3 -Acetylpyridine

The //NMR spectrum contains five signals with integral levels in the ratios 1 1 1 1 3 four lie in the shift range appropriate for aromatics or heteroaromatics and the fifth is evidently a methyl group. The large shift values (up to Sh = 9.18, aromatics) and typical coupling constants 8 and 5 Hz) indicate a pyridine ring, which accounts for four out of the total five double-bond equivalents. 

Four multiplets between Sh = 7.46 and 9.18 indicate monosubstitution of the pyridine ring, either in the 2- or 3-position but not in the 4-position, since for a 4-substituted pyridine ring an AA XX system would occur. The position of the substituents follows from the coupling constants of the threefold doublet at Sh = 7.46, whose shift is appropriate for a P-proton on the pyridine ring (A). 

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Pyridyl)hydrazine (Aldrich), 4-acetylpyridine (Acros), N,N,N -trimethylethylenediamine (Aldrich), methylrhenium trioxide (Aldrich), InQj (Aldrich), Cu(N0j)2-3H20 (Merck), Ni(N03)2-6Il20 (Merck), Yb(OTf)3(Fluka), Sc(OTf)3 (Fluka), 2-(aminomethyl)pyridine (Acros), benzylideneacetone (Aldrich), and chalcone (Aldrich) were of the highest purity available. Borane dimethyl sulfide (2M solution in THE) was obtained from Aldrich. Methyl vinyl ketone was distilled prior to use. Cyclopentadiene was prepared from its dimer immediately before use. (R)-l-acetyl-5-isopropoxy-3-pyrrolin-2-one (4.15) has been kindly provided by Prof H. Hiemstra (University of Amsterdam). 

A distorted tetrahedral copper(II) center has been proposed [185] for [Cu(37)Cl2] where 37 is 4-acetylpyridine thiosemicarbazone with the ring nitrogen not coordinated. 

A qualitatively new approach to the surface pretreatment of solid electrodes is their chemical modification, which means a controlled attachment of suitable redox-active molecules to the electrode surface. The anchored surface molecules act as charge mediators between the elctrode and a substance in the electrolyte. A great effort in this respect was triggered in 1975 when Miller et al. attached the optically active methylester of phenylalanine by covalent bonding to a carbon electrode via the surface oxygen functionalities (cf. Fig. 5.27). Thus prepared, so-called chiral electrode showed stereospecific reduction of 4-acetylpyridine and ethylph-enylglyoxylate (but the product actually contained only a slight excess of one enantiomer). 

More recently, Lees and Adamson (37) have used flash photolysis to investigate the reaction of W(C0) with 4-acetylpyridine (L) in methylcyclohexane (S). A transient with Amax 425 nm is assigned to W(C0)5S (c.f. the matrix data (21) W(CO)5...CH4 in solid CH4 has Amax 415 nm) and the overall reaction can be summarised ... 

The surface-enhanced Raman spectra (SERS) provide information about the extent of protonation of the species adsorbed at the silver/aqueous solution interface. The compounds investigated were 4-pyridyl-carbinol (1), 4-acetylpyridine (2), 3-pyridine-carboxaldehyde (3), isonicotinic acid (4), isonicotinamide (5), 4-benzoylpyridine (6), 4-(aminomethyl)pyridine (7) and 4-aminopyridine (8). For 1, the fraction of the adsorbed species which was protonated at -0.20 V vs. SCE varied with pH in a manner indicating stronger adsorption of the neutral than the cationic form. The fraction protonated increased at more negative potentials. Similar results were obtained with 3. For all compounds but 4, bands due to the unprotonated species near 1600 cm-1 and for the ring-protonated species near 1640 cm-1 were seen in the SERS spectra. 

As seen with 4-acetylpyridine, the relative intensities of the 1600 and 1640 cm features, at constant solution pH, are insensitive to electrode potential. Again, this behavior may be associated with the relatively weaker basicity of 3 and 2 (pKa = 3.51 and 3.73. respectively) compared to 1 (5-76) and 4-pyridinecarboxaldehyde (4.78) though the exact reason is not known. The latter two show... 

Pyridylcarbinol, 4-acetylpyridine, 3-pyridine-carboxaldehyde and 4-aminomethylpyridine were obtained from Aldrich Chemical Company (Milwaukee, Wisconsin) and were purified by distillation at reduced pressure. 4-Benzoylpyridine was recrystallized from ethanol. 4-Aminopyridine (G. Frederick Smith Chemical Company), isonicotinic acid (Aldrich) and isonicotinamide (Aldrich) were used as received. Triply distilled water was used. All other reagents were analytical reagent grade. 

One more example of metal ion catalysis will be considered briefly. In a now classic paper, Cox (1974) showed that the enolization of 2-acetylpyri-dine (but not 4-acetylpyridine) is catalysed by divalent transition metal ions. Proton abstraction by acetate ions is strongly accelerated by Zn2+, Ni2+ and Cu2+ ions and the transition state stabilization by these ions roughly parallels their abilities to bind to the substrate (Table A6.5). The three metal ions are significantly superior to the proton as electrophilic catalysts, no doubt because they can chelate to both the pyridine nitrogen and the... 

The HOPG (highly oriented pyrolytic graphite) carbon electrode chemically modified with (5[-phenylalanine at the basal surface led to 2% ee in the reduction of 4-acetylpyridine [377]. A cathode modified with a chiral poly(pyrrole) reduced 4-methylbenzophenone or acetophenone in DMF/LiBr and phenol as proton donor to 1-phenylethanol with up to 17% ee [382]. Alkyl aryl ketones have been reduced to the corresponding alcohols at a Hg cathode in DMF/water in the presence of (1R,2S)-A,A-dimethylephedrinium tetrafluorobo-rate (DET), producing (5 )-l-phenylethanol with 55% ee from acetophenone. Cyclovoltammetry supports an enantioselective protonation of the intermediate (PhCOH(CH3)) [383]. 

A number of other spectrophotometric reagents and combinations thereof have been used and compared with NBP 4-p3ridinecarboxaldehyde 4-nitrophenylhydra-zone 4-pyridinecarboxaldehyde 2-benzothiazolylhydrazone 4-acetylpyridine 4-nitrophenylhydrazone 4-acetylpyridine 2-benzothiazolylhydrazone [62]. S -Dodecylisothiouronium bromide has been used with primary and secondary alkyl halides [63]. 4-Nitrothiophenol has been claimed to be better than NBP, but only when used in combination with HPLC and not as a stand-alone reagent [64]. 

Derivatisation with NBP 4-pyridinecarboxaldehyde 4-nitropheny Ihydrazone 4-pyridinecarboxaldehyde 2-benzothiazolylhydrazone 4-acetylpyridine 4-nitrophenyIhydrazone 4-acetylpyridine 2-benzothiazolyUiydrazone... 

Like 2,2 - and 2,3 -bipyridines, 2,4 -bipyridine is formed by a number of reactions where one of the pyridine rings is built up from simpler components. Thus 4-(aminomethyl)pyridine with acetylene or acetaldehyde at 450"C affords 2,4 -bipyridine and 4-cyanopyridine reacts with acetylene at 120 C under pressure in the presence of a cobalt catalyst to give 2,4 -bipyridine in over 90% yield. 4-Acetylpyridine with acrolein and ammonia in the presence of dehydrating and dehydrogenating catalysts also gives 2,4 -bipyridine. A number of minor routes to 2,4 -bipyridine are worthy of... 

Dipole moment studies and molar Kerr constants, in C6Hi2 at 25 °C, have proved of much use in adducing the conformations of acylpyridines (73JCS(P2)l46l)..4-Formylpyridine is planar, but the acetyl group appears to be twisted about 25° from the plane of the pyridine ring in 4-acetylpyridine. The conformation of 4-benzoylpyridine must be defined by two angles 6 and 4> as in (262). The preferred conformation is calculated to be 6 = = 25°, consistent with the result for 4-acetylpyridine. 

The product (mp 122-146°C, 33-36 g, 81-88%) can be shown from its 1H NMR spectrum (Note 3) to he a 5 1 mixture of the E- and Z-isomer of 4-acetylpyridine oxime. To obtain pure E-isomer (Note 4), the product is recrystallized twice as follows. The crude product is dissolved in 600 mL of hot water in a 2-L Erlenmeyer flask, the hot solution decanted from any undissolved residue, and the supernatant liquid is allowed to cool slowly to 30°C during 2-3 hr by placing the flask on a cork ring. The precipitate is collected at this temperature by suction filtration. A second crystallization hy the same procedure yields pure E-oxime, which is dried under reduced pressure over Drierite to constant weight. The yield of E-4-acetylpyridine oxime, mp 154-157°C, (Note 5) is 27.1-28.3 g (66-69%). 

C. 232-Diethoxy-2-(4-pypidyl)ethylamine. To a 2-L, round-bottomed flask containing 80 mL of absolute ethanol (Note 9) and fitted with a magnetic stirrer and a reflux condenser with a drying tube is slowly added potassium metal (7.60 g, 0.19 mol) (Note 10). When the metal has dissolved, the solution is cooled to 0-5°C and E-4-acetylpyridine tosylate (55.1 g, 0.19 mol)... 

The cathodic pinacolisation of 2- and 4-acetylpyridine, which had been investigated by one of the present authors (231-233), offered the chance for a complete kinetic analysis as the respective current voltage curves are of reversible character. They allow for evaluation of the kinetics of consecutive reactions, and one can show that at low pH reaction, Eq. (45c) is only possible if strong surfactants are absent. Such surfactants, by occupying the electrode surface, displace ketyl radicals, RiR2(OH)C , from the electrode surface because the latter are relatively weakly adsorbed and cannot compete with strong surfactants in adsorption. Ketyl radicals dissolved in aqueous or organic solvents of low pH are protonated in a fast almost diffusion-controlled reaction. After protonation they are further immediately reduced to form the monomeric carbinol instead of the hydrodimer—the pinacol ... 

If as surface active agent with the reduction of 2- and 4-acetylpyridine the optically active proton-donating alcaloids strychninium or brucinium are adsorbed at the cathode, relatively high yields of optically active alcohol (benzhydrol) are obtained (234, 235). 

The three acetylpyridines have been reduced in the presence of catalytic concentrations of different alkaloids in attempts to induce optical activity in the products 412 The reduction of 3-acetylpyridine gave optically inactive alcohols under all conditions employed, whereas optically active pyridyl-ethanols are produced from 2- and 4-acetylpyridine at 0°C, in a 1 1 aqueous-ethanolic acetate buffer with strychnine (5 x 10-4 M) as chiral catalyst. Under these conditions protonated, adsorbed strychnine is probably acting as a chiral acid. The pinacols obtained as side products were all optically inactive. 

Substituted dihydropyridines can be aromatized in various ways, e.g. with nitrous fumes (NO-N204). Compound (482) is converted into 4-acetylpyridine by sulfur, or to 4-ethylpyridine by Zn-HOAc. 

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