Other Substitution Reactions

Radicaloid substitution has not been extensively studied in the thiophene series. Molecular orbital calculations indicate that substitution should occur in the a-position. This has been found to be the case in the Gomberg-Bachmann coupling of diazohydroxides with thiophenes which has been used for the preparation of 2-(o-nitro-phenyl) thiophene, 2-(p-toluyl) thiophene, and 2-(p-chloro-phenyl)thiophene. Coupling in the /8-position has been used for the preparation of 1,3-dimethyl-4,5-benzisothionaphthene (148) from 2-amino-tt-(2,5-dimethyl-3-thienyl)cinnamic acid (149). A recent investigation describes the homolytic phenylation of 2- and 3-phenyl- 

The halogens of halothiophenes are more labile than those of the corresponding benzenes in accordance with theoretical considera-tions which indicate that thiophenes should also undergo nucleophilic substitutions more rapidly than benzenes. Hurd and Kreuz found that in qualitative experiments 3,5-dinitro-2-chlorothiophene was more reactive toward piperidine and methanolic potassium hydroxide than 2,4-dinitrochlorobenzene. A quantitative study on the reaction of the six isomeric bromonitrothiophenes with piperidine (Table V) shows that the thiophenes react about one thousand times 

Ckimpounds Rate constants of pseudo first order Relative rate 

Nucleophilic substitution has been used for the preparation of many thiophenes. For instance, 2-phenylthio-3,4-dinitro-5-piperidino-thiophene (155) has been prepared through stepwise reaction of (150) with different nucleophiles. Nitrothienols and derivatives of them have been obtained from halogenated nitrothiophenes. Allyl ethers have been prepared by the reaction of 5-chJoro-4-nitro-2-acetylthiophene, 3-nitro-2-chlorothiophene, and 2-nitro-3-bromothio- 

Halothiophenes, which are not activated through the presence of —I—M-substituents, undergo substitution smoothly under more forcing conditions with copper salts in pyridine or quinoline. Hence 3-cyanothiophene and 5-methyl-2-cyanothiophene have been obtained from the corresponding bromo compounds. 2-Bromothiophene reacts readily with aliphatic cuprous mercaptides in quinoline at 200°C to give thioethers in high yields. The use of the copper-catalyzed Williamson synthesis of alkoxythiophenes from iodo- or bromo-thiophenes and alcoholate has been mentioned before. The reaction of 2-bromothiophene with acetanilide in nitrobenzene in 

Alkyl radicals generated efficiently from allylsulfones in 80% aqueous formic acid induced a cyclization reaction on aromatic and heteroaromatic compounds to provide polycyclic aromatic and heteroaromatic derivatives (Eq. 7.17).  

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Other substitution reactions have been described with ketones, epoxides, anhydrides, acyl haUdes, amides, and imidates, among others (4). 

The general mechanistic framework outlined in this section must be elaborated by other details to fully describe the mechanisms of the individual electrophilic substitutions. The question of the identity of the active electrophile in each reaction is important. We have discussed the case of nitration, in which, under many circumstances, the electrophile is the nitronium ion. Similar questions arise in most of the other substitution reactions. 

The effects of substituents in the thiophene nucleus on the reactions discussed in the foregoing and on other substitution reactions will be given in Sections IV and V. The reactivity of the functional groups will be discussed in Section VI. 

It is thus apparent that the selectivity of a reagent toward thiophene and benzene can differ appreciably, and this difference in selectivity is also strongly noticeable in the proportions of 2- and 3-isomers formed. Although in certain reactions no 3-isomer has been detected, appreciable amounts have been found in other reactions. Thus 0.3% of the 3-isomer has been found in the chlorination of thiophene.- Earlier results indicated that 5-10% 3-nitrothiophene is formed in the nitration of thiophene and a recent gas-chromatographic analysis by Ostman shows that the mononitrothiophene fraction contains as much as 16% of the 3-isomer. It appears that gas-chromatographic analysis should be very useful for the detection of small amounts of 3-isomers in other substitution reactions. However, from routine analyses of IR spectra, it appears to the present author that the amount of 3-isomers formed in acylation, formylation, and bromina-tion of thiophene are certainly less than a few per cent. 

Further examples of electrophilic substitutions of thiopyrans at position 3 and 5 or at position 4 after deprotonation (83AHC145, Section V,G.) have been described in the last decade. Other substitution reactions are still rare. 

In the last two decades a number of phenomena found many years ago in azo coupling and other substitution reactions have been elucidated with regard to their structural and mechanistic basis. These include charge-transfer complex formation, radical pairs as transient intermediates, and changes in product ratios due to mixing effects — a phenomenon which was not understandable at all only a few years ago (see Secs. 12.8 and 12.9). 

Replacement of aromatic halogens with OAr groups (example 4, Table IX) seems to follow the same patterns already mentioned for other substitution reactions. 

Chemical synthesis can include chlorination, alkylation, nitration, and many other substitution reactions. Separation processes include filtration, decantation, extraction, and centrifugation. Recovery and purification are used to reclaim solvents or excess reactants as well as to purify intermediates and final products. Evaporation and distillation are common recovery and purification processes. Product finishing may involve blending, dilution, pelletizing, packaging, and canning. Examples of production facilities for three groups of pesticides foUow. 

Many boron hydrides, especially the higher boranes, undergo halogenation, alkylation and other substitution reactions when treated with electrophiles. Such reactions are catalyzed by acids, yielding a variety of stable products. 

In other substitution reactions, such as halogenation, the reactivity determinations are necessarily based on the quantitative analysis of product mixtures. The results can often be dubious, especially if individual site reactivities show a wide spread. Protodedeuteration is not subject to this limitation because the reactivities of individual positions are determined in separate experiments. 

Naphthalene also undergoes the other substitution reactions described for benzene. For example, it is acylated under standard Friedel-Crafts conditions ... 

The reaction chemistry of the 1,3,2-dioxastannolanes is vast and has been put to great use in various aspects of organic chemistry. Diorganotin derivatives of carbohydrates incorporate the dioxastannolane ring, and the structures of two such derivatives have already been commented on. The synthetic applications of intermediates of this type have been reviewed elsewhere (214-216) and are not discussed further. Substitution reactions have also proved useful synthetically, for example, in the formation of cyclic tetralactones [Eq. (52)] and urethanes (217-219), a subject which has also been reviewed (220). Two other substitution reactions using electrophilic carbon are shown in Eqs. (53) and (54), which typify several others of the same type (221,222). 

Other substitution reactions lead to more crystalline phases. Reaction of (4-aminopyridine)i/4FeOCl with methanol at 100 °C, for example, gives crystalline FeOOMe. Reactions with aliphatic and aromatic alkoxides and acids, of the type shown in equations (13) and (14), have also been studied. More rigid and longer molecules, such as 4-hydroxybenzoic acid, can crosslink the iron oxide layers. An initial intercalation step that causes an expansion of the FeOCl interlayer distance is followed by a second substitntion step leading to layer crosslinking. 

There is a marked contrast between zinc and cadmium in the context of complexing of the 2+ ions with bipy, studied by high-pressure stopped-flow. There is a striking difference between the two elements, with Zn + reacting progressively more slowly with bipy as pressure increases, Cd + more rapidly. The Activation Volume (Ay ) for the zinc reaction is -1-7.1 cm mol whereas for cadmium the value is -5.5 cm mol . These values suggest that the substitutions are 7d and 4 in character respectively. AT values for the reverse, dissociation, reaction and A " values for formation and for dissociation, are all consistent with this assignment of mechanism. Positive activation volumes for a few other substitution reactions at Zn +aq also indicate h mechanisms, as proposed many years ago in discussions of ultrasonic data on complex formation from Zn +aq. 

Measurements of optical rotations have been used to follow the course of other substitution reactions (5, 5, 8, 70, 72). The loss or retention of optical activity or inversion during a substitution process gives useful information concerning the mode of attack and the symmetry of intermediates or activated complexes. Studies of racemization and isomerization have led to elucidating the mechanism of stereochemical rearrangements in the fine work of Fay and Piper 20) with metal complexes of unsymmetrical 1,3-diketones. 

Other substitution reactions we ve seen include some of the reactions used for preparing alkyl halides from alcohols. We said in Section 10.7, for example, that alkyl halides can be prepared by treating alcohols with HX—reactions now recognizable as nucleophilic substitutions of halide on the protonated alcohols. Tertiary alcohols react by an S>jl pathway involving unimolecular dissociation of the protonated alcohol to yield a carbo-cation, whereas primary alcohols react by an 8 2 pathway involving direct bimolecular displacement of H2O from the protonated alcohol (Figure 11.23). 

The reaction between acetylacetone and copper(II) to form the mono complex is considerably slower than other substitution reactions of Cu(II). Pearson and Anderson [98] have discussed the system in terms of the following equilibria... 

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