Reactivity, substituent effects

Wladislaw et al. examined the reactivity-substituent effect relationship in the photo-cychzation of the adducts 44 of cyclopentadiene with p-benzoquinone. Some substituted adducts 44h and 44i do not undergo photocychzation. Table 22.2 shows the quantum yield (Ojei) for photocycHzation of the mono-substituted adducts 44a-i, relative to that of the unsubstituted adduct 44j for which Owas assumed to be 1.00. These data show not only that the adducts 44h,i,j do not photocyclize but also that adduct 44g photocyclizes inefficiently. It is proposed that the factor that determines the photocychzation efficiency is the difference between the energy levels of the two interacting orbitals (HOMO- HOMO ) since the cyclization is most probably initiated by a photochemical electron transfer (PET)."... 

A familiar feature of the electronic theory is the classification of substituents, in terms of the inductive and conjugative or resonance effects, which it provides. Examples from substituents discussed in this book are given in table 7.2. The effects upon orientation and reactivity indicated are only the dominant ones, and one of our tasks is to examine in closer detail how descriptions of substituent effects of this kind meet the facts of nitration. In general, such descriptions find wide acceptance, the more so since they are now known to correspond to parallel descriptions in terms of molecular orbital theory ( 7.2.2, 7.2.3). Only in respect of the interpretation to be placed upon the inductive effect is there still serious disagreement. It will be seen that recent results of nitration studies have produced evidence on this point ( 9.1.1). 

QUANTITATIVE CORRELATIONS OF SUBSTITUENT EFFECTS The theories outlined above are concerned with the way in which substituents modify the reactivity of the aromatic nucleus. An alternative approach to the effects of substituents is provided by quantitative... 

If this electrostatic treatment of the substituent effect of poles is sound, the effect of a pole upon the Gibbs function of activation at a particular position should be inversely proportional to the effective dielectric constant, and the longer the methylene chain the more closely should the effective dielectric constant approach the dielectric constant of the medium. Surprisingly, competitive nitrations of phenpropyl trimethyl ammonium perchlorate and benzene in acetic anhydride and tri-fluoroacetic acid showed the relative rate not to decrease markedly with the dielectric constant of the solvent. It was suggested that the expected decrease in reactivity of the cation was obscured by the faster nitration of ion pairs. 

The reaction of MeO /MeOH with 2-Cl-5(4)-X-thiazoles (122) follows a second-order kinetic law, first order with respect to each reactant (Scheme 62) (297, 301). A remark can be made about the reactivity of the dichloro derivatives it has been pointed out that for reactions with sodium methoxide, the sequence 5>2>4 was observed for monochlorothiazole compounds (302), For 2.5-dichlorothiazole, on the contrary, the experimental data show that the 2-methoxy dehalogenation is always favored. This fact has been related to the different activation due to a substituent effect, less important from position 2 to 5 than from... 

The reaction of 2.4-dimethylthiazole with butyllithium shows that, in contrast to 2-methylthiazole, the benzyl position (the 2-position) is the most reactive. The effect of the substituent in the 4-position may well be steric 4-r-butyl-2-methylthiazole in the same reaction gives no 5-substituted product (223). 

The nucleophilic reactivity of 2-halogenothiazoles is strongly affected by the substituent effect, depending on the kind of substitution reaction. Positions 4 and 5 can be considered as meta and para , respectively, with regard to carbon 2 and to groups linked to it consequently, it is possible to correlate the reactivity data with Hammett s relationships. 

Regarding the substituent effect on reactivity of groups in positions 4 and 5 there is little information in the literature. The reactivity of halogen in position 5 seems to be increased when an amino group is present in position 2. Substitution products are easily obtained using neutral nucleophiles such as thiourea, thiophenols, and mercaptans (52-59). 

A nitro group behaves the same way m both reactions it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution) Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution) By being aware of the connection between reactivity and substituent effects you will sharpen your appreciation of how chemical reactions occur... 

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... 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

Having considered how solvents can affect the reactivities of molecules in solution, let us consider some of the special features that arise in the gas phase, where solvation effects are totally eliminated. Although the majority of organic preparative reactions and mechanistic studies have been conducted in solution, some important reactions are carried out in the gas phase. Also, because most theoretical calculations do not treat solvent effects, experimental data from the gas phase are the most appropriate basis for comparison with theoretical results. Frequently, quite different trends in substituent effects are seen when systems in the gas phase are compared to similar systems in solution. 

Ipso substitution, in which the electrophile attacks a position already carrying a substituent, is relatively rare in electrophilic aromatic substitution and was not explicitly covered in Section 10.2 in the discussion of substituent effects on reactivity and selectivity Using qualitative MO cOTicepts, discuss the effect of the following types of substituents on the energy of the transition state for ipso substitution. 

It has long been known that the Diels-Alder reaction is particularly efficient and rapid when the dienophile contains one or more electron-attracting groups. These substituent effects are illustrated by the data in Table 11.3. In the case of the diene, reactivity is increased by electron-releasing substituents. Some illustrative data are given in Table 11.4. 

Both the reactivity data in Tables 11.3 and 11.4 and the regiochemical relationships in Scheme 11.3 ean be understood on the basis of frontier orbital theory. In reactions of types A and B illustrated in Seheme 11.3, the frontier orbitals will be the diene HOMO and the dienophile LUMO. This is illustrated in Fig. 11.12. This will be the strongest interaction because the donor substituent on the diene will raise the diene orbitals in energy whereas the acceptor substituent will lower the dienophile orbitals. The strongest interaction will be between j/2 and jc. In reactions of types C and D, the pairing of diene LUMO and dienophile HOMO will be expected to be the strongest interaction because of the substituent effects, as illustrated in Fig. 11.12. 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

Next we turn to the magnitudes of the p constants. Evidently if p = 0, there is no substituent effect on reactivity. Moreover because p = -I-1.000 by definition for the aqueous ionization of benzoic acids, we have a scale calibration of sorts. Wiberg gives examples of p as a measure of the extent of charge development in the transition state. McLennan" has pointed out that p values must first be adjusted for the transmission factor before they can be taken as measures of charge devel-... 

The acid cleavage of the aryl— silicon bond (desilylation), which provides a measure of the reactivity of the aromatic carbon of the bond, has been applied to 2- and 3-thienyl trimethylsilane, It was found that the 2-isomer reacted only 43.5 times faster than the 3-isomer and 5000 times faster than the phenyl compound at 50,2°C in acetic acid containing aqueous sulfuric acid. The results so far are consistent with the relative reactivities of thiophene upon detritia-tion if a linear free-energy relationship between the substituent effect in detritiation and desilylation is assumed, as the p-methyl group activates about 240 (200-300) times in detritiation with aqueous sulfuric acid and about 18 times in desilylation. A direct experimental comparison of the difference between benzene and thiophene in detritiation has not been carried out, but it may be mentioned that even in 80.7% sulfuric acid, benzene is detritiated about 600 times slower than 2-tritiothiophene. The aforementioned consideration makes it probable that under similar conditions the ratio of the rates of detritiation of thiophene and benzene is larger than in the desilylation. A still larger difference in reactivity between the 2-position of thiophene and benzene has been found for acetoxymercuration which... 

The reactivities of compounds of type 6 with aniline in acetone correlate quite well with substituent effects, and autocatalysis is unimportant here. In the less polar tetrahydrofuran, where the hydrochloride is only partly soluble, the reaction shows autocatalysis when aniline and -chloro aniline are reactants but not when the more basic -toluidine is involved. In these cases the solubility of the acidic product may also influence the differential behavior observed. 

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