Multiple substitution reactions

Multiple substitution reactions are commonly encountered in industrial practice. They may be represented in general form as ... 

Illustration 9.4 indicates how the concepts we have developed may be used in attempting to develop a rational reactor design for carrying out multiple substitution reactions. 

Good yields of the desired product can be obtained only when k1 > k2. Among the industrially significant reactions of this type are those involving partial oxidation and multiple substitution. Reactions represented by equation 12.3.136 were discussed in detail in Section 9.2, and that material is also pertinent here. 

While the approaches utilizing pyridine derivates often appeared promising on paper, in reality, multiple substitution reactions, complex chemistries, and several important compromises were generally required to install the desired C2-, C3-, C4-, and C5-tetra-substitution pattern and furnish an appropriately functionalized 6-azaindole. A closer look at the electronic pattern for a typical pyridine ring revealed that the C3 and C5 positions are the most difficult to... 

Scheme 13 Flexible tripodal ligand TCPSB, used for studying multiple substitution reactions at the metal centers. (Reproduced with permission from Ref 83. Copyright 2011 American Chemical Society.)...

More elaborate approaches make use of multiple substitutions to generate additional information. Consider a reaction in which substitutions can be made at two sites, X and y, so that the observed response is a function of both substituents, f x,y). Expanding this in a Taylor s series gives... 

Copper-mediated Addition and Substitution Reactions of Extended Multiple Bond Systems... 

The second of the resonance structures is the source of the radical reactivity displayed during oxidation and the Mn(III) in this structure must be low-spin to preserve multiplicity. Substitution at the meso-position could provide steric hindrance to analogous decompositions and reactions of the Mn(IV) complexes of ethyl- and benzylmalonic acids, and a conventional one-equivalent oxidation step becomes dominant. 

There are innumerable industrially significant reactions that involve the formation of a stable intermediate product that is capable of subsequent reaction to form yet another stable product. These include condensation polymerization reactions, partial oxidation reactions, and reactions in which it is possible to effect multiple substitutions of a particular functional group on the parent species. If an intermediate is the desired product, commercial reactors should be designed to optimize the production of this species. This section is devoted to a discussion of this and related topics for reaction systems in which the reactions may be considered as sequential or consecutive in character. 

We are now prepared to develop quantitative relations for series-parallel reactions of the multiple substitution type considered above. 

At first the reactions of monochlorosilanes and siloxanes with lithium trimethylsilanolate, lithium phenyldimethylsilanolate, and lithium isopropylate were followed by gaschromatography, H NMR spectroscopy, and by nephelometric measurements [3,4]. Di- and trichlorosilanes and -siloxanes were then investigated in order to study the influence of strongly electron attracting substituents at the reaction centre [5], To prevent multiple substitution lithium ferr-butylate was used as the nucleophile for these compounds. All reactions gave high yields of products and no by-products were formed. 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

Another series of nuclear substitution reactions of kojic acid might be represented as the addition of kojic acid to reactive multiple bonds, follow-... 

A final example concerns the question to what extent a multiple series of ligand substitution reactions can lead to the irreversible exchange of two metal centers. The system studied in our laboratories involved the exchange of Mn and Cr in the series of reactions shown in Scheme 3 (93). 

Nucleophilic substitution reactions of sulfinate ions 106 Addition of sulfinate ions to multiple bonds 108 Radical reactions of sulfinic acids 110... 

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