Premium
Solid‐State Molecular Organization and Solution Behavior of Methane‐1,1‐Diphosphonic Acid Derivatives of Heterocyclic Amines: The Role of the Topochemical Ring Modification and the Intramolecular Hydrogen Bonds in Monosubstituted Piperid‐1‐ylmethane‐1,1‐diphosphonic Acids
Author(s) -
MatczakJon Ewa,
VidenovaAdrabińska Veneta,
Burzyńska Agnieszka,
Kafarski Paweł,
Lis Tadeusz
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200400348
Subject(s) - intramolecular force , hydrogen bond , chemistry , ring (chemistry) , methane , solid state , organic chemistry , polymer chemistry , molecule
The crystal structures of 3‐methylpiperid‐1‐ylmethane‐1,1‐diphosphonic ( 2 ), 4‐methylpiperid‐1‐ylmethane‐1,1‐diphosphonic ( 3 ), 2‐ethylpiperid‐1‐ylmethane‐1,1‐diphosphonic ( 4 ), and 2‐methylpiperid‐1‐ylmethane‐1,1‐diphosphonic ( 5 ) acids have been determined and are discussed with respect to their molecular organization and crystal‐packing preferences. The chair conformation, predominant also in solution, favors equatorial positioning of the bulky subsituents of the heterocyclic N and C atoms. The molecular geometry also provides access to intramolecular hydrogen‐bond formation between the axial protons located on the nitrogen atoms, as well as the carbon atoms closest to it, and phosphonic/phosphonate oxygen atoms. The molecules preferably arrange in monolayers, observed in all crystals with an exception of 3 . The layers are held in place in the third direction through van der Waals interactions. The analysis of two‐dimensional hydrogen‐bonded networks is concentrated on revealing how the substituent's topology of the molecule affects the solid‐state organization in well‐defined structures and is aimed at unraveling the consequences and the possible conformational changes by stepwise network disruption upon crystal dissolution in water. The solution NMR studies are focused on revealing the role that the topochemistry of the substituent plays for the stereodynamics in 2 – 5 . It is demonstrated that in constrast to piperid‐1‐ylmethane‐1,1‐diphosphonic acid ( 1 ), in which the ring inversion/rotation around the CN bond concerted with the NH⋅⋅⋅O hydrogen‐bond breaking/formation process leads to a mixture of two interconverting conformers, the concerted NH⋅⋅⋅O breaking/rotation/NH⋅⋅⋅O formation process in 2 and 3 allows for a predominance of one conformer in solution. However, placement of a substituent at 2‐position in the ring hampers the rotation around the CN bond; this makes 4 and 5 significantly less flexible relative to compounds 1 – 3 . In addition, both compounds 4 and 5 are proved to exist as a mixture of two conformers, the equilibrium of which in acidic solution is shifted towards the conformer found in solid state. In alkaline solutions of 4 and 5 , the equilibrium is shifted towards the conformer that is forced by the flipping of the heterocyclic ring. These results correlate well with recently documented differences in the biological potency of this group of compounds.