Electron donor and acceptor properties of alkyl substituents

The polar effects of alkyl substituents in electrophilic and nucleophilic chemical and electronic transitions is discussed. The question of the importance of hyperconjugation in the electron donor properties of alkyl substituents is raised. In view of the cogent arguments of Dewar, it is doubtful whether quantum mechanical calculations embodying hyperconjugation constitute proof of this effect. That the art of quantum mechanics may not yet be sufficiently developed to be used as proof for or against secondary resonance effects also is evidenced by the calculations of Simpson, who found that an internal dispersion force model (in which conjugation was neglected) reproduced the properties of butadiene just as satisfactorily as the models embodying conjugation. The experimental facts do not unequivocally support the hyperconjugation hypothesis and indeed are, at least in part, contradictory to it. In particular, the demonstration that the Baker-Nathan Effect² may be due to the influence of alkyl substituents on the differential solvation of ground and transition states casts doubt on the interpretation that this experimental effect is due to a dominant role of C-H hyperconjugation.

In nucleophilic chemical reactions, rate or equilibrium constants for para (or meta) alkyl derivatives are somewhat smaller than those of the corresponding hydrogen compounds. A number of authors have interpreted this in terms of a permanent electron donor role of alkyl substituents (e.g. by hyperconjugation) relative to the hydrogen substituent. However, this static viewpoint of substituent effects fails to account for the finding that p-alkyl substituents function as apparent electron acceptors (relative to the p-hydrogen substituent) in appreciably lowering the energy of the nucleophilic principal electronic transition of phenol, anisole, aniline and N,N-dimethylaniline. These results are qualitatively rationalized in terms of ‘substituent-polarizability” and electronegativity.

The p-neopentyl substituent lowers the energy of both electrophilic and nucleophilic electronic transitions to an appreciably greater extent than either the p-methyl or p-t-butyl substituent. This extra stabilizing effect of the neopentyl substituent on both electron deficient and electron rich centers may be due to an internal dispersion force interaction, since the geometry of the neopentyl compounds is particularly favorable for such an interaction.     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.     

Syntheses of 6,8-disubstituted-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphates

A series of 6,8-disubstituted-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphates were prepared employing preformed 9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphate precursors. Three synthetic approaches were utilized to accomplish the syntheses. The first approach involved a study of the order of nucleophilic substitution, 6 vs 8, of the intermediate 6,8-dichloro-9-β-D-ribofuranosyipurine 3′,5′-cyclic phosphates ( 2 ) with various nucleophilic agents to yield 8-amino-6-chloro-, 8-chloro-6-(diethylamino)-, 6-chloro-8-(diethylamino)-, 6,8-bis-(diethylamino)- and 8-(benzylthio)-6-chloro-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphate (4, 9, 10, 11, 13) respectively and 6-chloro-9-β-D-ribofuranosylpurin-8-one 3′,5′-cyclic phosphate ( 5 ) and 8-amino-9-β-D-ribofuranosylpurine-6-thione 3′,5′-cyclic phosphate ( 6 ). The order of substitution was compared to similar substitutions on 6,8-dichloropurines and 6,8-dichloropurine nucleosides. The second scheme utilized nucleophilic substitution of 6-chloro-8-substituted-9-β-D-ribofuranosylpurine 3′,5′-cyclic, phosphates obtained from the corresponding 8-subslituted inosine 3′,5′-cyclic phosphates by phosphoryl chloride, 6,8-bis-(benzylthio)-, 6-(diethylamino)-8-(benzylthio),8-(p-chlorophenylthio(-6-(diethylamino)- and 6,8-bis-(methyl-thio)-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphates ( 14, 12, 20 , and 21 ) respectively, were prepared in this manner. The final scheme involved N¹-alkylation of an 8-substituted adenosine 3′,5′-cyclic phosphate followed by a Dimroth rearrangement to give 6-(benzylamino)-8-(methylthio)- and 6-(benzylamino)-8-bromo-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphate ( 24 and 25 ).     

Silver-modified mobile phase for normal-phase liquid chromatographic determination of prostaglandins and their 5,6-trans isomers in prostaglandin bulk drugs and triacetin solutions

A silver-modified, normal-phase, high-performance liquid chromatographic system has been developed for prostaglanding bulk drugs and triacetin solutions. Silver nitrate present in the mobile phase results in high selectivity for cis/trans isomers with conventional silica columns. Prostaglandins were esterified with alpha-bromo-2'-acetonaphthone prior to chromatography to provide high detectability at 254 nm. For dilute triacetin solutions, a sample preparation scheme based on gravity-flow chromatography with silica columns was developed to isolate the prostaglandin from triacetin prior to derivatization. The analytical technique was applied to triacetin solutions containing as little as 10 micrograms/ml arbaprostil [15-(R)-methyl-PGE2].     

Mild and efficient functionalization at C6 of purine 2'-deoxynucleosides and ribonucleosides

[reaction: see text] Treatment of sugar-protected inosine and 2'-deoxyinosine derivatives with a cyclic secondary amine or imidazole and I(2)/Ph(3)P/EtN(i-Pr)(2)/(CH(2)Cl(2) or toluene) gave quantitative conversions into 6-N-(substituted)purine nucleosides. S(N)Ar reactions with 6-(imidazol-1-yl) derivatives gave 6-(N, O, or S)-substituted products. The 6-(benzylsulfonyl) group underwent S(N)Ar displacement with an arylamine at ambient temperature.     

Determination of the natural abundance delta15N of nicotine and related alkaloids by gas chromatography/isotope ratio mass spectrometry

A method is described by which the natural abundance delta15N values of nicotine, analogues, and metabolites can be determined. The alkaloids are extracted from their biological matrix by solid-phase extraction and analysis is conducted using isotope ratio mass spectrometry interfaced to gas chromatography. Repeatability and precision are sufficient to allow differences in the delta15N values of less than 1.0 per thousand to be satisfactorily measured, with a standard deviation routinely less than 0.5 per thousand. The methodology has been tested by determining the changes in the delta15N values of nicotine, N-methyl-2-phenylpyrrolidine and their respective demethylation products, nornicotine and 2-phenylpyrrolidine, during biotransformation by cell suspension cultures of Nicotiana species. Sufficient precision and reproducibility were obtained to allow the kinetic isotope effects associated with the demethylation reaction to be calculated.     

Polyazanaphthylene nucleosides II. Synthesis of β-D-ribofuranosyl derivatives of 4-quinazolone

The preparation of N¹ (2,3-O-isopropylidene-β-D-ribofuranosyl)-4-quinazolone ( 6 ) and N³-β-D-ribofuranosyI-4-quinazolone ( 3b ) are reported. The N³ derivative was prepared by the direct condensation of 4-trimethylsilyloxyquinazoline ( 2 ) and 2,3,5-tri-O-benzoyl- D - ribofuranosyl bromide. The N¹ derivative was prepared from the previously reported N¹ -β-D-ribofuranosyl-2,4-quinazolinedione via the cyclonucleoside 4 .     

Effects of Adsorbed Polyaniline on Redox Processes on As(2)O(3) Surfaces

Polyaniline deposited on As(2)O(3) surface resulted in a new material, which was characterized by infrared spectoscopy, thermogravimetry, differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and cyclic voltammetry. The mass percentage of polymer deposited on oxide surface is approximately 13%. The scanning electron microscopy images as well as the X-ray diffraction patterns provided conclusive evidence that the oxide surface is coated by the polymer. The cyclic voltammograms of the polyaniline adsorbed on As(2)O(3) surface showed that the adsorbate exerts remarkable effects on redox processes on this oxide. The pure oxide exhibited two oxidation/reduction peaks at 0.25/-0.06 and 0.47/-0.25 V attributed tentatively to the processes As(2)O(3)(s)+6H(+)+6e(-)=2As(s)+3H(2)O and As(s)+3H(+)+3e(-)=AsH(3)(g), respectively. The polyaniline-coated sample exhibited a better-defined voltammogram in which the first oxidation peak of the oxide had its intensity increased about four times. Copyright 2000 Academic Press.     

Hydrothermal deamidation of 4-N-acylcytosine nucleoside derivatives: efficient synthesis of uracil nucleoside esters

[reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine derivatives in superheated water/DME solutions (oil bath at 125 degrees C) undergo hydrolytic deamidation (and/or N-deacylation). Acylated starting materials derived from arylcarboxylic acids give the corresponding uridine esters cleanly, and such derivatives crystallize selectively from the cooled reaction mixtures in high yields.