Rationally Designing Regiodivergent Dipolar Cycloadditions: Frontier Orbitals Show How To Switch between [5 + 3] and [4 + 2] Cycloadditions

A pyridinium zwitterion substrate is employed with two different types of transition metal catalysts to develop a regiodivergent cycloaddition. The pyridinium zwitterion is a highly reactive dipolar substrate that can undergo a dipolar cycloaddition with various reactants. It has multiple reaction sites, and the chemoselectivity is determined by the electronic demand of the catalyst–substrate complex. The reaction with nucleophilic Pd reagents affords fused N-heterocyclic compounds via regioselective [4 + 2] cycloaddition. The origin of the site selectivity and the mechanism of this reaction are investigated in this combined experimental and computational study. We found that the pyridinium zwitterion plays a completely different role in the palladium(0)-catalyzed [4 + 2] cycloaddition reaction and in the rhodium­(II)-catalyzed [5 + 3] cycloaddition, which was examined experimentally in a previous study. The frontier molecular orbitals of the pyridinium substrate and activated catalyst complex reveal that the pyridinium zwitterion can act as both a nucleophile and an electrophile depending on the reaction partner in a manner much more defined than that of conventional substrates, leading to the observed regiodivergent chemical reactivity

Room-Temperature Ring-Opening of Quinoline, Isoquinoline, and Pyridine with Low-Valent Titanium

The complex (PNP)­TiCH^<i>t</i>Bu­(CH₂^<i>t</i>Bu) (PNP = N­[2-P^<i>i</i>Pr₂-4-methyl­phenyl]₂^–) dehydrogenates cyclo­hexane to cyclo­hexene by forming a transient low-valent titanium-alkyl species, [(PNP)­Ti­(CH₂^<i>t</i>Bu)], which reacts with 2 equiv of quinoline (<b>Q</b>) at room temperature to form H₃C^<i>t</i>Bu and a Ti­(IV) species where the less hindered C₂N₁ bond of <b>Q</b> is ruptured and coupled to another equivalent of <b>Q</b>. The product isolated from this reaction is an imide with a tethered cyclo­amide group, (PNP)­TiN­[C₁₈H₁₃N] (<b>1</b>). Under photolytic conditions, intra­molecular CH bond activation across the imide moiety in <b>1</b> occurs to form <b>2</b>, and thermolysis reverses this process. The reaction of 2 equiv of isoquinoline (<b>Iq</b>) with intermediate [(PNP)­Ti­(CH₂^<i>t</i>Bu)] results in regio­selective cleavage of the C₁N₂ and C₁H bonds, which eventually couple to form complex <b>3</b>, a constitutional isomer of <b>1</b>. Akin to <b>1</b>, the transient [(PNP)­Ti­(CH₂^<i>t</i>Bu)] complex can ring-open and couple two pyridine molecules, to produce a close analogue of <b>1</b>, complex (PNP)­TiN­[C₁₀H₉N] (<b>4</b>). Multi­nuclear and multi­dimensional NMR spectra confirm structures for complexes <b>1</b>–<b>4</b>, whereas solid-state structural analysis reveals the structures of <b>2</b>, <b>3</b>, and <b>4</b>. DFT calculations suggest an unprecedented mechanism for ring-opening of <b>Q</b> where the reactive intermediate in the low-spin manifold crosses over to the high-spin surface to access a low-energy transition state but returns to the low-spin surface immediately. This double spin-crossover constitutes a rare example of a two-state reactivity, which is key for enabling the reaction at room temperature. The regio­selective behavior of <b>Iq</b> ring-opening is found to be due to electronic effects, where the aromatic resonance of the bicycle is maintained during the key CC coupling event