How Robust Is the Reversible Steric Shielding Strategy for Photoswitchable Organocatalysts?

Abstract

A highly appealing strategy to modulate a catalyst’s activity and/or selectivity in a dynamic and noninvasive way is to incorporate a photoresponsive unit into a catalytically competent molecule. However, the description of the photoinduced conformational or structural changes that alter the catalyst’s intrinsic reactivity is often reduced to a handful of intuitive static representations, which can struggle to capture the complexity of flexible organocatalysts. Here, we show how a comprehensive exploration of the free energy landscape of N-alkylated azobenzene-tethered piperidine catalysts is essential to unravel the conformational characteristics of each configurational state and explain the experimentally observed reactivity trends. Mapping the catalysts’ conformational space highlights the existence of false ON or OFF states that lower their switching ability. Our findings expose the challenges associated with the realization of a reversible steric shielding for the photocontrol of Brønsted basicity of piperidine photoswitchable organocatalysts.

From Organic Fragments to Photoswitchable Catalysts: The OFF–ON Structural Repository for Transferable Kernel-Based Potentials

“…To demonstrate the power of this approach, we revisit the conformational behavior of two N-alkylated azobenzene-tethered piperidine photoswitches (PS1 and PS2, Figure ), which catalyze the Henry reaction of nitroalkanes and aldehydes. , The steric shielding of the piperidine lone pair and, therefore, the catalytic activity are controlled by the light-driven ( E )-to-( Z )-isomerization process, with the ( Z )-isomer being the catalytically active species (i.e., the “ON” state). As recently shown by our group, the lack of highly structured configurations decreases the effectiveness of the steric shielding strategy. This leads to a population of false ON and false OFF states in both the ( E )- and ( Z )-configurations that lead to activation/deactivation of the catalyst, even without a formal configurational change.…”

“…Particularly, it is not only the unique chemical components but also the dynamic movements of these organic molecules that are intrinsically linked to their functionality (e.g., the flexible nature of organocatalysts influences both selectivity and reactivity). , Such problems are particularly well illustrated by photoswitchable organocatalysts (i.e., photochromic molecules featuring a catalytic site that can be toggled between two stereoelectronic states with different reactivities and flexibilities when acted upon by appropriate wavelengths of light). − While data-driven discovery pipelines exist to engineer molecular photoswitches with desired photophysical properties, − fewer studies have focused on investigating chemical reactivity as a function of the rich conformational and configurational behavior of these organocatalysts. Add to this the requirement that each configurational state [e.g., ( E )- or ( Z )-isomer] uniquely corresponds to an “ON” or “OFF” reactivity state, and it becomes clear that a thorough description of conformational states is needed to fully grasp the catalytic properties. In such cases, accurate MD simulations with enhanced sampling techniques are necessary since the energetic ordering of conformations is dictated by the subtle interplay between full entropic and anharmonic contributions, noncovalent interactions, and environmental effects.…”

Dithienylethene-Based Photoswitchable Phosphines for the Palladium-Catalyzed Stille Coupling Reaction

“…Because of their fundamental role in modern synthetic chemistry, transition metal complexes are among the principal targets of photoswitchable catalysis. − Reversible light control of the catalytic activity of these compounds is generally accomplished by introducing photochromic ligands (e.g., photoswitchable phosphines). In most of the cases, the geometrical changes that these ligands undergo upon photoisomerization cause catalyst reactivity modulation, − for instance, by distorting the structure around the catalytic site − or varying the separation distance between two cooperative active metal centers. , However, the actual impact of these effects on catalytic activity and selectivity can be detrimentally affected by catalyst conformational flexibility and be dependent on substrate size and geometry. An alternative, less exploited approach to light-control the performance of transition metal catalysts is to capitalize on the electronic changes that occur upon ligand photoisomerization. − For this strategy, dithienylethenes (DTEs) are the photochromic units of choice because, in contrast to azobenzenes and stilbenes, they undergo a large modification in electronic structure when reversibly toggling between their ring-open ( o ) and ring-closed ( c ) isomers …”

“…In most of the cases, the geometrical changes that these ligands undergo upon photoisomerization cause catalyst reactivity modulation, 15 − 17 for instance, by distorting the structure around the catalytic site 19 − 21 or varying the separation distance between two cooperative active metal centers. 22 , 23 However, the actual impact of these effects on catalytic activity and selectivity can be detrimentally affected by catalyst conformational flexibility 24 and be dependent on substrate size and geometry. An alternative, less exploited approach to light-control the performance of transition metal catalysts is to capitalize on the electronic changes that occur upon ligand photoisomerization.…”

Electronic Influences on the Dynamic Range of Photoswitchable Dithienylethene–Thiourea Organocatalysts

“…Over the last two decades, many organocatalysts have challenged their metal counterparts by being cheaper, environmentally benign, as well as air-stable, and moisture insensitive. − However, despite the advances in the field, there are only a few reports of photoswitchable organocatalysis, − and the use of DTE is even rarer. ,,− Dithienylethene-based organocatalysts utilize azole, N-heterocyclic carbenes, , pyridine, and pyridinium ions, ,, which do not rely on noncovalent interactions with their substrate as is the case for the thiourea moiety. , Photoswitchable thiourea organocatalysts, on the other hand, have only been reported with azobenzene as the switching module . However, thermal reversibility and the need for prolonged ultraviolet (UV) irradiation plague these derivatives and limit their practical use.…”