(Self) assembled news: recent highlights from the Supramolecular Chemistry literature (Quarter 3, 2023)

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No more phosphate phrustration for anion transport

Phosphate, which exists as a mixture of H₂PO₄^– and HPO₄^2– at neutral pH, is a crucial biological anion. This pH dependency, as well as a relatively high hydration enthalpy and a tendency to self – associate [1] make it difficult to design hosts for. Indeed, until now, no synthetic transporters had been reported for this anion. Recently however, Hennie Valkenier and co-workers described a strapped calix[4]pyrrole that can transport this anion across lipid membranes [2]. The receptor incorporates eight N – H hydrogen bond donors, four from the calix[4]pyrrole and four from a bis-urea strap (Figure 1). Initial anion binding titrations in 0.5% H₂O in DMSO revealed that the receptor was highly selective for H₂PO₄^– over Cl^– and bound H₂PO₄^– much more strongly than the parent calix[4]pyrrole, which displays negligible H₂PO₄^– binding.

Figure 1. Chemical structure and molecular model of Valkenier and co-workers’ phosphate transporter.

The team reported two different approaches to measure transport: either using ³¹P NMR spectroscopy, or using a selective phosphate sensor reported by Stephen Butler and his team [3]. These assays revealed that the receptor functions by three different mechanisms: as a uniport in the presence of valinomycin (transporting H₂PO₄^– into the vesicle with valinomycin transporting K⁺ to maintain charge balance), as a H₂PO₄^–/Cl^– antiport (transporting H₂PO₄^– in and Cl^– out), or as a Cs⁺/H₂PO₄^– symport (transporting H₂PO₄^– and Cs⁺ together). A study of the pH-dependence of anion transport revealed that H₂PO₄^– is transported in preference to the more hydrophilic anion HPO₄^2–.

Subtle variations tweak pseudorotaxane selectivity

Aromatic amide-based ‘aramide’ macrocycles [4] have a rich host – guest chemistry, and are known to form [2]pseudorotaxanes and [3]pseudorotaxanes where one or two aramide macrocycles are threaded by a guest [5]. In a recent paper, Lihua Yuan and colleagues demonstrated how very subtle differences in guest structure can tip the balance from [2] to [3]pseudorotaxane formation [6]. They studied the interaction of an aramide macrocycle with four different threads, which contained two pyridinium groups separated by C₄, C₆, C₈ or C₁₀ alkyl chains. When small alkyl chains (C₄ or C₆) were used, [2]pseudorotaxanes were formed, however adding just two extra carbons to give the C₈-containing thread resulted in formation of the [3]pseudorotaxane. There was negative cooperativity in binding, i.e. binding of the first macrocycle disfavoured binding of the second (cooperativity factor, α = 0.09) although this was still quite favourable with K₂ = 2,600 M⁻¹. When the longest C₁₀ thread was used, [3]pseudorotaxanes were again formed, but now with positive cooperativity (α = 5.5). It is remarkable that such subtle changes in thread structure give such dramatically different association properties.

Switching on enzymatic γ-cyclodextrin synthesis

Cyclodextrins are some of the oldest known macrocycles, and exist primarily as α-, β-, and γ-cyclodextrins comprised of six, seven and eight glucose monomers, respectively. As the most soluble of the common cyclodextrins, γ-cyclodextrin is potentially the most useful but is typically difficult to produce and purify. Sophie Beeren’s group has previously shown that subjecting cyclodextrins or linear α-1,4-glucan to the enzyme CGTase establishes a Dynamic Combinatorial Library of cyclodextrins [7], which can be biased by addition of guests that bind to one specific macrocycle. The library is kinetically trapped, as the ultimate thermodynamic product is glucose, but it is stable for usefully long periods of time.

In recent work, the group showed that the cis form of a photoswitchable diazo template binds strongly to γ-cyclodextrin and can thus bias the library towards this macrocycle, while the trans form displays negligible binding [8]. The photoswitchable template does not bias the library to the γ-macrocycle quite as effectively as previous templates reported in the group (which can give > 99% selectivity [7]), but the procedure has two major advantages. Firstly, heating the library both denatures the enzyme stopping further equilibration and also causes cis-to-trans isomerisation of the photoswitch, releasing it from the macrocycle. Secondly, adding acid to the system precipitates the template, which can then be isolated and re-used.

In brief

Prize for women in supramolecular chemistry network

The Women in Supramolecular Chemistry network (WISC) was launched in 2019 as an area-specific and community-led project aiming to support women and other marginalised groups within supramolecular chemistry [9]. WISC recently won the Hildegard Hamm-Brücher Award from the Gesellschaft Deutscher Chemiker (GDCh, the German Chemical Society). This award, which includes a substantial cash prize, honours ‘exemplary behaviour in promoting more equal opportunities in chemistry.’ More information about WISC and their projects and publications can be found at their website, www.womeninsuprachem.com.

Circular sandwiches

Peter Roesky and colleagues have reported the challenging synthesis of nanoscale, circular sandwich complexes dubbed ‘cyclocenes’ [10]. While 1D polydecker sandwich complexes were previously known, here the authors have introduced a bend in each sandwich subunit in order to form a closed loop. They achieved the required bend using cyclooctatetraenide (Cot^TIPS) ligands with sterically bulky substituents. Reaction with divalent alkaline earth and lanthanide iodides yielded cyclic, multidecker sandwich complexes of the general formula [cyclo-M^II(μ-η⁸:η⁸-Cot^TIPS)]₁₈ (Figure 2). Solid state analysis revealed that the rings had an inner diameter of roughly 17 Å, and outer diameters around 38 Å. This exciting new class of metallacycle could find myriad applications within supramolecular chemistry and beyond.

Figure 2. X-ray crystal structure of [cyclo-Sr^II(μ-η⁸:η⁸-Cot^TIPS)]₁₈, (disorder and hydrogen atoms omitted for clarity).

Multifunctional SCCs for theranostics

Casini and co-workers have added both radiolabelling and biological targeting functionality to Supramolecular Coordination Complexes (SCCs) [11]. They synthesised a ligand including a cyclic peptide that targets the somatostatin-2 receptor [12] (over-expressed in a variety of tumours) and a DOTA [13] chelator for binding to ¹⁷⁷Lu³⁺, and studied a range of resulting SCCs formed with Pd²⁺. Importantly they considered strategies to improve the stability of the SCCs in biological media, with heteroleptic cage-like assemblies showing the most promise. This work could pave the way for combined theranostic applications of multifunctional SCCs.

AI mines the MOF literature

Yaghi and co-workers have created a ‘ChatGPT Chemistry Assistant’ which can reliably mine and tabulate synthetic information from the scientific literature [14]. Their prompt engineering workflow combines three different text mining processes, programmed by ChatGPT itself. Here they used the workflow to collate diverse conditions for MOF syntheses, incorporating 11 synthesis parameter variables (such as temperature, solvent and crystallisation method) and one synthesis outcome target (the formation of single crystals). They found that the data could be used to build predictive models for reaction outcomes and learned key insights into obtaining highly crystalline MOF samples. They were also able to derive accurate answers from their ‘Chemistry Assistant’, enabling a data-to-dialogue transition. There is great potential for similar workflows to accelerate the research process within other fields of chemistry.

Disclosure statement

Cally Haynes is a Vice Chair of WISC. The section on their recent prize was conceived and written by Nicholas White.