Supramolecular Chemistry - 2009 - Steed - Molecular Guests in Solution.pdf

Molecular Guests in Solution 6 ‘I envy not in any moods The captive void of noble rage, The linnet born within the cage, That never knew the summer woods.’...

Molecular Guests in Solution 6 ‘I envy not in any moods The captive void of noble rage, The linnet born within the cage, That never knew the summer woods.’ — Alfred, Lord Tennyson (1809–1892), In Memoriam  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 308 Molecular Guests in Solution 6.1 Molecular Hosts and Molecular Guests 6.1.1 Introduction The host-guest binding of a neutral (usually organic) molecule may occur via its physical imprison- ment either as part of a solid-state network, forming a solid-state inclusion compound (clathrate), or a metal-organic framework complex (see Chapters 7 and 9, respectively), or within the cavity of a solution species such as a cavitand (a molecule such as a calixarene possessing a permanent and intrinsic guest-binding cavity). In general, the binding of neutral, non-polar organic molecules in non-polar solvents by the majority of cavitands is relatively weak because there is no significant enthalpic gain from strong host–guest interactions. Solid-state complexes are widespread, however, because of the need to pack efficiently in the crystal lattice – unfilled holes are relatively unstable and hence very uncommon because there is a loss of stabilisation from the van der Waals interactions between all molecules. In solution, interactions between the guest and the host may be either very limited (e.g. van der Waals interactions) or of significant stability (e.g. hydrogen bonds). Significant binding of polar or charged molecular guests is observed in many hosts, with binding of alkyl ammonium cations being particularly common. In non-polar solvents such binding often takes the form of specific host-guest dipole–dipole or hydrogen-bond interactions, often with charge assis- tance (i.e. the interaction is strengthened by ion–dipole interactions). Hydrophobic portions of the guest are sequestered within hydrophobic portions of the host. In water, polar groups on the host and guest are highly solvated and hence organic guest binding relies much more on the hydrophobic effect. In order to achieve molecular guest complexation in solution as well as in the solid state, it is necessary for the host to possess a permanent, intrinsic cavity, or to organise or self-assemble (Chapter 10) several components in solution in order to produce one. In this chapter, we will examine a variety of individual host molecules that possess intrinsic curvature, allowing them to include guest species in a capsular manner to give complexes that are stable, in principle, in all phases of matter (solid, solution and gas phase). Just as with cation and anion complexation, solution binding constants (Section 1.4) can be measured and the information used to derive structure–function relationships useful in host design. We will examine the more classical field of solid state clathrate or lattice inclusion chemistry in Chapter 7 and the highly topical solid state inclusion compounds formed by robust, infinite coordination network solids in Chapter 9. 6.1.2 Some General Considerations Schneider, H. J., ‘Mechanisms of molecular recognition - investigations of organic host guest complexes’, Angew. Chem., Int. Ed. Engl. 1991, 30, 1417–1436. Broadly speaking the same kinds of supramolecular interactions that govern ion binding are also relevant to molecular complexation but there is a significant change of emphasis and importance. The concept of cooperativity between binding sites is still relevant, however what constitutes the binding sites themselves can be more difficult to recognise. The larger surface area of molecular guests means that, depending on solvent, van der Waals and hydrophobic/solvophobic interactions become much more important at the expense of point interactions such as hydrogen bonding and dipolar interactions. For example, Figure 6.1 shows a number of systems that illustrate nicely that strong complexation Supramolecular Chemistry, 2nd edition J. W. Steed and J. L. Atwood © 2009 John Wiley & Sons, Ltd ISBN: 978-0-470-51233-3  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Molecular Hosts and Molecular Guests 309 (a) (b) (c) (d) – O OH H – O O O O + + N N N N – N H H N + + O – Me3N N NMe3 O H O_ O O O O H O HO OH – HO O + NMe R 3 16.0 in H2O > 25 in CHCl3 6 in H2O 25 in H2O (e.g. choline) Figure 6.1 Interactions between open, extended surfaces with the relevant solvent and interaction energy (∆G/kJ mol1). can readily occur at open, extended receptor surfaces. Note that the receptor combination that relies primarily on hydrogen bonding interactions (Figure 6.1b) achieves strongest complexation in chloro- form, a non-polar solvent, while the remaining systems benefit from the hydrophobic effect in water. While surface interactions are significant, however, three-dimensional preorganisation of the receptor usually leads to substantial increases in affinity. This is in principle because spherical particles (guests) in a hemispherical cavity, experience four times as much dispersive binding force as on a planar surface. Moreover this factor increases to six with a cylindrical cavity and approximately eight with a fully encompassing spherical cavity. As a result hosts, or host components, that have some kind of intrinsic curvature so that they can wrap around guests, are enduringly popular, as we will see in the next section. There are some exceptions to this rule, however, generally arising from negative preorganisation or unfavourable solvation effects in the three-dimensional host. For example, the binding constants for the binding of the fluorescent guest 8-anilinonapthalene sulfonate (ANS) by the cyclic diphenylmethane derivative 6.1 and the bicyclic, potentially 3D-encapsulating analogue 6.2 are 2.0
105 M1 and 0.4
105 M1, respectively in water. H2 + N N + + NH2 + N H + + N NH2 H2 H + + N+ + N N N H2 H2 6.1 6.2 Broadly speaking the important types of interaction in molecular host-guest complexes are listed below. 1. Hydrophobic binding. The hydrophobic effect can have both enthalpic and entropic components, although the classical hydrophobic effect is entropic in origin (Section 1.9.1). Studies on the associations between planar aromatic molecules show an approximately linear relationship between the interaction energy and their mutual contact surface area with slope 64 dyn cm1, very close to the macroscopic surface tension of water (72 dyn cm1). Hence, in the absence of specific host or guest interactions with the solvent the hydrophobic effect can be calculated solely from the energy required to create a free surface of 1 Å2 which amounts to 7.2
1012 J or 0.43 kJÅ2 mol1.  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 310 Molecular Guests in Solution 2. Electrostatic interactions involving permanent charges (salt bridges). According to the Bjerrum model the binding constant between two ions A and B– can be described in terms of the product of the ionic charges zA·zB and the mean effective distance between the ions. These parameters along with the dielectric permittivity (ε) determine the magnitude of the Bjerrum function Q(b). The 3 4π N  ZA ZB  binding constant is then given by: K =   ⋅ Q(b ). This equation predicts a linear dependence 1000  ε kT  of ln K with zA and zB which is obeyed for many simple inorganic ions. Significant deviations are noted for more complex organic ions, however. The effect of the medium is such that decreases in dielectric constant lead to significant increases in association as a result of decreased dielectric shielding. 3. Induced dipolar interactions. The electron clouds in many (especially large) organic molecules are readily polarised resulting in the formation of induced dipoles that can interact, resulting in complex stabilisation. Both cations and anions can induce dipoles in aromatic molecules, for example. 4. π-π Interactions and charge transfer. Edge-to-face and face-to-face (stacking) π−π interac- tions are discussed in Section 1.8.7. Stacking interactions between an electron poor and electron rich partner can result in the transfer of electron density from the HOMO of the donor to the low-lying LUMO of the acceptor. The viologens (N,N′-disubstituted-4,4′-bipyridyl derivatives) for example are particularly electron-poor and form charge transfer complexes of the type shown in Figure 6.1a, as evident from the observation of charge transfer transitions in their UV-Vis absorption spectra. 5. Hydrogen bonding. A typical hydrogen bonded complex is shown in Figure 6.1b. Hydrogen bonding in neutral molecule complexes is most significant in non-polar solvents where the polar hydrogen bonding donor and acceptor groups are relatively unsolvated. 6.2 Intrinsic Curvature: Guest Binding by Cavitands 6.2.1 Building Blocks Individual host molecules possessing an intrinsic cavity that is present in both the solid state and in solution are termed cavitands. A cavitand is defi ned as a molecular container with an enforced, concave surface. The molecular cavity is generally open at one end. Inclusion of guest species within a cavitand results in a cavitate (or caviplex). Molecules or fragments that possesses intrinsic curvature (i.e. are structurally bent or curved) may be used to bind guest molecules in both solu- tion as well as the solid state since dissolution of the host does not result in disappearance of the cavity. Intrinsically curved molecular building blocks that are reasonably synthetically accessible are relatively uncommon, and as a result cavitand hosts and a wide range of related species tend to fall into loose families. These families may be grouped according to the kinds of building blocks used to impart curvature and hence achieve a concave binding pocket. A range of examples of synthetically accessible cavitands and curved precursors that have been used to host molecular guests are shown in Figure 6.2. In addition to intrinsically curved species, there exists a vast range of hosts that may be broadly termed cyclophane hosts, which make use of bridged aryl rings as container walls with a wide variety of flexible or angled spacers that enable the host to close in on itself. The following sections present a brief overview of the intracavity inclusion chemistry of some important hosts in both aqueous and non-aqueous media and the concepts that result from such studies.  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 311 H HO OH HO OH HO OH H H NH HO N OH N N O H O H O H H O R H R H Glycoluril R R Kohnkene precursor 6.4 6.5 resorcarene 6.3 R R R R = CH3, CH2CH2Ph etc. N N R R R R Tröger's base 6.6 triphenylmethane R = H, Me OH OH HO 6.8 OH H2 calixarene R = H, CH3, t-Bu C O 3.118 OH OH diphenylmethane OH HO OH 6.9 OH cholic acid OH O O OH 6.11 O O HO OH HO O OH CO2H CO H 2 O O O O CO2H O OH HO O O O HO O OH OH OH Kemp's triacid O HO O O O CTV 6.12 X OH HO OH 6.10 X α-cyclodextrin X 6.7 triethylbenzene 'pinwheel' 6.13 Figure 6.2 Range of curved building blocks and structural types. 6.2.2 Calixarenes and Resorcarenes Stibor, I. and Lhoták, P. ‘Calixarenes and their Analogues: molecular complexation’, in Encyclopedia of Supramolecular Chemistry, Atwood, J. L., Steed, J. W., eds. Marcel Dekker: New York, 2004; vol. 1, pp. 628–635. The synthesis and nomenclature of calixarenes such as 3.118 has already been in introduced (Section 3.14 - For an introduction to calixarenes and the history of their development see Box 3.4) in the context of their widespread applications as hosts for cations, generally binding to metals through their phenolic oxygen atoms. Closely related are the resorcarenes (or calixresorcarenes), such as 6.3, which are prepared in similar fashion to the calixarenes by condensation of resorcinol (3-hydroxy- phenol) with aldehydes, as shown in Scheme 6.1.1 In this case, acid-catalysed conditions are used and the preparation does not work with formaldehyde itself because of polymerisation reactions occurring from the 2-position. A wide range of other aldehydes are highly effective, however, and commonly acetaldehyde (giving methyl ‘feet’ to the resorcarene bowl) or 2-phenylethanal (resulting in enhanced  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 312 Molecular Guests in Solution 1 1 R R HO OH HCl (37%), R2CHO HO OH 80 o C, 16 h, 75 % 2 R1 = H, OH, alkyl R 4 R2 = alkyl, aryl Scheme 6.1 Typical synthesis of resorcarenes. solubility of the product in organic solvents) are used. Both calixarenes and resorcarenes possess a bowl-shaped conformation in their most stable forms. In the case of resorcarenes, this bowl is wider and shallower than in the calixarene analogues as a consequence of the presence of the ‘upper rim’ hydroxy substituents, which stabilise the bowl by intramolecular hydrogen bonding. Both calixarenes and resorcarenes bearing small substituent groups are relatively conformationally mobile, adopting partial cone, 1,2-alternate and 1,3-alternate conformations as well as the cone form (Figure 3.79). Indeed, resorcarenes are significantly more conformationally mobile with free energy activation barriers ∆G‡ for conformational interconversion of 18.4 kJ mol1 for resorcarenes with R1  n-hexyl and R2  H. This may be compared with values in the range 63–67 kJ mol1 in CDCl3 for calixarenes, where the cyclic lower-rim intramolecular hydrogen bonding is much stronger than the analogous upper-rim interactions in compounds such as 6.3 (Figure 6.3). In both cases, however, it is generally the cone conformation that is the only one to exhibit significant binding of organic guest molecules. A typical solid-state structure of cone p-t-butylcalixarene (3.118) binding toluene is shown in Figure 1.23 (note that it is the aliphatic methyl end of the toluene that is extended into the cavity). Solid state 2H and 13C NMR results indicate that the toluene is static at 129 K but at 180 K is undergoing rapid 180 o flips about its molecular C2 axis with an activation energy of 34 kJ mol1.2 Intracavity inclusion of a wide range of aromatic guest molecules in a similar 1:1 fashion has been observed for numerous calix[n]arenes and while the cavity is somewhat chlorophobic, there is an absence of specific host-guest interactions, with space-filling and the consequent gain in van der Waals interactions being the main driving force. Thus a long molecule such as an alkane will curl up to fill space rather than adopt the sterically more favourable all-trans conformation. In the case of p-iso-propyl calixarene, which forms a 1:1 complex with p-xylene, heating in the solid state results in loss of half of the guest molecules to form a cage-like 2:1 structure in which the two guest methyl substituents are H O O H O H H O O H H O O H H H O O O H H O O H Figure 6.3 Upper- and lower-rim intramolecular hydrogen-bonding interactions in calixarenes and resorcarenes, which stabilise the cone conformations.  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 313 R R O OH R O H R OH O + O Mo O N H O O R OH R O OH R R Figure 6.4 Capsule of [MoO(p-t-butylcalixarene–4H)]·(p-t-butylcalixarene)·H2O·NO2Ph (R  t-Bu).3 each complexed by different calixarenes. A similar arrangement is observed for the anisole complex of 3.118, although the anisole guest molecules are highly disordered. A related encapsulating behaviour is also observed for the Mo(VI) derivative of the tetraanion of 3.118, [MoO(p-t-butylcalixarene- 4H)], which forms an amazing solid state complex with free 3.118, a water molecule and nitrobenzene (Figure 6.4).3 In every case, the closest contacts are between the CH3 groups and the aromatic rings with a distance of about 3 Å from the upper-rim alkyl substituents of the host to the guest aryl ring. The calixarene phenolic groups can be extensively derivatised, forming complexes with oxophilic metals as in the Mo(VI) example above and with non-metals. The double-cone structure of the silicon derivative 6.14 inspired M. Wais Hosseini and co-workers from the University of Strasbourg, France, to prepare (solid-state) inclusion polymers termed koilates (from the Greek word κοιλοσ meaning hollow) based on linear extended guests such as hexadiyne (Figure 6.5). The double calixarenes (koilands) exhibit a natural tendency to stack bowl-to-bowl in their solid state structures and hence combining a long linear guest with the double receptor gives a 1:1 inclusion polymer. Unfortunately, however, the koilate is too unstable to exist in solution.4 A wide range of such solid-state inclusion complexes is formed by both calixarenes and resorcarenes with aromatic and aliphatic guests (haloalkanes, acetone, dmf, dmso etc.), generally stabilised by weak interactions of the C—H … π type. Calixarenes also possess a well-defined cavity and form similar complexes, whereas the higher calixarenes such as calixarene and calixarenes (calixarenes all the way up to calixarene have been prepared and isolated chro- matographically by the group of C. David Gutsche5) form much less defined cavities and often do not exhibit the formation of such well-defined nesting or encapsulated species. One exception to this R O R R R O O O Si H3C CH3 R R R O O O R O Si H3C CH3 R Si O O O R O R R Si O O O R R R O R Figure 6.5 Combination of a double calixarene koiland (6.14) with a long, linear guest such as hexadiyne gives an inclusion polymer or koilate (two repeat units shown).4  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 314 Molecular Guests in Solution rule, however, is the inclusion of the fullerenes within calixarenes and cyclotriveratrylene (CTV, 6.10), see Section 7.8.2. Despite these interesting complexation modes observed in the solid-state, however, there is little evidence for significant binding of neutral, underivatised calixarenes to the majority of molecular guests in non-aqueous solution. The calixarene cavities are relatively small and too conformationally mobile to offer significant solvophobic protection, while the absence of strong host–guest interactions means that there is little enthalpic stabilisation of the complexes. An exception is the complexation of amines by alkylcalixarenes, which gives binding constants in CD3CN of the order of 10 4 M1. This complexation is thought to occur by a two-stage mechanism involving initial protonation of the amine by one of the acidic calixarene phenolic groups, followed by binding of the guest cation by the resulting calixarene anion. The complex is thus stabilised significantly by ionic interactions. Similarly, even neutral calixarenes can form stable complexes with a variety of organic ammonium cations in solution. For example the N-methylpyridinium cation is bound by methoxy derivatives of a range of calix[n]arenes (n  4, 6 and 8) in a 10:1 mixture of CDCl3:CD3CN, with interaction energies in the range 4.3–5.7 kJ mol1. It is likely that the ammo- nium cations interact with the polar lower rim of the calixarene rather than the hydrophobic cavity. What affinity calixarene do have for truly neutral molecular guests is highly solvent dependent, with the choice of a solvent that it not bound by the cavity being crucial. Thus in CCl4 for example (a solvent that does not enter the cavity), binding constants of up to 230 M1 have been observed for small guests such as nitromethane by the rigidified, preorganised calixarene 6.16. One remarkable example of a calixarene binding a gaseous guest, NO2, has been reported by Dimitry Rudkevich of the University of Texas Arlington, USA. Nitrogen dioxide is a gas of particular interest because of its environmental effects and hence there is significant research into its sequestration. Bubbling NO2 into chloroform solutions of both cone and 1,3-alternate conformers of O-hexyl-p-t-butylcalixarenes gives an immediate colour change from colourless to deep purple as a consequence of the formation of charge-transfer calixarene complexes of the highly reactive NO cation arising from disproportiona- tion of two molecules of NO2 into NO and NO3. Over a period of hours the calixarenes are chemi- cally nitrated, however the NO complexes can be stabilised by adding a Lewis acid, SnCl4. Treatment with alcohols re-generates the calixarene host unchanged.6 Related work on other O-alkyl analogues gives binding constants in excess of 5
105 M1 for NO binding as the SbF6 salt in CD2Cl2 and an X-ray crystal structure shows the NO ion deeply embedded in the calixarene cavity, Figure 6.6.7 Other interesting supramolecular chemistry of gases in solid hosts is covered in more detail in Section 7.9, while gas binding by molecular hosts has been recently reviewed.8 In aqueous solution, water-soluble calixarenes have the potential to bind much more strongly to organic guests than in lipophilic media because of the hydrophobic effect (Section 1.9). Unfortunately, p-alkylcalixarenes are not water-soluble and must be derivatised in order to take them up into aqueous Figure 6.6 X-ray crystal structure of the NO complex of O-propyl-p-t-butylcalixarene, propyl groups and hydrogen atoms removed for clarity (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced by permission).  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 315 solution. This has been most simply achieved by sulfonation of the upper-rim substituents to give a range of p-sulfonatocalix[n]arenes (6.15a–e), generally as the sodium salts, which are highly water-soluble. SO3Na + N n = 4, 6.15a n = 5, 6.15b n = 6, 6.15c n = 7, 6.15d OH n = 8, 6.15e O O n O O adamantyltrimethylammonium O O 6.16 Compound 6.15a proves to be very acidic in aqueous solution, consistent with the protonation of amine guests by 3.118, with a fi rst pKa value of about 3.3, compared to pKa of 11 for the remain- ing three phenoxy protons. It is generally accepted that this acidity arises as a consequence of the stabilisation of the deprotonated phenoxy anion, by intramolecular hydrogen bonding. Compound 6.15a forms strong complexes in aqueous solution with cationic organic molecules, the binding constant for the adamantyltrimethylammonium cation, for example, being 21 000 M1. It is also able to bind neutral molecules such as toluene, although the binding constant is only 7.0 M1. Solid-state complexes of 6.15a–c all form bilayer structures in which the hydrophobic calixarene portion alternates with hydrophilic layers comprising water molecules, Na ions and the calix- arene sulfonate functions. These structures closely resemble naturally occurring clay minerals, as we will see in Section 7.8. Other water-solubilising substituents such as aminomethyl and carboxyethyl functionalities have also been appended to calixarenes, as in compounds 6.17 and 6.18, which were studied in dilute acid or base, respectively. Complexation studies with aromatic compounds such as durene and napthalene in water gave binding constants in the range 6
102  1.5
10 4 M1. Similar studies on the larger-cavity derivative 6.19 with a range of aromatic guests from durene to chrysene give a linear correlation of binding constant with the number of aromatic rings in the guest, with the binding for the four-ring chrysene being 7.0
10 4 M1. CO2H N 1 R NaO3S SO3Na HO OH OH OH OH OH n n n 4 SO3Na n = 4, 6 and 8, 6.17 n = 4, 6 and 8, 6.18 n = 4, 6.19 R1 = H, 6.20a Me, 6.20b OH, 6.20c Sulfonated resorcarenes have also been prepared, and their ability to bind a range of sugars and cyclohexanols in aqueous solution has been examined. This work followed from an observation that monolayer assemblies of alkyl derivatives of resorcarenes can detect ribose at concentrations down to 4
105 M at aqueous solution-electrode interfaces. Binding constants for hosts 6.20a–c are given in Table 6.1. The primary point of interaction is of the guest organic moieties with the apolar region of the host with no hydrogen bonds between host and guest, consistent with the fact that no binding is observed in organic media for lipophilic resorcarene hosts where the main driving force for complexation is  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 316 Molecular Guests in Solution Table 6.1 Binding constants for sulfonated resorcarenes with various alcohol guests. K/M–1 Guest number 6.20a 6.20b 6.20c t Bu OH 6.21 4.2 19 24 6.22 30 200 92 6.23 29 180 160 6.24 16 125 64 6.25 14 80 80 6.26 1.8 6.0 8.4 6.27 ⬃0 ⬃0 ⬃0 hydrogen bonding. Both derivatives 6.20b and 6.20c bind guests more strongly than the parent compound, despite the different polarities of their substituents and the degree to which they donate electrons into the aryl rings. It seems that relatively hydrophobic guests such as 6.21 bind preferentially 6.20b to 6.20c, whereas the opposite is true for the hydrophilic 6.26. The highly hydrophilic 6.27 is not bound at all. Overall, the results suggest significant C—H … π interactions from the guest to the host electron-rich aryl rings (both CH3 and OH substituents are electron donating). While the native calixarenes and resorcarenes do not generally posses significant solution affinity for organic molecules, their binding ability may be enhanced markedly by elaboration of the cavity. Synthesis of deeper cavities has the dual effect of increasing the degree of guest shielding from solvent and often results in rigidification of the host, increasing its degree of preorganisation and preventing the cavity from collapsing in on itself. For example, work by Cram et al.9 has resulted in the preparation of a range of multiply bridged resorcarenes such as 6.28 and 6.29, which exhibit significantly reduced conformational mobility in solution. The substituents, X, are excellent functional groups for even fur- ther elaboration of these materials. The presence of a rigid molecular cavity means that compounds 6.28 and 6.29 invariably crystallise with an intracavity guest, and a large range of X-ray structures have been undertaken by Cram’s group with guests such as SO2, CS2, CH3C≡ CH, MeCN and CH2Cl2. Cavitand 6.29 has a vase-shaped cavity that is large enough to accommodate Me2NCHO in the solid state. In solution, the most effective host is the dimethylsilyl derivative (6.28e), which has a tall, narrow cavity suitable for inclusion of linear guests such as those listed above. Compound 6.28e is prepared readily from the octol resorcarene 6.3 by treatment with SiMe2Cl2. The X-ray crystal structure of the CS2 complex of 6.28e is shown in Figure 6.7, indicating clearly the neat fit of the linear  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 317 Figure 6.7 X-ray crystal structure of host 6.28e with CS2 guest. (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced by permission). guest, threaded through the narrow aperture formed by the host methyl substituents. In non-polar solvents (CDCl3, C6D6), the free energy of complexation, –∆Gº, for this complex is around 8 kJ mol1. Calixarenes may also be transformed into effective solution hosts by other ways of elaborating the upper rim. The readily available nature of the calixarene framework has resulted in the synthesis of a number of hosts that use the calixarene as a spacer and rigid, three-dimensional anchor or molecular platform upon which to build other binding groups. This is analogous to the chemistry of the calix-crowns described in Section 3.14. One particularly good example of this approach is the addition of 2,4-diaminotriazine groups on to two opposite calixarene aryl moieties to give the receptor 6.30. Functionalisation of the lower rim with bulky alkyl ether chains forces the two triazine moieties to position themselves parallel to each another. In this preorganised conformation, they act as an effective hydrogen-bonding receptor for barbiturates.11 Remarkably, closely related chiral derivatives of 6.30 form chiral helical molecular capsules in both solution and in the solid-state involving three bifunctionalised calixarenes and six 5,5′-diethylbarbituric acid guests (Figure 6.8). Spontaneous non-covalent chiral resolution is observed.12 Figure 6.8 Structure of the chiral nine-molecule assembly formed by three compounds of type 6.30 with resolved diethylbarbituric acid derivatives. (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced by permission).  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 318 Molecular Guests in Solution _ CO2 Na+ _ H CO2 Na+ N N HN N + OH choline O O N O O Et Et + OH N carnitine _ CO2 Et Et O O O + O N P O O O O N NH dodecyl phosphocholine (DPC) _ _ N 6.31 N O Na+ O2C O H _ Na+ S O Na+ O2C O sodium dodecyl sulfate (SDS) Closely related to 6.29 is the resorcarene 6.31. The peripherial carboxylate groups impart water solubility and the compound is able to bind strongly to biologically relevant guests such as choline in aqueous solution with Ka in excess of 10 4 M1 with slow exchange between bound and free guests on the NMR spectroscopic time scale (for reasons explained in Section 6.2.3). The cation-π interactions of the trimethylammonium group with the resorcarene aromatic rings are a significant factor in the complexation and, in contrast, the related carnitine is much more weakly bound (102 M1) because of the anionic residue. While large ammonium cations are not bound at all, the trimethylammonium head group in dodecyl phosphocholine (DPC) should be able to fit inside the receptor, however it is the doedcyl chain that is included. Analogous results are observed with other surfactants such as sodium dodecyl sulfate (SDS – an anionic surfactant that is used in household products such as toothpastes, shampoos, shaving foams and bubble baths for its thickening effect and its ability to create a lather) are similar with significant upfield shifts in the 1H NMR spectra of the complexes indicating that around eight of the twelve carbon atoms are included in the cavity, Figure 6.9.13 The inclusion of the alkyl chain is driven by the burial of the hydrophobic surface (some 230 Å2) and consequent release of intra-cavity water, attractive van der Waals interactions with the cavity and Figure 6.9 (a) 1H NMR spectrum of the DPC complex of 6.31 showing the upfield (to negative ppm) chemical shifts of the included CH3– and CH2– groups of the DPC dodecyl chain (see Box 3.3 for a discussion of the effect of inclusion on chemical shift), (b) reference spectrum of DPC in the absence of host showing the numbering scheme. (Reprinted from with permission from AAAS).  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 319 the fact that the alkyl chain of volume 126 Å3 is an excellent fit to the cavity which has a volume of 225 Å3. This ratio represents a packing efficiency of ca. 56 % which is an almost ideal ratio (see also cavity occupancy factor, Section 6.6.5). The hydrophobic inclusion affinity is sufficient to overcome unfavourable gauche interactions along the chain that result when it is coiled from the favourable all-trans conformation into a compressed, helical conformation in order to include the maximum number of methylene groups. Each gauche interation destabilises the conformer by ca. 2.5 kJ mol1 and there are around five in the bound complex (see Section 3.7.2 for an explanation of trans and gauche conformations). Elaboration of the calixarene upper rim with more extensive functionality gives a class of highly ‘multi- valent’ (sometimes co-operative, see Section 1.5) receptors, i.e. receptors capable of multiple interactions with large guest species, particularly biomolecules. The role of the calixarene is simply that of a scaffold for the multiple binding functionality. Good examples are a series of carbohydrate derived receptors prepared by Rocco Ungaro and co-workers, of the University of Parma, Italy as in hosts such as 6.32. In addition to acting as biological energy sources, carbohydrates are increasingly recognised as fundamental substrates for specific receptors in biological processes such as intercellular communica- tion, cell trafficking, immune response, infections by bacteria and viruses, and the growth and metastasis (transmission from an original site to elsewhere in the body via blood vessels or the lymphatic system, for example) of tumour cells. All these processes occur due to binding of the carbohydrate residues present on cell surfaces by carbohydrate receptors. In general individual carbohydrate groups are only weakly bound and hence these recognition events depend on the simultaneous complexation of several identical glycoside (carbohydrate precursor) residues, exposed at the substrate surface, by proteins that possess a number of equivalent binding sites. This is an aspect of multivalency that is sometimes called the glycoside cluster effect. Receptor 6.32 is water soluble, but tends to aggregate to form micelles or vesicles (Chapter 13). It binds strongly to lectin proteins such as Concanavalin A (ConA) in the way shown in Figure 6.10.14 Elaboration of the calix[n]arene framework with guanidinium functionalities gives 6.33a (n  4, 6 or 8). Electrophoretic mobility shift assay measurements* show that these hosts bind strongly to both linear and plasmid (cyclic) DNA and can also deliver DNA into cells (transfection). The calixarene derivative binds to DNA through guanidinium–phosphate electrostatic interactions and con- denses a single DNA filament into a tightly coiled knot through intramolecular hydrophobic interactions Figure 6.10 Aggregation and lectin binding by multivalent calixarene carbohydrate-based receptors such as 6.32.14 * The electrophoretic mobility shift assay is a technique commonly used to analyze interactions of DNA with proteins or other DNA-binding ligands. When subjected to electrophoresis (migration under an electric field), free DNA will migrate differently than a DNA-protein complex. When a protein binds to a DNA fragment it hinders the fragment’s movement through a gel and so bound DNA is shifted higher on the gel plate compared to unbound DNA.  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 320 Molecular Guests in Solution Figure 6.11 AFM images of (left) 1 nM supercoiled plasmid DNA (left) and (right) condensed blobs of 1 nM supercoiled plasmid DNA in the presence of 1 mM of calixarene 6.33a (n  4). Each image is 2
2 µm. (Reproduced by permission of The Royal Society of Chemistry). of the liphophilic chains at the calixarene lower rim. Atomic force microscope (AFM) images of the DNA are shown in Figure 6.11. HO O OH _ SO3 H N HO NH2 OH + HN S HN NH2 a R = Alkyl 4 b R = (CH2CH2O)4 O 4 n OR OR O R = alkyl 6.32 6.33 6.34 In a remarkable example of multiple host-guest association the related calixarene 6.33b, which pos- sesses long polyethyleneglycol tails terminated by a hydrophobic adamantyl group, has been assem- bled on a cyclodextrin functionalised gold surface. The cyclodextrin binds to the gold via a thioether linkage forming a self-assembled monolayer (SAM – see Section 13.2.2). Cyclodextrins (discussed in Section 6.3), like calixarenes, have a hydrophobic cavity suitable for binding the adamantyl terminus of 6.33b with a binding constant of around 104 M1 in water. By immobilising the cyclodextrins on a gold surface, this affinity increases to a striking 1015 M1 as measured by surface plasmon resonance (see Section 13.2.2), giving a surface-anchored calixarene held by host-guest chemistry that cannot be removed even by a vast excess of free cyclodextrin. In a final elaboration, the surface anchored calixarene was used to form an egg-shaped closed capsule by adding the complementary sulfonate 6.34, Figure 6.12. The capsule could only be disrupted by adding excess KCl which weakens the electrostatic interactions between the two components.14 The basis for this capsule chemistry is discussed in Section 10.6. 6.2.3 Dynamics of Guest Exchange in Cavitates In the complexes examined so far in complexation of cations (Chapter 3), anions and neutral species, the overall message that has come across has suggested that capsular complexes, in which the guest  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 321 Figure 6.12 The molecular capsule 6.33b·6.34 held by interactions to cyclodextrins as a self-assembled monolayer on gold. (Reproduced by permission of The Royal Society of Chemistry). (ion or molecule) is encased entirely within an essentially closed host, exhibit characteristically high binding constants and slow guest exchange with those in the outside medium. This was well estab- lished by comparing the binding of alkali metal cations by the two-dimensional crown ethers with complexation by the three-dimensional spherands. We will see later (Section 6.7) that this observation is also borne out in neutral molecule binding by a comparison of the calixarenes and resorcarenes with spherical hemicarcerands, and especially carcerands, in which there is no measurable guest exchange at all. In the case of neutral molecules, the reason for the tight binding within the three-dimensional hosts is steric imprisonment as opposed to favourable enthalpic attraction. It is interesting to speculate, however, upon the mechanism of guest entry and exit from ‘open’ container molecules (cavitands) such as p-t-butylcalixarene (3.118). A guest that exhibits a good fit within the calixarene bowl must enter and exit through the open top of the host, as part of an exchange process. Since the guest fits the host cavity, there clearly is not enough room for more than one guest to enter or leave a cavity at a time. To put this another way, the mechanism for guest exchange must be a disassociative one: the original guest must leave the cavity before a new guest can enter. This implies that there must be some kind of intermediate stage in which the host is empty. The host, in effect, contains a vacuum at this stage. Energetically, this is a highly unfavourable situation since the van der Waals interactions between the guest and host surfaces are lost without any compensating interaction (as in the old saying ‘Nature abhors a vacuum’). Consequently the activation energy required for such guest exchange should be extremely high and hence the guest exchange kinetics should be slow. In fact, we know that for open, flexible hosts such as calixarene, guest exchange (with other guests and with solvent) is extremely rapid under ambient conditions. So, how do we explain this apparent contradic- tion? The answer lies in the host’s ability to distort temporarily in order to avoid presenting an empty cavity. Host distortion is concerted with guest exit, and hence the guest exchange transition state is only mildly energetically unfavourable as a consequence of small increases in bond strain. Upon entry of the new guest, the host can, of course, relax back to its previous conformation. In the case of the calixarenes, this distortion takes the form of a ‘pinch’ from C4v to C2v symmetry (Scheme 6.2).15 This feature becomes of critical importance when the host is rigid, or when such conformational change is associated with a large enthalpic destabilisation. Indeed, it is interesting to speculate upon guest exchange rates in a theoretical host that is entirely rigid. Would guest exchange become impossible  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 322 Molecular Guests in Solution distortion 'pinches' cavity to minimise empty volume recomplexation - host relaxes disassociative guest decomplexation C4v C 2v C4v Scheme 6.2 Cavity volume is minimised during the decomplexation process for flexible hosts such as unmodified calixarenes. because of the resulting vacuum? The effect would be akin to trying to empty a bottle of milk by up-ending it. The milk is unable to rush out in accordance with the force of gravity because of the vacuum that would be left behind. Air is unable to get in to fill the vacuum because the milk is in the way. The result is (at best) a very turbulent, slow exit for the milk. A rigid host has been designed in order to test this theory.16 The host is based on resorcarene (6.3) with the resorcarene upper rim elaborated with a rigid network of hydrogen bond donors and acceptors (6.35). The hydrogen-bonding moieties result in a deep, open cavity of C4v symmetry, somewhat resembling a whisky tumbler in shape (Figure 6.13). The host is able to adopt both C4v and C2v conformations, but the presence of the cyclic hydrogen-bonding network strongly favours the C4v form. Large guests such as adamantane fit snugly within this molecular tumbler, giving an 1H NMR spec- troscopic signal at –1 ppm, consistent with the shielding effects expected from the host aromatic rings. Crucially, separate signals are observed for bound and free adamantane guest, indicating that guest exchange is slow on the NMR time scale. Such an observation is contrary to expectation because the cavity is open and unobstructed, but is consistent with the difficulty in removing guest or solvent from the cavity without leaving a vacuum. In fact, guest exchange does occur slowly by a flower-like opening out of the hydrogen-bonded substituents, breaking the hydrogen-bonded network. Dynamic NMR measurements indicate a large activation barrier of 71 kJ mol1 for the guest exchange process, and it is thought that this energy barrier is associated directly with the loss of the enthalpic stabilisation of the hydrogen bonds. These results suggest that for all ‘open’ cavitand hosts, neutral organic guest binding in solution may be enhanced dramatically by the construction of rigid concave surfaces with a single, relatively narrow exit and entry aperture. We will come across another example in which guest removal causes host ‘implosion’ later on in Section 6.6.6. Figure 6.13 The ‘whisky tumbler’ shape of 6.35 which possesses an upper rim rigidified by intramo- lecular hydrogen bonding interactions.16  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 323 6.2.4 Glycoluril-Based Hosts Kim, K., Selvapalam, N., Ko, Y. H., Park, K. M., Kim, D., Kim, J., ‘Functionalized cucurbiturils and their applications’, Chem. Soc. Rev. 2007, 36, 267–279. Glycoluril (6.4), because of its curved backbone and versatile derivatisation chemistry, has been used as a fundamental building block in the synthesis of a number of curved ‘barrel-shaped’ hosts, molecular clips and three-dimensional capsules that form via self-assembly (Section 10.6.1). The curvature of diphenylglycoluril is illustrated by the ‘molecular clip’ derivative 6.36, which is able to act as a host to aromatic guests such as resorcinol in which the two resorcinol hydroxyl groups point downwards into the molecular cleft in order to hydrogen bond with the host carbonyl oxygen atoms.17 Binding constants of up to 105 M1 in chloroform have been observed. The structure of the host is shown in Figure 6.14. Molecular clips such as 6.36 have been elaborated into molecular ‘baskets’ such as 6.37. The naphthalene derivative 6.37 can exhibit several conformations that interconvert slowly on the NMR spectroscopic time scale, of which only the anti-anti isomer is suitable for guest inclusion, but the syn-anti predominates. The compound shows allosteric binding (Section 1.5) of alkali metal cations and aromatic molecular guests because the binding of metals such as K to the azacrown ether portion of the molecule converts it exclusively to the anti-anti conformation. Thus binding of a second K ion is ca. 100 times more favourable than the first. In the presence of K the affinity for molecular guests such as 1,3-dinitrobenzene increases by a factor of 2–6 depending on solvent.17 Related baskets can self-assemble into spherical vesicles or tube-like structures depending on the influence of 1:1 or 1:2 alkali metal cation binding. O O O N O N N ON N O N N N N N N N N N N N N N N O N NO N N O N O O O Cucurbituril 6.38 Figure 6.14 X-ray structure of glycoluril-based host 6.36 showing the intrinsic curvature.17  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 324 Molecular Guests in Solution Scheme 6.3 Synthesis of cucurbituril. The most well known glycoluril-based host is cucurbituril (6.38). Cucurbituril (pronounced ‘kyu ker bit yur eel’) is named because of the resemblance of the barrel-shaped molecule to a gourd or pumpkin of the Cucurbitaceae family, particularly the jack-o-lantern, Cucurbita pepo. Compound 6.38 has been known since 1905, although its full characterisation had to wait until the work of William Mock from the University of Chicago, USA, who characterised it by X-ray crystallography and other techniques in the early 1980s. The compound is readily prepared by condensation of glycoluril with formaldehyde. This gives an initial substance that remains poorly characterised, but is probably a cross-linked aminal type polymer. The material is highly intrac- table and, in efforts to solubilise it, Behrend, who carried out the original 1905 work, treated it with hot, concentrated sulfuric acid, which slowly dissolved it. The resulting solution was diluted with cold water and subsequently boiled, eventually giving a crystalline precipitate, later shown to be 6.38 (Scheme 6.3). The clean formation of this remarkable hexamer is thought to occur via a templated reaction (Section 3.9.1) in which oxonium ions (probably H3O) hydrogen bond to the carbonyl oxygen atoms at the top and bottom of the molecule. Cucurbituril is the hexameric member of a whole fam- ily of cucurbit[n]urils comprising anywhere from 5 to 11 glycoluril sub-units. No other glycoluril oligomers are found in the reaction shown in Scheme 6.3, although in 1992 Stoddart’s group were able to prepare a closely analogous pentamer, named decamethylcucurbituril, from dimethylg- lycoluril under milder acid conditions.18 However, in 2000 the group of Kim were able to modify the original reaction conditions to produce cucurbit[n]urils (CB[n]) where n  5 – 9.19 The lower reaction temperature in this case suggests that the hexamer is the thermodynamic product and the other homologues are kinetically trapped. As soon as it was prepared, it was recognised that not only was curcubituril remarkably chemically robust, but that it also formed a variety of crystal- line complexes with metal salts and dyestuffs. Systematic surveys have shown that the molecule is an effective host for protonated polyamines and metal ions in aqueous solution and the solid state, but not for neutral organic molecules. This inclusion chemistry arises from the presence of the barrel-shaped cavity that is approximate 6 Å deep, and the coordinating ability of the ring of carbonyl oxygen atoms. The pentameric decamethylcucurbituril has a narrower cavity and does not exhibit extensive inclusion chemistry. Cucurbituril is initially isolated as a remarkable inclusion complex with cucurbituril,20 Figure 6.15, but free cucurbituril can be isolated by displacing the smaller cucurbituril guest with melamine diamine followed by removal of the new guest through acylation and repeated washing.21 Inverted cucurbit[n]urils iCB[n] are also known in which one glycoluril unit is attached to the macrocycle in a concave fashion. Some cavity properties of the CB[n] and iCB[n] families are shown in Table 6.2. Because cucurbituril does not possess aromatic rings, it might be anticipated that the complexation- induced shifts in guest NMR spectra might be less than those observed in benzenoid derivatives (cf. Box 3.3). In reality, however, the aliphatic framework also results in a significant shielding effect. The 1H NMR spectrum of 1,5-diaminopentane in HCO2H-D2O solution, which exhibits two multiplets at δ 3.17 and 1.77 ppm in the absence of 6.38, exhibits two new signals at δ 2.73  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Intrinsic Curvature: Guest Binding by Cavitands 325 Figure 6.15 X-ray structure of the inclusion complex cucurbituril· cucurbituril.20 and 0.77 ppm, which replace those of the free guest as cucurbituril is added. Eventually a stable 1:1 host–guest adduct is formed in which the amine (which is diprotonated by the formic acid) is threaded through the host cavity. Guest exchange is slow on the 1H NMR time scale. For a series of diamine guests, NH 2 (CH 2) n NH 2 (n  1–10), in the same medium the highest binding constants occurred for n  5 and 6, corresponding to hydrophobic inclusion of the alkyl chain while allowing hydrogen bonding of the —NH3 groups to the carbonyl oxygen atoms (Figure 6.16). Note that there is a symmetry match between the three-fold symmetry of the ammonium substituent and the six-fold symmetry of 6.38, allowing the formation of three bifurcated, charge-assisted N —H … O hydrogen bonds. Cucurbituril and increasingly its higher homologues have been used extensively in a variety of host- guest chemistry and nanostructure assemblies. Of particular appeal are rotaxanes and molecular necklaces, mechanically interlocked assemblies of molecules based on CB. Efficient synthesis of 1D, 2D and 3D polyrotaxanes and molecular necklaces (cucurbituril beads linked by a macrocyclic molecule ‘string’) has been achieved by a combination of self-assembly and coordination chemistry. We discuss rotaxanes and molecular necklaces in Section 10.7, and cucurbil-based systems are summarised in a recent review.23 Table 6.2 Dimensions of the CB[n] and iCB[n] families (reproduced by permission of The Royal Society of Chemistry). a a b d b d c c CB[n]: n = 5,6,7,8,10 /CB[n]: n = 6,7 a CB CB CB CB CB iCB iCB Outer diameter/Å a 13.1 14.4 16.0 17.5 18.7–21.0 13.3–14.4 14.9–16.0 Cavity/Å b 4.4 5.8 7.3 8.8 10.7–12.6 4.2–5.8 5.7–7.3 c 2.4 3.9 5.4 6.9 9.0–11.0 3.9–5.5 5.4–6.1 Height/Å d 9.1 9.1 9.1 9.1 9.1 9.1 9.1 3 Cavity volume/Å — 82 164 279 479 870 — — 20 (a) determined from cucurbituril· cucurbituril.  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 326 Molecular Guests in Solution Figure 6.16 Relationship between binding constant with cucurbituril and chain length for protonated amines, NH2 (CH2) n, and diamines, NH2 (CH2) nNH2, in HCO2H-D2O. 6.2.5 Kohnkene Mathias, J. P. and Stoddart, J. F., ‘Constructing a molecular LEGO set’, Chem. Soc. Rev., 1992, 21, 215–225. In the mid 1980s, J. Fraser Stoddart and Franz Kohnke, then from the University of Sheffield, UK, developed another rather less studied curved building block 6.5, which is derived from the reaction of 1,2,4,5-tetrabromobenzene with furan (Scheme 6.4). Kohnkene (6.39), which was named after its creator, is a very rigid structure, and possesses a small elliptical cavity that is unsuitable for inclusion of molecular guest species. However, the molecule may be deoxygenated to give dideoxykohnkene O Br Br = O O O O Br Br BunLi toluene Kohnkene precursor 6.5 O O H H O O H H CH2Cl2 O O toluene 10 kbar heat H H heat O H H O O O O O H H O O O O O O H H Kohnkene 6.39 Scheme 6.4 Synthesis of Kohnkene by multiple Diels–Alder addition.  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Cyclodextrins 327 Figure 6.17 X-ray structures of (a) kohnkene and (b) dideoxykohnkene, showing the included water molecule in the latter. (6.40), which has a rather more square cavity, just the right size to include a single water molecule (Figure 6.17). This example highlights in particular the enormous difficulty and ingenuity required to prepare molecular cage compounds with even a small cavity, a difficulty that increases with cavity size. Stoddart and other co-workers have extended their general approach to form a versatile molecular tool kit that they term ‘molecular LEGO’ after the children’s building blocks, which has enabled them to produce varying sizes of kohnkene-type rings, molecular ‘waves’ (arising from anti-Diels–Alder additions) and even the cage compound (6.41), which they named trinacrene, after the old name, Trinacria, for Franz Kohnke’s native Sicily. O O O H H O O H H O O O H H O O H H O O O dideoxykohnkene 6.40 Trinacrene 6.41 6.3 Cyclodextrins Szejtli, J. ‘Introduction and overview of cyclodextrin chemistry’, Chem. Rev., 1998, 98, 1743–1753. 6.3.1 Introduction and Properties The chemistry of the calixarenes and cavitands (Section 6.2.2) demonstrates clearly that as a molecular cavity becomes more rigid (and therefore preorganised) and deeper, its ability to complex organic guest species in solution is enhanced. As we have seen in the glycoluril-based hosts (Section 6.2.4), linked aromatic rings (cyclophanes) are not the only way to introduce rigidity into a host design. Indeed the most common, most studied and cheapest commercially available hosts, the cyclodextrins, are fully saturated and rely upon a combination of intramolecular hydrogen bonding and a sharp radius of curva- ture in order to introduce rigidity. Cyclodextrins as a class are enormously important host compounds, with a wide variety of industrial uses in the food, cosmetics and pharmaceuticals sectors, generally as  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 328 Molecular Guests in Solution OH OH HO OH α-cyclodextrin OHO O O OH O O OH 6.7 HO HO HO OH O O O HO OH HO O O OH O OH HO OH HO O O OH HO O O OH HO O OH OH HO OH O O HO O O O OH HO OH OH O O HO OH HO O O OH OH OH OH OH O β-cyclodextrin HO HO O O HO OH HO O O 6.42 O HO O OH O HO OH γ-cyclodextrin OH OH O 6.43 O HO OH HO O OH 2 1 4 OH O OH 3 2 OH HO O OH HO 3 O O O O OH 4 5 1 5 6 HO HO OH O O HO O O O HO 6 OH OH 1,4-glycosidic link (a) (b) Figure 6.18 (a) The three most important cyclodextrins. (b) The 1,4-glycosidic link that joins adjacent D -glucopyranoside units. slow-release and compound-delivery agents. They are also of significant importance as enzyme mimics (Section 12.2). They have the particular advantage of being entirely nontoxic over a wide dosage range. So important are they that an entire volume of Comprehensive Supramolecular Chemistry is devoted to them.24 Industrial production of the most important member of the cyclodextrin family, β-cyclodextrin (6.42), is about 1500 tons per year, and its price is just a few US dollars per kilogram. Cyclodextrins are cyclic oligosaccharides comprising (usually) six to eight D-glucopyranoside units (Figure 6.18a), linked by a 1,4-glycosidic bond (Figure 6.18b). The three most important members of the cyclodextrin family are α-cyclodextrin (α-CD, 6.7), β-cyclodextrin (β-CD, 6.42) and γ-cyclo- dextrin (γ-CD, 6.43), which possess, respectively, six, seven and eight glucopyranoside units. Several other (minor) cyclodextrins are known, including δ-cyclodextrin and ε-cyclodextrin (nine and ten units, respectively), and the five-membered pre-α-cyclodextrin. The α, β, γ nomenclature serves to distinguish the different ring sizes of the homologous series and is essentially historical in nature. It is very widely used, however, despite the fact that it does not distinguish the ring size explicitly. This is unsurprising, since systematic names for the cyclodextrins are extremely cumbersome. Other terms for β-cyclodextrin include cyclomaltoheptose, cycloheptaglucan and cycloheptaamylose, with analogous terms for the other members of the family. The cyclodextrin portion of the name comes from dextrose, an early synonym for glucose. Other cyclic oligosaccharides derived from mannose and galactose are also known, but are much less studied. The shape of a cyclodextrin is often represented as a tapering torus or truncated funnel and, like the upper and lower rims of calixarenes, there are two different faces to the cyclodextrins, referred to as the primary and secondary faces. The primary face is the narrow end of the torus, and comprises the  10.1002/9780470740880.ch6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9780470740880.ch6 by Uva Universiteitsbibliotheek, Wiley Online Library on [16/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Cyclodextrins 329 Figure 6.19 Anatomy of the cyclodextrins. primary hydroxyl groups. The wider secondary face contains the —CH2OH groups. The six-membered D-glucopyranoside rings are linked edge to edge, with their faces all pointing inwards towards a central hydrophobic cavity of varying dimensions. It is this cavity, coupled with the water solubility derived from the hydrophilic alcohol functionalities, that gives the cyclodextrins their unique complexation ability in aqueous solution. A functional scheme of cyclodextrin anatomy, along with the cavity sizes is shown in Figure 6.19. Important parameters are given in Table 6.3. Table 6.3 Characteristics of α-, β- and γ-Cyclodextrins. α β γ Number of glucose units 6 7 8 Ring size 30 35 40 Internal cavity centre 5.0 6.2 8.0 diameter (Å) Solubility in water (g L –1,25ºC) 145 18.5 232 ∆H solution (kJ mol ) o –1 32.1 34.7 32.3 ∆S solution (J K mol ) o –1 –1 57.7 48.9 61.4 [α] D25ºC 150.5 162.0 177.4 Cavity volume (Å3) 174 262 427 Cavity volume in 1 g 0.10 0.14 0.20 cyclodextrin (cm3) Crystalline water (wt. %) 10.2 13.2–14.5 8.13–17.7 pKa (25ºC, by potentiometry) 12.33 12.20 12.08 Rate of hydrolysis by A. oryzae Negligible Slow Rapid α-amylase Common guests Benzene, phenol Napthalene, 1-anilino-8- Anthracene, crown ethers, napthalenesulfonate 1-anilino-8-napthalene- sulfonate