Jan Rohovec

Cyclam derivatives with methylphosphonic acid arms in position 1,8 and substituent R = H, Me, CH₂Ph in positions 4 and 11 are synthesised by Mannich reaction of an appropriate cyclam derivative, formaldehyde and phosphonic acid/diethyl phosphite followed by removal of protecting benzyl groups from nitrogen atoms. Mono(methylphosphonic acid) derivative of cyclam can be obtained by a similar route. Crystal structures of four phosphonic acid derivatives show the same ring conformation and orientation pendants due to strong intramolecular hydrogen bonds between phosphonate oxygen atoms and protonated nitrogen atoms adjacent over ethylene chains. The hydrogen bonds are stable even in aqueous solution. Activation parameters for destabilisation of the conformation are estimated from temperature-dependent NMR measurement. The protonation constants determined confirm the expected high basicity of the compounds and its dependence on the nitrogen atom substituents. The enhanced basicity of the nitrogen atoms non-bonded to methylenephosphonic acid moiety, is explained by the presence of the strong hydrogen bonds.

1-Alkyl and 1,8-dialkyl-1,4,8,11-tetraazacyclotetradecanes (alkyl = benzyl or methyl) were synthesised through cis-aminal of cyclam which was obtained by reaction of glyoxal and cyclam. The corresponding trans-aminal was synthesised from the respective linear tetraamine and glyoxal followed by cyclisation using 1,2-dibromoethane. The trans-aminal derivatives cannot be used for preparation of cyclam or its derivatives due to exceptional stability of the aminal bridge. The different reactivity of both cis- and trans-aminals is discussed on the basis of the X-ray structures determined for a series of the cyclam derivatives and could be explained by steric hindrance in the trans-aminals.