Active Template Synthesis Research Articles

Synthesis of a [2]catenane by ring closing metathesis of a [2]rotaxane prepared by crown ether active templation.

The high yielding synthesis and spectral characterization of a [2]catenane prepared by Grubbs catalyzed ring closing metathesis of a [2]rotaxane prepared by crown ether active template synthesis is described.

Crown Ether Active Template Synthesis of Rotaxanes**

AbstractRotaxanes are interlocked molecules that consist of a macrocycle encircling a stoppered thread. The ability to control relative component positions makes rotaxanes ideal building blocks for constructing functional and responsive molecular machines. Despite the potential of rotaxanes, their challenging synthesis limits their application. One approach to construct rotaxanes is to use an active template synthesis, where a reaction that forms the thread is accelerated in the cavity of a macrocycle. An emerging method of active template synthesis that exploits the ability of crown ether macrocycles to accelerate simple organic reactions is discussed herein. Crown ether active template synthesis (CEATS) permits the rapid and simple synthesis of rotaxanes containing a wide range of functionality. Integrating rotaxane formation with chemical reaction networks has permitted the construction of molecular machines. The simplification of rotaxane synthesis will facilitate their widespread study and application.

Compact Rotaxane Superbases.

Challenges for the development of efficacious new superbases include their ease of synthesis, chemical stability, and high basicity, while minimizing nucleophilicity is important for reducing unwanted side reactions. Here, we introduce a new family of organic superbases, compact amine-crown ether rotaxanes, which show desirable characteristics in all these respects. Metal-free active template synthesis provides access to a range of rotaxanes with as little as three atoms between the stoppering groups, locking the location of a small crown ether (21C7 and 24C8 derivatives) over the amine group of the axle. The forced proximity of the interlocked protophilic components results in pKaH+ values as high as 32.2 in acetonitrile, which is up to 13 pKaH+ units greater than the pKaH+ values of the non-interlocked components, and brings the free base rotaxanes into the basicity realm of phosphazene superbases. The rotaxane superbases are generally chemically stable and, in a model reaction for superbases, eliminate HBr from a primary alkyl bromide with complete selectivity for deprotonation over alkylation. Their modest size, ease of synthesis, high basicity, low nucleophilicity, and, in the best cases, rapid substrate deprotonation kinetics and excellent hydrolytic stability make compact amine-crown ether rotaxane superbases intriguing candidates for potential applications in synthesis and supramolecular and materials chemistry.

Weak functional group interactions revealed through metal-free active template rotaxane synthesis

Modest functional group interactions can play important roles in molecular recognition, catalysis and self-assembly. However, weakly associated binding motifs are often difficult to characterize. Here, we report on the metal-free active template synthesis of [2]rotaxanes in one step, up to 95% yield and >100:1 rotaxane:axle selectivity, from primary amines, crown ethers and a range of C=O, C=S, S(=O)2 and P=O electrophiles. In addition to being a simple and effective route to a broad range of rotaxanes, the strategy enables 1:1 interactions of crown ethers with various functional groups to be characterized in solution and the solid state, several of which are too weak — or are disfavored compared to other binding modes — to be observed in typical host–guest complexes. The approach may be broadly applicable to the kinetic stabilization and characterization of other weak functional group interactions.

Spontaneous Assembly of Rotaxanes from a Primary Amine, Crown Ether and Electrophile.

We report the synthesis of crown ether-ammonium, amide and amine [2]rotaxanes via transition state stabilization of axle-forming reactions. In contrast to the two-step "clipping" and "capping" strategies generally used for rotaxane synthesis, here the components assemble into the interlocked molecule in a single, reagent-less, step under kinetic control. The crown ether accelerates the reaction of the axle-forming components through the cavity to give the threaded product in a form of metal-free active template synthesis. Rotaxane formation can proceed through the stabilization of different transition states featuring 5-coordinate (e.g., SN2) or 4-coordinate (e.g., acylation, Michael addition) carbon. Examples prepared using the approach include crown-ether-peptide rotaxanes and switchable molecular shuttles.

Efficient Multicomponent Active Template Synthesis of Catenanes.

We describe a simple and high yielding active template synthesis of [2]catenanes. In addition to mechanical bond formation using a single premacrocycle bearing an azide and alkyne moiety, our method is also suitable for the co-macrocyclization of readily available bis-alkyne and bis-azide comonomers and even short alkyne/azide components which oligomerize prior to mechanical bond formation.

2]Rotaxanes comprising a macrocylic Hamilton receptor obtained using active template synthesis: synthesis and guest complexation

A macrocyclic ring comprising multiple hydrogen-bonding sites as well as metal-chelating sites is shown to play the role of ligand in active templated, copper-catalysed [2]rotaxane formation via Huisgen and Glaser reactions. The crystallographic structure and copper ion binding studies are provided for the free macrocycle, along with molecular modelling, barbital, N,N′-trimethyleneurea and copper (I) binding information for the new rotaxanes.

Goldberg Active Template Synthesis of a [2]Rotaxane Ligand for Asymmetric Transition-Metal Catalysis.

We report on the active template synthesis of a [2]rotaxane through a Goldberg copper-catalyzed C-N bond forming reaction. A C2-symmetric cyclohexyldiamine macrocycle directs the assembly of the rotaxane, which can subsequently serve as a ligand for enantioselective nickel-catalyzed conjugate addition reactions. Rotaxanes are a previously unexplored ligand architecture for asymmetric catalysis. We find that the rotaxane gives improved enantioselectivity compared to a noninterlocked ligand, at the expense of longer reaction times.

CuAAC "click" active-template synthesis of functionalised [2]rotaxanes using small exo-substituted macrocycles: how small is too small?

Two "small" 22- and 24-membered exo-alcohol functionalised pyridyl macrocycles are exploited in the CuAAC active-template synthesis of [2]rotaxanes. The 24-membered macrocycle forms [2]rotaxanes in good yields while the smaller 22-membered macrocycle does not lead to interlocked products.

Synthesis of a C1-symmetric Box macrocycle and studies towards active-template synthesis of mechanically planar chiral rotaxanes

A C1-symmetric Box macrocycle has been synthesized for the first time. The Box macrocycle along with other C1 and C2-symmetric Box ligands were evaluated and compared as ligands in the Cadiot–Chodkiewicz, oxidative Heck and CuAAC ‘click’ reactions as part of our studies towards achieving active-metal template synthesis of mechanically planar chiral rotaxanes. This study constitutes the first report of Cadiot–Chodkiewicz and CuAAC ‘click’ reactions using Box ligands, as well as the first dedicated study of oxidative Heck reactions using Box ligands.

Diels−Alder Active-Template Synthesis of Rotaxanes and Metal-Ion-Switchable Molecular Shuttles

A synthesis of [2]rotaxanes in which Zn(II) or Cu(II) Lewis acids catalyze a Diels-Alder cycloaddition to form the axle while simultaneously acting as the template for the assembly of the interlocked molecules is described. Coordination of the Lewis acid to a multidentate endotopic 2,6-di(methyleneoxymethyl)pyridyl- or bipyridine-containing macrocycle orients a chelated dienophile through the macrocycle cavity. Lewis acid activation of the double bond causes it to react with an incoming "stoppered" diene, affording the [2]rotaxane in up to 91% yield. Unusually for an active-template synthesis, the metal binding site "lives on" in these rotaxanes. This was exploited in the synthesis of a molecular shuttle containing two different ligating sites in which the position of the macrocycle could be switched by complexation with metal ions [Zn(II) and Pd(II)] with different preferred coordination geometries.

Ligand-assisted nickel-catalysed sp3–sp3 homocoupling of unactivated alkyl bromides and its application to the active template synthesis of rotaxanes

An efficient, mild and operationally simple Ni-catalysed sp3-carbon-to-sp3-carbon homocoupling of unactivated alkyl bromides has been developed and utilised in the active metal template synthesis of an alkyl chain axle [2]rotaxane. The key to the transformation is the use of tridentate nitrogen-donor-atom (terpy or pybox derived) ligands which inhibit competing β-hydride elimination of alkyl-Ni intermediates.

Active Template Synthesis of Rotaxanes and Molecular Shuttles with Switchable Dynamics by Four‐Component PdII‐Promoted Michael Additions

Mach's mit Michael: Wiederholte Palladium(II)-vermittelte konjugierte 1,4-Additionen verknüpfen vier Komponenten in einem Eintopfverfahren in 99 % Ausbeute zu Rotaxanen (siehe Struktur) und molekularen Shuttles. Bei diesem Prozess handelt es sich um die erste Reaktion mit einem aktiven Templat, bei der das Templatmotiv im verzahnten Produkt erhalten bleibt.

Active Template Synthesis of Rotaxanes and Molecular Shuttles with Switchable Dynamics by Four‐Component PdII‐Promoted Michael Additions

Taking the Michael: Rotaxanes (see structure) and molecular shuttles are prepared in up to 99 % yield by successive PdII-promoted 1,4-conjugate additions in a one-pot four-component assembly process. This process represents the first active template reaction in which the template motif is retained in the interlocked product.