Compounds heteroaromatic

The molecular ion peak of heteroaromatics and alkylated heteroaromatics is intense. Cleavage of the bond /3 to the ring, as in alkylbenzenes, is the general rule in pyridine, the position of substitution determines the ease of cleavage of the /3-bond (see below). 

Localizing the charge of the molecular ion on the heteroatom, rather than in the ring 7r structure, provides a satisfactory rationale for the observed mode of cleavage. The present treatment follows that used by Djerassi (Budzikiewicz et al., 1967). 

5 Benzyl Halides. The molecular ion peak of benzyl halides is usually detectable. The benzyl (or tropylium) ion from loss of the halide (rule 8, Sec- 

A similar cleavage is found in pyrazines since all ring substituents are necessarily ortho to one of the nitrogen atoms. 

Beynon, J. H. (1960). Mass Spectrometry and Its Application to Organic Chemistry. Amsterdam Elsevier. 

The molecular ion peak of heteroaromatics and alkylated heteroaromatics is intense. Cleavage of the bond 

The five-membered ring heteroaromatics (furan, thiophene, and pyrrole) show very similar ring cleavage patterns. The first step in each case is cleavage of the carbon-heteroatom bond. 

Many reduced heteroaromatic compounds are important and are dealt with in the General Chapters and appropriate Monograph Chapters, but usually more briefly than for the corresponding heteroaromatic systems because of this overall similarity with the corresponding acyclic compounds. 

Carbon-13 signals of parent heteroaromatic compounds [433-464] (Table 4.67) occur between 105 and 170 ppm. CNDO calculations performed for six-membered heteroaromatic compounds such as pyridine and azines [456, 458, 465] give a linear correlation between carbon-13 shift and total electron density at the individual carbon. The experimental slope, 160 ppm per electron, is the same as that found for monocyclic aromatic compounds (Section 4,11.1). The 13C shift values of pyrrole (107-117 ppm) and pyridine 

Increments for a larger number of substituents in various positions permit 13C shift predictions of pyrroles [435], thiazoles [437], indoles [445], and pyridines [452], Similarly to benzene, substituted carbon shifts essentially are related to substituent electronegativity, while ortho- and para-like carbons are predominantly affected by mesomeric (resonance) effects of donor (( — )-M) or acceptor substituents as shown for methoxy 

Indolizine Pyrrolo[2,3-]pyridine Pyrrolo[2,3-d]pyrimidine Purine 

The lone-pair electrons of bridgehead nitrogens in indolizine and its aza analogs [458] are delocalized, as concluded from carbon-13 shifts and in accordance with CNDO calculations All ring carbons of the parent indolizine except C-5 and C-9 (Table 4.67) are shielded (99-120 ppm) due to the (+ )-M electron releasing effect of the bridgehead nitrogen. 

Aromatic nitrogen heterocycles display considerable medium shifts (Section 3.1.4). Carbon-13 shifts of pyridine decrease in a but increase in [i and y position upon addition of water (Fig. 4.12). The dilution effect is explained in terms of intermolecular hydrogen bonding between pyridine and water [99]. 

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 

8-methoxyquinoline, however, the electron-releasing effect of the methoxyl counterbalances the electron-withdrawing effect of the heterocyclic nitrogen and the homolytic amination leads in high 5deld to only one of the 6 possible isomers (Table 3). Heteroaromatics activated towards electrophilic species, such as furan and pyrrole, are not suitable for homolytic amination owing to their low stability under the reaction conditions. Thiophene, however, has been aminated to 2-alkylamino derivatives 

Fragments m/z 39,50-53, 63-65,75-78, Often doubly charged fragment ions 

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In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

Diazo coupling involves the N exocyclic atom of the diazonium salt, which acts as an electrophilic center. The diazonium salts of thiazoles couple with a-naphthol (605). 2-nitroresorcinol (606), pyrocatechol (607-609), 2.6-dihydroxy 4-methyl-5-cyanopyridine (610). and other heteroaromatic compounds (404. 611) (Scheme 188). The rates of coupling between 2-diazothicizolium salts and 2-naphthol-3.6-disulfonic acid were measured spectrophotometrically and found to be slower than that of 2-diazopyridinium salts but faster than that of benzene diazonium salts (561 i. The bis-diazonium salt of bis(2-amino-4-methylthiazole) couples with /3-naphthol to give 333 (Scheme 189) (612). The products obtained from the diazo coupling are usuallv highly colored (234. 338. 339. 613-616). 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

A/-sulfonated ayiridines have also been used in Friedel-Crafts reactions (qv) (63). The successful C-alkylation of the heteroaromatic compounds indole (qv) [120-72-9] (64—66) and thiophene [110-02-1] (67) with a2itidines has also been reported ... 

Indole is a heteroaromatic compound consisting of a fused benzene and pyrrole ring, specifically ben2o[ ]pyrrole. The systematic name, IJT-indole (1) distinguishes it from the less stable tautomer 3JT-indole [271-26-1] (2). Iff-Indole [120-72-9] is also more stable than the isomeric ben2o[ ] pyrrole, which is called isoindole, (2H, (3) and IH (4)). A third isomer ben2o[i ]pyrrole is a stable compound called indoli2idine [274-40-8] (5). 

The classical structures of pyrrole, furan and thiophene (31) suggest that these compounds might show chemical reactions similar to those of amines, ethers and thioethers (32) respectively. On this basis, the initial attack of the electrophile would be expected to take place at the heteroatom and lead to products such as quaternary ammonium and oxonium salts, sulfoxides and sulfones. Products of this type from the heteroaromatic compounds under consideration are relatively rare. 

Pyrroles, furans and thiophenes undergo photoinduced alkylation with diarylalkenes provided that the alkene and the heteroaromatic compound have similar oxidation potentials, indicating that alkylation can occur by a non-ionic mechanism (Scheme 20) (81JA5570). 

The validity of the Hammett relationship log K/Ko = pa- has been extensively investigated for five-membered heteroaromatic compounds and their benzo analogues. The ratio Pheterocycie/Pbenzene is closest to Unity for thiophene. Judged from work on the polarographic reduction of nitro compounds, the ability to transmit electronic effects is HC=CH = S < O < NH. 

A quantitative study has been made on the effect of a methyl group in the 2-position of five-membered heteroaromatic compounds on the reactivity of position 5 in the formylation and trifluoroacetylation reaction. The order of sensitivity to the activating effect of the substituent is furan > tellurophene >selenophene = thiophene (77AHC(2l)ll9). 

Hetero[13]annulene, bis-dehydro-dimethylated structure, 7, 716 H etero[ 17]annulenes H NMR, 7, 719, 721 restricted structure, 7, 720 Heteroaromatic compounds reactions... 

Small shift values for CH or CHr protons may indicate cyclopropane units. Proton shifts distinguish between alkyne CH (generally Sh = 2.5 - 3.2), alkene CH (generally 4, = 4.5-6) and aro-matic/heteroaromatic CH (Sh = 6 - 9.5), and also between rr-electron-rich (pyrrole, fiiran, thiophene, 4/ = d - 7) and Tt-electron-deficient heteroaromatic compounds (pyridine, Sh= 7.5 - 9.5). 

In contrast to H shifts, C shifts cannot in general be used to distinguish between aromatic and heteroaromatic compounds on the one hand and alkenes on the other (Table 2.2). Cyclopropane carbon atoms stand out, however, by showing particularly small shifts in both the C and the H NMR spectra. By analogy with their proton resonances, the C chemical shifts of k electron-deficient heteroaromatics (pyridine type) are larger than those of k electron-rieh heteroaromatic rings (pyrrole type). 

Substituent effects (substituent increments) tabulated in more detail in the literature demonstrate that C chemical shifts of individual carbon nuclei in alkenes and aromatic as well as heteroaromatic compounds can be predicted approximately by means of mesomeric effects (resonance effects). Thus, an electron donor substituent D [D = OC//j, SC//j, N(C//j)2] attached to a C=C double bond shields the (l-C atom and the -proton (+M effect, smaller shift), whereas the a-position is deshielded (larger shift) as a result of substituent electronegativity (-/ effect). 

Structure elucidation does not necessarily require the complete analysis of all multiplets in complicated spectra. If the coupling constants are known, the characteristic fine structure of the single multiplet almost always leads to identification of a molecular fragment and, in the case of alkenes and aromatic or heteroaromatic compounds, it may even lead to the elucidation of the complete substitution pattern. 

Table 2.5. Typical HH coupling constants (Hz) of aromatic and heteroaromatic compounds...

In the case of alkenes and aromatic and heteroaromatic compounds, analysis of a single multiplet will often clarify the complete substitution pattern. A few examples will illustrate the procedure. 

In the chemical shift range for alkenes and aromatic and heteroaromatic compounds enol ether fragments (furan, pyrone, isoflavone, 195-200 Hz) ... 

The heteroaromatic compounds can be divided into two broad groups, called n-excessive and n-deficient, depending on whether the heteroatom acts as an electron donor or an electron acceptor. Furan, pyrrole, thiophene, and other heterocyclics incorporating an oxygen, nitrogen, or sulfur atom that contributes two n electrons are in the rr-exeessive group. This classification is suggested by resonance structures and confirmed by various MO methods. ... 

Scheme 10.3. Activation Hardness for Aromatic and Heteroaromatic Compounds ...

The regioseleciivicy of Fnedel-Crafts-lypc acylations on heteroaromatic compounds has been studied intensively [57 58, 59] In the case of pyrroles, the orientation of the entering acyl group strongly depends on the bulkiness of the group at the nitrogen atom (equation 29)... 

Silver(I) triflate is widely applied to the preparation of various derivatives of triflic acid, both covalent esters [66] and ionic salts For example, it can be used for the in situ generation of iodine([) triflate, a very effective lodinatmg reagent for aromatic and heteroaromatic compounds [130] (equations 65 and 66)... 

General accounts of prototropic tautomerism have been presented by Ingold and Baker" these include an outline of the historical development of the subject in which heteroaromatic compounds are discussed incidentally, and, therefore, such a historical account will not be given here. Of historical interest are Eistert s book on tautomerism and mesomerism which was published in 1938, a review on — NH-CO— tautomerism by Arndt and Eistert published in 1938, and Heller s account of heterocyclic tautomerism which appeared in 1925. Although more recent works on heterocyclic chemistry (e.g., references 9-11) have dealt incidentally with tautomerism, no unified... 

Bromine titration has been applied to several heteroaromatic compounds, but it is not a reliable method. The assumption is often made that oxo structures react very slowly with bromine whereas the hydroxy forms react rapidly. Thus, 3,4-diphenylisoxazol-5-one when freshly dissolved in ethanol was found to react with 0.5 mole of bromine, but after standing it reacted with almost 1 mole. These observations led to the conclusion that the solid was in the CH... 

In the second method, which can be applied to compounds with an optically active center near the potentially tautomeric portion of the molecule, the effect of the isomerization on the optical activity is measured. In favorable cases both the rate of racemization and the equilibrium position can be determined. This method has been used extensively to study the isomerization of sugars and their derivatives (cf. reference 75). It has not been used much to study heteroaromatic compounds, although the very fact that certain compounds have been obtained optically active determines their tautomeric form. For example, oxazol-5-ones have thus been shown to exist in the CH form (see Volume 2, Section II,D,1, of article IV by Katritzky and Lagowski). 

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