Functionality (chemistry)

Résumé

In chemistry, functionality is the presence of functional groups in a molecule. A monofunctional molecule possesses one functional group, a difunctional two, a trifunctional three, and so forth. In organic chemistry (and other fields of chemistry), a molecule's functionality has a decisive influence on its reactivity. In polymer chemistry, the functionality of a monomer refers to its number of polymerizable groups, and affects the formation and the degree of crosslinking of polymers. Functionality in organic chemistry and material science In organic chemistry, functionality is often used as a synonym for functional group. For example, a hydroxyl group can also be called a HO-function. Functionalisation means the introduction of functional groups, for example

the functionalisation of a surface (e.g. silanization for the specific modification of the adhesion of a surface)
the functionalization of nanoparticles of a metal or metal oxide to stabilize such nanoparticle

Source officielle

https://en.wikipedia.org/wiki/Functionality_(chemistry)

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Cyclic peptide therapeutics fill the gap between small molecules (5000 Da) as a separate class of drugs, combining the advantages of both in terms of high selectivity, bioavailability, synthetic accessibility and low toxicity. However, their conformational flexibility and proteolytic instability results in fast metabolism. Therefore, modification of their chemical and structural properties at the proteolytically vulnerable sites can circumvent these deficiencies. Several strategies exist to stabilise peptides through local or global constraints, side chain functionalisation or amide bond surrogates. This thesis describes the development and application of two chemical transformations to peptides with the aim of greatly enhancing their metabolic stability either via side chain to side chain cyclisation or disulfide modification. Following the functionalisation, a comparative evaluation of the pharmacological properties of the modified peptides was conducted with respect to the parent peptides. The first cyclisation strategy aimed to apply the redox-neutral chemistry developed in the burgeoning field of borrowing hydrogen technology to peptides, as a new class of tolerable substrates. These would contain the requisite amine and alcohol functional groups enabling their direct coupling to form the lactam or N-alkylated cycle. Numerous investigations into this transformation with a plethora of substrates and catalysts did not lead to the desired cyclisation. For the second approach, a simple one-pot procedure for the 'stapling' of disulfide bonds in native peptides was developed. Tris(2-carboxyethyl)phosphine mediated reduction of the disulfide bond was followed by concomitant insertion of a 'doubly electrophilic' carbon bridge to form a physiologically stable dithioacetal bond. The reaction was performed under mild, biocompatible reaction conditions, allowing for the facile conversion of native peptides into more stable analogues. The protocol was applicable to a range of bioactive peptides with a multitude of reactive functional groups demonstrating the high versatility of this approach. The importance and utility of the modified analogues were verified by testing their binding affinity and biological activity against the corresponding parent peptides. The impact of the disulfide modification on these properties for each peptide were analysed on a case-by-case basis. The SCS modified analogues of Oxytocin and Vasopressin maintained binding affinities in the same order of magnitude as their respective parent compounds across all corresponding receptors. Nevertheless, this was not the case for SCS-Octreotide and SCS-Somatostatin. Those peptides which maintained comparable binding affinities were then tested for their functional activity at the receptors of biological interest. SCS-Oxytocin retained its agonist potency displaying sub-nanomolar activity at the Oxytocin receptor, whilst SCS-Vasopressin exhibited sub micromolar functional response at the Vasopressin 1A receptor. Then the stability of the modified peptides in human serum was evaluated. In some cases, the enhancement in serum stability was vastly increased. In particular our modified SCS-Oxytocin analogue clearly demonstrated a significant improvement in serum half-life, as well as heat and pH stability over its native parent form. This disulfide stapling method could have wide-reaching application for the development of more stable therapeutic analogues.

EPFL2016

Chargement

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons, they constitute privileged targets for the development of new and effective synthetic methods. The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular reactions have led to the development of tether systems that require additional steps for their introduction and removal. In situ tethering strategies have previously been explored within the Waser group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed carboetherification or amination reaction, leading to rapidly increase in complexity of simple substrates. So far, the in situ methodologies developed by the Waser group have focused on the functionalisation of alkenes from allylic amines and alcohols. In this regard, the goal of my PhD was to expand the in situ tethering methodologies established within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically, my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine, trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic required a change of ligand and base. The transformation was broadly tolerant towards substitution on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl furans. The identification of a sideproduct of the oxyalkynylation process led to the development of a carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation gave convenient access to diverse library of cyclic carbamates. Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2- amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially available Trost ligand.

EPFL2020

Chargement

Self-Healing Fiber-Reinforced Composites with Tailored Supramolecular Matrices

Federica Sordo

Fiber Reinforced Composites (FRCs), due to their intrinsic heterogeneity, are generally affected by complex multi-scale failure mechanisms leading to the formation of matrix cracks that are difficult to detect and repair. FRCs with the ability to heal and recover at least part of their initial properties after damage could present a solution to extend their lifetime and reliability. A possible approach is to introduce external healing agents in the matrix of the composite, through capsules or micro-channels, but this is often difficult to achieve in a high volume fraction reinforcement composite. An alternative approach is to rely on intrinsic self-healing polymers as matrices, which alleviates the need for additional phases beyond matrix and reinforcement. The present work investigated this second approach, by exploring for the first time the feasibility of processing glass fabric reinforced composites based on supramolecular hybrid network self-healing matrices and analysing their resulting properties and transfer of the self-healing ability to the composite. Hybrid networks based on epoxy chemistry, combining covalent cross-links and cooperative reversible hydrogen bonds, were selected as benchmark materials. These systems were charac- terized, in particular in terms of processing parameters and self-healing ability, and showed to be a-priori compatible with FRCs manufacturing techniques and demonstrated higher healing efficiency by increasing the H-bonds content in the polymer network, from none to 50%. On the other hand, networks characterized by large number of physical cross-links exhibited limited solvent and creep resistance, hindering their potential application. These issues were addressed by modifying the average functionality of the monomers through the combination of bifunctional and tetrafunctional epoxy resins in the compositions while keeping the use of a catalyst, leading to better controlled networks, both in terms of kinetics and final structure, and to propose a range of materials with several levels of compromise between self-healing efficiency, mechanical strength, creep resistance, and damping properties. In particular, 50% to 100% self-healing recovery of tensile properties were observed after one day, depending on the tetraepoxide content. In parallel, since the Tg of benchmark supramolecular hybrid net- works was in the range from 11-16 âŠC, an aliphatic diepoxide was introduced in the synthetic procedure to propose materials with a Tg down to -10 âŠC, to reach applications closer to those of elastomers. In view of FRCs development, the ability of partially supramolecular self-healing polymers to bond to inorganic reinforcements and to heal interfacial failure was then investigated: two dedicated butt joint-like and tack-like test methods were developed. Adhesion strength of the polymers cured on glass substrates decreased with increasing H-bonds content in the polymer networks (from 0 to 50 %) as the mechanical strength of the polymer also decreased, while the failure mechanism shifted from adhesive to cohesive due to the possibility to form hydrogen bonds with the glass substrates. Interface restoration through healing of the polymer matrices however increased from none to a strength recovery up to 70 % after 1 h healing time for the 50% H-bond polymer...

EPFL2016

Chargement

Self-Healing Fiber-Reinforced Composites with Tailored Supramolecular Matrices

Federica Sordo

EPFL2016

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

EPFL2020

EPFL2016