Deactivation by amino substituents

On addition of methyllithium in tetrahydrofuran/diethyl ether, pyrido[3,4-r/]pyridazine gives a 1 1 mixture of the two isomeric 1,2- and 4,3-addition compounds, i.e. 1-methyl-1,2-dihydropy-rido[3,4-r/]pyridazine (10) and 4-methyl-3,4-dihydropyrido[3,4-<7]pyridazine (11), which are readily oxidized by air to yield the fully aromatic systems (see Section 7.2.1.5.1.3).6 129 If the pyridazine ring is deactivated by amino substituents as in l,4-dimorpholino-7-phenylpyri-do[3,4-r/ pyridazine or its 5-methyl derivative, addition of organometallics such as benzyllithi-um, benzylmagnesium chloride or rcrt-butylmagnesium bromide occurs at the pyridine ring and yields 5-alkyl-5-methyl-l,4-dimorpholino-7-phenyl-5,6-dihydropyrido[3,4-d]pyridazines 12.119... 

The change of the orientational control by amino substituents in acid media or on complex formation is obviously supported by the bromination of iV,i T-dimethylaniline in sulfuric acid containing silver sulfate, which produces 60% of 3-bromo- and 20% 4-bromo-iV,i T-dimethylaniline . This result, again seemed to suggest that the appreciable para product in acidic halogenation of aromatic amines may be due to an ion-pair mechanism or to partial dissociation to the free base . Yet the formation of para products in the presence of excess of strong Lewis or Bronsted acid with aniline, could hardly indicate the presence of free amine, and there is evidence that electrophilic bromine attack, at the meta as well as at the para positions, occurs on deactivated anilinium ions . 

Note Even when two halogeno substituents occupy the activated 2- and 3-positions, it is usually possible to achieve monoaminolysis under gentle conditions after replacing one such halogeno substituent, the other is substantially deactivated by the adjacent amino group and hence requires more severe conditions to bring about diaminolysis. 

X is NR R2. The substituent is converted to a Z substituent via the low-lying a orbital, and the ring is deactivated toward further electrophilic attack. The ortho and para channels lead to products. The interaction diagram for an X -substituted pentadienyl cation, substituted in the 1-, 2-, and 3-positions, as models of the transition states for the ortho, meta, and para channels, are too complex to draw simple conclusions. The HOMO and LUMO of the three pentadienyl cations with an amino substituent are shown in Figure 11.3. Notice that the LUMO of each is suitable to activate the C—H bond at the saturated site toward abstraction by the base. Curiously, the meta cation has the lowest LUMO and should most readily eliminate the proton. The stabilities of the transition states should be in the order of the Hiickel n energies. These are 6a — 8.7621/ , 6a — 8.499 / , and 6a — 8.718 / , respectively. Thus the ortho and para channels are favored over the meta channel, and the ortho route is slightly preferred over the para route. Experimentally, para substitution products are often the major ones in spite of there being two ortho pathways. The predominance of para products is usually attributed to steric effects. 

Aromatic fluorine bonds can be activated or deactivated by substituents on the ring. Experimental results show that the aromatic C-F bond is activated for reduction if there is an electron-withdrawing group (e. g., ester and carbonitrile groups) or electron-releasing groups (c.g., hydroxy and amino groups) ortho or para to the fluorine atom. Substituents in meta positions usually decrease the reactivity. 

Arylamines can be particnlarly nmeactive as nncleophiles and for these, the nse of fluorine or a snlfone as a leaving gronp, or paUadinm-assisted displacement (4.2.10) of bromine may be necessary. A 2-chlorine, deactivated by the presence of a 6-amino substituent, can be efficiently displaced by arylamines with trimethylsilyl chloride in bntanol. The displacements of fluorine, chlorine and butyl sulfone by anilines are greatly accelerated by carrying ont the reactions in 2,2,2-trifluoroethanol, with the addition of excess triflnoroacetic acid. ... 

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