Five-membered heterocycles as novel molecular scaffolds for targeting triple hydrogen bonding interactions

  • Simone Armani

Student thesis: Doc typesDoctor of Sciences


Due to its prominent directionality and strength, H-bonds are ones of the most widely used non-covalent interactions in supramolecular chemistry. Despite its relative high strength (energy of an H-bond in the gas phase typically ranges between 0−5 Kcal mol−1) in comparison with other non-covalent interactions, association of two molecules by means of a single H-bond leads to complexes displaying low thermodynamical stabilities, thus limiting their exploitation in the non-covalent synthesis of functional materials for real-world applications. Thereby, when stronger interactions are required, the general engineering approach focuses on the covalent synthesis of rigid planar molecular scaffolding in which several H-bonding donating (D) and accepting (A) moieties are arranged into a so-called ‘H-bonding array’. Due to the selective recognition processes and to the tunability of their association strength, multiple H-bonding arrays have become an indispensable molecular module in the tool-box of supramolecular chemists, allowing, through selective self-assembly and/or self-organization processes, the bottom-up preparation of functional materials such as liquid crystals, patterned surfaces and supramolecular polymers. In principle, the stability of H-bonded supramolecular complexes could be modulated in an indefinite number of ways. For example, when stronger interactions (e.g., higher association constant values) are required, the increase of the number of the H-bonding sites represents one of the efficient strategy to reinforce the stability of the ultimate assembly. Nevertheless, a strong Ka value is not always requested. In fact, whilst highly stable complexes are required in the field of supramolecular polymers, whose properties at the molecular level (such as degree of polymerization, Dp, and viscosity) result linearly correlated to the Ka values, these may instead be detrimental for the construction of more sophisticated hierarchized nano-architectures, arising from a delicate interplay between internal (e.g. ii stacking, solvophobic/solvophilic interactions) and external (e.g. time, temperature, concentration, etc.) factors. The aim of this thesis is to design and synthesize novel triple H-bonding arrays (DAD, ADD and DDD) based on five-membered heteroaromatic rings. The proposed use of thiolyl, oxolyl, azolyl, and triazolyl scaffoldings for recognition systems, it is intended as a mean to better achieve the control on the binding properties and selectivity of triple H-bondind recognition arrays, allowing an easy tunability of the binding motifs. With the variation of the substituents and the heteroatom onto the hetero-aromatic rings, it has been intended to create a selection of versatile, structurally similar, host-guest pairs complexes that display different association constants (Ka) in order to better match the requirements of different supramolecular applications. Focusing on the most relevant factors that influence the association constants of hydrogen bonded complexes, in the first part of Chapter 1 the reader is introduced on how specific H-bonding arrays, featuring wide ranges of Ka values (spanning among eight orders of magnitude) can be designed. Subsequently, the second part is focused on the physical and chemical properties of a large variety of H-bonding assembled molecular modules that upon self-assembly and self-organization processes opened new ways towards novel fascinating applications. Figure 1 Designed H-bonding arrays based on 5-membered heterocycles. Chapter 2 deals with the description of the synthetic efforts undertaken towards the preparation of the DAD and DDD H-bonding arrays. The first two subsections (2.1-2) describe the rethrosynthetic approaches and the results of the unsuccessful methodological routes (through Buchwald-Hartwig amidation cross-coupling reactions, reduction of azido-derivatives and nucleophilic addition of organo-metallic reagents to isocyanate derivatives as produced through Curtius rearrangement) tackled to introduce amidic and/or ureidic functions at the 2-position of five-membered heteroaromatic rings. Several DAD H-bonding arrays based on thiolyl scaffolding were successfully synthesized (sections 2.3). Figure 2 Synthesized thiolyl DAD H-bonding arrays. In section 2.4 are presented the synthetic step undertaken in the attempt to generate DAD arrays based on oxalyl derivatives. Unfortunately the introduction of electron-donating groups such as amidic or carbamic functions to the ring led to very unstable intermediates, and thus the amido-oxolyl derivatives capable of recognition mediated by triple H bonding were never isolated. Figure 3 Synthesized oxolyl-protected DAD H-bond array. The synthetic strategies towards the synthesis of DDD arrays based on of azolyl scaffolding are described in section 2.5. Protected azolyl module 182 (see Figure 4) was synthesized in thirteen steps starting from the pyrrole module. Unfortunately, due to the complications encountered in the cleavage of the N-azolyl protecting group, the synthesis of the azolyl DDD H-bonding arrays based could not be finally accomplished. Figure 4 Synthesized azolyl-protected DDD H-bond array. Section 2.6 presents the synthesis of newly designed self-adapting ADD/DDD H-bonding array based on ureido-triazolyl scaffoldings. Exploiting the prototropic equilibrium of the triazole nucleus the modules synthesized are expected to show an ADD or a DDD arrangement of the binding sites depending on the H-bonding functionalities of the complementary guest used for the complexation. Figure 5 Synthesized triazolyl-based ureido H-bonding arrays. Prototropic self-adapting properties: from a DDD to a ADD H-bonding array. Due to solubility limitations in common organic solvents (e.g., CDCl3 and CD2Cl2), the molecular recognition ability in solution could not be studied and further modifications of the molecular structural properties are required.
Date of Award8 Apr 2011
Original languageEnglish
Awarding Institution
  • University of Namur
SupervisorDavide BONIFAZI (Supervisor), Enrico Dalcanale (President), Ivan Jabin (Jury), Tommaso Carofiglio (Jury) & Maurizio Prato (Co-Supervisor)


  • Hydrogen bonding
  • Five-membered heterocycles
  • Synthesis

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