The use of secondary interactions between substrates and catalysts is ap romising strategy to discover selective transition metal catalysts for atom-economy CÀHb ond functionalization. The most powerful catalysts are found via trial-and-error screening due to the low association constants between the substrate and the catalyst in whichs mall stereoelectronic modifications within them can lead to very different reactivities.T ocircumvent these limitations and to increase the level of reactivity prediction in these important reactions,w e report herein as upramolecular catalyst harnessing Zn•••N interactions that binds to pyridine-like substrates as tight as it can be found in some enzymes.T he distance and spatial geometry between the active site and the substrate binding site is ideal to target unprecedented meta-selective iridium-catalyzed CÀHb ond borylations with enzymatic Michaelis-Menten kinetics,b esides unique substrate selectivity and dormant reactivity patterns.

The implementation of interactions beyond hydrogen bonding in the 2nd coordination sphere of transition metal catalysts is rare. However, it has already shown great promise in last 5 years, providing new tools to control the activity and selectivity as here reviewed.

Palladium-catalyzed Wacker-type reactions occupy a central place in organic synthesis with important implications in industry. Pursuing more benign protocols by replacing palladium with first-row transition metals allowed the identification of iron as a privileged one in the last few years. Although the anti-Markovnikov selectivity for iron catalysts is well developed, the Markovnikov-selective reactions still afford significant quantities of alcohol side-products, and identification of reaction intermediates has remained elusive so far. Herein, we present an iron catalyst that affords Markovnikov ketone products from (hetero)aromatic and aliphatic olefins in up to 99% selectivity under ambient conditions with 190,000 turnover numbers and turnover frequencies of 74 h −1 at 50 °C. The catalyst design is based on the promiscuous activity encountered in the family of the cytochromes P-450 enzymes, and it enables the formation of iron-hydride species under catalytically relevant reaction conditions. Substrate scope assessment and mechanistic investigations suggest that the Markovnikov-selective catalytic cycle competes with unprecedented three additional catalytic cycles (alcohol formation, hydrogenation, and reductive homo-coupling) depending on the nature of the olefin and the reaction conditions.

Non‐biological catalysts following the governing principles of enzymes are attractive systems to disclose unprecedented reactivities. Most of those existing catalysts feature an adaptable molecular recognition site for substrate binding that are prone to undergo conformational selection pathways. Herein, we present a non‐biological catalyst that is able to bind substrates via the induced fit model according to in‐depth computational calculations. The system, which is constituted by an inflexible substrate‐recognition site derived from a zinc‐porphyrin in the second coordination sphere, features destabilization of ground states as well as stabilization of transition states for the relevant iridium‐catalyzed C−H bond borylation of pyridine. In addition, this catalyst appears to be most suited to tightly bind the transition state rather than the substrate. Besides these features, which are reminiscent of the action modes of enzymes, new elementary catalytic steps (i. e. C−B bond formation and catalyst regeneration) have been disclosed owing to the unique distortions encountered in the different intermediates and transition states.

The Wacker reaction is the oxidation of olefins to ketones and typically requires expensive and scarce palladium catalysts in the presence of an additional copper co-catalyst under harsh conditions (acidic media, high pressure of air/dioxygen, elevated temperatures). Such a transformation is relevant for industry, as shown by the synthesis of acetaldehyde from ethylene as well as for fine-chemicals, because of the versatility of a carbonyl group placed at specific positions. In this regard, many contributions have focused on controlling the chemo-and regioselectivity of the olefin oxidation by means of well-defined palladium catalysts under different sets of reaction conditions. However, the development of Wacker-type processes that avoid the use of palladium catalysts has just emerged in the last few years, thereby paving the way for the generation of more sustainable procedures, including milder reaction conditions and green chemistry technologies. In this Minireview, we discuss the development of new catalytic processes that utilize more benign catalysts and sustainable reaction conditions.

Selective iridium-catalyzed C–H bond borylations of unbiased or directing-group-free substrates typically occur under long reaction times and mild temperatures in order to avoid unselective processes including catalyst deactivation. Herein, we describe a supramolecular approach that enables the C–H bond borylation of challenging pyiridines and imidazoles in very short reaction times (up to 2 h) with a negligible incubation period for catalyst activation. The catalyst is based on a highly rigid zinc–porphyrin substrate-recognition site in the secondary coordination sphere and a triazolopyridine chelating fragment attached to the first coordination sphere at iridium. The borylation occurs at the C–H bond from the substrate located at four chemical bonds apart from the molecular recognition site with the selectivity being exclusively imposed by the distance between the active site and the molecular recognition site regardless of the nature of the N,N-chelating fragment coordinating to iridium as further supported by density functional theory (DFT) calculations. Additional studies (control experiments, nuclear magnetic resonance, and single-crystal X-ray diffraction) unraveled key catalyst deactivation pathways in which up to three different partners (water, methoxide ligands from the iridium precursor, and the triazolopyridine fragment) compete with the N-heterocycle substrate for binding to the molecular recognition site of the supramolecular catalyst. This fundamental understanding made possible the identification of a supramolecular catalyst featuring a 4-methyl substitution pattern in the first coordination sphere at iridium that provides a suitable balance of steric and electronic effects in both primary and secondary coordination spheres, thereby bypassing the manifold catalyst deactivation pathways. DFT calculations further indicated the importance of noncovalent interactions beyond the molecular recognition site on the stabilization of the different intermediates and transition sates.

The use of secondary interactions between substrates and catalysts is a promising strategy to discover selective transition metal catalysts for atom‐economy C−H bond functionalization. The most powerful catalysts are found via trial‐and‐error screening due to the low association constants between the substrate and the catalyst in which small stereo‐electronic modifications within them can lead to very different reactivities. To circumvent these limitations and to increase the level of reactivity prediction in these important reactions, we report herein a supramolecular catalyst harnessing Zn⋅⋅⋅N interactions that binds to pyridine‐like substrates as tight as it can be found in some enzymes. The distance and spatial geometry between the active site and the substrate binding site is ideal to target unprecedented meta‐selective iridium‐catalyzed C−H bond borylations with enzymatic Michaelis–Menten kinetics, besides unique substrate selectivity and dormant reactivity patterns.

The Wacker reaction is the oxidation of olefins to ketones and typically requires expensive and scarce palladium catalysts in the presence of an additional copper co-catalyst under harsh conditions (acidic media, high pressure of air/dioxygen, elevated temperatures). Such a transformation is relevant for industry, as shown by the synthesis of acetaldehyde from ethylene as well as for fine-chemicals, because of the versatility of a carbonyl group placed at specific positions. In this regard, many contributions have focused on controlling the chemo-and regioselectivity of the olefin oxidation by means of well-defined palladium catalysts under different sets of reaction conditions. However, the development of Wacker-type processes that avoid the use of palladium catalysts has just emerged in the last few years, thereby paving the way for the generation of more sustainable procedures, including milder reaction conditions and green chemistry technologies. In this Minireview, we discuss the development of new catalytic processes that utilize more benign catalysts and sustainable reaction conditions.