Ortho-substituent

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

When the phenyIhydra2one bears a meta-substituent, two isomeric indoles are possible ortho-substituents also frequentiy introduce compHcations. 

Significant quantities of the diphenoquinone are also produced if the ortho substituents are methoxy groups (36). Phenols with less than two ortho substituents produce branched and colored products from the reactions that occur at the open ortho sites. It is possible to minimize such side reactions in the case of o-cresol oxidation by using a bulky ligand on the copper catalyst to block the open ortho position (38). 

The aromatic ring of alkylphenols imparts an acidic character to the hydroxyl group the piC of unhindered alkylphenols is 10—11 (2). Alkylphenols unsubstituted in the ortho position dissolve in aqueous caustic. As the carbon number of the alkyl chain increases, the solubihty of the alkah phenolate salt in water decreases, but aqueous caustic extractions of alkylphenols from an organic solution can be accomphshed at elevated temperatures. Bulky ortho substituents reduce the solubihty of the alkah phenolate in water. The term cryptophenol has been used to describe this phenomenon. A 35% solution of potassium hydroxide in methanol (Qaisen s alkah) dissolves such hindered phenols (3). 

The enzyme catalyzes the hydrolysis of an amide bond linkage with water via a covalent enzyme-inhibitor adduct. Benzoxazinones such as 2-ethoxy-4H-3,l-benzoxazin-4-one [41470-88-6] (23) have been shown to completely inactivate the enzyme in a competitive and stoichiometric fashion (Eigure 5). The intermediate (25) is relatively stable compared to the enzyme-substrate adduct due to the electron-donating properties of the ortho substituents. The complex (25) has a half-life of reactivation of 11 hours. 

The ortho effect may consist of several components. The normal electronic effect may receive contributions from inductive and resonance factors, just as with tneta and para substituents. There may also be a proximity or field electronic effect that operates directly between the substituent and the reaction site. In addition there may exist a true steric effect, as a result of the space-filling nature of the substituent (itself ultimately an electronic effect). Finally it is possible that non-covalent interactions, such as hydrogen bonding or charge transfer, may take place. The role of the solvent in both the initial state and the transition state may be different in the presence of ortho substitution. Many attempts have been made to separate these several effects. For example. Farthing and Nam defined an ortho substituent constant in the usual way by = log (K/K ) for the ionization of benzoic acids, postulating that includes both electronic and steric components. They assumed that the electronic portion of the ortho effect is identical to the para effect, writing CTe = o-p, and that the steric component is equal to the difference between the total effect and the electronic effect, or cts = cr — cte- They then used a multiple LFER to correlate data for orrAo-substituted reactants. 

Many other definitions of an ortho substituent constant have been made Shorter has reviewed these. Charton analyzed Oo in terms of Oi and CTr, i.e., = a(Ti -I- fpoR, finding that the distribution of inductive and resonance effects (the ratio a/b) varies widely with the substituent and, therefore, that no general Oo scale is possible. Charton also subjected to analysis according to Eq. (7-47),... 

A further complication arises out of the fact that of all the orientations discussed only one, 5-R-3-Y, does not involve a vicinal relationship between at least two of the three structural features—substituent, side-chain, and heteroatom. In the cases of 4-R- and 5-R-2-Y the problem of vicinal relations appears not too serious, since this relation is equivalent to the problem of the constant ortho substituent. For this situation it was shown that the constant ort u) substituent, i.e., in this case the heteroatom, may make a contribution to the substituent-independent term (logA °) but generally leaves the reaction constant (p) unaffected. Where the substituent, however, is alpha to the heteroatom it appears likely that its electronic structure, and hence its <7-values, may be substantially affected. This appears particularly likely for large substituents and especially for those which can form a hydrogen bond with the heteroatom, such as CO OH. 

The importance of field effects of ortho substituents has been discussed by Miller and Williams. The effect of various factors on reaction rates is depicted throughout mainly by means of transition states rather than intermediate complexes whose properties are usually not rate-controlling. 

From Table 3, it can be seen that the reactivity of acyl acetanilide, such as BAA or AAA, is higher than that of the other reductant reported from our laboratory, i.e., acetanilide (AA), N-acetyl-p-methylaniline (p-APT), acetylacetone (AcAc), and ethyl acetoacetate (EAcAc). Moreover, the promoting activities of derivatives of acetoacetanilide were affected by the ortho substituent in benzene ring, and the relative rate of polymerization Rr) decreased with the increase of the bulky ortho substituent to the redox reaction between Ce(IV) ion and substituted acetoacetanilide. 

Molecular ion Although the molecular ion is always observed, the loss of 31 Daltons (OCFF) is the most intense ion. Generally, the acid and/or protonated acid is observed. Ortho substituents are distinguished by their large peaks at [M - 32]+, as well as [M - 31]+. A small peak is observed at [M - 60]+. 

Ortho substituent of methyl esters of aromatic acids. Loss of 31 also should be present. 

The data in the table show that the reaction is accelerated by —I substituents and vice versa consequently, substituent effects are most marked at the ortho position and Shatenshtein et al.590 have shown that a correlation exists between the log rate of exchange and the al values for the ortho substituents. This suggests that steric hindrance is very slight in the reaction, and this is entirely consistent with the reaction mechanism in which rate-determining attack on hydrogen occurs. 

The ortho effect has its origin in the ability of an ortho substituent to form a hydrogen bond with a hydrogen on the amine nucleophile58-61. The present... 

TABLE 1. Macroelectrolytes of (4-aminophenyl) phenyl sulphone (I) and (2-aminophenyl) phenyl sulphone (II) showing the effect of the electrode material and the influence of the ortho substituent ... 

On page 132, atropisomerism was possible when ortho substituents on biphenyl derivatives and certain other aromatic compounds prevented rotation about the bond. The presence of ortho-substituents can also influence the conformation of certain groups. In 88, R= alkyl, the carbonyl unit is planar with the trans C=0 - F conformer more stable when X=F. When X=CF3, the cis and trans are planar and the trans predominates. When R = alkyl there is one orthogonal conformation but there are two interconverting nonplanar conformations when R=0-alkyl. In 1,2-diacylbenzenes, the carbonyl units tend to adopt a twisted conformation to minimize steric interactions. " ... 

Unlike alkylation, Friedel-Crafts acylation has been generally considered to be irreversible, but a number of instances of electrofugal acyl groups have been reported, especially where there are two ortho substituents, for example the hydro-de-benzoylation of 42. ... 

If the aryl halide contains two ortho substituents, the reaction should not be able to occur. This is indeed the case. ... 

Additional ionization equilibria involving ortho substituents have been reported by Charton (34) to follow eq. (1). The results of our analysis of the data for aqueous ionization of 2-substituted pyridinium ions, -substituted anilinium ions, and -substituted phenols are given in Table XXVIII. Comparison with the corresponding meta and para data set results is also included. 

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