Explaining ortho/para ratios

We cannot, then, expect this approach to understanding chemical reactivity to explain everything. We should bear in mind its limitations, particularly when dealing with subjects like ortho/para ratios in aromatic electrophilic substitution, where steric effects are well known to be important. Likewise solvent effects (which usually make themselves felt in the entropy of activation term) are also well known to be part of the explanation of the principal of hard and soft acids and bases. Some mention of all these factors will be made again in the course of this book. Arguments based on the interaction of frontier orbitals are powerful, as we shall see, but they must not be taken so far that we forget these very important limitations. 

Dealumination of the ZSM-5 zeolite shows a great effect on ortho/ para selectivity in the acylation of phenol by AAC. Thus, for a phenol conversion of 20%, ortho/para selectivity is 7.0 when ZSM-5(41.8) is utilized, and becomes 13.0 in the presence of ZSM-5(42.4). This unexpected increase in the ortho/para ratio can only be explained by postulating that ortho-HAP and para-HAP result from different pathways. The ortho isomer is mainly produced in the pores, whereas para isomer production occurs only on the external acid sites. The ortho isomer can be formed by direct C-acylation of phenol with AAC this selective reaction can be related to the general mechanism reported in Scheme 5.1. ortho-HAP can also be obtained by the Fries rearrangement. On the contrary, the para-isomer is a secondary product and, therefore, it results from the acylation of phenol by PA according to Scheme 5.6. 

For the unsubstituted pyridinium cation, reaction at the 2- and at the 4-position is predicted according to the theory. Indeed, reaction of protonated pyridine with the tcrt-butyl radical at low conversions (<30%) afforded selectively the ortho- and para-substituted derivatives without any alkylation at the meta position [16], It turned out that the ortho-para ratio is highly solvent dependent. If the reaction is conducted in H2O, the para product is formed as the major compound (see 10, ortho. para — 23 77). The same reaction in benzene afforded mainly the ortho compound [ortho-.para = 11 29). The reversal of the selectivity can be explained by assuming a reversible initial radical addition, especially if the reaction is conducted in H2O [16]. Similar results were obtained for the reaction with the tetrahydrofuryl radical [16]. The alkylations are generally stopped at low conversions. Since the alkylated pyridinium cations are only slightly less electrophilic than the starting pyridinium cations, overalkylation competes at higher conversion. For example, ethylation of the pyridinium cation at 100% conversion afforded a mixture of mono-, double- and tri-ethylated pyridinium salts (—> 11a e) [17]. 

The ortho para ratio is also influenced by the nitration medium in a manner which cannot be explained by the Robinson-Ingold theory. The isomer distribution which results from the nitration of aniline and anilides in several nitrating media is shown in Table 4-6. 

The nitration of acetanilide with mixed acid yields nitroacetanilides in which the ortho para ratio is less than 0.1. When the nitration medium is nitric acid, this ratio is 0.7, when acetyl nitrate in acetic anhydride is used, the product is almost entirely o-nitroacetanilide. No satisfactory explanation has been given for these results. The 40-50 per cent yield of m-nitro-aniline that results from the nitration of aniline in mixed acid or in nitric acid can be explained in the following manner. In the strong acids, nitric and sulfuric acid, aniline is largely ionized. 

Explain the following observations (1) The ortho-para ratio of the products obtained by sulfonation of toluene is lower than that of nitration (2) The ortho-para ratio of the products obtained by nitration of isopropylbenzene is lower than that of nitration of toluene. 

The ortho/para alkylation ratio of the intramolecular nucleophilic substitution reaction of sodio-4-(3-hydroxyphenyl)butyl tosylate, according to Eq. (5-137), was shown to be solvent-dependent [381]. In general, an increase in the ortho/para alkylation ratio resulted when the polarity of the solvent was decreased. The orientation of the reaction was explained in terms of the nature of the association between the metal and phenolate ions in different solvents [381]. 

Ortho iPara Ratios. In the preceding paragraphs, the substituents were classified as ortho-para directing 6r meta directing, the difference being explained in terms of + I and —I effects and -hM and — M effects. The effect of a substituent on the ratio of ortho to para nitration products is also explained by these factors and an additional factor, the size of the substituent, which we shall call the steric factor. 

Friedel-Crafts methylation of methoxybenzene (anisole) with chloromethane in the presence of AICI3 gives a 2 1 ratio of ortho para products. Treatment of methoxybenzene with 2-chloro-2-methylpropane (terf-butyl chloride) under the same conditions furnishes only l-methoxy-4-(1,1-dimethylethyl) benzene (p-tert-butylanisole). Explain. (Hint Review Section 16-5.)... 

For toluene fluorination, the impact of micro-reactor processing on the ratio of ortho-, meta- and para-isomers for monofluorinated toluene could be deduced and explained by a change in the type of reaction mechanism. The ortho-, meta- and para-isomer ratio was 5 1 3 for fluorination in a falling film micro reactor and a micro bubble column at a temperature of-16 °C [164,167]. This ratio is in accordance with an electrophilic substitution pathway. In contrast, radical mechanisms are strongly favored for conventional laboratory-scale processing, resulting in much more meta-substitution accompanied by imcontroUed multi-fluorination, addition and polymerization reactions. 

The data in Table 15 reveal that the values of E/C ratios from the solid p-CD complexes are always lower than from benzene solutions. The degree to which the cis cyclization products are favored over the trans increases from 103a to 103e as expected from the model in Scheme 46. Also, the longer homologue of each ortho-, meta-, and para-methylated 103 yields the greater amount of cyclobutanols when irradiated in solid P-CD complexes. Thus, Scheme 46 explains qualitatively the photoproduct ratios from solid p-CD. 

Isomerization of arene oxides to phenols proceeds by complex and often multiple pathways660 668 that show a marked dependence on pH. Arene oxides as key intermediates provide the basis for explaining the ortho/meta/para isomer ratios observed in enzymatic hydroxylations.655a,b For example, the absence of m-cresol in the metabolites of toluene can be attributed to the fact that none of the three possible isomers of toluene oxide rearranges to this product. 

The relative reactivities of the ortho, meta and para carbon atoms should be proportional to the electron availability at these sites and+the relative probability of collision with a given NOT ion. It should be possible to calculate the sterfc effects on the collision frequencies and apply molecular orbital theory to determine the relative reactivities of the various sites. However, a more practical approach would be to assume that all the five carbon atoms encounter nitronium ions at equal frequencies and attribute the differences in the reactivity of the different positions to differences in the activation energies associated with those sites. According to this model, temperature is the only variable that affects the isomer ratio. Our plant experience indicates that this model is adequate for explaining and controlling the variation of the isomer ratio. 

The distribution of products obtained from the fluorination of phenol is dependent on the percentage conversion of the phenol, the reaction temperature and the solvent. When the fluorination of phenol is carried out at — 20 C the ratio of ortho to para monofluorophenols 4/5 is 22 1 at 10% conversion and 3.6 1 at 51 % conversion. This is explained by the further reaction of the ort/io-isomer 4 to unidentified polymeric material. Although the orihojpara ratio 4/5 is not significantly affected by the temperature of the fluorination, the conversion decreases with increasing temperature. At lower temperatures higher concentrations of dissolved fluorine are present in the reaction mixture and, thus, a higher conversion is observed. 

Acetyl hypofluorite will only fluorinate activated aromatic compounds and fluorinations arc generally performed at low temperatures. In general a mixture of products is formed, for example, the fluorination of anisole with acetyl hypofluorite results in a mixture of 2-fliioroanisole and 4-fluoroanisole (ratio 9.6 1) in 85% yield (Table 11). This preferential formation of the ortho-Komcr is explained by an addition-elimination mechanism with an intermediate 15. This mechanism is support by the fact that the addition product 16 from acetyl hypofluorite and pipcronal is isolated in 55 % yield. Selective fluorination is achieved when the para position is blocked by a second substituent (Table 12). This approach has been used to selectively fluorinate an aromatic ring in peptide 17. " ... 

With TS-1 as the catalyst, the oxidation products of phenol are hydro-quinone and catechol (para- and ort/to-hydroxyphenol), with minor yields of water and tar formed as by-products. Numerous early papers are concerned with this reaction (218), and patents (219) have been iiled. In the reaction catalyzed by TS-1, the conversion of phenol and the selectivity to dihydroxy products are significandy higher than achievable by either radical-initiated oxidation or acidic catalysts. The catechol/hydroquinone molar ratio is within the range of 0.5—1.3 and depends on the solvent. When the reaction occurs in aqueous acetone, the ratio is close to 1.3. It is believed that the product ratio is the result of restricted transition-state selectivity as well as mass transport shape selectivity associated with the different diffusivities of the ortho and para products. Hydroxylation at the para-position of phenol should be less hindered relative to that at the ortho-position, and hydroqui-none has a smaller kinetic diameter than catechol, facilitating diffusion. Tuel and Taarit (220) proposed that catechol is mainly produced at the external surface of TS-1 crystals. Thus, the different catechol/hydroquinone ratios obtained when methanol or acetone is used as a solvent could be explained by either rapid or very slow poisoning of external sites by organic deposits, respectively. Accordingly, the authors were able to show that tars were easily dissolved by acetone (i.e., external sites for catechol formation remained available in this solvent) while they were insoluble in methanol. 

---