Nucleophilicities and carbon basicities of pyridines

Rate and equilibrium constants for the reactions of pyridines with donor‐substituted benzhydrylium ions have been determined spectrophotometrically. The correlation equation log k(20 °C)=s(N+E), in which s and N are nucleophile‐specific parameters and E is an electrophile‐specific parameter, has been used to determine the nucleophilicity parameters of various pyridines in CH₂Cl₂ and aqueous solution and to compare them with N of other nucleophiles. It is found that the nucleophilic organocatalyst 4‐(dimethylamino)pyridine (DMAP) and tertiary phosphanes have comparable nucleophilicities and carbon basicities despite widely differing Brønsted basicities. For that reason, these reactivity parameters are suggested as guidelines for the development of novel organocatalysts. The Marcus equation is employed for the determination of the intrinsic barriers of these reactions.     

The ground state basicities of a series of substituted crotonaldehyde

DFT (B3LYP 6-31G(d)) calculations with complete geometry optimizations are carried out on a series of substituted crotonaldehyde and their O-protonated counterparts. The gas phase O-protonation turns out to be exothermic case and the local stereochemical disposition of the proton is found to be almost the same in each case. The presence of substituent is seen to cause very little change of the protonation energies (PE) relative to the unsubstituted crotonaldehyde. Electron releasing substituents increase PE by 0.002–0.004 hartree and the electron withdrawing substituents decrease it by 0.01 hartree. Computed protonation energies are sought to be correlated with a number of computed system parameters such as the net charge on the carbonyl oxygen, charge on the proton of the unprotonated and the protonated species.     

Coupling constants in N-substituted pyridines and their relation with electronegativity

The coupling constants obtained from the complete spectral analysis of series of 1- and 3-substituted pyridine N-imides are related linearly to the electronegativities of the substituent atoms. The main conclusions of the papers by Cox, Castellano and Sun, and Castellano and Kostelnik are substantiated. The inductive effects of the first atoms of the substituents largely determine the coupling between protons in the ring system; delocalisation of π-electrons in the ring produces a much smaller effect.     

Specificity of 15N NMR chemical shifts to the nature of substituents and tautomerism in substituted pyridine N-oxides

¹H, ¹³C, and ¹⁵N NMR chemical shifts have been measured for 2-aminopyridine N-oxide (1), its eleven derivatives (2–10, 13, 14), and 3-Cl and 3-Br substituted 4-nitropyridine N-oxides (11, 12). δ(¹⁵N) of pyridine ring nitrogen in 2-acetylaminopyridine N-oxides are 5.9–11.5 ppm deshielded from those in 2-aminopyridine N-oxides. When amino and acetylamino substituents are in 4-position, δ(¹⁵N) of ring nitrogen is 21.3 ppm deshielded in the acetylated derivative. The strong resonance interaction between 2-amino and 5-nitro groups reflects in the decrease of amino nitrogen shielding about 5.3–17.9 ppm. Also, ¹H and ¹³C NMR spectral data are in agreement with ¹⁵N NMR results reflected as deshielded amino protons and carbons C-2 and C-5. The pyridine nitrogen chemical shift in all amino- and acetylamino derivatives vary between ?101.2 and ?126.7 ppm, which has been connected with the tautomeric balance in our earlier studies.     

Improved methodologies for the preparation of highly substituted pyridines

[reaction: see text] Two separate strategies have been developed for the preparation of highly substituted pyridines from 1,2,4-triazines via the inverse-electron-demand Diels-Alder reaction: a microwave-promoted, solvent-free procedure and a tethered imine-enamine (TIE) approach. Both routes avoid the need for a discrete aromatization step and offer significant advantages over the classical methods, giving a wide variety of tri-, tetra-, and penta-substituted pyridines in high, optimized yields.     

Direct fluorination of substituted pyridines

The direct fluorination of pyridines bearing alkyl, halogen, ester, or ketone functions has been employed to prepare the corresponding 2-fluoro-substituted pyridines.     

NMR studies of substituted pyridines

Proton magnetic resonance chemical shifts and coupling constants for a series of 2-substituted-5-nitropyridines and 2-substituted-3-nitropyridines, both in the free base and protonated forms, are reported. The substituents were chloro, bromo, iodo, and hydroxyl. The effect of the substituents on the chemical shifts are substantial but not unusual. The coupling constants are less sensitive to the nature of the substituent and are perturbed only slightly when the ring nitrogen is protonated. This latter observation is consistent with the results of LCAO-MO calculations.     

Synthesis of pyrylium salts and pyridines containing heterocyclic substituents

A method of synthesizing pyrylium salts with heterocyclic substituents in the ring, has been investigated. The synthesis was carried out in two stages: alkaline condensation of aromatic and heterocyclic aldehydes with methyl ketones to give 1, 5-diketones, followed by cyclization to pyrylium salts by treatment with triphenylmethyl perchlorate. Pyridines containing heterocyclic substituents were obtained by treating the pyrylium salts with ammonia.     

Three-component coupling sequence for the regiospecific synthesis of substituted pyridines

A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.     

IR studies in the substituted benzaldehyde series provide a new definition of sigma-plus constants of ionic substituents

Fourier-transform IR frequencies nu(C=O) and integrated intensities A(C=O) of the carbonyl groups of a series of benzaldehydes (53 compounds) have been measured in dimethyl sulphoxide. Excellent and satisfactory correlations have been found between nu(C=O) and sigma(+) substituent constants of the m- and p-substituted compounds. Diortho-substituted compounds deviate strongly from the correlation lines because of the steric ortho-effects mainly. sigma(+) constants of ionic substituents (10 examples) have proved satisfactorily valid in the series studied.     

Quaternization of electron-deficient pyridines containing two electron-withdrawing substituents

Methyl triflate is an efficient agent for the quaternization of nitropyridines containing an additional electron-withdrawing substituent. When triethyloxonium hexachloroantimonate is used as the quaternizing agent, -elimination occurs with formation of protic pyridinium salt and ethylene.M. V. Lomonosov Moscow State University, 119899 Moscow, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 53–54, January, 2000.     

Microwave spectra of deuterated pyridines and the structure of pyridine

Summary 2 D-, 3 D-, and 4 D-pyridine were prepared by the action of Zn, D₂O and D₂SO₄ on the corresponding halopyridines. The infrared absorption curves showed that the samples obtained were practically pure. The microwave spectra were taken and interpreted. Based on the data so obtained and on data for ordinary pyridine the magnitudes of the 10 geometrical parameters of pyridine were calculated for 7 different models. Only one of these, however, is consistent with valence-theory aspects.

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Zusammenfassung Durch Einwirkung von Zink, Deuteriumoxyd und Deuteriumsulfat auf die entsprechenden Halogenpyridine wurden 2-D-, 3-D- und 4-D-Pyridin hergestellt. Die davon hergestellten IR-Absorptionskurven erwiesen die Reinheit dieser Präparate, deren Kurzwellenspektren aufgenommen und interpretiert wurden. Auf Grund dieser Spektren und der entsprechenden Daten für gewöhnliches Pyridin wurde die Größe der 10 geometrischen Parameter für 7 Modelle von Pyridin errechnet. Nur eines davon stimmt mit den Forderungen der Valenztheorie überein.

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Résumé On a préparé les 2 D-, 3 D- et 4 D-pyridine par action de Zn, D₂O et D₂SO₄ sur les halopyridines correspondantes. Les produits obtenus sont pratiquement purs ainsi que le montrent les spectres d'absorption infra-rouge. On a enregistré et interprété les spectres de micro-ondes. A partir de ces données et des données relatives à la pyridine ordinaire, on a calculé 10 paramètres géométriques de la pyridine pour 7 modèles différents. Un seul de ces modèles cependant est acceptable du point de vue de la théorie des valences.

     

Studies with polyfunctionally substituted heteroaromatics: New routes for the synthesis of polyfunctionally substituted pyridines and 1,2,4-triazolo[1,5-a]pyridines

The 1-substituted ethylidenemalononitriles 1a–c condensed with triethyl orthoformate in refluxing acetic anhydride to yield the dienes 2a–c . On the other hand, a mixture of N,N-dimethylformamide and triethyl orthoformate condensed with 1a–d to yield the N,N-dimethylaminopentadienonitriles 2d–g . The pentadienonitriles 2d–g were also formed from the reaction of 1a–d with dimethylformamide dimethylacetal in refluxing acetic acid. When compounds 1a–c were treated with dimethylformamide dimethylacetal in refluxing p-xylene, a mixture of 3 , 4 and 2e–g was formed. The reaction of 2a , b with hydrazine hydrate afforded the N-amino-2-iminopyridines 5a , b . These were converted into the triazolo[1,5-a]pyridines 8a–d on treatment with benzoyl chloride and with dimethylformamide dimethylacetal. On the other hand, the reaction of 2c with hydrazine hydrate afforded the pyrazolo[3,4-b]pyridine 7c . Treatment of 2a , c or 2e , g with cyanoethanoic hydrazide afforded the N-(cyanoacetamido)pyridines 9a , b . The dienes 2d , f , g afforded the pyridones 11a–c on treatment with acetic acid and hydrochloric acid mixture. Compounds 11b , c were also formed on treatment of 2b , c with acetic acid hydrochloric acid mixture. The reaction of 2d , g with ethanolic sodium ethoxide gave the ethoxypyridines 13a , b .     

Syntheses in the pyridine series

A new procedure for preparing 2-methyl-6-methoxy-4-thioquinolone (I), 2-methyl-7-chloro-4-thioquinoline (II), 2-thiopyridone (III) and 5-nitro-2-thiopyridone (IV) has been proposed. This involves the reactions of the corresponding halogen derivatives of quinoline and pyridine with sodium thiosulfate. Compounds I and II were synthesized for the first time.     

Syntheses in the pyridine series

It has been shown that when they are heated in 2 N caustic soda solution alkyl pyrid-2-yl sulfides are hydrolyzed at the Py-S bond with the formation of pyridones and the corresponding thiols. The latter were determined quantitatively by iodometric titration.For part VIII, see [1].     

Syntheses in the pyridine series

The conditions for obtaining some -dialkylaminoethyl pyrid-4-yl sulfide N¹-oxides and their quaternary salts have been studied. It has been shown that the addition of alkyl iodides to the bases obtained takes place in a similar manner to their addition to pyrid-4-yl sulfides not containing a N-oxide group.For part VII see [1]     

Gas chromatographic separation of substituted pyridines

Capillary gas chromatographic methodology for separation of complex mixtures of substituted pyridines has been demonstrated on polar (CAM) and non-polar (DB-5) columns. Separations are characterized by high resolution, high sensitivity, a wide dynamic detector range, and good reproducibility. For the first time, Kováts retention indices have been calculated for pyridine and substituted pyridines. Correlations of retention indices with physico-chemical properties, such as hydrogen bonding, pyridine pKa and Hammett substituent constants are discussed.