Substitution, anodic

Anodic substitution denotes those electrochemical processes in which the group X, mostly hydrogen, of a substrate RX is replaced anodically by a substituent Nu, e.g., OR, OCOR, NHCOR. 

Mechanistically, these reactions can be divided into three classes  

Nucleophilic substitution of an anodically generated radical cation (Eq. (91))  

The preparative scope of anodic substitution has not been systematically studied yet. Its synthetic potential can be judged from the possibilities i) to utilize the class of nucleophiles for radical substitution processes and ii) to join two reagents of equal polarity (b, c)by preceding oxidation, a reaction that cannot be matched by conventional synthesis. Thus the choice of reagents for radical substitution is considerably broadened and new combinations of synthetic building units are offered. 

The literature on anodic substitution up to 1961 has been reviewed by Tomilov 16  

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Common reactions are the anodic substitution of hydrogen atoms in organic compounds by halide or other functional groups ... 

It seems that no general mechanistic description fits all these experiments. Some of the reactions proceed via an addition-elimination mechanism, while in others the primary step is electron transfer from the arene with formation of a radical cation. This second mechanism is then very similar to the electrochemical anodic substitution/addition sequence. 

Therefore, achievement of this desired substitution, particularly the formation of a carbon-carbon bond at the a position is one of most important goals of modern organofluorine chemistry. Although anodic substitution is a characteristic of certain electrolytic reactions, no results pertaining to the electrolytic substitution of trifluoromethylated compounds have been reported. Recently, the use of the electrochemical technique has opened new avenues for the realization of such nucleophilic substitution [40-42] and construction of a carbon-carbon bond [43-45]. 

Here, regioselective anodic substitutions of heteroatom compounds having fluoroalkyl groups and the effects of fluorine atoms on both the synthetic behavior and the oxidation potentials will be mainly discussed. 

These facts indicate that an a-trifluoromethyl group remarkably promotes anodic substitutions with oxygen nucleophiles. Since these are very few successful examples of anodic methoxylation of phenylalkyl sulfides are known, it is notable that an a-trifluoromethyl group facilitates the anodic methoxylation. Therefore, such anodic substitutions have been systematically investigated from both mechanistic and synthetic aspects [42]. 

By the way, trifluoroacetaldehyde is a versatile fluoro building block. However the chemical or electrochemical oxidative transformation of trifluoro-ethanol to trifluoroacetaldehyde has been unsuccessful. Trifluoroacetaldehyde is therefore generally produced by the reduction of trifluoroacetic acid ester or acid chloride using an excess of LAH. The anodic substitution at fluoroaikyl phenyl sulfides is a useful alternative because it realizes the transformation of economical trifluoroethanol to highly valuable trifluoroacetaldehyde equivalents as shown in Scheme 6.5. 

CH-bonds for anodic substitution can be those in alkanes and aryl compounds as well as those activated by an aryl, alkoxy, thio, amino group, or a double bond. 

For the anodic substitution of unactivated CH-bonds, some fairly selective reactions for tertiary CH-bonds in hydrocarbons and y—CH-bonds in esters or ketones are available [85-87]. However, in some cases, a better control of follow-up oxidations remains to be developed. Chemically, a number of selective reactions are available, such as the ozone on silica gel for tertiary CH-bonds [88], the Barton or Hoffmann-LoefHer-Freytag reaction for y-CH-bonds [89], and for remote CH-bonds, Cprop)2NCl/H [90, 91], photochlorination of fatty acids adsorbed on alumina [92] or template-directed oxidations [93]. 

Scheme 4 Anodic substitution and addition with cyclohexene (15) via a radical cation.

In the case of the steroid (38), anodic substitution allowed the selective substitution of the benzyhc hydrogen atom by a methoxy group, whose elimination afforded (39) and overall led in a three... 

Scheme 10 Synthesis of a corticoid precursor (39) by anodic substitution.

Oxidative S—C bond cleavage, followed by the attack of a nucleophile on the carbocation formed, is a classical anodic substitution reaction. In this way, OH [60], AcNH [61], AcCH2 [62], and CH2=CHCH2 [63] groups were introduced to replace the RS fragment. 

Scheme 17 Anodic substitution of a-silylated alkyl phenyl sulfides.

Scheme 59 Anodic substitution of aromatic compounds with electrogenerated...

Scheme 31 Anodic substitution of an N-a-thiogroup with fluoride.

Chemoselective oxidation of 3-arylsul-fenylmethyl-A -cephem affords 3-meth-oxymethyl-A -cephem in an anodic substitution. From the two thioethers, the arylthio group is more easily oxididized to a radical cation, that then undergoes cleavage to a thiyl radical and a carbocation (Fig. 31) [152]. 

Substitution Anodic substitution designates the oxidative replacement of a hydrogen atom, a silyl, or a carboxyl group (non-Kolbe electrolysis) by a nucleophilic carbon or heteroatom. 

Anodic substitution of a carboxylic acid involves decarboxylation to an alkyl radical... 

Anodic substitution reactions of aromatic hydrocarbons have been known since around 1900 [29, 30]. The course of these processes was established primarily by a study of the reaction between naphthalene and acetate ions. Oxidation of naphthalene in the presence of acetate gives 1-acetoxynaphthalene and this was at first taken to indicate trapping of the acetyl radical formed during Kolbe electrolysis of... 

Fluorinated Organics Hydrocarbons, aliphatic carboxylic acids, sulfonic acids, amines, etc. Dia Nippon (Japan) 3M (US)b Not available Not available Anodic substitution... 

Anodic substitution in the aromatic nucleus, the side chains of aromatic compounds, and the ally lie position of double bonds. 

Anodic substitution in the alpha-position to hetero atoms. 

Several industrial processes make use of anodic substitution in the side chain of alkyl aromatic compounds. Thus, aromatic aldehydes or aldehyde dimethyl acetals are generated at graphite electrodes in methanol. A typical example is the formation of 4-methoxybenzaldehyde (anisaldehyde) dimethyl acetal starting from 4-methoxytoluene [4] ... 

Anodic substitution can also occur easily in the a-position to heteroatoms like nitrogen or oxygen. Thus, the indirect electrochemical oxidation of ethylene glycol dimethyl ether in methanol using tris(2,4-dibromophenyl)amine as redox catalyst leads to the formation of 2-methoxyacetaldehyde dimethylacetal [25] ... 

The solubility of the components in the solvent must be sufficient. To improve the solubility, cosolvents can be used. Another possibility is the application of a two-phase system or an emulsion in the presence of phase-transfer catalysts. A two-phase system also has advantages in product isolation and continuous electrolysis procedures. A typical example is the synthesis of p-methoxy benzonitrile by anodic substitution of one methoxy group in 1,4-dimethoxybenzene by the cyanide ion (Eq. 22.21). The homogeneous cyanation system (acetonitrile, tetraethylammonium cyanide) [24] can be efficiently replaced by a phase-transfer system (dichloro-methane, water, sodium cyanide, tetrabutylammonium hydrogen sulfate) [71]. 

Organosilicon compounds bearing heteroatoms generally undergo anodic substitutions with the elimination of a silyl group in a manner similar to that observed for benzylsilanes and allylsilanes as shown in equation 20. 

The electrooxidation procedure has been used in the preparation of a key intermediate for the fi /-helminthosporal synthesis 93). Aromatic steroids have been functionalized by means of anodic substitution introducing nucleophiles in the benzylic position 94a) or at the aromatic nucleus 94b). 

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