Substitution, electrophilic multiple substituents

Effects of Multiple Substituents on Electrophilic Aromatic Substitution... 

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

In spite of the general ambiphilicity of phosphonio-substituted phosphoHde derivatives, the aromaticity of the phosphoHde ring [10, 11] tends to reduce their electrophilicity while the intramolecular compensation of the negative charge by the phosphonio-substituents lowers at the same time their nucle-ophilicity [15, 16]. Bis-phosphonio-benzophospholides and -1,2,4-diaza-phospholides are therefore less reactive towards electrophiles and nucleophiles than other types of phosphorus containing multiple-bond systems and lack the notorious hydrolytic instabihty of many of these species [15, 16, 24]. Reactions are observed, however, with sufficiently strong electrophiles such as triflic acid or methyl triflate, or nucleophiles such as OH" or lithium alkyls, respectively. 

A similar problem of complex formation may be encountered if either amino or phenol groups are present in the substrate, and the reaction may fail. Under such circumstances, these groups need to be blocked (protected) by making a suitable derivative. Nevertheless, Friedel-Crafts acylations tend to work very well and with good yields, uncomplicated by multiple acylations, since the acyl group introduced deactivates the ring towards further electrophilic substitution. This contrasts with Friedel-Crafts alkylations, where the alkyl substituents introduced activate the ring towards further substitution (see Section 8.4.3). 

The equimolar mixture of bromine trifluoride and bromine can be employed for the bro-mofluorination of fluorine-free alkcncs such as (Z)- and( )-l,2-dichloroethene, methyl acrylate and its a-substituted derivatives.1 The reactions are carried out in l,l,2-trichoro-l,2,2-tri-fluoroethane (CFC-113) using a 25-35 % excess of bromine trifluoridc/ bromine. The direction of the bromine monofluoride" addition to multiple bonds in the esters, much as in other electrophilic reactions, depends on the electronic nature of the substituent R. 

Apparently, the discrepancies detected for the substitution data are largely the consequence of a multiplicity of minor influences operative in the transition state. The deviations are sufficiently diverse in character to require the significance of additional influences on the stability of the transition state. Four other important factors are complexing of the substituent with the electrophilic reagent or catalyst, the involvement of 7r-complex character in the transition state for the reaction, rate effects originating in the rupture of carbon-hydrogen bonds, and differential solvation of the electron-deficient transition states. 

The substitution pattern of TfOH-mediated electrophilic aminomethylation of psoralens (furo-coumarins) by V-(hydroxymethyl)phthalimide has been elucidated <85JHC73>. Multiple phthal-imidoylated adducts were obtained when a B-ring hydroxy or methoxy activating group was present, and these resisted simple cleavage with NH2NH2. However, this two-step procedure to aminomethyl group introduction worked well when the psoralens contained only methyl substituents. 

Beyond the present applications of the electrophilicity index in organic chemistry, there are some others that are being considered in our group. For instance, based on the encouraging results that follow from the comparison between the electrophilicity index and the reaction rate coefficients, it is expected that quantitative comparisons between the electrophilcity index and the Hammett substituent constants may open the possibility of having new theoretically predicted a values that have not been yet experimentally determined. Consider for instance the case of multiple substitutions where the additivity rules may not apply. 

The electrophilic aromatic substitutions that we studied in Sections 15-9 and 15-10 can be stopped at the monosubstitution stage. Why do Friedel-Crafts alkylations have the problem of multiple electrophilic substimtion It is because the substituents differ in electronic structure (a subject discussed in more detail in Chapter 16). Bromination, nitration, and sulfonation introduce an electron-withdrawing group into the benzene ring, which renders the product less susceptible than the starting material to electrophilic attack. In contrast, an alkylated benzene is more electron rich than unsubstituted benzene and thus more susceptible to electrophilic attack. 

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