Ortho substituents reactions

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 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. 

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. 

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. 

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

The use of oxazolines in aromatic substitution is a valuable synthetic tool.2 The o-methoxy- or o-fluorophenyloxazoline reacts readily with a variety of organofithium or Grignard reagents to displace only the ortho substituent. In this fashion a number of ortho-substituted benzoic acids, benzaldehydes, and unsymmetrical biphenyls are accessible. The reaction takes place under very mild conditions, usually at or below room temperature, and thus allows a number of other sensitive groups to be present. 

Recently (22,23), we observed that quinine catalyzes the 1,2-addition of phosphite esters to benzaldehydes. When the aldehyde has an ortho substituent, preferably one that aids in restricting the rotation of the aldehyde group, asymmetric induction takes place. In these reactions quinine is 20 times as effective a catalyst as is triethylamine (83) (eq. [23]). Although the e.e. in the reaction shown in eq. [23] is 26% when R = nitro, this percentage rises to 80% when di-/-butyl phosphite is used (see also eq. [3]). 

For entries 3-5 the increase in molecular weight observed can be assigned to the increase in the rate of insertion and the rate of termination remains practically the same. An increase of the rate of polymerisation with the steric bulk of the ligand is usually ascribed to the destabilisation of the alkene adduct while the energy of the transition state remains the same. As a chain transfer reaction presumably P-hydride elimination takes place or traces of water might be chain transfer agents. Chain transfer does occur, because a Schulz-Flory molecular weight distribution is found (PDI 2, see Table 12.2). Shorter chains are obtained with a polar ortho substituent (OMe, entry 2) and in methanol as the solvent, albeit that most palladium is inactive in the latter case. 

The metalloporphyrin-initiated polymerizations are accelerated by the presence of steri-cally hindered Lewis acids [Inoue, 2000 Sugimoto and Inoue, 1999]. The Lewis acid coordinates with the oxygen of monomer to weaken the C— O bond and facilitate nucleophilic attack. The Lewis acid must be sterically hindered to prevent its reaction with the propagating center attached to the prophyrin structure. Thus, aluminm ortho-substituted phenolates such as methylaluminum bis(2,6-di-/-butyl-4-methylphenolate) accelerate the polymerization by factors of 102-103 or higher. Less sterically hindered Lewis acids, including the aluminum phenolates without ortho substituents, are much less effective. 

Nucleophilic displacement of Z-, 4-, and 6-halo substituents by alkoxy or aryloxy ions occurs readily except in the presence of strongly electron-releasing substituents in the ring <1994HC(52)1>. Stepwise reaction can be achieved with di- and trihalo-pyrimidines, with the more reactive 4-position being the first site of reaction. For example, even with the presence of a bulky ortho substituent such as a 5-bromine atom, selective methanolysis at the 4-position was still observed with 5-bromo-2,4-dichloropyrimidine 179 <2006TL4415>. 

It is especially noteworthy that this reaction sequence to ( + )-ancistrocladisine (8) offers the unique possibility of synthesizing a natural biaryl compound with two identical ortho-substituents, e.g, methoxy groups, next to the biaryl linkage (see also the nonstereoselective synthesis of ancistrocladisine as a mixture of all four possible stereoisomers13). 

From the understanding, provided by the calculations, of the mechanism by which lb cyclizes, what can be predicted about how the rate of this reaction might be affected by substituents on the benzene ring The substiment effects would, in fact, be expected to be small, except for possible steric effects due to substituents in the ortho positions. If both ortho positions are substimted, one would expect to see a decrease in rate, relative to unsubstituted lb. On the other hand, if only one ortho position is substituted, cyclization should be about as fast as in unsubstituted lb but cyclization should preferentially occur at the unsubstituted ortho carbon. Additional (8/8)CASPT2/6-31G calculations by Bill Kamey in our group and subsequent experiments by the Platz group confirmed these qualitative predictions about the effects of ortho substituents. 

Stability, activity and chemo- and enantioselectivity increased with increasing steric demand of the ortho substituent R. Introduction of the trimethylsilyl group at this position (ligand 38) therefore resulted in an excellent enantioselective system which belongs among the best Pd catalysts described so far for asymmetric hydrovinylation. Almost 70% conversion was observed within 15 min. The product was obtained in 78.5% ee and only a small amount of the isomerization products was detected in the reaction mixture. However, at higher conversions, isomerization of the product to the internal achiral olefin took place. Therefore,... 

Intramolecular coupling of diazonium salts with ortho substituents bearing an active methylene grouping or its equivalent gives rise to cinnolines, which may be considered a class of cyclic azo compounds. Three name reactions are cited here for reference only. 

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