Chapter 1: Introduction: History and Development

Supramolecular chemistry, an emerging field of chemistry, focuses on the study of non-covalent interactions such as hydrogen bonding, π–π stacking, and hydrophobic, electrostatic, and van der Waals interactions that modulate molecular recognition and self-assembly. The significance of supramolecular chemistry has been recognized by two Nobel prizes: Cram, Lehn and Pedersen in 1987;^1,2  Sauvage, Stoddart and Feringa in 2016.^3–5  At the core of supramolecular chemistry is the fine control and understanding of such non-covalent interactions. One sub-category of supramolecular chemistry is the formation of host–guest complexes through molecular recognition between a molecular receptor (the host) and a ligand (guest). Commonly known host molecules include crown ethers, cyclodextrins, and calixarenes; the guest molecules encapsulated by the aforementioned hosts are determined by the structures and physicochemical properties of the corresponding hosts. More recently, cucurbiturils are another family of macrocyclic host molecules that have gained attention as prominent host molecules (Figure 1.1).

Cucurbiturils are a family of macrocyclic host molecules that have more recently risen to prominence. They are easily accessible macrocycles that display remarakble recognition properties. In 1905, the first synthesis of cucurbituril was reported by the German chemist Behrend. Although no structural determination was demonstrated at the time, we now know it was cucurbit[6]uril.⁶  The report described the acidic condensation of glycoluril with formaldehyde to afford an insoluble polymeric material, also known as Behrend's polymer. Behrend suggested that this material contained “at least three molecules of glycoluril” condensed with twice as many equivalents of formaldehyde, based on elemental analysis. From this analysis he proposed (we now know incorrectly) the formula C₁₈H₁₈N₁₂O_6.^6,7  He indicated that this molecule was exceptionally stable, even in the presence of oxidative reagents such as KMnO₄. Investigations on its properties revealed that it could form co-crystals with KMnO₄, AgNO₃, methylene blue and Congo red.

Almost 80 years later, in 1981, Mock and Freeman revisited the original synthesis to further investigate such intriguing properties of cucurbituril with modern structural characterization techniques such as X-ray crystallography and NMR.⁸  These methods revealed that the structure is a highly symmetric, macrocyclic molecule consisting of a hexameric glycoluril unit with a hydrophilic rim on each side comprised of ureido carbonyls and a hydrophobic interior. Mock named this molecule “cucurbituril” due to its structural resemblance to a pumpkin, a member of the cucurbitaceae family (Figure 1.1). At the time, the hexameric glycoluril-based macrocycle “cucurbituril” was reported as the sole product. However, it turns out that “cucurbituril” was a member of the cucurbit[n]uril family, which consists of macrocycles with varying numbers of n glycoluril units (the “cucurbituril” reported by Mock corresponds to cucurbit[6]uril). Cucurbit[n]uril is often abbreviated as CB[n], CBn, or Q[n], where n is the number of glycoluril units in the macrocycle. For the purpose of consistency, this book will use the CB[n] abbreviation.

Mock also explored the host–guest chemistry of CB[6] to determine what features of guests are important for binding using NMR spectroscopy by systematically examining various substrates.⁹  In these studies, Mock discovered that numerous alkyl(di)-ammonium species formed strong 1 : 1 inclusion complexes with CB[6] in aqueous formic acid solution, due to the poor solubility of CB[6] in common solvents. Compared to other non-natural synthetic hosts such as cyclodextrins, calixarenes, and crown ethers, CB[6] displayed high binding affinity and specificity. He also measured the kinetics of the binding of host–guest complexes and revealed that CB[6] exhibits slow association rates and even slower dissociation rates. This is attributed to the barrel-like structure and the portals acting as a barrier to guest entry and exit. He was also interested in using CB[6] as an enzyme mimic by utilizing the confined environment of the CB[6] cavity to promote chemical reactions. He demonstrated this using amine-functionalized substrates for the azide–alkyne click reaction,^10,11  so that they would bind to the portal of CB[6] and the subsequent triazole formation could occur inside the CB[6] cavity. Despite the accelerated rate of reaction, the resulting triazole could not be dissociated from the CB[6] cavity and thus this process did not display the turnover desirable for truly catalytic reactions.

Another application of CB[6] that Mock first developed was a CB-based switchable pseudorotaxane.¹²  CB[6] shuttling down an oligoamine chain from the aromatic position to in-between the aliphatic positions was realized by taking advantage of the difference in pK_a between aromatic and aliphatic amines. It is noteworthy that this switchable pseudorotaxane was reported before the well-recognized molecular shuttle¹³  and switch¹⁴  by Stoddart. In the 1990s, significant contributions to CB[6] chemistry were achieved by Buschmann and others while exploring its dye complexation behaviour,^15,16  its binding to cations,¹⁷  and the calorimetric determination of binding constants for amino acids and amino alcohols.¹⁸  At this point, the host–guest chemistry of CB[6] was studied only under strongly acidic conditions due to the poor solubility of CB[6] in common solvents. Kim and co-workers reported the first investigation of the CB[6] host–guest chemistry in neutral aqueous media¹⁹  which in turn allowed for expanding its host–guest chemistry and also built supramolecular assemblies using CB[6], including mechanically interlocked molecules such as 1-, 2-, and 3-dimensional (1D, 2D, and 3D) polyrotaxanes²⁰  and “molecular necklaces”.²¹ 

Although the aforementioned reports demonstrated some of the potential of CBs, they were still not as recognized in the field of host–guest chemistry. Cyclodextrins (CD) and calixarenes were still regarded as the desirable molecular containers in part because they come in a range of sizes (CD: six to eight sugar moieties, calixarenes: four and six phenolic moieties) whereas CB[6] was the only homologue known pre-2000, so CDs and calixarenes had a greater range of host–guest chemistry. The water-soluble nature of CDs also rendered them more desirable to work with and useful for practical applications, in contrast to CB[6], which is practically insoluble in water. These are the challenges that CBs needed to overcome if they were to compete with and substitute the CDs.

Breakthroughs in several areas have fuelled the growth and development of CB chemistry. The synthesis, isolation, and characterization of other family members (n=5, 7, and 8) by Kim and coworkers²²  addressed the aforementioned downside of CBs not offering a variety of cavity size. CB[6] is the major product of the acid-catalyzed formaldehyde-glycoluril reaction; however, careful control of the reaction temperature allows access to differently sized CBs (CB[n], (n=5, 7, and 8)). Independently, Day and co-workers synthesised and isolated these CB homologues along with CB[5]@CB[10].²³  The increased dimensions of the expanded family members enrich and diversify the host–guest chemistry of CBs. CB[7] is appreciably more soluble in water than CB[6], which has helped in applying CB[n] chemistry towards biological applications in aqueous conditions. Other guests of CB[7] include redox sensitive molecules such as ferrocene²⁴  and methyl viologen,^25,26  which allows external control of the complexes’ stability;²⁷  and fluorescent dye molecules, which enable the development of sensors and assays.²⁸  The large cavity of CB[8] allows for the formation of homo-²²  and hetero-ternary complexes,²⁹  which has been transformative in the field of supramolecular chemistry; the resulting stable ternary complexes can be applied to the formation of supramolecular architectures such as supramolecular polymers,³⁰  block copolymers³¹  and nanostrucutres.³²  CB[8] can also serve as a reaction container for various reactions. Further details on the host–guest chemistry of CBs are introduced in Chapter 3.

When protonated guests become included by macrocyclic hosts, the pK_a value of the guests becomes shifted.³³  To which direction the pK_a shifts is relevant to the characteristics of the host molecule, resulting from the change in preference for the binding of the protonated form compared with its conjugate base. Interestingly, protonated cationic guests that bind to CB[n] have shown an increase in the pK_a value owing to the higher binding constant of cationic species over the non-protonated conjugate bases.³³  This phenomenon is a trait that differentiates CB[n]s over CDs, whereas CDs prefer binding with neutral and anionic guests resulting in a decrease in the pK_a value. Such a pK_a shifting nature of CB[n]s has found applications in molecular switches, sensors, assays, and drug delivery systems.³⁴  Further details on such applications of CB[n]s are described in Chapters 6, 10 and 11.

In addition to the CB[n] homologues, several achievements have been accomplished in preparing and studying the respective host–guest interactions of derivatives, analogues, and congeners of the CB[n] family. These include acyclic oligomers of glycoluril, substituted CB[n] molecules (replacement of CH protons with alkyl and aryl groups), inverted cucurbit[n]urils (iCB[6] and iCB[7]), and the chiral bis-nor-seco-CB[6] and bis-nor-seco-CB[10] species.³⁵  The host–guest chemistry of hemicucurbiturils, which are macrocycles composed of ethyleneurea repeating units linked by one row of methylene bridges (thus the nomenclature derived from being “half” of CBs) have been investigated as well. Detailed discussions on the analogues and derivatives are found in Chapters 19 and 20.

The high affinity of CB[n] complexes makes them incredibly robust such that they stand out from other synthetic receptors. As previously mentioned, various guest molecules that bind to CB[6] have been explored. Over the years, increasingly high affinity guests (for CB[7] in particular)^36–38  have been introduced resulting in a 10¹⁷ M⁻¹ affinity binder for CB[7].³⁹  Studies have demonstrated that the high binding affinity of CBs can be attributed to multiple non-covalent interactions, a non-classical hydrophobic effect arising from the release of high-energy water from the cavity of CBs. In addition, gas phase investigations of CB[n] allowed for better understanding of absolute and relative bond strengths between the host and guest molecules in the absence of solvent. Further details on the thermodynamic basis of such guest binding properties are described in Chapter 4, and gas phase CB[n] studies in Chapter 9. The host–guest complexes are robust enough to persist in biological media, where there are numerous interfering and competing molecules. This has allowed supramolecular chemistry to be utilized in biological settings; for example, supramolecular hydrogels composed of CB[8]⁴⁰  or CB[6]⁴¹  remain intact in in vivo experiments. Guest exchange has also been demonstrated inside live cells and this has been used to activate cytotoxic nanoparticles,⁴²  among other applications. Further details on the utilization of such high-affinity complexes are introduced in Chapters 16, 17, and 18.

The development of synthetic methods for the functionalization of CB[n]s, which has allowed the remarkable properties to be applied to the preparation of functional materials, has certainly played a major role in expanding the application of CBs in diverse research areas. CB family members are quite unreactive, but they can be hydroxylated with oxidizing reagents allowing for the CB[n] to be modified or grafted to a solid surface.⁴³  Rather than modifying CB[n]s directly, an alternative approach is to use modified glycolurils as starting materials for CB[n] synthesis, which can be used for non-hydroxyl modifications.⁴⁴  Some prominent applications of functionalized CB[n]s include supramolecular Velcro, where two surfaces, one covalently modified with CB[7] and the other with ferrocenemethylamine, allow the host–guest chemistry to be demonstrated in a bulk material.⁴⁵  CB[7] has also been attached to a support bead to facilitate the capture of ferrocenylated biomolecules.⁴⁶  Polymeric CB[n] nanocapsules and polymers have also been prepared from appropriately functionalized CB[n]s to produce materials that can be modified on the surface through non-covalent interactions. More in-depth discussions on the applications of functionalized CB[n]s are introduced in the following chapters. The most efficient current method to functionalize CBs appears to be the photochemical oxidation of CB[5]–CB[8],^43,47  which allows monohydroxylation of CB derivatives, although the products need to be separated by chromatography. Challenges still remain in the search for scalable methods to produce such functionalized CBs. Further details on synthetic methods for the functionalization of CB[n]s are described in Chapter 2.

The importance of the homologue syntheses can be seen in publication statistics (Figure 1.2). Since the initial isolation of other family members, publications have steadily increased; now there are, on average, almost three publications per week involving CBs. The number of research groups using CBs has also grown to the extent that a dedicated CB meeting or conference has been held every two years since 2007.

This chapter introduced a brief overview of CB chemistry, including its history followed by its growth and development over the years. As mentioned earlier, the greatly increased number of publications related to CBs (including a number of excellent review articles and books from various perspectives,^7,24,48–56  which are recommended for a more detailed look at areas that interest the readers) since the synthesis, isolation, and characterization of the CB family members in 2000 demonstrates the continuous growth in interest in CB chemistry (Figure 1.2). Nevertheless, numerous challenges and opportunities remain in the search for novel utilizations of the unique features of CBs. The potential applications of CBs may include, but are not limited to, molecular containers, material science, and biology. The contents of this book are aimed to deliver the current status of CB chemistry and its applications, identifying new opportunities for further research.

Chapter 2 introduces the synthesis, mechanism of formation, structural features, and functionalization of CB family members. It is aimed to deliver a general overview of the initial discovery to recent developments in synthetic methodologies for the preparation of CB family members. Moreover, reported studies on the detailed investigation on the mechanism of CB formation, as well as key structural features of CB family members are showcased. Then two aforementioned approaches of introducing functional groups on the rim or outer wall of cucurbiturils are described. One involves utilizing the building block approach, where the functional group is installed during the macrocyclization of CBs (further details on the building block approach are also discussed in Chapter 19). The other applies direct functionalization of CBs, which installs the desired functional group through chemical and photochemical methods on the skeleton of CB macrocycles.

Chapters 3 and 4 describe the key properties, supramolecular host–guest chemistry and the thermodynamic basis of host–guest binding of CB homologues. Among many reported supramolecular macrocycles, CB[n]s are particularly unique due to their inclination to recognize cationic and neutral guests in aqueous media. A wide variety of host–guest complexes formed with CB[n]s, including single-cavity and twisted CB[n]s, are introduced as well as corresponding applications with a focus on the field of drug and biomolecule recognition. Due to the differing inner cavity volumes of CB[n] hosts, ranging from 68 to 691 Å,³  they exhibit unique selectivity for differently sized guest molecules and ions. CB[5] can bind small gas molecules, CB[6] binds aliphatic chains, CB[7] can include aromatic and polycyclic guests, CB[8] allows for the binding of two complementary guests, while CB[10] can bind other small host molecules, as well as transition metal complexes. The driving force of the host–guest complexation is attributed to the hydrophobic effect in terms of the release of high-energy waters from the cavity upon guest inclusion, as well as favorable ion–dipole interactions between the polar carbonyl portals and charged centers on cationic guests. The ultra-high binding constants (up to 10¹⁷ M⁻¹) observed with certain dicationic guests and CB[7] arise from optimal packing of the hydrophobic cavity with the guest core and the placement of the cationic group adjacent to each portal.

Chapter 5 provides an overview of organic reactions that occur inside the cavity of CB[n]s and at the proximity of their carbonyl portals under aqueous conditions. The principle of such enhancement or inhibition of transformations carried out inside or “near” CB[n]s is by bringing reactants together or separating them, and by stabilizing or destabilizing reactants and transition states of rate-determining steps. Due to the nature of reactants being arranged inside the cavity of CB[n]s during chemical transformation, the reactions proceed in a highly regio- and stereoselective manner. This chapter introduces redox processes, isomerizations, [2+2], [3+2], [4+2] and [4+4] cycloadditions, as well as various nucleophilic additions utilizing CB[n]s as reaction vessels.

Chapter 6 introduces the applications of CB[n]s in the field of sensors and assays. Chemical sensors and assays are essential devices in determining the concentration or functional activity of (bio)analytes. Biomolecular recognitions such as antibody–antigen interactions or protein–ligand interactions have been the main factor in conventional well-established assays. Since the last decade, supramolecular receptors have proven as useful alternatives affording new assays for previously undetectable analytes as well as for the development of refined assay procedures. This chapter provides a review of sensors and assays, in which the host–guest interactions of CB[n]s are key components. Optical methods such as absorption, fluorescence, and circular dichroism spectroscopy, and a summary of NMR-based bioimaging with CB[n]s are described.

Chapter 7 highlights non-covalent complexes formed by CB[n] hosts with redox active guests, defined as molecules containing a residue capable of reversible electron transfer at accessible potentials. This chapter will be focused on host–guest complexes mainly consisted of cobaltocenium, ferrocene and viologen derivatives as guests, and CB[7] and CB[8] as the hosts. The resulting complexes demonstrated high stabilities, with binding affinities from micromolar to femtomolar levels. Ironically, the high thermodynamic stability of these complexes makes it difficult to develop redox switchable supramolecular systems based on these complexation phenomena. However, strategic design has allowed for generation and characterization of several systems in which effective redox switching is possible, either on its own or coupled to proton transfer. This chapter will also pay close attention to the complexation-induced changes in electrochemical potentials and kinetics in these supramolecular systems.

Chapter 8 introduces the advances and challenges in the field of CB[n]-based coordination chemistry. CB[n]s display superior molecular recognition properties in aqueous media, as described in previous chapters. In particular, the interaction of CB[n]s with various metal ions established CB[n]-based coordination chemistry as an increasingly important area in CB[n] chemistry. This chapter elaborates on the CB[n]-based coordination topic from the following aspects: (1) simple coordination complexes of CB[n]s with metal ions; (2) poly-dimensional coordination polymers of CB[n]s with metal ions; and (3) potential applications of CB[n]-based coordination complexes and polymers.

Chapter 9 introduces studies of CB[n]s and their complexes in the gas phase. Investigations of CB[n] chemistry in the gas phase range from simple mass spectrometric determinations of complex stoichiometry to sophisticated multi-stage experiments that probe structure, reaction kinetics, or spectroscopy in the absence of solvent while using microgram or smaller amounts of material. This chapter describes the electrospray and matrix-assisted laser desorption methods used to introduce CB[n] complexes into the gas phase, and briefly introduces the computational, collision-induced dissociation, ion mobility, kinetic, and spectroscopic techniques used to study them, along with corresponding examples reported in recent literature.

Chapter 10 illustrates the utilization of CB[n]s and CB[n]-type derivatives as drug delivery vehicles either in their simplest form as a drug–host complex or in more decorated forms such as nanoparticles; the structural integrity of the nanoparticle is maintained and supported by secondary molecular interactions with molecular hosts, while the drug is held within the structure. Initial evaluations of drug delivery through in vitro analysis for both diseased and healthy cells have revealed positive and encouraging outcomes, which led the way to ex vivo and in vivo drug delivery studies using only the free hosts to evaluate their toxicology; the free hosts demonstrated high biocompatibility with healthy tissue and animal models. Pharmacokinetics is also discussed with and without drug association. Other features, such as increased bioavailability, drug retention and targeted delivery, are also highlighted with reported examples. In contrast to examples of drug delivery, sequestration is also presented as a method of encapsulation, deactivation and excretion as an aid to anesthesia recovery.

Chapter 11 highlights several useful characteristics and mechanical properties of CB[6] and bambusurils (BUs), which provide interesting opportunities in the design and synthesis of machines, switches and cargo delivery devices. This chapter introduces three selected CB-based tools and applications: (1) molecular rotary motors that utilize the shuttling motion of CBs along polyaminated threads, CB-based high-speed rotary motors and exploration of new binding mechanisms; (2) sensory devices that detect and quantify specific analytes via single or multiple binding events, as well as switch devices generated by bistable rotaxanes; and (3) utilization of CBs for controlled cargo delivery and release, as well as the use of hetero-BUs for multiple anion binding, channeling and ion transport. Such fascinating properties of CB[6] and BUs as main components of molecular machines, switches and cargo delivery devices will be applied in the near future to drug delivery, targeting and release, diagnostics and analytical chemistry, as well as new materials, including advanced macromolecules, functional nanocapsules, and innovative supramolecular architectures.

Chapter 12 introduces (supra)molecular switches based on the properties of CB[7] and CB[8] as appropriate hosts for the complexation of aromatic stimuli-responsive guests. The resulting CB[7]- and CB[8]-based stimuli-responsive aggregates are examined in two perspectives: the source of external stimulation, and the type of structural modification produced on the complex. While the structural features of CB[7] would serve as starting points for the discussion of binary host–guest switches, the ability of CB[8] to complex two identical or complementary guests would allow for the preparation of intricate CB[8]-based homo- and heteroternary stimuli-responsive assemblies. This chapter not only aims to provide an analysis of simplified models, but also introduce the implementation of these into functional chemical systems.

Chapter 13 focuses on the utilization of CB[n]s for the functionalization and controlled assembly of organic and inorganic nanoparticles. The direct electrostatic interactions of the CB[n] carbonyl rims with metallic nanoparticle surfaces and how such interactions can promote controlled aggregation of nanoparticles are investigated. Applications of such interactions in nanoparticle formation, surface enhanced Raman spectroscopy (SERS), catalysis and nanowire formation are discussed in this chapter. Indirect functionalization of nanoparticles can be accomplished by complexation of CB[n]s with surface-bound ligands. Consequently, nanoparticles can be assembled through such indirect functionalization. This methodology can be extended to controlled assembly and disassembly of nanoparticles by employing stimuli-responsive guests. Lastly, the use of CB[n]s in the formation of nanoparticles and colloidosomes through host–guest interactions is demonstrated. The wide applicability of CB[n]-based nanosystems makes them attractive in triggered assembly and delivery but also undiscovered areas yet to be investigated.

Chapter 14 reviews the use of CB[n] host–guest interactions in polymeric systems. This chapter focuses on the utilization of CB[8] in generating polymeric materials, as CB[8] is capable of binding two guests inside its cavity. Many researchers harness the unique properties of CB[n], particularly CB[8], in either constructing supramolecular polymers from small building blocks, or preparing polymeric materials in the micro- to macro-scale through the guest-functionalized polymers. The application of CB[8]-mediated host–guest chemistry in supramolecular polymers, single chain nanoparticles, vesicles and micelles, microcapsules, and hydrogels is introduced, while some examples based on other CB[n] homologues are also mentioned.

Chapter 15 discusses the recent progress in CB[6]-based polymeric materials, focusing on polymer nanocapsules and two-dimensional (2D) polymer films. Direct functionalization of CB[6] opened up opportunities for chemists to prepare CB[6] derivatives with multiple reactive functional groups at the periphery that can be polymerized to produce highly cross-linked 2D polymer networks, which can eventually turn into polymer nanocapsules or 2D polymer films having accessible CB[6] cavities. This chapter also introduces covalent and non-covalent post-synthetic modifications, which can easily alter the surface properties of the polymer nanocapsules and 2D polymer films, making them useful in a wide range of applications including drug delivery, biomedical imaging, catalysis, and separation. In addition, reversible interconversion of two different morphologies (nanocapsule and 2D film) by utilizing the reversible disulfide linkages is discussed.

Chapter 16 highlights the recent development in the employment of CB host–guest interactions for the fabrication of a wide range of surface-based platforms. Fundamental CB[n]-mediated molecular recognition studies on surfaces that have led to various biomedical and bioanalytical applications are reviewed. This chapter also outlines the characteristics of CB[n]-mediated host–guest complexes on surfaces, which are intrinsically dynamic and can rearrange, while some of the interactions are reversible upon applying stimuli.

Chapter 17 provides an overview CB[n]s interacting with epitopes on proteins. This chapter illustrates the potential of this highly efficient supramolecular chemistry on proteins. Protein elements contain a combination of hydrophobic and polar recognition motifs and hand-in-glove sterically matching amino acid residues, allowing CB[n]s to be ideal for use as recognition tools. In particular, the tuneable chemical properties of CB homologues have been shown to be ideally suited to bind different molecular epitopes on proteins, including two-fold epitope binding by CB[8], as demonstrated by the examples on N-terminal and mid-chain amino acid binding as well as multiple amino acid epitope recognition. Strategic merging of molecular recognition concepts of CB[n]s and protein engineering allows for functional modulation and the study of protein activity or controlled protein assembly. This chapter also highlights enzyme activity regulation, inhibition of amyloid aggregation, directed protein-wire assembly, and generation of supramolecular biopharmaceuticals by molecular recognition of proteins with CB[n]s.

Chapter 18 introduces the application of ultrastable synthetic binding pairs between CB[7] and its guests as a supramolecular latching system. The unique features of the synthetic binding pairs, including their small size with exceptionally high binding affinity, bio-orthogonality in binding, chemical tractability, scalable synthesis, and robust chemical structures enable the pairs to be applied in various areas. Moreover, accurate and precise analysis of bioimaging and proteomics can be accomplished by taking advantage of interesting unique features of this binding pair system such as delicate control of host–guest binding affinities by treatment with stronger guest molecules on-demand and negligible interferences of the binding properties from endogenous biomolecules.

Chapter 19 discusses how the tight CB[n]–guest binding affinities allowed the performance of mechanistic studies of the CB[n] forming reaction to enable the creation of new CB[n]-type receptors and assesses how the structural changes impacted their molecular recognition properties. Development of new CB[n]-type receptors was achieved by systematically exchanging, deleting, or augmenting the building blocks during the synthesis. Such novel CB[n]-type receptors have greatly expanded the range of applications of CB[n]. With the advances in the synthesis of CB[n] homologues and derivatives, it is now possible to prepare host molecules in a tuneable manner to meet the requirements of the desired application. Along with other chapters on CB[n] and analogue synthesis (Chapters 2 and 20), this chapter aims to demonstrate synthetic pathways to strategically design suitable CB hosts for specific applications.

Chapter 20 introduces hemicucurbiturils (hemiCB[n]s), a class of macrocycles consisting of ethyleneurea building blocks linked by one row of methylene bridges. The key feature of hemiCB[n]s is their ability to form strong supramolecular complexes with anionic species, even under aqueous conditions. HemiCB[n]s also include bambusurils and biotinurils as special examples of these macrocycles. In this chapter, the fundamental properties, synthesis, host–guest properties and applications of hemiCB[n]s are discussed. In particular, the similarities and differences between different types of hemiCB[n] derivatives will be highlighted.