Michel Gravel’s research while affiliated with University of Saskatchewan and other places

An expedient method to prepare thiazolium salts using the P2S5-Py2 complex or P4S10 has been studied. A variety of thiazolium salts can be rapidly accessed by the clean reaction between readily available α-formamido ketones and these reagents. The pure thiazolium salts are obtained via simple filtration followed by salt metathesis with sodium tetrafluoroborate or sodium tetraphenylborate. The method is suitable for a variety of substituents on the heterocycle. The use of these reagents confers a practical advantage over the use of Lawesson’s reagent, making the purification of the thiazolium salt straightforward.

Natural bond orbitals (NBOs) provide the familiar Lewis type (2c–2e⁻) localized description of a molecule. Interactions between nearly filled (2e⁻ π or σ) orbitals and empty (π* or σ*) anti‐bonding orbitals represent delocalization in the system and creates a framework to study stereoelectronic interactions. Here we show that deleting the interactions (NBODel) between π and π* orbitals in aromatic systems and acquiring the energy with the NBO program provides a highly intuitive and quantitative picture of π‐aromaticity that correlates with the well‐established nucleus‐independent chemical shift (NICS) method. This natural bond orbital resonance energy (NBO‐RE) measures the vertical resonance energy (VRE) of aromatic systems without the use of an external reference structure. The NBO‐RE method is applicable to the study of local aromaticity in polycyclic aromatic hydrocarbons (PAHs) and other non‐planar systems.

N-Heterocyclic carbene (NHC) organocatalyzed transformations of redox-active chemical manifolds is a powerful strategy for interconverting and expanding the chemical space. This approach in the context of ring expansion holds promise for preparing lactones from plentiful redox active aldehydes, despite a lack of rigorous mechanistic insights into the underlying elements governing this reactivity and with-it relevance to other NHC organocatalyzed transformations. Herein, in investigating this reactivity under the lens of modern day quantum mechanical calculations, we explore the mechanism of redox-active/ring expansion reactions of aldehydes furnishing lactone products by means of NHC organocatalysis. Through this comprehensive study, the underpinning mechanism of Breslow intermediate formation and ensuing downstream processes such as intermolecular C-C bond formation providing benzoin products versus intramolecular redox pathways are outlined. Notably, this study of NHC organocatalysis reveals the diverse role of bases as cooperative agents in directing and selectively routing reactivity, as highlighted here toward ring expanded lactone products.

An expedient method to prepare thiazolium salts using the P2S5-Py2 complex or P4S10 has been studied. A variety of thiazolium salts can be rapidly accessed by the clean reaction between readily available α-formamido ketones and these reagents. The pure thiazolium salts are obtained via simple filtration followed by salt metathesis with sodium tetrafluoroborate or sodium tetraphenylborate. The method is suitable for a variety of substituents on the heterocycle. The use of these reagents confers a practical advantage over the use of Lawesson’s reagent, making the purification of the thiazolium salt straightforward.

In this work we describe the synthesis of a long sought after planar [10]annulene. Remarkably, the efforts also led us to discover a completely unexpected and highly aromatic cyclopropa mono-trans[10]annulene. The parent [10]annulene (cyclodecapentaene) is non-planar and thus non-aromatic because the aromatic stabilization energy is not sufficient to overcome the strain involved in expanding CCC bond angles from the standard 120° to the necessary 144°. Interestingly, it was theorized by Schleyer (10.1021/ja953126i) that planar structures could be attained by adding cyclopropane (or cyclobutane) rings to the periphery. We opted to target the dicyclopropa[10]annulene derivative that was proposed as it was a formal cyclopropanation of our previously found stable dehydrocyclopropa[10]annulene (10.1038/s44160-022-00135-z, 10.26434/chemrxiv.14458653.v1). It was also presumed that the symmetry present within the structure would make the Kekulé structures degenerate, thus improving aromaticity substantially. However, we were uncertain if the structure would be kinetically stable and wished to attempt a synthesis to investigate it further. In this paper we describe our evolving synthetic strategy that ultimately led us to the preparation of the dicyclopropa[10]annulene. Interestingly we noted that the framework itself was rather unstable and degraded quite rapidly. We also observed that the final preparation of the desired material led to a significant side product that was identified as a cyclopropa mono-trans[10]annulene. This side product was completely unexpected and found to be more kinetically persistent than the original target.

Natural bond orbitals (NBOs) provide the familiar Lewis type (2c-2e-) localized description of a molecule. Interactions between nearly filled (2e-) orbitals and empty (π* or σ*) anti-bonding orbitals represent delocalization in the system and creates a framework to study stereoelectronic interactions. Here we show that deleting the interactions between π and π* orbitals in aromatic systems and acquiring the energy with the NBO program provides a highly intuitive and quantitative picture of π-aromaticity that correlates with the well-established nucleus-independent chemical shift (NICS) method. This natural bond orbital resonance energy (NBO-RE) measures the vertical resonance energy (VRE) of aromatic systems without the use of an external reference structure. The NBO-RE method is applicable to the study of local aromaticity in polycyclic aromatic hydrocarbons (PAHs) and other non-planar systems.

A route for the synthesis of 1,2,4-triazolium salts via oxidation of a thione precursor is demonstrated. N-Pentafluorophenyl-substituted salts are produced in 20-63% overall yields. Isolation and purification of the azolium salts are simplified compared to the traditional synthetic route. Late-stage selection of the counterion allows the synthesis of a variety of salts from a parent thione. The salts have been compared in Stetter and cross-benzoin reactions with an appreciable counterion effect in both reactions.

Aromaticity is a phenomenon that is linked to the improved stability of organic compounds. Its occurrence is predicted by Hückel’s rule, which states that an aromatic compound must be flat, fully conjugated and have (4n + 2) π electrons. The most encountered aromatic structure is the benzenoid ring, which is observed in a wide variety of pharmaceuticals and organic materials. Expanded monocyclic structures are also of substantial interest as they would allow one to experimentally investigate the relationships between aromaticity, stability, reactivity and ring size. However, larger rings such as [10]annulene are often non-planar and non-aromatic due to angle strain present in their planar conformation. Inspired by earlier computational work, we show here that the presence of both a fused cyclopropane and an internal alkyne in a [10]annulene framework provides a planar and highly aromatic structure. The resulting dehydro[10]annulene is bench stable and can be stored for extended periods of time. [10]annulene derivatives are typically non-planar and non-aromatic, with aromatic planar variants suffering from kinetic instability. Now, the synthesis of a planar and aromatic dehydro[10]annulene featuring a fused cyclopropane and an internal alkyne is reported. The resulting hydrocarbon is bench stable and can be stored for extended periods of time.

As the next neutral structure following Hückels rule, a planar and aromatic [10]annulene is ideal to study the link between ring size and aromaticity. However, the puckered geometry of the parent [10]annulene suggests that the aromatic stabilization energy is not sufficient to overcome the ring strain that exists when the system is forced into planarity. It has been shown computationally that this ring strain can be alleviated through the addition of two or more cyclopropane rings to the periphery, thereby creating theoretically aromatic structures. An alternative strategy to eliminating the issue of ring strain was demonstrated experimentally with the successful preparation of the highly aromatic 1,6-didehydro[10]annulene. However, the system rapidly cyclizes at -40°C to a naphthalene diradical due to the close proximity of the in-plane p-orbitals present in the system. Here we show that cyclopropanating one side of the unstable annulene successfully prevents the destabilizing cross-ring interaction while maintaining a highly aromatic structure. Remarkably, the formed [10]annulene is bench stable and can be stored for extended periods of time.<br