Regioselectivity electrophilic substitution, monosubstituted

Chapter 15 described the use of this transformation in the preparation of monosubstituted benzenes. In this chapter we analyze the effect of such a first substituent on the reactivity and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifically, we shall see that substituents on benzene can be grouped into (1) activators (electron donors), which generally direct a second electrophilic attack to the ortho and para positions, and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such as the analgesics depicted on the previous page. 

A peculiar complex is formed by if coordination of Os(II) ammine complex to one of the double bonds of benzene rings, rather than rf coordination, and the coordinated benzene rings show interesting reactivity [82]. For example, Os(II) coordinates regioselectively to the 2,3-double bond of anisole to form the complex 333, and hence localization of the remaining 7r-electrons occurs. As a result, at 20 °C an electrophile attacks easily at C(4) due to electron-donation of the methoxy group. The 4H-cationic intermediate 334 is stabilized by backdonation from the metal, and the monosubstitution product 334 is formed without deprotonation. The / ara-substituted anisole 335 is... 

Regioselectivity in the formation of regioisomers is also observed in electrophilic aromatic substitution reactions. In the case of monosubstituted benzene derivatives, there are three possible regiosomeric products that form at different rates, based on the mechanism of the reaction (see Figure 13). see also Berzelius, Jons Jakob Chirality Dalton, John Davy, Humphry Molecular Structure Scheele, Carl Wohler, Friedrich. 

Thus, with electron-rich or electron-poor monosubstituted alkenes, the reaction with tri-fluoroacetonitrile oxide is more regioselective than with benzonitrile oxides. and the oxygen of the nitrile oxide adds to the substituted carbon. With other dipolarophiles, cyeloaddition is less regioselective. Competitive reactions include an electrophilic addition on the nitrile oxide, in particular with 1,1-disubstituted alkenes. and a further cyeloaddition which can occur when the dipolarophile is used in excess. ... 

Another methodology applied to the monosubstitution of diols is the use of copper complexation of dianions. The dianion is first formed by reaction of a diol with two equivalents of NaH. The copper complex is then formed by addition of a copper salt. Reaction of the copper complex with various electrophiles (alkyl halides, acyl chlorides) then gives the selectively protected products. As with the phase-transfer technique, very little disubstitution is observed. However, as illustrated in Scheme 3.16, the regioselectivity is reversed (i.e., 4,6-diols give mainly 4-substitution and 2,3-diols give mainly 3-substitution). Using this technique, both alkylations (benzylation, allylation) and acylations (acetylation, benzoylation, pivaloylation) have been carried out. As usual, the degree of selectivity depends on reaction conditions and structural factors [44]. 

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