Nitrogen deactivation

Despite its V excessive character (340), thiazole, just as pyridine, is resistant to electrophilic substitution. In both cases the ring nitrogen deactivates the heterocyclic nucleus toward electrophilic attack. Moreover, most electrophilic substitutions, which are performed in acidic medium, involve the protonated form of thiazole or some quaternary thiazolium derivatives, whose reactivity toward electrophiles is still lower than that of the free base. 

The presence of the pyridine-like nitrogen deactivates the 1,3-azoles toward electrophilic attack, and increases their affinity towards nucleophilic attack. 

Hydrolysis of N205 on sulfuric acid represents a very efficient channel for nitrogen deactivation. Measurements using large 100-pm droplet trains [75,96] and submicron sulfuric acid aerosols [73,77] indicate high uptake probalilities (y = 0.1), without strong dependence on f SO, concentration or temperature. The data were fitted into an uptake model [96], Uptake coefficients over on water-ice (y = 0.02), SAT ((y = 0.006) and NAT (y= 0.0003) are much suppressed [86,90]. 

Oxazole, imidazole, and thiazole can be formally derived from furan, pyrrole, and thiophene respectively by replacement of a CH group by a nitrogen atom at the 3 position. The presence of this pyridine-like nitrogen deactivates the 1,3-azoles towards electrophilic attack and increases their susceptibility towards nucleophilic attack (see later). These 1,3-azoles can be viewed as hybrids between furan, pyrrole, or thiophene, and pyridine. 

Nitrogen deactivation effects of commercial feedstocks as reported by Jacob et al (14) was represented by an equation of the following form. 

Three features are evident from these results, (a) Nitrogen deactivates much more strongly in the azoles than in pyridine. This is the first indication of the phenomenon, and the reasons for it are not yet apparent, (b) Nitrogen deactivates much more strongly across the 2,3-bond compared to the 3,4-bond. This is expected because of bond fixation, and these results provide the first direct quantitative evidence, (c) Nitrogen deactivates more strongly between the 2,3-position compared to the 2,5-positions. This has been indicated by analyses given earlier in this chapter, and the present results provide the first direct quantitative confirmation. 

Comparison of the reactivity of the 1- and 3-positions in isoquinoline with those of the corresponding position in naphthalene shows that nitrogen deactivates much less strongly across the 2,3-bond than across the... 

The powder is released periodically to a gas-powder separation system (4). It is depressurized to a purge column (5) where moist nitrogen deactivates the catalyst and removes any remaining monomer. The monomer is concentrated and recovered. The powder is converted into a variety of pelletized resins (6) tailored for specific market applications. 

The homoljdic amination is of less use with heterocyclic than with homocyclic aromatic compounds because either the heteroccylic compounds are too deactivated (protonated heteroaromatic bases) or they are unstable in the strongly acidic medium usually required by the reaction. Thus, quinoline cannot be aminated because the protonated heterocyclic nitrogen deactivates both rings. In the... 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

The pyridine-like nitrogen of the 2H-pyrrol-2-yiidene unit tends to withdraw electrons from the conjugated system and deactivates it in reactions with electrophiles. The add-catalyzed condensations described above for pyrroles and dipyrromethanes therefore do not occur with dipyrromethenes. Vilsmeier formylation, for example, is only successful with pyrroles and dipyrromethanes but not with dipyrromethenes. 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

One reason for the low reactivity of pyridine is that its nitrogen atom because it IS more electronegative than a CH in benzene causes the rr electrons to be held more tightly and raises the activation energy for attack by an electrophile Another is that the nitrogen of pyridine is protonated in sulfuric acid and the resulting pyndinium ion is even more deactivated than pyndine itself... 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Phytofluene [540-05-6] M 549.0, b 140-185°(bath temp)/0.0001m A (Xmax) 1350 (348nm) in pet ether, X ax 331, 348, 267. Purified by chromatography on partially deactivated alumina [Kushwaha et al. J Biol Chem 245 4708 1970]. Stored as a soln in pet ether under nitrogen at -20°. 

Structures that incorporate the —N = CH— unit, such as pyridine, are rr-deflcient and are deactivated to electrophilic attack. Again, a resonance interpretation is evident. The nitrogen, being more electronegative than carbon, is a net acceptor of n electron density. 

For pyridine, the reactivity toward electrophilic substitution is 3 > 4, 2. The ring nitrogen acts as a strongly destabilizing internal electron-withdrawing substituent in the 2- and 4-intermediates. The nitrogen also deactivates the 3-position, but less so than the 2- and 4-positions. 

Lewis acid catalysts such as aluminum chloride and iron(III) halides also bond to nitrogen to strongly deactivate the ring toward Friedel-Crafts reactions and halogenation. 

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