Electrophilic substitution reactions,

III. Reactivity of the Selenazole Ring 1. Electrophilic Substitution Reactions... 

The most widely studied electrophilic substitution reactions are haloge-nation and nitration. Two main types of substrates are possible alkyl-thiazoles and arylthiazoles. 

All the halogenothiazoles, depending on the electron-withdrawing power of the halosubstituent, together with the electron-withdrawing power of the azasubstituent, are only slightly susceptible to electrophilic substitution reactions such as nitration, sulfonation, and so on, while the polyhalogenatjon reaction can take place. 

The 2-nitrothiazole can be reduced to the corresponding aminothiazole by catalytic or chemical reduction (82, 85, 89). The 5-nitrothiazole can also be reduced with low yield to impure 5-aminothiazole (1, 85). All electrophilic substitution reactions are largely inhibited by the presence of the nitro substituent. Nevertheless, the nitration of 2-nitrothiazoIe to 2,4-dinitrothiazole can be accomplished (see Section IV). 

Reactions of the Aromatic Ring. The reactions of the aromatic ring of the Cg aromatic isomers are generally electrophilic substitution reactions. All of... 

Reactions. The CF O— group exerts predominant para orientation in electrophilic substitution reactions such as nitration, halogenation, acylation, and alkylation (350). 

Iron Porphyrins. Porphyrias (15—17) are aromatic cycHc compouads that coasist of four pyrrole units linked at the a-positions by methine carbons. The extended TT-systems of these compounds give rise to intense absorption bands in the uv/vis region of the spectmm. The most intense absorption, which is called the Soret band, falls neat 400 nm and has 10. The TT-system is also responsible for the notable ring current effect observed in H-nmr spectra, the preference for planar conformations, the prevalence of electrophilic substitution reactions, and the redox chemistry of these compounds. Porphyrins obtained from natural sources have a variety of peripheral substituents and substitution patterns. Two important types of synthetic porphyrins are the meso-tetraaryl porphyrins, such as 5,10,15,20-tetraphenylporphine [917-23-7] (H2(TPP)) (7) and P-octaalkylporphyrins, such as 2,3,7,8,12,13,17,18-octaethylporphine [2683-82-1] (H2(OEP)) (8). Both types can be prepared by condensation of pyrroles and aldehydes (qv). 

The earliest reported reference describing the synthesis of phenylene sulfide stmctures is that of Friedel and Crafts in 1888 (6). The electrophilic reactions studied were based on reactions of benzene and various sulfur sources. These electrophilic substitution reactions were characterized by low yields (50—80%) of rather poorly characterized products by the standards of 1990s. Products contained many by-products, such as thianthrene. Results of self-condensation of thiophenol, catalyzed by aluminum chloride and sulfuric acid (7), were analogous to those of Friedel and Crafts. 

Electrophilic substitution reactions of diarylamines are easily accompHshed since the amino group activates the aromatic ring. Thus, DPA reacts with bromine or chlorine to form the 2,2H,4 tetrahalo derivative nitration usually produces the trinitro compound. 

The aromatic nature of lignin contrasts with the aliphatic stmcture of the carbohydrates and permits the selective use of electrophilic substitution reactions, eg, chlorination, sulfonation, or nitration. A portion of the phenoUc hydroxyl units, which are estimated to comprise 30 wt % of softwood lignin, are unsubstituted. In alkaline systems the ionized hydroxyl group is highly susceptible to oxidative reactions. 

Reactions. In general, isoquiaoline undergoes electrophilic substitution reactions at the 5-position and nucleophilic reactions at the 1-position. Nitration with mixed acids produces a 9 1 mixture of 5-nitroisoquiaoline [607-32-9] and 8-nitroisoquinoline [7473-12-3]. The ratio changes slightiy with temperature (143,144). Sulfonation of isoquiaoline gives a mixture with 5-isoquiaolinesulfonic acid [27655-40-9] as the principal product. 

Electrophilic substitution reactions of unsubstituted quinoxaline or phenazine are unusual however, in view of the increased resonance possibilities in the transition states leading to the products one would predict that electrophilic substitution should be more facile than with pyrazine itself (c/. the relationship between pyridine and quinoline). In the case of quinoxaline, electron localization calculations (57JCS2521) indicate the highest electron density at positions 5 and 8 and substitution would be expected to occur at these positions. Nitration is only effected under forcing conditions, e.g. with concentrated nitric acid and oleum at 90 °C for 24 hours a 1.5% yield of 5-nitroquinoxaline (19) is obtained. The major product is 5,6-dinitroquinoxaline (20), formed in 24% yield. 

Quantitative data are available on the effect on electrophilic substitution reactions of the fusion of a benzene ring to the b face of a furan or thiophene ring. The overall effect is to decrease reactivity this decrease is much more pronounced in the case of fusion to a furan than to a thiophene ring. As a consequence the overall reactivities of benzo[Z)]furan and benzo[Z)]thiophene are approximately equal 71AHC(13)235). 

In view of the overall increased reactivity of furan compared with thiophene it would be anticipated that furan would be less regioselective in its reactions with electrophiles than thiophene. Possible reasons for the high regioselectivity of furan in electrophilic substitution reactions include complex formation between substrates and reagents and the ability of heteroatoms to assist in the stabilization of cationic intermediates (80CHE1195). 

It is also of significance that in the dilute gas phase, where the intrinsic orientating properties of pyrrole can be examined without the complication of variable phenomena such as solvation, ion-pairing and catalyst attendant on electrophilic substitution reactions in solution, preferential /3-attack on pyrrole occurs. In gas phase t-butylation, the relative order of reactivity at /3-carbon, a-carbon and nitrogen is 10.3 3.0 1.0 (81CC1177). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the... 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

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). 

In an attempt to protect thiophenols during electrophilic substitution reactions on the aromatic ring, the three substituted thioethers were prepared. After acetylation... 

An 5-l-/w-nitrophenyl-2-benzoylethyl thioether was used to protect thiophenols -during electrophilic substitution reactions of the benzene ring. ... 

The relationships between substituents and the typical electrophilic substitution reactions, such as those listed in Scheme 10.1, can be summarized as follows ... 

There is another important factor in the low reactivity of pyridine derivatives toward electrophilic substitution. The —N=CH— unit is basic because the electron pair on nitrogen is not part of the aromatic n system. The nitrogen is protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions. The formal positive charge present at nitrogen in such species further reduces the reactivity toward electrophiles. 

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

Fluorocylatwn of enarnines and enamides has been intensively studied by different groups [78, 79, 80 SI] The effectiveness of this particular electrophilic substitution reaction becomes obvious when the nitrogen atom of the enamine moiety is engaged in an aromatic system [82 S3] or when the olefinic system is part of an aromatic nucleus [84] (equations 37 and 38) A further extension of this reaction is demonstrated by the tnfluoracetylation of aldehyde dialkyl hydrazones [S5 86] (equation 39)... 

Other typical electrophilic aromatic substitution reactions—nitration (second entr-y), sul-fonation (fourth entry), and Friedel-Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo electrophilic substitution reactions that are limited to only the most active aromatic compounds these include nitrosation (third entry) and coupling with diazonium salts (seventh entry). 

Equation (7-85) is a selectivity-reactivity relationship, with lower values of Sf denoting lower selectivity. Lower values ofpt correspond to greater reactivity, with the limit being a partial rate factor of unity for an infinitely reactive electrophile. This selectivity-reactivity relationship is followed for the electrophilic substitution reactions of many substituted benzenes, although toluene is the best studied of these. 

In an attempt to protect thiophenols during electrophilic substitution reactions on the aromatic ring, the three substituted thioethers were prepared. After acetylation of the aromatic ring (with moderate yields), the protective group was converted to the disulfide in moderate yields, 50-60%, by oxidation with hydrogen peroxide/boiling mineral acid, nitric acid, or acidic potassium permanganate. ... 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

---