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Structural systematics of drug-like molecules: from benzamides to tennimides

Mocilac, Pavle (2012) Structural systematics of drug-like molecules: from benzamides to tennimides. PhD thesis, Dublin City University.

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Abstract

A structural systematic study was undertaken on benzamides, carbamates and substituted benzamide derivatives as 3×3 isomer grids comprising N-(pyridyl)benzamide (Fxx and Mxx) (x = para-/meta-/ortho-) and N-(phenyl)pyridinecarboxamide (NxxF and NxxM) grids. These were synthesised and characterised, with their crystal structures determined by single crystal X-ray diffraction. Five series of CxxR (R = CH3, OCH3, F, Cl, Br) carbamate isomer grids have been synthesised and characterised, with some pertinent structures determined by X-ray diffraction. Ab initio modelling, conformational analysis and comparisons of experimental solid state with optimised molecular geometries have facilitated an examination of the relationships between conformations and inter/intramolecular interactions, rationalisation of differences between the solid state and calculated structures, as well as the presence of molecular disorder and polymorphism. New classes of macrocycles have been developed including tetramers and trimers, based on our earlier research on benzamides and carbamates. These systems include various para-substituted derivatives (F, Cl, Br, CH3 CO2CH3) and have been fully characterized by 1H, 13C, 19F NMR and IR spectroscopy, while their crystal and molecular structures have been determined by single crystal X-ray diffraction. The development of tennimides and trezimides as new macrocycles based on an imide backbone, presents an important entry point into a potentially fruitful area. Furthermore, discovery of trezimides is especially important since no analogous macrocycle has been reported. Synthesis of tennimides and trezimides has been accomplished using a one-step synthetic strategy over a range of derivatives and presents a basis for synthesis of analogous macrocycles. Tennimides and trezimides proved to be rigid and stable compounds. The determining factors in the cyclisation are (i) the presence of the imide ortho-pyridine/pyrimidine rings and (ii) the inherent ability of the imide group to twist by 80-120°, as measured by the 'CO···CO' torsion angle, providing a 'hinge' for ring closure or helical assembly. The trezimides can adopt two distinct conformations in the solid state, (though one is preferred), whereas the tennimides adopt discrete conformational states as oc, cc and oo that highlight subtle macrocyclic geometric changes on cavity opening (o) and closing (c) (though these interconvert in solution).

Item Type:Thesis (PhD)
Date of Award:November 2012
Refereed:No
Additional Information:The thesis describes the structural systematic study of benzamides and carbamates in Chapters 1 and 2. Development of the benzamide research led to an entry point into two new classes of macrocycles namely trezimides and tennimides as detailed in Chapter 3.
Supervisor(s):Gallagher, John F.
Uncontrolled Keywords:Benzamides; Carbamates; Trezimides; Tennimides
Subjects:Physical Sciences > Organic chemistry
Physical Sciences > Chemistry
Physical Sciences > Crystallography
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Irish Government HEA PRTLI-T3 programme
ID Code:17256
Deposited On:26 Nov 2012 16:20 by John Gallagher. Last Modified 26 Nov 2012 16:20

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