Serendipitous macrocycles

Dissolve ethylenediamine (0.67 mL, 0.6 g, 10 mmol) in methanol (50 mL). Prepare a solution of dimethyl 2,6-pyridinedicarboxylate (1.95 g, 10 mmol) in methanol (50 mL). A little gentle warming may be necessary for complete dissolution. Combine the solutions and agitate briefly to ensure complete mixing then leave the colourless solution at room temperature for 3 to 4 days, or until no further precipitation of colourless crystals is observed. Filter to isolate the white powdery tetralactam (14), as a methanol solvate. 

In 1967 Charles J. Pedersen, then 2 years away from retirement as a research chemist with Du Pont, published an extensive paper detailing the preparation of 33 cyclic polyethers [1], His thorough investigation of these macrocycles was the culmination of several years work initiated by the accidental preparation of dibenzo[18]crown-6 [2], The compound formed as a result of trace amounts of catechol that had contaminated 2-(hydroxyphenoxy)tetrahydropyran used in the synthesis of the original target compound, bis[2-(hydroxyphenoxy)ethyl]ether. The dibenzocrown ether thus became the first of the crown ethers, as Pedersen called them, to be isolated. 

The literature on crown ethers and their complexes is vast, with approximately 5000 papers citing the term as a key word, and the best introduction to their chemistry is through review articles and books [4-7]. Suffice to say that applications run the range from simple cation detection by piezoelectric sensors [8] to the detection of metals in blood [9] and the more complicated problems of neurotransmitter [10] and biologically relevant sugar derivatives [11]. 

Diethylene glycol [FLAMMABLE] Dry 1,4-dioxane [FLAMMABLE] Dichloromethane [TOXIC] 

Note This procedure should be carried out, wherever practical, in a fume hood as a large volume of flammable f-butanol is used. 

---

With the gift of hindsight, it is obvious that the majority of synthetic chemists would turn to macrocyclic compounds in the first instance for a ready source of molecular receptors. Indeed, this is exactly what has happened, although the most popular line (that concerned with macrocyclic polyethers) to date was to come on the scene serendipitously at just the right time. To their credit, synthetic chemists grasped the opportunity and wasted no time in developing the chemistiy of the crown ethers. 

In a serendipitous fashion, a novel mixed valence tetranuclear copper(II)/copper(III) dithiocarbamate [2]catenane was prepared in near quantitative yield by partial chemical oxidation of a preformed dinuclear copper(II) naphthyl dtc macrocycle (Scheme 6).49 X-ray structure, magnetic susceptibility, ESMS and electrochemical studies all support the tetranuclear catenane dication formulation. The combination of the lability of copper(II) dtc coordinate bonds and favourable copper(II) dtc-copper(III) dtc charge transfer stabilisation effects are responsible for the high yielding formation of the interlocked... 

We have seen how elegantly transition metals can template the formation of knots, but what about Nature s favourite templating interaction, the hydrogen bond A remarkably efficient molecular trefoil knot synthesis based on this interaction was reported by Vogtle and co-workers, who made a knotane in 20% yield [39]. This amazing route (Fig. 11) was uncovered serendipitously during the synthesis of catenanes. The crystal structure of the compound was the definitive proof for the structure, because neither NMR nor mass spectrometry could tell it apart conclusively from the macrocycles that are also formed. 

Recently a new synthesis of homoporphyrins was discovered serendipitously by Smith and coworkers [19]. These investigators found that treating the unsym-metrically substituted a,c-biladiene salt 42 with copper (II) afforded the copper containing macrocycle 43. Attempts to remove copper with sulfuric add and trifluoroacetic acids resulted in ring expansion to the free-base homoporphyrin 44... 

For the purposes of this review, heterosapphyrins are defined as being sap-phyrin-like macrocycles in which a furan, thiophene, or selenophene subunit serves to replace one or more of the pyrrole rings. Interestingly, like the pentaazasapphyr-ins, this class of macrocycles has its origins in a serendipitous discovery. It occurred during efforts directed toward the synthesis of the heteroatom analogs of corrole. Specifically, as first reported by Johnson and coworkers in 1969, reaction of... 

Rather serendipitously, transition metal macrocycles display electronic transitions in the U Vand visible spectral regions with very large cross sections. These conditions do not only lead to increased sensitivity in reflectance measurements in this energy range, but also contribute to enhance Raman signals through electronic resonances. This sub-section addresses salient aspects of in situ spectroscopy as applied to the study of macrocydic modified surfaces of relevance to the electrochemical reduction of dioxygen. 

A high dilution reaction that might have been expected to produce a macrocycle, serendipitously yielded an entirely new kind of catenane (Fig. 6) and led to the characterization of a different family of hydrogen-bonded templates." Structural and isomer studies led to the conclusion that the threaded macrocycle is the critical intermediate in the catenane formation, making this a classic template process. " ... 

A remarkably efficient molecular trefoil knot synthesis based on organic templates was reported by VOgtle and coworkers, who serendipitously made and astutely identified the knotane. In the course of the synthesis of [ ]catenanes, reaction of the simple precursors 9 and 10 in the presence of triethylamine under high dilution conditions (10 mM in dichloromethane) produced three colorless products macrocycle 11 (15% yield, 1 1 ratio of reagents... 

Very recently, tetrabutylammonium chloride or bromide salts (TBACl/Br) were serendipitously found to be capable of achieving efficient folding-promoted chemo-and regio-selective demethylations, eliminating up to two out of five methyl groups situated in similar macrocyclic chemical microenvironments as in 16a [74, 75]. By combining with the one-pot synthesis of 16a in 46 % yield, macrocyclic anionic pentamers can now be prepared in just two steps with an overall yield of 45 % within a day rather than 5-10 % yields after months efforts. Efficient... 

---