Heteroatom, orientation

The bicyclic 5-5 heterocycles with 1 2-heteroatom orientation cover a range of known topological types the parent aromatic heterocycles for which derivatives are currently known are shown in Figure 1. The chemistry of the heterocycles covered in this chapter is exceptionally diverse and various aspects were discussed in CHEC(1984)... 

Figure 1 Known bicyclic 5-5 heterocycles with 1 2-heteroatom orientation I stituted parent is known).

Nothing has been reported about the relationship between the thermodynamic aspects of the bicyclic 5-5 heterocycles with l 2-heteroatom orientation and their physicochemical properties (bp, mp, volatility, chromatographic behavior). 

Since their introduction by Huisgen (see <1995H(40)1> and references therein), the 1,3-dipolar cycloaddition remains the single most powerful method for the construction of five-membered heterocycles. Literature examples of this approach in an inter- and intramolecular fashion for the assembly of nonconjugated examples of bicyclic 5-5 heterocycles with l 2-heteroatom orientation are common. Heterocycles with either [1,2,4], [1,2,5], or [1,2,6] heteroatom locants (204, 205, and 206, respectively) can be assembled utilizing this approach. The stereoelectronic aspects of the various cycloaddition strategies are not discussed here. 

Peri-annelated heterocyclic systems 411 with the inverse heteroatom orientation are formed on heating anthraquinone-1 -carboxylic acid 410 in aqueous solution of hydroxylamine hydrochloride (64MI1). 

Separation of the oxygen atoms by three or four carbon atoms diminishes the concentration of donor groups within the macrocycle and also introduces potential conformational difficulties. The propylenedioxy residue, —OCH2CH2CH2O—, can assume several different conformations. In order for the two oxygen atoms to be focused on a cation, the propylene unit must assume a halfchair arrangement (Figure 2). Likewise, when four methylenes are present, an unfavorable, eclipsed conformation is required to achieve the same heteroatom orientation. 

Chelation itself is sometimes useful in directing the course of synthesis. This is called the template effect (37). The presence of a suitable metal ion facihtates the preparation of the crown ethers, porphyrins, and similar heteroatom macrocycHc compounds. Coordination of the heteroatoms about the metal orients the end groups of the reactants for ring closure. The product is the chelate from which the metal may be removed by a suitable method. In other catalytic effects, reactive centers may be brought into close proximity, charge or bond strain effects may be created, or electron transfers may be made possible. 

A positively charged heteroatom can be balanced by a negatively charged substituent, and if they are oriented favourably relative to each other the charges may formally cancel. Thus, the 2- and 4-pyridone structures (26, 27 X = NH) and the corresponding pyrones... 

Orientation in azole rings containing three or four heteroatoms Effect of azole ring structure and of substituents Proton acids on neutral azoles basicity of azoles Proton acids on azole anions acidity of azoles Metal ions... 

Orientation in azole rings contqining three or four heteroatoms... 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

Neutral azoles are readily C-lithiated by K-butyllithium provided they do not contain a free NH group (Table 6). Derivatives with two heteroatoms in the 1,3-orientation undergo lithiation preferentially at the 2-position other compounds are lithiated at the 5-position. Attempted metallation of isoxazoles usually causes ring opening via proton loss at the 3-or 5-position (Section 4.02.2.1.7.5) however, if both of these positions are substituted, normal lithiation occurs at the 4-position (Scheme 21). 

The incorporation of heteroatoms can result in stereoelectronic effects that have a pronounced effect on conformation and, ultimately, on reactivity. It is known from numerous examples in carbohydrate chemistry that pyranose sugars substituted with an electron-withdrawing group such as halogen or alkoxy at C-1 are often more stable when the substituent has an axial, rather than an equatorial, orientation. This tendency is not limited to carbohydrates but carries over to simpler ring systems such as 2-substituted tetrahydropyrans. The phenomenon is known as the anomeric ect, because it involves a substituent at the anomeric position in carbohydrate pyranose rings. Scheme 3.1 lists... 

A further complication arises out of the fact that of all the orientations discussed only one, 5-R-3-Y, does not involve a vicinal relationship between at least two of the three structural features—substituent, side-chain, and heteroatom. In the cases of 4-R- and 5-R-2-Y the problem of vicinal relations appears not too serious, since this relation is equivalent to the problem of the constant ortho substituent. For this situation it was shown that the constant ort u) substituent, i.e., in this case the heteroatom, may make a contribution to the substituent-independent term (logA °) but generally leaves the reaction constant (p) unaffected. Where the substituent, however, is alpha to the heteroatom it appears likely that its electronic structure, and hence its <7-values, may be substantially affected. This appears particularly likely for large substituents and especially for those which can form a hydrogen bond with the heteroatom, such as CO OH. 

The relative orientation of the substituent and the side-chain— in terms of the benzene ortho, meta, para scheme—is an added complication. Following the practice first established by Hammett in treating the furoic acids, it is customary to treat the heteroatom QNH, S, O) as if it had replaced a vinyl group (—CH=CH—) in benzene. Thus, the 4-R-2-Y and 5-R-3-Y relationships become meta, and 5-R-2-Y becomes para. 

For hydroxy- and mercaptoazoles, hydroxy-oxo and thiol-thione tautomeric equilibria depend strongly on the orientation of the substituents and heteroatoms. Most 2- and 5-hydroxy(mercapto)azoles exist mainly as 0X0 (thione) tautomers, but the corresponding 3- and 4-isomers often prefer the hydroxy (mdrcapto) forms. 

Alkylvinylacetylenes react with 1,3-dipoles exclusively across the terminal unsubstituted bond, whether it is a double or triple bond (80UK1801). 1-Heteroalk-1-en-3-ynes behave quite differently in these reactions. Orientation is largely determined by the nature of heteroatom. 

It is difficult to treat the effect of a heteroatom on the localization energies of aromatic systems, but Brown has derived molecular orbital parameters from which he has shown that the rates of attack of the phenyl radical at the three positions of pyridine relatively to benzene agree within 10% with the experimental results. He and his co-workers have shown that the formation of 1-bromoisoquinoline on free-radical bromination of isoquinoline is in agreement with predictions from localization energies for physically reasonable values of the Coulomb parameters, but the observed orientation of the phcnylation of quinoline cannot be correlated with localization ener-... 

An alternative method of studying the molecular motions of a polymeric chain is to measure the complex permitivity of the sample, mounted as dielectric of a capacitor and subjected to a sinusoidal voltage, which produces polarization of the sample macromolecules. The storage and loss factor of the complex permitivity are related to the dipolar orientations and the corresponding motional processes. The application of the dielectric thermal analysis (DETA) is obviously limited to macromolecules possessing heteroatomic dipoles but, on the other hand, it allows a range of frequency measurement much wider than DMTA and its theoretical foundations are better established. 

The substitution of a heteroatom for an a-sulfoxy methylene group substantially increases the preference for an axial orientation of the sulfoxide oxygen320, despite the smaller space requirement of the sulfur with its lone pairs, compared to that of a methylene group321, at least in the case of 1,3-dithiolane oxides. The substituting heteroatom, therefore, should decrease the conformation stability (i.e. lower the barrier to chair-chair interconversion). 

Second-row heteroatoms are known to show a substantial anomeric effect. There appears to be evidence for a reverse anomeric effect in 2-aminotetrahydro-pyrans. ° It has been called into question whether a reverse anomeric effect exists at all. ° In 94, the lone-pair electrons assume an axial conformation and there is an anomeric effect. In 95, however, the lone-pair electron orbitals are oriented gauche to both the axial and equatorial oc-CH bond and there is no anomeric effect. ... 

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