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The self-association of caffeine in solution, driven by the hydrophobic effect, is a simple example of molecular aggregation. It obeys an isodesmic association model in which each successive binding occurs with the same equilibrium constant. Here, we describe an activity for chemistry students that explores this phenomenon using nuclear magnetic resonance (NMR) spectroscopy. By analyzing concentration-dependent chemical shift changes in the 1H NMR spectra of caffeine dissolved in D2O, students are introduced to uses of NMR spectroscopy beyond structure elucidation. They gain hands-on experience in quantifying supramolecular equilibria and consider their results in the context of molecular-level interactions. 

Despite their structural similarities, ortho-phenylenes and 2,3-quinoxalinylenes (i.e., poly(quinoxaline-2,3-diyl)s), well known as foldamers and helical polymers, respectively, exhibit distinctly different conformational behavior. o-Phenylenes tend to fold into compact helices with every fourth ring stacked, whereas 2,3-quinoxalinylenes favor extended helices with no backbone stacking. To understand this difference, we have studied short o-arylenes with different sequences of benzene and pyrazine units. Through a combination of crystallography, variable-temperature NMR spectroscopy, and DFT calculations, we find that pyrazines favor extended helical conformations as a result of two effects. First, within an o-arylene architecture, pyrazines experience weaker arene–arene interactions. Cofacial packing of the rings is therefore less favorable. Second, bipyrazine units lead to an increase in vibrational entropy for extended conformers. Consequently, at higher temperatures (including room temperature), extended helices are favored for the heterocycle-containing systems. 

Foldamers, oligomers that adopt well‐defined conformations, represent an efficient strategy toward nanoscale structural complexity. While most foldamers fold into helices, many abiotic foldamers are built from achiral repeat units and therefore do not have a preferred twist sense. Their handedness can, however, be controlled by attaching groups with chirality centers to the foldamer backbone. This process allows chiral information from readily available compounds to be amplified into larger‐scale structural asymmetry and translated into functional behavior. This review describes mechanisms whereby the point chirality of chiral “controller” groups directs foldamer twist sense. We highlight examples of aromatic oligoamides, oligohydrazides, oligoindoles, oligo(ortho‐phenylenes), oligooxymethylenes, and oligo(aminoisobutyric acids), examining cases where the controller groups are attached at either the helices’ termini or sides. Our emphasis is on applying intuitive concepts from conformational analysis and, where appropriate, computational modeling of small substructures. In each case, we consider first short‐range interactions that orient the controller group relative to its direct point of attachment to the foldamer, and then its long‐range interactions with more‐distant parts of the oligomer. Together, these interactions allow the twist sense to be predicted (or at least rationalized). Understanding these mechanisms should facilitate the design of systems with dynamic control over helicity. 

Chemical reactions that mimic the function of ATP hydrolysis in biochemistry are of current interest in nonequilibrium systems chemistry. The formation of transient bonds from these reactions can drive molecular machines or generate materials with time-dependent properties. While the behavior of these systems can be complicated, the underlying chemistry is often simple: they are therefore potentially interesting topics for undergraduate introductory organic chemistry students, combining state-of-the-art advances in systems chemistry with straightforward reactions. Here, a teaching experiment has been developed that explores the transient assembly of benzoic acid derivatives driven by carbodiimide hydration. Working in teams, students examine the formation and decomposition of anhydrides from two benzoic acids using a carbodiimide “fuel”. The students examine classic reaction kinetics of anhydride hydrolysis using two independent methods, NMR and IR spectroscopies. They then explore how the amount of carbodiimide affects the lifetimes of precipitates of benzoic anhydride as a simple example of out-of-equilibrium self-assembly. 

The self-assembly of foldamers into macrocycles is a simple approach to non-biological higher-order structure. Previous work on the co-assembly of ortho -phenylene foldamers with rod-shaped linkers has shown that folding and self-assembly affect each other; that is, the combination leads to new emergent behavior, such as access to otherwise unfavorable folding states. To this point this relationship has been passive. Here, we demonstrate control of self-assembly by manipulating the foldamers' conformational energy surfaces. A series of o -phenylene decamers and octamers have been assembled into macrocycles using imine condensation. Product distributions were analyzed by gel-permeation chromatography and molecular geometries extracted from a combination of NMR spectroscopy and computational chemistry. The assembly of o -phenylene decamers functionalized with alkoxy groups or hydrogens gives both [2 + 2] and [3 + 3] macrocycles. The mixture results from a subtle balance of entropic and enthalpic effects in these systems: the smaller [2 + 2] macrocycles are entropically favored but require the oligomer to misfold, whereas a perfectly folded decamer fits well within the larger [3 + 3] macrocycle that is entropically disfavored. Changing the substituents to fluoro groups, however, shifts assembly quantitatively to the [3 + 3] macrocycle products, even though the structural changes are well-removed from the functional groups directly participating in bond formation. The electron-withdrawing groups favor folding in these systems by strengthening arene–arene stacking interactions, increasing the enthalpic penalty to misfolding. The architectural changes are substantial even though the chemical perturbation is small: analogous o -phenylene octamers do not fit within macrocycles when perfectly folded, and quantitatively misfold to give small macrocycles regardless of substitution. Taken together, these results represent both a high level of structural control in structurally complex foldamer systems and the demonstration of large-amplitude structural changes as a consequence of a small structural effects.