Charles Romain

Oxetanes display properties comparable to ketone carbonyl groups and are increasingly explored as bioisosteres. However, does the comparison hold for the most common carbonyl derivatives: do amino-oxetanes resemble amides? Here, we present a matched molecular pair study of 12 3-aryl-3-amino-oxetane and benzamide matched molecular pairs to assess their viability as isosteres. Across the surveyed physicochemical properties (pH stability, solubility, lipophilicity, clearance, permeability), amino-oxetanes exhibited broadly comparable profiles to their amide counterparts. Amino-oxetanes maintain both the H-bond acceptor and H-bond donor capabilities of analogous amides. These findings support the potential of amino-oxetanes as amide replacements. However, crystal structure analysis highlights the conformational differences and alternative exit vectors available through introduction of the oxetane ring. The preferred gauche conformation makes the torsion angle and exit vectors of amino-oxetanes more similar to sulfonamides, and therefore better like-for-like topological replacements. Overall, amino-oxetanes present an attractive design option to modulate physicochemical properties and chemical topology.

The development of artificial intelligence and machine learning in chemistry is opening new avenues for data-driven discoveries. However, the application of such methodologies in polymer chemistry has been hampered due to the complex structure–properties relationship of polymers and the lack of (meta)data available. Recent efforts have been made to experimentally determine or computationally evaluate thermodynamic parameters associated with (de)polymerisation reactions, such as enthalpy and entropy of polymerisation, as well as ceiling temperature, to design polymers primed for chemical recycling. Here, we report TROPIC (Thermodynamics of Ring-Opening Polymerisation Informatics Collection), an open-source database harnessing experimental and computational thermodynamic parameters for ring-opening polymerisation (ROP) from the academic literature. TROPIC links thermodynamic parameters with the experimental conditions or the computation methodologies used to determine them, to allow further analysis. TROPIC can be accessed via an interactive website or application programming interface (API) and presents a first step towards facilitating the data-driven discovery of novel functional polymers.

Oxetanes have been established to display properties comparable to carbonyl groups in ketone derivatives and are increasing-ly explored as bioisosteres. However, does the comparison hold for other common carbonyl derivatives: do amino-oxetanes resemble amides? Here, we present a matched molecular pair study of twelve (12) 3-aryl-3-amino-oxetane and benzamide matched molecular pairs to assess their viability as isosteric replacements. Across the surveyed physicochemical properties (pH stability, solubility, lipophilicity, clearance, permeability), amino-oxetanes exhibited comparable profiles to their amide counterparts, while displaying improved solubility. The aryl amino-oxetane motif is more basic than an amide, yet offers significant reduction of amine basicity in comparison to the benzylamine. These findings support the potential of amino-oxetanes as amide replacements. However, analysis of crystal structures of the amino-oxetane and benzamide pairs highlights the conformational difference and alternative exit vectors available through introduction of the oxetane ring. Amino-oxetanes maintain both the H-bond acceptor and H-bond donor capabilities of analogous amides. Amino-oxetanes have significantly lower barriers to rotation, allowing for the potential to flexibly accommodate binding sites of interest. However, the preferred gauche conformation makes the torsion angle and exit vectors of amino-oxetanes more similar to sulfonamides, and on this basis amino-oxetanes provide better like-for-like topological replacements for sulfonamides rather than of amides. Overall, amino-oxetanes present an attractive design option to modulate physicochemical properties and explore chemical topology.

The microwave-assisted reaction of functionalized dihydroisoquinolines with Meldrum's acid unveiled a one-step, divergent access to rare polycyclic pyrimidinones and oxazinanediones. The outcome hinged on the identity of the C1 substituent (R) of the dihydroisoquinolines, where hydrogen favored pyrimidinones, while aryl and alkyl groups afforded oxazinanediones. DFT calculations elucidated the underlying mechanism of this divergence, revealing shared intermediates whose fate is dictated by the stereoelectronic properties of the R group.

Exploiting non-covalent interactions (NCIs) has become a powerful tool in catalyst design, including those for polymerisation reactions.