O- and S-substituted

A strictly dehned region of chemical shifts of C2, C4, and C5 atoms in A-oxides of 4A-imidazoles allows to dehne clearly the position of the A-oxide oxygen atom (102). Chemical shifts of the a-C nitrone group in a-N-, O-, and S-substituted nitrones are located in the region of 137 to 150 ppm (388, 413). On the basis of 13C NMR analysis of 3-imidazoline-3-oxide derivatives, the position of tautomeric equilibria in amino-, hydroxy-, and mercapto- nitrones has been estimated. It is shown that tautomeric equilibria in OH- and SH-derivatives are shifted toward the oxo and thioxo forms (approximately 95%), while amino derivatives remain as amino nitrones (413). In the compounds with an intracyclic amino group, an aminonitrone (A) - A-hydroxyaminoimino (B) tautomeric equilibrium was observed (Scheme 2.76), depending on both, the nature of the solvent and the character of the substituent in position 2 of the heterocycle (414). 

An ytterbium binaphthol catalyst was successfully applied in the cycloaddition reactions of 3-carbomethoxy-2-pyrone (454) with O- and S-substituted olefins like 455 and 280d. Upon heating, the products lost carbon dioxide to yield chiral cyclohexadienes 456 (equation 136). S-substituted olefins generally gave higher ee values than the corresponding 0-substituted ones. 

The mono-thio, -seleno and -telluro analogues of phosphonic and phosphinic acids are tautomeric (equations 1, 2 and 4). In the case of the sulphur-containing compounds, an attempt has been made to estimate the equilibrium compositions of a variety of acids by means of physicochemical measurements. The alkali metal salts of phosphonothioate and phosphinothioate acids possess anions which are mesomeric and, theoretically, it is possible for such ions to act as sources of both O-and S-substituted products. The same products can be obtained through reactions between the free acids and diazoalkanes, and because these reactions are relatively fast, it might be expected that the composition of the product mixtures might be a reflection of the tautomer composition of the acids. 

During continuous research efforts, Fu designed and synthesized new tertiary phosphines of type 14 that made it feasible to develop catalytic diastereo-and enantioselective [3-t2] cycloadditions of racemic, ysubstituted allenoates and allenamides with functionalized electron-deficient olefins, thus providing stereoconvergent processes to access structurally and stereochemically diverse cyclopentenes with heteroatom (N, P, O, and S)-substituted quaternary stereocenters (Scheme 7.26) [45]. 

Since such heavy metals contain many more electrons than the light atoms, H, N, C, O, and S, of the protein, they scatter x-rays more strongly. All diffracted beams would therefore increase in intensity after heavy-metal substitution if all interference were positive. In fact, however, some interference is negative consequently, following heavy-metal substitution, some spots measurably increase in intensity, others decrease, and many show no detectable difference. 

A kinetic study of the nucleophilic substitution of Cl in [FeCp(PhCl)]+ BF by these different N-, O-, and S-anionic nucleophiles was performed using the titration of displaced Cl- by AgN03. The reactivity order increases according to the sequence ... 

The [2 + 2] photodimerization of a, j8-unsaturated sulfones is correctly viewed as a photoreaction of alkenes, rather than the sulfone group, and this aspect has been reviewed recently by Reid, as part of a wider survey of the photoreaction of O- and S-heterocycles. The topic continues to attract considerable interest and a few recent examples, as well as some synthetic applications, will be discussed here. Much of the photodimerization work has been carried out on the benzo[fc]thiophene (thianaphthene) 1,1-dioxide system. For example. Porter and coworkers have shown that both 3-carboxybenzo[i]thiophene 1,1-dioxide (65) and its methyl ester give only the head-to-head (hth), anti dimer (66) on irradiation in ethanol. In a rather unusual finding for such systems, the same dimer was obtained on thermal dimerization of 65. Similar findings for a much wider variety of 3-substituted benzo[fi]thiophene 1,1-dioxides have been reported more recently by Geneste and coworkers . In the 2-substituted analogs, the hth dimer is accompanied by some of the head-to-tail (htt), anti dimer. The formation of the major dimer appears to proceed by way of an excited triplet and the regiochemistry observed is in accord with frontier MO theory. 

Fig. 37.3. Principal components biplot showing the positions of 6 substituted oxazepine (O) and 6 substituted thiazepine (S) neuroleptics with respect to three physicochemical parameters and two biological activities [41,43]. The data are shown in Table 37.6. The thiazepine analogs are represented by means of filled symbols. The horizontal and vertical components represent 50 and 39%, respectively, of the variance in the data.

The development of the chemistry of carbene complexes of the Group 8a metals, Ru, Os, and Ir, parallels chemistry realized initially with transition metals from Groups 6 and 7. The pioneering studies of E. O. Fischer and co-workers have led to the characterization of many hundreds of carbene complexes in which the heteroatoms N, O, and S are bonded to the carbene carbon atoms. The first carbene ligands coordinated to Ru, Os, and Ir centers also contained substituents based on these heteroatoms, and in this section the preparation and properties of N-, O-, S-, and Se-substituted carbene complexes of these metals are detailed. 

Halide displacement from the carbene ligands of Ru, Os, and Ir halocarbene complexes by N-, O-, and S-based nucleophiles frequently leads to the formation of new heteroatom-substituted carbene complexes. This important class of reactivity will be discussed in more detail in Section V,D, but it is appropriate here to illustrate the scope of this method with several examples ... 

The most widely used method for the preparation of [l,2,4]triazolo[3,4-A][l,3,4]thiadiazoles 85 employs 4-amino-5-thio-4/7-[l,2,4]triazoles 83 or 4-amino[l,2,4]-triazole-5(47T)-thiones 84 as starting materials. The reaction of the triazoles 83 or 84 with carbonic acid derivatives furnishes [l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles with a heteroatom substituent (N, O, S) at position 6 the O- and S-functions are formulated as 6-hydroxy and 6-thio derivatives 85a or as thiadiazol-(5/7)6-ones and -thiadiazole-(577)6-thiones 85b, respectively reaction with carboxylic acid derivatives provides the 6-substituted-[l,2,4]triazolo[3,4-4][l,3,4]-thiadiazoles 85c (Equation 20 Table 3). 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

Harger has studied the rearrangement of A-substituted N-phosphinoylhydroxylamines in the presence of base . He proposed a concerted mechanism based on the observed retention of the configuration at the phosphorous center during the transposition , and on studies with 0-labelled compounds . Similar cyclic transition states 572 were proposed in the base-induced rearrangement of A,0-bis(diphenylphosphinoyl)hydroxylamines (571) (equation 254). However, in the rearrangement of O-benzoyl-A-(diphenylphosphino-thiol)hydroxylamine where a transposition of O and S atoms occurs, the proposed cyclic transition state has sulfur participation . 

Some of these N-, O-, and S-atom-functionalized polycyclic aromatic compounds (PACs) are powerful bacterial mutagens and animal, and possible human, carcinogens, e.g., the exocyclic nitro-substituted PAH 1-nitropyrene, VI, which is a primary pollutant in diesel exhaust (IARC, 1989). The endocyclic heterocyclic PAC dibcnz[fl,/ ]acridine, VII, is also classified as a possible human carcinogen (IARC, 1987 see Sections B and C). 

Substitutive nomenclature is employed for exo-cyclic N-PACs (and the O- and S-PACs). Functional groups such as amino (-NH2), cyano (- C=N), nitro (-NOz), and hydroxyl (-OH) are attached as prefixes to the parent PAH, e.g., 1-nitropyrene, VI. 

The study of the monoanions of a third class of phosphorus-containing monoesters, the phosphoramidates, has been restricted for the present to p- and o-substituted aryl phosphoramidates, and phosphoramidate and its O-methyl derivatives13-16. Two striking differences from the behavior of O- and S-phos-phate monoester monoanions are noted in the experimental criteria compiled in order to postulate mechanism (a) solvolysis in mixed organic solvents, particularly 50% v/v dioxan-water, results in a 50% decrease in the rate of hydrolysis of o- and p-substituted aryl phosphoramidate monoanions and all ionic forms of phosphoramidate and its O-methyl derivatives excepting the parent monoanion, and (b) partitioning of the aryl phosphoramidates and phos-... 

The formation of a large variety of bis chelates with selenosalicylaldimines containing bulky N-substituents has been reported.215 The bivalent Co and Zn complexes are believed to be tetrahedral, whereas the Ni chelates are cis planar. A kinetic study of the enantiomerization of the tetrahedral Zn11, Cd11 and Pb11 bis chelates of an isopropyl-substituted form, and its O and S analogues, showed the values for the reactions to be affected by both choice of metal and O, S or Se donor atom.216... 

The first stage (addition-elimination) is well known with CN and a variety of N-, O- and S-nucleo-philes.7-72-75 The detachment of the product arene from the Fe is more difficult. The conversions in equation (22) demonstrate the stability of the arene-Fe bond toward oxidation, as a side chain methyl is converted to a carboxylic acid, and suggest the generality of heteroatom substitution under mild conditions.76... 

Jochims and co-workers438 synthesized l-oxa-3-azabutatrienium and l-thia-3-azabutatrienium chloroantimonates [Eq. (4.132)]. X-ray structure analysis of the phenyl-4-bromophenyl-substituted derivatives shows bent structures (C = N = C angles for X = O and S, respectively, are 129° and 139°). Bond distances indicate that all possible mesomeric structures contribute to the structure of the O analog. In contrast, the mesomeric form with a C=S+ moiety appears to be less important. 13C NMR data suggest a certain delocalization of the positive charge into the aromatic rings. 

In Eq. (3) [S]o and [S]f are starting and ending substrate concentrations. S approaches [S] when substrate consumption is minimal, and S is substituted for [S] to correct for excess substrate consumption. In these analyses, however, substrate inhibition can be a problem if the product has a similar affinity to the substrate. Fortunately, most P450 oxidations produce products that are less hydrophobic than the substrates, resulting in lower affinities to the enzymes. There are exceptions, including desaturation reactions that produce alkenes from alkanes (10) and carbonyl compounds from alcohols. These products have hydrophobicities that are similar or increased relative to their substrates. 

The product obtained (formula B in Figure 9.12) is, in the broadest sense of the word, an acetal. This is a collective term for compounds of the structure R R2C(Nu)2, where Nu can be OR3 (so-called 0,0-acetal), SR3 (so-called S,S-acetal), or NR3R4 (so-called N,IV-acetal). O, O- and S S-acetals are isolable compounds. AjIV-acetals can in general only be isolated when they are cyclic or substituted on both N atoms by an electron acceptor. There are also mixed acetals, compounds R R2C(Nu)2 with two different substituents Nu, such as R R2(OR3)(OR4) (so-called mixed QO-acetal) or R R2(OR)(SR) (so-called QS-acetal). 

A deeper insight into the electronic properties of S-O and S-C bonds in sulphonates has been obtained by studying the substituent effect on 33S NMR parameters in some 3- and 4-substituted benzenesulphonates33 63 and 2-substituted ethanesulphonates.35... 

Nitrogen in positions a to the principal heteroatom will lower the reactivity more than nitrogen in -positions. [The same rule applies to benzo-substituted six-membered heterocycles (Chapter 11)]. Hence, 1,3-azoles are more reactive than 1,2-azoles. This will be more true for compounds containing O and S rather than NH, because the differences in the a- and (3-positional reactivities are greater for the former compounds. 

Benzene is aromatic because it has six electrons in a cyclic conjugated system. We know it is aromatic because it is exceptionally stable and it has a ring current and hence large chemical shifts in the proton NMR spectrum as well as a special chemistry involving substitution rather than addition with electrophiles. This chapter and the next are about the very large number of other aromatic systems in which one or more atoms in the benzene ring are replaced by heteroatoms such as N, O, and S. There are thousands of these systems with five- and six-membered rings, and we will examine just a few. 

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