In this thesis an orientating investigation is described as a first contribution to the knowledge of the reactivities of monohalogenopyridines towards potassium tert -butoxide in dimethyl sulfoxide (DMSO) and tert -butylalcohol. It is connected with extensive studies carried out to date on the behaviour of halogeno- azahetarenes in other strongly basic media, especially potassium amide in liquid ammonia and lithium piperidide and piperidine in ether.
As an introduction a survey is given of mechanisms occurring in reactions of halogenoarenes with hydroxide and alkoxides. Furthermore the physical properties and the most important chemical reactions of the solvent DMSO, to be expected in our investigation, are discussed. Special attention is paid to reactions of the anion of DMSO and of nucleophiles formed from its thermal decomposition, with halogenoarenes and other aromatic compounds (Chapter 1).
Various procedures used for carrying out reactions and the analytical methods are described in detail (Chapter 2).
Results are given of experiments on tert -butoxylations of 3- and 4- halogenopyridines in DMSO.
3-Fluoropyridine yields 3- tert -butoxypyridine and its decomposition product 3-hydroxypyridine by the addition-elimination (AE) mechanism; 3-chloro-, 3-bromoand 3-iodopyridine yield 3- tert -butoxy- and 3-hydroxypyridine together with the cinesubstitution products 4- tert -butoxy- and 4-hydroxypyridine by the EA- mechanism via 3,4-didehydropyridine; ratio of 3- and 4-substituted products 1: 2. As by-products from the latter reactions 4-hydroxy-3-(methylthio)pyridine, 1-(4'- pyridyl)-4-pyridone and 4-aminopyridine are isolated.
4-Fluoropyridine again only gives 4-substituted pyridines. The other 4-halogenopyridines yield the same products as obtained from the 3-halogenopyridines. The ratios of 3- and 4-substituted products are different however, 4-chloro- and 4-iodopyridine reacting by both the EA- and AE-mechanisms.
In tert -butylalcohol, in which solvent the basic properties of tert -butoxide are lower than in DMSO, 3-fluoro-, 4-fluoro- and 4-bromopyridine are converted according to the AE-process, but 3-bromopyridine according to the EA-mechanism producing 3-substituted compounds together with many substances in low yields i.e. 4-hydroxypyridine, P(4'-pyridyl)-4-pyridone, 4-aminopyridine and a tarry mass (Chapter 3).
tert -Butoxylations in DMSO in the presence of potassium thiophenoxide proceed as follows. From 3- and 4-fluoropyridine 3- and 4- tert -butoxy- and -hydroxypyridine are formed respectively by the AE-mechanism. 3-Bromopyridine is transformed by tert -butoxide into 3,4-didehydropyridine and subsequently mainly into a mixture of 3- and 4-(phenylthio)pyridine (ratio about 1 : 1) bij addition of thiophenoxide to the triple bond in the intermediate. 3-Chloropyridine reacts analogously, but at a very low rate. 4-Bromo-, 3-iodo- and 4-iodopyridine react likewise via the EA-mechanism and simultaneously via the AE-process with thiophenoxide, 4-chloropyridine being converted chiefly by the latter process. The divergence in the rates of reaction with tert -butoxide and thiophenoxide is explained in terms of competition of more or less hard nucleophiles on more or less hard substrates.
In tert -butylalcohol tert -butoxide and thiophenoxide are less selective when converting 3-fluoro-, 4-fluoro- and 4-bromopyridine by the AE-mechanism. 3-Bromopyridine was shown to react partially via 3,4-didehydropyridine (Chapter 4).
On reacting 2-halogenopyridines with potassium tert -butoxide in DMSO 2- fluoropyridine is found to change into 2- tert -butoxy- and 2-hydroxypyridine in high yields, following the AE-pathway. The other 2-halogenopyridines give together with these products, 2-(methylthio)pyridine, 2-hydroxy-4-methyl- and 2-hydroxy-6-methylpyridine (the last-mentioned derivatives being obtained by subsequent actions of methylsulfinylcarbanion and tert -butoxide) in a total yield lower than that of 2-fluoropyridine, due to side reactions possibly starting with an attack at C 6 . It is remarkable that the methylsulfinylcarbanion substitutes exclusively at C 4 and C 6 .
From all 2-halogenopyridines in tert -butylalcohol exclusively 2- tert -butoxy- and 2-hydroxypyridine were obtained in high yields by the AE-mechanism (Chapter 5).
tert -Butoxylations of 2-bromopyridine in the presence of phenoxide showed that the occurrence of any didehydropyridine as intermediate in these reactions can be excluded. When using thiophenoxide as nucleophile, the tert -butoxylation did not allow its formation owing to the side reaction of thiophenoxide with the substrate by the AE-pathway. Whereas 2-fluoropyridine only yields 2- tert -butoxypyridine the other substrates are converted into both 2- tert -butoxypyridine and 2-(phenylthio)pyridine, the ratio of these compounds decreasing in the series Cl>Br>J. This result can again be explained by the fact that a hard nucleophile as tert -butoxide shows a preference for the hardest substrate. This hypothesis is confirmed by the observation that on conversion of 2-halogenopyridines with thiophenoxide alone, the rate of substitution at C 2 increases in the order F < Cl < Br < J.
In tert -butylalcohol the ratios of rates when converting 2-fluoro- and 2- bromopyridine by tert -butoxide and thiophenoxide respectively were diminished again (Chapter 6).
tert -Butoxylations of 3-bromo-2-ethoxy-, 4-bromo-2-ethoxy- and 3-bromo-5-ethoxypyridine in the presence of thiophenoxide yielded mixtures from which chiefly ethoxy(phenylthio)pyridines were isolated, probably formed via ethoxy-3,4-didehydropyridines as intermediates. In spite of polarization of the triple bond by the ethoxy-group, thiophenoxide is a suitable substance for trapping the didehydropyridines. The addition of the very nucleophilic thiophenoxide on 5-ethoxy-3,4-didehydropyridine occurs exclusively at C 3 , the directing effect of the ethoxy-group surpassing completely that of the ring nitrogen atom. The addition on the extra bond in 2-ethoxy-3,4-didehydropyridine also takes place, though to a small extent, at C 3 . Thus, the influence of this ethoxy-group is lower due to mesomeric interaction with the ring nitrogen atom. tert -Butoxylations of 2-bromo-3- ethoxy- and 2-bromo-6-ethoxypyridine in DMSO in the presence of thiophenoxide yield only 3-ethoxy-2-(phenylthio)- and 2-ethoxy-6-(phenylthio)pyridine respectively. Thus it may be concluded that no reaction proceeds via any didehydropyridine (Cf. the aminations of these substrates with potassium amide via the ethoxy-2,4-didehydropyridines) (Chapter 7).
Finally the divergence in the course of the reactions of halogenopyridines with potassium- tert -butoxide, potassium amide and lithium piperidide in various solvents - a second nucleophile being present or not - is discussed (Chapter 8).
|Qualification||Doctor of Philosophy|
|Award date||7 Feb 1975|
|Place of Publication||Wageningen|
|Publication status||Published - 1975|
- addition reactions