7r-complexes, these effects are very much weaker in the latter circumstances than in the former the heats of formation just quoted should be compared with the relative rates of chlorination and bromination of benzene and mesitylene (i 3 o6 x 10 and i a-Sq x 10 , respectively, in acetic acid at 25 °C). 

Given that many electrophiles form r-complexes with aromatic hydrocarbons, and that such complexes must be present in solutions in which electrophilic substitutions are occurring, the question arises... 

We have seen ( 6.2.3) hat there is a close relationship between the rates of electrophilic substitutions and the stabilities of tr-complexes, and facts already quoted above suggest that no such relationship exists between those rates and the stabilities of the 7r-complexes of the kind discussed here. These two contrasting situations are further illustrated by the data given in table 6.2. As noted earlier, the parallelism of rate data for substitutions with stability data for o"-complexes is not limited to chlorination ( 6.2.4). Clearly, rr-complexes have no general mechanistic or kinetic significance in electrophilic substitutions. 

TABLE 7.1 Partial rate factors for some electrophilic substitutions of toluene... 

The use of q and tt separately as reactivity indices can lead to misleading results. Thus, whilst within the approximations used, the use of either separately leads to the same conclusions regarding electrophilic substitution into halogenobenzenes ( 9.1.4), the orientation of substitution in quinoline ( 9.4.2) cannot be explained even qualitatively using either alone. By taking the two in combination, it can be shown that as the values of Sa are progressively increased to simulate reaction, the differences in SE explain satisfactorily the observed orientation. ... 

M.o. theory and the transition state treatment In 1942 Wheland proposed a simple model for the transition state of electrophilic substitution in which a pair of electrons is localised at the site of substitution, and the carbon atom at that site has changed from the sp to the sp state of hybridisation. Such a structure, originally proposed as a model for the transition state is now known to describe the (T-complexes which are intermediates in electrophilic substitutions... 

The isolated molecule treatment of reactivity, which, in both the electronic theory and in m.o. theory, attempts to predict the site of electrophilic substitution from a consideration of the electron densities... 

The model adopted by Ri and Eyring is not now acceptable, but some of the more recent treatments of electrostatic effects are quite close to their method in principle. In dealing with polar substituents some authors have concentrated on the interaction of the substituent with the electrophile whilst others have considered the interaction of the substituent with the charge on the ring in the transition state. An example of the latter method was mentioned above ( 7.2.1), and both will be encountered later ( 9.1.2). They are really attempts to explain the nature of the inductive effect, and an important question which they raise is that of the relative importance of localisation and electrostatic phenomena in determining orientation and state of activation in electrophilic substitutions. 

The best-known equation of the type mentioned is, of course, Hammett s equation. It correlates, with considerable precision, rate and equilibrium constants for a large number of reactions occurring in the side chains of m- and p-substituted aromatic compounds, but fails badly for electrophilic substitution into the aromatic ring (except at wi-positions) and for certain reactions in side chains in which there is considerable mesomeric interaction between the side chain and the ring during the course of reaction. This failure arises because Hammett s original model reaction (the ionization of substituted benzoic acids) does not take account of the direct resonance interactions between a substituent and the site of reaction. This sort of interaction in the electrophilic substitutions of anisole is depicted in the following resonance structures, which show the transition state to be stabilized by direct resonance with the substituent ... 

There were two schools of thought concerning attempts to extend Hammett s treatment of substituent effects to electrophilic substitutions. It was felt by some that the effects of substituents in electrophilic aromatic substitutions were particularly susceptible to the specific demands of the reagent, and that the variability of the polarizibility effects, or direct resonance interactions, would render impossible any attempted correlation using a two-parameter equation. - o This view was not universally accepted, for Pearson, Baxter and Martin suggested that, by choosing a different model reaction, in which the direct resonance effects of substituents participated, an equation, formally similar to Hammett s equation, might be devised to correlate the rates of electrophilic aromatic and electrophilic side chain reactions. We shall now consider attempts which have been made to do this. 

The more extensive problem of correlating substituent effects in electrophilic substitution by a two-parameter equation has been examined by Brown and his co-workers. In order to define a new set of substituent constants. Brown chose as a model reaction the solvolysis of substituted dimethylphenylcarbinyl chlorides in 90% aq. acetone. In the case ofp-substituted compounds, the transition state, represented by the following resonance structures, is stabilized by direct resonance interaction between the substituent and the site of reaction. 

The applicability of the two-parameter equation and the constants devised by Brown to electrophilic aromatic substitutions was tested by plotting values of the partial rate factors for a reaction against the appropriate substituent constants. It was maintained that such comparisons yielded satisfactory linear correlations for the results of many electrophilic substitutions, the slopes of the correlations giving the values of the reaction constants. If the existence of linear free energy relationships in electrophilic aromatic substitutions were not in dispute, the above procedure would suffice, and the precision of the correlation would measure the usefulness of the p+cr+ equation. However, a point at issue was whether the effect of a substituent could be represented by a constant, or whether its nature depended on the specific reaction. To investigate the effect of a particular substituent in different reactions, the values for the various reactions of the logarithms of the partial rate factors for the substituent were plotted against the p+ values of the reactions. This procedure should show more readily whether the effect of a substituent depends on the reaction, in which case deviations from a hnear relationship would occur. It was concluded that any variation in substituent effects was random, and not a function of electron demand by the electrophile. ... 

The use of Brown s equation (logiQ kjkf, = p+cr+) with electrophilic substitutions in general has been fully discussed and reference will be made later to its treatment of particular substituents in nitrations. 

The selectivity relationship merely expresses the proportionality between intermolecular and intramolecular selectivities in electrophilic substitution, and it is not surprising that these quantities should be related. There are examples of related reactions in which connections between selectivity and reactivity have been demonstrated. For example, the ratio of the rates of reaction with the azide anion and water of the triphenylmethyl, diphenylmethyl and tert-butyl carbonium ions were 2-8x10 , 2-4x10 and 3-9 respectively the selectivities of the ions decrease as the reactivities increase. The existence, under very restricted and closely related conditions, of a relationship between reactivity and selectivity in the reactions mentioned above, does not permit the assumption that a similar relationship holds over the wide range of different electrophilic aromatic substitutions. In these substitution reactions a difficulty arises in defining the concept of reactivity it is not sufficient to assume that the reactivity of an electrophile is related... 

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

Norman, R. O. C. Taylor, R. (1963). Electrophilic Substitution in Ben-zenoid Compounds. London Elsevier. 

When the /)-positions are considered it is seen that they follow the sequence of inductive effects, and not of hyperconjugation. In this respect nitration is unusual amongst electrophilic substitutions. ... 

The problem of electrophilic substitution into the anilinium ion has been examined by the methods of m.o. theory. Attempts to simulate the --inductive effect in Hiickel M.o. theory by varying the Coulomb integral of C(j) (the carbon atom to which the NH3+ group is attached) remove 7r-electrons from the o- and -positions and add them to the... 

M.o. theory has had limited success in dealing with electrophilic substitution in the azoles. The performances of 7r-electron densities as indices of reactivity depends very markedly on the assumptions made in calculating them. - Localisation energies have been calculated for pyrazole and pyrazolium, and also an attempt has been made to take into account the electrostatic energy involved in bringing the electrophile up to the point of attack the model predicts correctly the orientation of nitration in pyrazolium. ... 

Numerous m.o.-theoretical calculations have been made on quinoline and quinolinium. Comparisons of the experimental results with the theoretical predictions reveals that, as expected (see 7.2), localisation energies give the best correlation. jr-Electron densities are a poor criterion of reactivity in electrophilic substitution the most reactive sites for both the quinolinium ion and the neutral molecule are predicted to be the 3-, 6- and 8-positions. ... 

Calculations for electrophilic substitution in the quinolinium ion can be compared with experiment, and for a range of values of h the predicted order of positional reactivities, s 8>6>3>7, agrees moderately well in a qualitative sense with the observed order of s 8>6>7>3 (table 10.3). Further evaluation of the method must await the results of more extensive calculations for a range of aromatic systems. 

Ten years ago we became interested in the possibility of using nitration as a process with which to study the reactivity of hetero-aromatic compounds towards electrophilic substitution. The choice of nitration was determined by the consideration that its mechanism was probably better imderstood than that of any other electrophilic substitution. Others also were pursuing the same objective, and a considerable amount of information has now been compiled. 

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