Incorporation of 2,5-dihydroxyterephthalate as a covalent scaffold in the axis of a 30-membered all-carbon macrocycle provides access to a modular series of rotaxanes. Installment of tethered alkynes or azides onto the terephthalic phenolic hydroxyl functionalities, which are situated at opposite sides of the macrocycle, gives versatile prerotaxane building blocks. The corresponding [2]­rotaxanes are obtained by introduction of bulky stoppering (“capping”) units at the tethers and subsequent cleavage of the covalent ring/thread ester linkages. Extension of this strategy via coupling of two prerotaxanes bearing complementary linker functionalities (i.e., azide and alkyne) and follow-up attachment of stopper groups provide efficient access to [n]­rotaxanes. The applicability and modular nature of this novel approach were demonstrated by the synthesis of a series of [2]-, [3]-, and [4]­rotaxanes. Furthermore, it is shown that the prerotaxanes allow late-stage functionalization of the ring fragment introducing further structural diversity.

Mechanically interlocked molecules (MiMs) such as catenanes and rotaxanes exhibit unique properties due to the mechanical bond which unites their components. The translational and rotational freedom present in these compounds may be harnessed to create stimuli-responsive MiMs, which find potential application as artificial molecular machines. Mechanically interlocked structures such as lasso peptides have also been found in nature, making MiMs promising albeit elusive targets for drug discovery. Although the first syntheses of MiMs were based on covalent strategies, approaches based on non-covalent interactions rose to prominence thereafter and have remained dominant. Non-covalent strategies are generally short and efficient, but do require particular structural motifs which are difficult to alter. In a covalent approach, MiMs can be more easily modified while the components may have increased rotational and translational freedom. Both approaches have complementary merits and combining the unmatched efficiency of non-covalent approaches with the scope of covalent syntheses may open up vast opportunities. In this review, recent covalently templated syntheses of MiMs are discussed to show their complementarity and anticipate future developments in this field.

Understanding natural phenomena is an important aim of science. Since the turn of the millennium the notion of scientific understanding has been a hot topic of debate in the philosophy of science. A bone of contention in this debate is the role of truth and representational accuracy in scientific understanding. So-called factivists and non-factivists disagree about the extent to which the theories and models that are used to achieve understanding must be (at least approximately) true or accurate. In this paper we address this issue by examining a case from the practice of synthetic chemistry. We investigate how understanding is obtained in this field by means of an in-depth analysis of the famous synthesis of periplanone B by W. Clark Still. It turns out that highly idealized models—that are representationally inaccurate and sometimes even inconsistent—and qualitative concepts are essential for understanding the synthetic pathway and accordingly for achieving the synthesis. We compare the results of our case study to various factivist and non-factivist accounts of how idealizations may contribute to scientific understanding and conclude that non-factivism offers a more plausible interpretation of the practice of synthetic chemistry. Moreover, our case study supports a central thesis of the non-factivist theory of scientific understanding developed by De Regt (Understanding scientific understanding. Oxford University Press, New York. https://doi.org/10.1093/oso/9780190652913.001.0001 , 2017), namely that scientific understanding requires intelligibility rather than representational accuracy, and that idealization is one way to enhance intelligibility.