John A. Zoltewicz

Quaternization of Heteroaromatic Compounds: Quantitative Aspects

Publisher Summary This chapter focuses on important developments dealing with quaternization of annular nitrogen atoms of heterocyclic compounds. The chapter is essentially divided into two main parts. The first part describes the main electronic and steric factors of heteroaromatic nucleophilic reactants that influence their reactivity. The second part provides references to recent important developments. The chapter considers six-membered heteroaromatic rings before five-membered ones as the six-membered rings are studied in greater detail and consequently their reactions are better understood. The chapter notes that quaternization of an annular nitrogen atom is carried out with a wide range of alkylating agents. Most quaternization reactions involving an annular nitrogen atom and an alkylating agent proceed by way of an S N 2 reaction in which the inversion of configuration of a chiral reagent takes place. One novel method, which indicates that the transition state is early, involves the study of volume changes. Many approaches are made to obtain information about the nature of the transition state of quaternization reactions, including a study of kinetic isotope effects.

Long Range Transmission of Polar Effects in Cholinergic 3-Arylideneanabaseines. Conformations Calculated by Molecular Modelling

Benzylidene products resulting from acid-catalyzed aldol condensations of aryl aldehydes and anabaseine at position 3 of the tetrahydropyridine ring have E stereochemistry. In spite of a chemical shift scale ranging only over 0.11 ppm the methylene protons (H-6) adjacent to the imino group of the tetrahydropyridine ring show an excellent Hammett correlation using σ M and σ P values. Methoxy and chloro groups in an ortho position require a σ I parameter. Substrates with one or two ortho methyl groups deviate. AM1 and MM2 calculations indicate that both the phenyl and pyridyl rings are twisted out of a common plane defined by the central ring

Atropisomerism of cofacial pyridine rings. Synthesis, proton NMR spectra and conformations of 1,8-di(3′-pyridyl)naphthalene

Abstract The title compound prepared by Pd-catalyzed coupling of 1,8-dibromonaphthalene and diethyl(3-pyridyl)borane shows syn-anti diastereoisomerism due to restricted rotation at ambient temperatures. AM1 and PM3 computations indicate the preferred T-shaped transition state for rotation has a highly deformed naphthalene ring. There is a slight preference for H4′ and not the nitrogen lone electron pair to be directed at the face of the other pyridyl ring.

Diastereomers of a cofacial ternaphthalene and two azaternaphthalenes. Syntheses and barriers to isomerization

Abstract The title compounds, a mixture of anti and syn diastereomers, were prepared by Pd-catalyzed coupling of areneboronic acids with hetaryl halides. Energy barriers for the interconversion of the diastereomers obtained by kinetic and computational studies show a dependence on the location of the annular nitrogen atom, the ortho providing a smaller barrier than the meta nitrogen atom.

A method of predicting the site of alkylation of heterocyclic polyazines from kinetic data on model compounds

Abstract A method is presented which enables calculation of isomer ratios resulting from the N-methylation of polyazines in dimethyl sulfoxide. The method assumes that substituent and annular nitrogen atom effects on reactivity are additive in the absence of steric factors. Kinetic studies on model azines provide rate factors which are employed in the calculations. Observed and calculated isomer ratios are compared for a number of polyazines. An extension to N-oxidation is suggested.

Deuterodecarboxylation: A convenient method for the preparation of labeled pyridines

Abstract Deuterodecarboxylation, the replacement of a COOD group by a D atom, proceeds with high specificity in good yields for a series of pyridine-2-carboxylic acids. Isomeric pyridine-carboxylic acids require higher temperatures to achieve decarboxylation and give multiply deuterated products. Positions adjacent to the ring N are especially favored in the H—D exchange reactions. The role of ylid intermediates is discussed. It is suggested that the decarboxylation method of labeling may be applicable to a wide variety of heterocyclic systems. A statistical method is given for calculating a mass distribution from NMR data for a sample of partially deuterated pyridines.

Inter-ring directed ortho lithiation by the 2-pyridyl group in bipyridines

Abstract Kinetically enhanced metallation by the 2-pyridyl group of 2,2′-bipyridine or 2,4′-bipyridine (BPY) in the presence of lithium 2,2,6,6-(tetramethyl)piperidide directs lithiation to the ortho position of the adjacent ring. Representative electrophiles convert the lithiated material to a number of substituted products. The stannylated BPY products were coupled with 3-iodopyridine in the presence of Pd(PPh 3 ) 4 to give two novel terpyridines.

Hydrolysis of cholinergic anabaseine and N-methylanabaseine: Influence of cosolvents on the position of the ring-chain equilibrium—Compensatory changes

Abstract The position of the ring-chain equilibrium established by the addition of water to the iminium ring (Im) in the title compounds and subsequent ring cleavage to give the acyclic conjugate acid amino ketones (AK) were investigated by proton NMR using D2O, dimethyl sulfoxide (DMSO)-d6, and CD3OD solvents. A linear free energy relationship expressing the change in the logarithmic value of the equilibrium constant [AK] ([Im][D 2 O]) for the mixed solvent with the mole fraction of water added to methanol is found for the substrates, giving the equilibrium constants for the pure solvents. Equilibrium constants for the pure solvents increase in the order water, methanol, DMSO. Although there is less water in the largely nonaqueous solvents, the increase in the magnitude of the equilibrium constants partially compensates for this decrease, thereby resulting in a moderated reduction of the value of the ratio [AK] [Im] . Replacement of the deuteron bonded to the imine nitrogen atom by a methyl group causes much more acyclic keto-ammonium ion to form in D2O due to steric compression between this methyl group and the adjacent pyridine ring causing an increase in energy of about 1.7 kcal/mol.

Mechanism of pyridyne formation from halopyridines

Abstract Rates of hydrogen-deuterium exchange of 3-chloro- and 3,5-dichloropyridine in MeOD-MeONa were studied. Deuterodeprotonation of 3-chloropyridine at 110·2° is 53 times faster at H-4 than at H-2. At 75° the value of the ortho chloro rate factor for exchange is 800; the para nitrogen rate factor is 3000. Interrupted dehydrohalogenation of 3-chloropyridine-2 or 4-d and 3-iodopyridine-4d in NH3NaNH2 to give 3,4-pyridyne results in no detectable loss of label at 2 in the chloropyridine but reduction and enrichment of 4-d in the chloro and iodo compounds, respectively. Results are interpreted in terms of the reactions of halopyridyl anions.

NUCLEOPHILIC SUBSTITUTION REACTIONS OF THIAMIN AND ITS DERIVATIVES

In the 1930s several groups world-wide were in a race to determine the structure of thiamin or vitamin B, (I). Williams was the first to succeed, largely because of an accident. He observed that thiamin rapidly cleaves into two fragments in the presence of sulfite ion, produced by the addition of sulfur dioxide to water. One product is the insoluble pyrimidinylmethylsulfonate ion (11), the other a soluble thiazole (111):’