The Effect of Substituents on Reactivity

As with disubstituted benzenes, if one of the substituents can be incorporated into a name, that name is used and the incorporated substituent is given the 1-position. The ring is then numbered in the direction that results in the lowest possible numbers in the name of the compound. 

5-bromo-2-nitrobenzoic acid 3-bromo-4-chlorophenol 2-ethyl-4-iodoaniline 

Like benzene, substituted benzenes undergo the five electrophilic aromatic substitution reactions listed in Section 19.13 halogenation, nitration, sulfonation, and Friedel-Crafts acylation and aklyation. 

Now we need to find out whether a substituted benzene is more or less reactive than benzene itself. The answer depends on the substituent. Some substituents make the ring more reactive toward electrophilic aromatic substitution than benzene, and some make it less reactive. 

As a result, substituents that donate electrons to the benzene ring increase benzene s nucleophilicity and stabilize the partially positively charged transition state, thereby increasing the rate of electrophilic aromatic substitution these are called activating substituents. In contrast, substituents that withdraw electrons from the benzene ring deaease benzene s nucleophilicity and destabilize the transition state, thereby decreasing the rate of electrophilic aromatic substitution these are called deactivating substituents. 

---

The effect of substituents on reactivity may be understood in terms of Fig. 31. The ground state profile (unbroken bold line) is the result of the mixing of DA, D+A- and 3D 3A configurations (107). Substituent effects on reactivity appear to be dominated by their effect on D+A. Substituents that stabilize D+A lower its energy along the entire reaction co-ordinate (broken line) and lead to a lower energy reaction profile (broken bold line). 

These rearrangements may involve formation of diradicals as discrete intermediates, or they may be concerted processes in which bond breaking and bond making occur simultaneously. Their insensitivity to nitric oxide and oxygen and the absence of dimeric products suggest that long-lived radicals are not intermediates. The effects of substituents on reactivity can be accounted for in terms of either a concerted or a diradical mechanism. However, the... 

The effect of substituents on the rate of the reaction catalysed by different metal ions has also been studied Correlation with resulted in perfectly linear Hammett plots. Now the p-values for the four Lewis-acids are of comparable magnitude and do not follow the Irving-Williams order. Note tlrat the substituents have opposing effects on complexation, which is favoured by electron donating substituents, and reactivity, which is increased by electron withdrawirg substituents. The effect on the reactivity is clearly more pronounced than the effect on the complexation equilibrium. 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

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 effect of substituents on electrophilic substitution can be placed on a quantitative basis by use ofpartial rate factors. The reactivity of each position in a substituted aromatic compound can be compared with that of benzene by measuring the overall rate, relative to benzene, and dissecting the total rate by dividing it among the ortho, meta, and para... 

The competition between these two reactions is determined by the effect of substituents on the conformation and reactivity of the diradical intermediate. 

Gronowitz et al. have discussed the effects of substituents on chemical reactivity and on ultraviolet (XJV), infrared (IR), and nuclear magnetic resonance (NMR) spectra in terms of simple resonance theory,They assume resonance structures (1-5) to contribute to a —I—M (Ingold s terminology) 2-substituted thiophene, resonance forms (6-10) to the structure of a drI-fM 2-substituted thiophene, forms (11-16) to a —I—M 3-substituted thiophene, and forms (17-22) to a I -M 3-substituted thiophene. 

The reaction is less selective than the related benzoylation reaction (/pMe = 30.2, cf. 626), thereby indicating a greater charge on the electrophile this is in complete agreement with the greater ease of nuclophilic substitution of sulphonic acids and derivatives compared to carboxylic acids and derivatives and may be rationalized from a consideration of resonance structures. The effect of substituents on the reactivity of the sulphonyl chloride follows from the effect of stabilizing the aryl-sulphonium ion formed in the ionisation step (81) or from the effect on the preequilibrium step (79). 

Apeloig and Kami (13) have also studied the effects of substituents on the reactivity of silenes by the frontier molecular orbital (FMO) approach. They have concluded that, concerning electronic factors, the polarity of the carbon-silicon double bond, and thus the coefficients of the frontier orbitals, play a more important role than the energies of these orbitals in controlling the reactivity of silenes. 

Hammond postulate has been used to explain the effect of substituents on the rate of benzilic acid rearrangements, mechanism of electrophillic aromatic substitution reactions and reactions involving highly reactive intermediates such as carbonium ions and carbon ions. 

The introduction of a substituent in an organic compound may affect its reactivity in a given reaction. A number of quantitative relationships have been suggested in connection with the effect of substituents on the rate constant of the reaction. Such structure-reactivity co-relations are helpful in predicting the reactivity of organic compounds in various reactions and also in verifying the reaction mechanism. One such useful relationship was proposed by Hemmett, which relates the equilibrium and rate constants for the reaction of meta and para substituted benzene derivatives. 

Contrary to the above expectations, the bromination of anisole (Tee and Bennett, 1984) and of phenols (Tee and Bennett, 1988a) in the presence of a-CD is not strongly retarded, so that some form of catalysis must occur. In some cases, actual rate increases are observed in spite of the several complexations that reduce the free reactant concentrations. Analysis of the effects of substituents on the kinetics leads to the conclusion that the catalysis by a-CD most probably results from reaction of CD-bound bromine with free substrate (12a) and that the a-CD-Br2 complex is 3-31 times more reactive than free Br2 towards phenols and phenoxide ions (cf. Tee et al., 1989). For the kinetically equivalent reaction of the substrate CD complex with free bromine (12b), the rate constants (A 2 ) for phenols do not correlate sensibly with the nature and position of the substituents, and for three of the phenoxide ions they have unrealistically high values, greater than 10u m 1 s . 

Analysis of the SN2 process in terms of the four configurations [20] to [23] indicates that the effect of substituents on the identity exchange process is not affected by [20] and [21]. This is because for N = X these two configurations are equivalent, and the effect of substitution on reactivity for these two configurations will exactly cancel out. The change in reaction rate will therefore be governed by configurations [22] and [23]. 

If the nucleophilic site (HOMO) involves a nonbonded pair of electrons (path a), a stable covalently bonded complex will form. If the HOMO is a a bond, direct reaction is unlikely unless the bond is high in energy and sterically exposed, as in a three-membered ring, but if the bond is to H, hydride abstraction may occur (path b, steps 1 and 2) or a hydride bridge may form (path 6, step 1). The last two possibilities are discussed further in Chapter 10. If the HOMO is a n bond, a n complex may result (path c, step 1), or, more commonly, donation of the n electrons results in the formation of a a bond at the end where the n electron density was higher, the other end becoming Lewis acidic in the process (path c, steps 1 and 2). The effects of substituents on olefin reactivity were discussed in Chapter 6. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Considering the effect of substituents on overall reactivity, the trifluoroacetylation of 2-methylthiophene at position 5 is 600 times faster than that of thiophene. The methyl group at positions 3, 4 and 5 of thiophene has been shown to increase the rate of hydrogen-isotope exchange at position 2 by factors of 340, 12 and 200 respectively the values alternate as in the benzene series (71PMH(4)55)... 

It is in this area of dienone photochemistry that the effect of structure on reactivities of excited states seems to be especially complex. For example, Kropp has shown that the presence of the 4-methyl group in santonin is responsible for preferential formation of the fused 5,7 ring system in photosantonic lactone.403 An analogous cross-conjugated dienone with a 2-methyl substituent yields only a spiro compound in acidic media,404 while a dienone with neither 2- nor 4-substituents yields mixtures of the two types of products.409... 

The effect of substituents on the reactivity of phenols with epichlorohydrin hot been examined also by Bradley and co-workers.283 In contrast with earlier observations made by Boyd and blade with othyfene oxide and propylene oxide, the most acidio phenols are the ones giving maximum yields with epichlorohydrin. This indicated that in this particular reaction the relative concentration of phenoxide ions rather than their nucleophiBcity is the overriding factor in determining the rates of addition. 

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. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

---