Product Distribution from Precursor Bite Angle Variation in Multitopic Alkyne Metathesis: Evidence for a Putative Kinetic Bottleneck

Abstract

In the dynamic synthesis of covalent organic frameworks and molecular cages, the typical synthetic approach involves heuristic methods of discovery. While this approach has yielded many remarkable products, the ability to predict the structural outcome of subjecting a multitopic precursor to dynamic covalent chemistry (DCC) remains a challenge in the field. The synthesis of covalent organic cages is a prime example of this phenomenon, where precursors designed with the intention of affording a specific product may deviate dramatically when the DCC synthesis is attempted. As such, rational design principles are needed to accelerate discovery in cage synthesis using DCC. Herein, we test the hypothesis that precursor bite angle contributes significantly to the energy landscape and product distribution in multitopic alkyne metathesis (AM). By subjecting a series of precursors with varying bite angles to AM, we experimentally demonstrate that the product distribution, and convergence toward product formation, is strongly dependent on this geometric attribute. Surprisingly, we discovered that precursors with the ideal bite angle (60°) do not afford the most efficient pathway to the product. The systematic study reported here illustrates how seemingly minor adjustments in precursor geometry greatly affect the outcome of DCC systems. This research illustrates the importance of fine-tuning precursor geometric parameters in order to successfully realize desirable targets.

The Chemistry of Porous Organic Molecular Materials

“…[191] The use of POCs as porous building blocks offers a comparable solution to this problem for molecular materials, although in some (rare) cases, self-catenation of organic cages can also occur, [192][193][194] and this does not always destroy porosity, as demonstrated by Mastalerz and co-workers. [195] There are several possible synthetic routes to POCs; imine condensation, [16,22,24,56,144,[146][147][148][196][197][198][199][200][201][202][203][204][205][206] alkyne methasis, [23,194,[207][208][209][210][211][212][213] and boronic ester condensation [122,195,[214][215][216] are the most commonly used (Figure 7a), although there is scope adopt other bond-forming chemistries. [217][218][219] POC synthesis has been discussed in several recent reviews, [6,8,143,…”

“…[6,8,183,219,220] By contrast, the use of irreversible chemical pathways to synthesize organic cages is rarer. [23,29,194,[207][208][209][210][211][212][224][225][226][227][228][229][230][231][232][233][234][235][236][237] However, metal-catalystassisted cross-coupling, [23,237,238] nucleophilic aromatic substitution, [234] "click chemistry," [235] and the Wittig reaction [236] are irreversible synthetic routes that have been developed for POC synthesis. More commonly, the design of new POCs has been focused on varying the geometry, the number of reactive groups, and the size of the organic precursor.…”

Macrocycles of higher ortho-phenylenes: assembly and folding

“…This is a straightforward application of the concept of the minimization of strain in the assembly of macrocycles and cages, well-known in both metal-coordination and dynamic covalent systems. [51][52][53][54][55] Both the relative stabilities of different o-phenylene folding states E rel and bite angles b are straightforward to predict using DFT optimizations. For simplicity and efficiency, and anticipating the more-complex deca(o-phenylene) systems discussed below, we decided to focus on the unsubstituted hexa(o-phenylene); while the substituents will certainly affect the stabilities of o-phenylene conformers, the trend in stabilities and the bite angles should be consistent.…”

Computationally-inspired discovery of an unsymmetrical porous organic cage

“…Both properties were calculated with the use of pyWindow, 35 a python package we have developed for the structural analysis of discrete porous molecules (see the Supporting Information for full details). To identify the most likely structural isomer of our synthesized cage, we applied the following criteria to successively narrow down the possibilities: (i) remove cages that are collapsed or that have cavities smaller than 3.64 Å, which corresponds to the kinetic diameter of N2, on the basis that sorption analyses suggest that the molecule contains an intrinsic void large enough to accommodate N2; (ii) remove candidates that fall outside the energy range of 60 kJ mol -1 from the lowest energy remaining isomer-this assumes that the lowest energy isomers are the most likely to be obtained experimentally (i.e., thermodynamic control), 36 but by having a large window, we also consider that there may be kinetic bottlenecks in the synthesis; 37 (iii) select only the isomers that are completely unsymmetrical and that therefore contain 12 unique imine environments, to match NMR observations; and, finally; (iv) select the structural isomer with the lowest mean absolute error (MAE) between calculated and experimental 1 H NMR chemical shifts.…”