Side-chain Substitution

In the case of alkyl-substituted aromatics, the predominant reaction path very often is side-chain acyloxylation. By using Pd-coated cathodes in an undivided cell, it is possible to avoid the formation of the side chain-substituted products, because under these conditions the benzyl ester undergoes cathodic cleavage into the starting compounds 161)  

The anodic phosphorylation is another interesting possibility for the functionalization of aromatics. Initially approtic electrolytes (e.g. CH3CN/NaC104 162 163 ) were used. Hoechst164 was also successful in carrying out the synthesis in protic electrolytes. 

In addition to the cathodic hydrodimerization of activated olefins [see 3.2.1.1], the electrosyntheses of substituted benzaldehydes are among the few electroorganic reactions which are carried out on a large scale industrially. 

The anodic acetoxylation of alkyltoluenes was first studied in industry by Mobil 

Quaternary ammonium salts were used as supporting electrolytes in this reaction by Mitsubishi168) and others  

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The presence of the L-form of mannose is unusual. The side-chain substitution is randomly distributed (242) approximately two-thirds of the side chains ate rhamnose. The repeat unit may also contain an 0-acyl group, but the distribution of these units has not been completely determined. The polymer is moderately soluble in water but is insoluble in isopropanol solutions, which are used to obtain the polymer from the culture medium. A method for producing a rapidly hydrating form of welan is avaUable (243). 

Steroids (1) are members of a large class of lipid compounds called terpenes that are biogenicaHy derived from the same parent compound, isoprene, C Hg Steroids contain or are derived from the perhydro-l,2-cyclopentenophenanthrene ring system (1) and are found in a variety of different marine, terrestrial, and synthetic sources. The vast diversity of the natural and synthetic members of this class depends on variations in side-chain substitution (primarily at C17), degree of unsaturation, degree and nature of oxidation, and the stereochemical relationships at the ring junctions. 

If chlorine and bromine are allowed to act upon an aromatic hydrocarbon like toluene, which has a side-chain, substitution may occur in the nucleus or the side-chain, according to the conditions. Generally speaking, in the cold and in presence of a halogen carrier, nuclear substitution occurs, Irut at a high temperatuie the halogen passes into the side-chain (see Piep. 

Unfortunately, complexes 39 and 40 are still more prone to decomposition than catalyst 16. Therefore, Grubbs sought to investigate a series of new ruthenium catalysts bearing NHCs with varying degrees of iV-heterocyclic backbone and aryl side chain substitution, and catalysts 16 and 30a were chosen as basic catalyst structures [57]. In 2009, complexes 41a-c and 42a-c were prepared to attempt to understand how the degree of substitution on the backbone influences catalyst activity and lifetime (Fig. 3.15). 

Fig. 3.24 Catalysts 59-61 with different side chain substitutions...

The lUPAC name of cannabidiol is 2-[(lS, 6iI)-3-methyl-6-prop-l-en-2-yl-l-cyclohex-2-enyl]-5-pentyl-benzene-1,3-diol. Cannabidiol (CBD, 2.9) in its acidic form cannabidiolic acid (CBDA, 2.10) is the second major cannabinoid in C. sativa besides A9-THC. As already mentioned for A9-THC, variations in the length of the side chain are also possible for CBD. Important in this context are the propyl side chain-substituted CBD, named cannabidivarin (CBDV, 2.11), and CBD-C4 (2.12), the homologous compound with a butyl side chain. Related to the synthesis starting from CBD to A9-THC as described in Sect. 3.1, it was accepted that CBDA serves as a precursor for THCA in the biosynthesis. Recent publications indicate that CBDA and THCA are formed from the same precursor, cannabigerolic acid (CBGA), and that it is unlikely that the biosynthesis of THCA from CBDA takes place in C. sativa. 

The side-chain substitution of toluene, p-chlorotoluene, etc. is industrially practised. This reaction is carried out in a photochemical reactor. It is an exothermic reaction in which HCl is produced. The reaction is consecutive, and hence CL first reacts with toluene reacts to form the desired benzyl chloride, which is then converted to benzal chloride, and finally benzotrichloride. We may, however, well be interested in the selectivity to benzyl chloride. An additional complication arises due to nuclear chlorination, which is most undesirable. A distillation-column reactor can offer advantages (Xu and Dudukovic, 1999). 

One of the first pharmacological classes to be studied by medicinal chemists was local anesthetics. Many of the guiding principles which are used to this day, for example, molecular dissection, side chain substitution and inversion, and the like, were first developed in the course of those early researches. 

For long chains of these reactions, each step must be exothermic. Typical examples include Cl2 in carboxylic acids, and BrCCl3 in alkyl aromatics. The products are variable substitution and side chain substitution compounds, respectively. 

The aromatic mono-olefins have been studied more extensively and intensively than any other class of monomers. Styrene, in particular, has received much attention, but nuclear and side-chain substituted styrenes are still largely unexplored, except in regard to copolymerization. The only other aromatic monomers which have been studied in any detail are a-methylstyrene [1] and 1,1-diphenylethylene and some of its derivatives [10]. It is strange that even readily available monomers, such as indene [80] and acenaphthylene [54b, 81], have hardly been investigated. 

See Shoppee (1972 359), citing C. K. Ingold and E. Rothstein, "The Nature of the Alternating Effect in Carbon Chains. Pt. XXV. The Mechanism of Aromatic Side-Chain Substitution," JCS 131 (1928) ... 

Substituent effects on benzene photochemistry in the presence of amines are described53 in equations 19-21. The a-C—H of an amine is shown to add photolytically to the 2,5-positions of toluene (equation 19). In contrast, trifluoro-substituted benzene was excited to react with trimethylamine to give 50 and 52 by a side-chain substitution. This chemistry arose from facile defluorination of the anion radicals of 49 and 51. 

The substituent effects on the photochemistry between benzene and secondary aliphatic amines53 were studied. Irradiation of toluene or chlorobenzene with diethylamine results in the formation of mixtures of addition and substitution products (equations 34 and 35). Irradiation of anisole or benzonitrile with diethylamine gives the substitution product 7V,7V-diethylaniline (equations 36 and 37). Irradiation of benzylfluoride with diethylamine results in a side-chain substitution (equation 38). The photoreaction of p-fluorotoluene with diethylamine gives both substitution and reduction products (equation 39). 

Anodic Side Chain Substitution of Aromatic Compounds. 159... 

Nuclear aromatic substitution occurs by way of an ECiyECfi-sequence as shown in Scheme 9, path (b). It occurs at the carbon atom with the highest positive charge density and in alkylbenzenes competes with side chain substitution via an ECgEC/v process by deprotonation of the radical cation to form a benzyl radical. 

Scheme 9, path d). An increasing number of alkyl substituents at the benzylic carbon (toluene 28.6%, ethyl benzene 50.5%, isopropylbenzene 46.7% [191]) and electrolytes of lower nucleophilicity (TBAOAc, HOAc [192]) favor side chain substitution. Table 13 presents some selected examples of aromatic nuclear substitution with different nucleophiles X or HX (Eq. 19). 

Anodic side chain substitution is a competing reaction to nuclear substitution of aromatic compounds. In side chain substitution, the first formed acidic radical cation is deprotonated at the a-carbon atom of an alkyl group to form a radical. This is further oxidized to a benzyl cation, which reacts with a nucleophile (Scheme 9, path d). The factors that influence the ratio of nuclear to side chain substitution have been described in 5.4.1. 

I 5 Anodic Reactions of Alkanes, Alkenes, and Aromatic Compounds Tab. 14 Anodic side chain substitution... 

Benzylic CH bonds Benzylic CH bonds can be preferentially substituted at the anode by oxidation of the aromatic ring to a radical cation, which can undergo side-chain substitution at the benzylic carbon atom and/or nuclear substitution. Benzylic substitution preponderates, when there is an alkyl substituent at the aromatic carbon bearing the highest positive charge density in the radical cation, while a hydrogen at this position leads to a nuclear substitution [16]. Anodic benzylic substitution is used in technical processes for the conversion of alkyl aromatics into substituted benzaldehydes [17, 18]. Anodic benzylic substitution has been used for the regioselective methoxylation of estratrienone at C9 (Fig. 4) [19]. 

The two examples of adsorbed side chain substituted macromolecules, i.e., the poly(n-butyl acrylate) brush and the tris(p-undecyloxybenzyloxo) benzoate jacketed polystyrene, demonstrate two rather complementary aspects of the interaction of such molecules with a planar surface. In the first case the two-dimension to three-dimension transition results in a cooperative collapse of an extended coil conformation to a globule. The second case shows a rather high degree ordering with a distinct orientation of the backbone in the substrate plane. Combination of both effects and partial desorption can lead to a repta-tion-hke directed motion as depicted schematically in Fig. 36. 

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