The reactivity of substituted purines in strongly basic medium : the occurrence of geometrical isomerism in the anions of aromatic amino compounds

N.J. Kos

Research output: Thesisinternal PhD, WU


In this thesis two subjects are described: a. the amination of substituted purines by potassium amide in liquid ammonia and b. the occurrence of geometri cal isomerism in the anions of aromatic amino compounds.<p/>It is shown that the first step in the amination of purines, being present as anions under these strongly basic conditions, is the formation of a σ-adduct as position 6 to give a 6-amino-1,6-dihydropurinide. If position 6 is occupied by a blocking group an attack at position 2 or 8 does not occur. The further reaction course depends on the nature of the substituents and their position in the purine ring. i. If a leaving group (Cl,SCH <sub><font size="-1">3</font></sub> ) is present at the same position where the amide ion has attacked, this substituent is expelled (S <sub><font size="-1">N</font></sub> (AE) mechanism). In case no leaving group is present a Chichibabin amination occurs due to expulsion of a hydride ion from position 6 (this reaction is described in Chapter 2).<p/>The Chichibabin amination can also occur at position 6 when a leaving group (Cl,SCH <sub><font size="-1">3</font></sub> ) is present at position 8. ii. In the last-mentioned system a <em>tele</em> substitution is possible besides the S <sub><font size="-1">N</font></sub> (AE) reaction. This reaction is exemplified in the conversion of 8-chloropurine into adenine (formed besides 8-chloro adenine). The σ-adduct at position 6 is protonated at position 8, after which dehydrohalogenation occurs (S <sub><font size="-1">N</font></sub> (AE) <em><sup><font size="-1">tele</font></SUP></em> , see Chapter 3). iii. If a leaving group is present at position 2 (Cl,F,SCH <sub><font size="-1">3</font></sub> ) the σ-adduct at position 6 undergoes ring opening of the pyrimidine ring with expulsion of the leaving group. The resulting imidazole derivative undergoes ring closure to give a 2-aminopurine. This type of reaction is referred to as an S <sub><font size="-1">N</font></sub> (ANRORC) mechanism and is described in Chapter 4.<p/>It has been established that in an S <sub><font size="-1">N</font></sub> (AE) mechanism the second step, involving the expulsion of the leaving group, is fast; the intermediary a-adduct cannot be observed. However, in the Chichibabin amination, <em>tele</em> amination and reaction according to the S <sub><font size="-1">N</font></sub> (ANRORC) mechanism, the second step is slow and therefore the σ-adduct can be observed by low temperature NMR spectroscopy.<p/>In Chapter 5 a new method is presented for the reductive removal of amino and alkylamino groups from position 6 of 9-substituted purines with sodium in liquid ammonia. The reaction involves reduction of the N(1) - C(6) bond, followed by elimination. This reaction is of special interest since the alternative method for the removal of amino groups i.e. the diazotization cannot be used with alkylamino groups. Therefore this new method is especially useful for the deamination of 6-(alkylamino)-9-substituted purines.<p/>In the last part of this thesis the occurrence of geometrical isomerism in the anions of aromatic amino compounds in liquid ammonia containing potassium amide is described. It is shown that this phenomenon occurs even in anilines, where the rotational barrier will be lower than in azaaromatic systems. This is confirmed by the occurrence of coalescence with increasing temperature (Chapter 6). The <sup><font size="-1">1</font></SUP>H and <sup><font size="-1">13</font></SUP>C NMR spectra of the anions of aminopyridines, aminopyrimidines and N-methylaminopyridines are assigned to the <em>syn</em> - and <em>anti</em> isomers. It has been revealed that in all these anions the <em>ortho</em> hydrogen atom in the s <em>yn</em> position relative to the lone pair resonates at a lower field than the hydrogen atom in the <em>anti</em> position. For the <sup><font size="-1">13</font></SUP>C NMR shifts of the <em>ortho</em> carbon atoms it was found that in the anions of N-methylaminopyridines the <em>ortho</em> carbon atom in the <em>syn</em> position relative to the lone pair resonates at lower field than the <em>ortho</em> carbon atom in the <em>anti</em> position. In the anions of aminopyridines and aminopyrimidines this phenomenon is reversed. We have also shown that the presence of a methyl group <em>ortho</em> to the anionic amino group causes a preference for the isomer, in which the proton of the NH group is in a <em>syn</em> position relative to the methyl group. This is explained in terms of the electron pair being "larger" than a proton, but it is possible that the preferred isomer is also stabilized by a better solvation and by an electronical effect.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
Award date6 May 1981
Place of PublicationWageningen
Publication statusPublished - 1981


  • amines
  • azines
  • chemical reactions
  • chemistry
  • kinetics
  • purines
  • pyridazines
  • pyrimidines
  • stereochemistry
  • isomers
  • heterocyclic compounds

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