3.

Molecular Hosts and Molecular Guests in Solution

Introduction
The host-guest binding of a neutral (usually organic) molecule may occur via its physical
imprisonment either as part of a solid-state network, forming a solid-state inclusion compound (clathrate), or
a metal-organic framework complex, 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
stabilization 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
assistance (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 organize or
self-assemble several components in solution in order to produce one.

Some General Considerations

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 recognize. 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.

The important types of interaction in molecular host-guest complexes are listed below.
1. Hydrophobic binding
2. Electrostatic interactions involving permanent charges (salt bridges)
3. Induced dipolar interactions.

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 4. π-π Interactions and charge transfer
5. Hydrogen bonding.

Intrinsic Curvature: Guest Binding by Cavitands

Individual host molecules possessing an intrinsic cavity that is present in both the solid state and in
solution are termed cavitands. A cavitand is defined 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 solution 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.

Cucurbiturils
Glycoluril (6.4), because of its curved backbone and versatile derivatization 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.

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.

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 Scheme 6.3 Synthesis of cucurbituril

Figure 6.15 X-ray structure of the inclusion complex cucurbit[10]urilꞏ cucurbit[5]uril

Inclusion complex of cucurbituril and Tinosorb S

The commercial sunscreen agent Tinosorb S (TS) is a promising oil-soluble broad spectrum UV
filter. The synthesis water-dispersible inclusion complex of TS using cucurbituril[6] was carried out via a
supramolecular approach in the solid state by using the high-speed vibration milling technique. The
formation and the photophysical properties of the solid inclusion complex were investigated by
spectroscopic techniques such as UV–vis spectrophotometry, Fourier-transform infrared and solid-state

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1
HNMR spectroscopy as well as by thermal gravimetric analysis and X-ray diffractometry. An increase in
the absorbance and a shift of the maximum absorption from 380 nm to 345 nm for the inclusion complex
were observed in comparison to the precursor complex TS. The stochiometric ratio of cucurbituril and TS in
the inclusion complex was found to be 2:1.

Figure 1. Structural formula of 2,4,-bis-{[4-(2-ethylhexyloxy)-2-hydroxy]-phenyl}-6-(4-methoxyphenyl)-(1,3,5)-

triazine(Tinosorb S, TS).

Figure 2. Energy-minimized models of cucurbituril (A), TS (B) and the inclusion complex (C) of both precursors
(software: Spartan`04).

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 FT-IR spectra of educts and the product

It was found that the inclusion complex contains both CB[6] and TS. From the spectra, it was
observed that the bands at 2870 and 2927 cm1 (two aliphatic side chains in TS) were shifted to 2872 and
2930 cm1, respectively, in the inclusion complex and this result complements the computer calculation.

Solid-state NMR spectra of educts and the product

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 The peaks of CB[6] at 5.92 and 4.31 ppm were shifted to 5.68 and 3.93 ppm, respectively, in the
inclusion complex. This is in accord with the literature and can be considered as a normal shift of the
inclusion complex. The peak of aliphatic side chains in TS at 0.92 ppm was shifted to 1.16 ppm in the
inclusion complex, which is an abnormal shift of inclusion complexes. The portal carboxyl groups in CB[6],
which have a high electronegativity, are responsible for the downfield shifts of the peaks of the aliphatic side
chain. Strong electronegative groups can reduce the local diamagnetic shielding.

From the energy-minimized computer calculation, it was shown that a 3:1 molar ratio of CB[6] and
TS is possible in the inclusion complex, where the cavity of two CB[6] units were involved in the complex
formation with two alkyl side chains of TS and another one with the methoxy substituent of TS. The
inclusion formation with the methoxy group of TS is not as strong as the alkyl side chains (see Figure 2).
Overall, a 2:1 stochiometric ratio of CB[6] and TS was found in the inclusion complex, which is also in
good agreement with the infrared and 1HNMRspectroscopic analytical data. The 2:1 stochiometric ratio
model is described in the following figure.

The inclusion complex model based on the experimental result – 2:1 stochiometric ratio of CB[6] and TS

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Cyclodextrins
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
curvature 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 slow-
release and compound-delivery agents. They are also of significant importance as enzyme mimics.

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-cyclodextrin (γ-CD,
6.43), which possess, respectively, six, seven and eight glucopyranoside units.

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 Figure 6.19 Anatomy of the cyclodextrins

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 Figure 6.20 Two views of the X-ray crystal structure of form I of α-CD hydrate

Degradation of starch with a variety of enzymes in the presence of water gives rise to the dextrins,
which result from the hydrolysis of glycosidic linkages. Dextrins are used in the food, textile and paper
industries, and are consumed in the production of bread, beer etc. If dextrins are degraded by the
glucosyltransferase enzyme, the primary product of the chain splitting (a linear oligosaccharide) undergoes
intramolecular cyclization, without the involvement of water, to give the cyclodextrins. Individual
cyclodextrins are isolated from the mixture by complexation with non-polar guests such as toluene (Figure
6.21), which results in dramatic decreases in solubility. Industrially produced cyclodextrins are generally
over 99 per cent pure.

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 Figure 6.21 Isolation of the cyclodextrins by glucosyltransferase degradation of starch

Generally, interaction of a cyclodextrin with an apolar guest molecule in water results in the formation
of 1:1 molecular inclusion compounds, in which the guest in included within the cyclodextrin cavity. Higher
equilibria involving the formation of 1:2 complexes, or multiple aggregates involving more than one
cyclodextrin, are common, and often exist simultaneously. The driving force for guest inclusion involves a
number of contributions, the importance of which is still a matter of some debate. Chiefly the factors of
importance are:
 steric fit;
 release of high-energy water;
 hydrophobic effects;
 van der Waals interactions;
 dispersive forces;
 dipole–dipole interactions;
 charge-transfer interactions;
 electrostatic interactions; and
 hydrogen bonding.

Solid-state cyclodextrin complexes generally fall into three broad categories – channel, cage and layer –
depending on the orientations of the cyclodextrin moieties and the connectivity between one cavity and the
next. Further subdivisions are observed depending upon the relative orientations of the primary and
secondary faces. The possible packing modes are illustrated in Figure 6.23.

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Figure 6.23 Schematic representation of the packing of cyclodextrin structures. (a) Head-to-head channel type; (b)
head-to-tail channel type; (c) cage type; (d) layer type; and (e) layer type composed of β-CD dimers.

Figure 6.24 Cage arrangement for β-CD ꞏ benzyl alcohol

A water-soluble inclusion complex of benzaldehyde-1,3,4-thiadiazoline with 𝛽-CD

The synthesis of water-soluble inclusion complex (2c) of benzaldehyde-1,3,4-thiadiazoline (2b) and
β-cyclodextrin (β-CD) was carried out in DMF by stirring at room temperature for 48 hours. A
stoichiometric ratio of benzaldehyde-1,3,4-thiadiazoline and β-cyclodextrin was 1:1. Cytotoxicity test results
showed that the prepared water soluble supramolecular/inclusion complex was more toxic in a factor of five
compare to water insoluble benzaldehyde-1,3,4-thiadiazoline because of its enhanced bioavailability.

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 Table 1. Spectral data of compounds β-CD, 2b, and 2c

β-CD 2b 2c
IR (cm1)
3284 (OH) 3356 (OH)
3012 (C=CH) 3020 (C=CH)
2922 (CH) 2931 (CH)
1693 (C=O) 1695 (C=O)
1612 (C=N) 1610 (C=N)
1
HNMR ()
7.52 (3H, Ar) 7.48 (3H, Ar)
7.94 (2H, Ar) 7.90 (2H, Ar)

Figure X: Thermal gravimetric analysis data of 2b, β-CD, and inclusion complex, 2c.

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 The TGA of the inclusion complex 2c (Figure X) in nitrogen atmosphere shows the first step of the
mass loss near at 100 oC which can be ascribed to the total loss of the crystallization of water in β-CD.
Decomposition of benzaldehyde thiadiazoline began at approximately 260 oC, whereas the decomposition of
both the inclusion complex and β-CD after the water loss did not start below 300 oC due to the destruction of
β-CD molecule. Therefore, the decomposition temperature of the inclusion complex was increased by at
least 40 oC upon inclusion. The encapsulated 2c molecule did not undergo any decomposition while the host
remained intact. Even though the TGA data indicate the formation of the inclusion complex, it is very
difficult to elucidate the stoichiometric ratio of β-CD and benzaldehyde thiadiazoline in the product. In most
cases, β-CD can form complexes with guest molecules in a ratio of 1:1, 1:2, or 2:1. The theoretical,
calculated mass content of β-CD in the complex for these three ratios could be 72.7, 57.2, and 84.2%,
respectively. The TGA data of the inclusion compound showed that the total mass loss at around 300 °C is
75.84%. This value indicates that the ratio between β-CD and 2c complex is of 1:1 type. At the same
temperature, pure β-CD lost 87.5% of its initial mass, and the mass loss observed for the inclusion
compound compared to that of the benzaldehyde thiadiazoline, 2b is due to the presence of β-CD in the final
product.

Cyclophanes
The term ‘cyclophane’ literally means any organic molecule containing a bridged aromatic ring.
They have been treated separately partly because they possess a number of properties unique to the presence
of multiple benzenoid rings and partly because they have been studied so extensively. The chemistry of
aromatic rings and their evolution towards cyclophanes with interesting electronic and structural properties
has long aroused interest (Figure 6.30).

Figure 6.30 Illustration from a spoof issue of Berichte der Durstigen Chemischen Gesellschaft (Berlin, 1886) showing
(a) monkeys grasping one another’s limbs, an image that originally inspired Kekulé’s structure of benzene and (b) a
facetious benzene ‘tautomer’ in which the monkeys are allowed to use their tails instead of their feet for bonding. The
purported effect was termed a ‘caudal residual affinity’.

Cyclophane Nomenclature

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 In general, any aromatic ring bridged by at least one aliphatic n-membered bridge with n ≥ 0 is
termed a cyclophane (a contraction of cyclophenylene alkane). The number of atoms, n, in each bridge is
denoted in square brackets in front of the name ‘cyclophane’, starting with the longest one along with a
designator (ortho-, meta- or para- or numbers in brackets) indicating the substitution pattern of the aromatic
ring(s). For multibridged arenes the number of equal bridges can be indicated as a subscript to the number of
carbon atoms they contain.

Complexes of cyclophanes

Figure 6.34 Molecular host and guests and X-ray structure of the 1:1 6.67ꞏdurene complex showing the intracavity
complexation of durene

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Figure 6.39 (a) Binding of p-benzoquinone by 6.78 (R = CH2, substituents omitted for clarity), (b) X-ray crystal
structure of 6.78

Synthesis of Cyclophanes

Scheme 6.7 Macrocycle synthesis via sulfur extrusion

Scheme 6.9 Preparation of a simple cyclophane via (a) Wurtz coupling and (b) 1,6-elimination

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 Scheme 6.11 Suzuki-Miyaura cross-coupling and alkene ring closing metathesis reactions

Cryptophanes
The very versatile and readily prepared saucer-shaped building block cycloveratrylene (CTV, 6.10)
has an extensive classical inclusion chemistry, although strangely in the case of small guests this behavior is
not linked to its intrinsic molecular cavity.

Cavitand 6.85 and pyridyl and phenanthroline-bridged analogues possess deep, permanent cavities
capable of binding neutral molecules such as CH2Cl2 in both solution and the solid state. In uncomplexed
6.85, the m-xylyl bridges are highly mobile; however, this mobility is reduced significantly upon guest
complexation. Molecular mechanics calculations suggest that the cavitate 6.85ꞏCH2Cl2 is more stable than
the free host by 57.3 kJ mol1, although this large value should not be confused with a solution binding
constant, since it does not take account of competitive effects of the medium.

Scheme 6.15 Synthesis of CTV-based cavitands

Clearly, deepening the CTV cavity to form cavitands is highly effective in enhancing the solution
binding characteristics of the basic CTV motif. However, we saw in the case of the cryptands that host–
guest affinity is enhanced even further by the formation of a closed, three-dimensional shell that can entirely
encapsulate the guest species. The three-dimensionality confers preorganisation, serves to protect the guest
from the solvent medium, and slows down guest exchange kinetics. A range of three-dimensional CTV-
based hosts have been prepared by André Collet (Lyon, France), in which two CTV type cavities face one
another and are linked covalently by —(CH2)n —, —CH2—CH=CH—CH2 — or —CH2—C≡C—CH2—
bridges (n = 3–8). Aryl-bridged analogues have also been prepared by capping of CpFe+ based podand
anion-binding hosts such as 4.66. These capsular hosts have been given the name cryptophanes by analogy

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with the cryptands (the -phane ending comes from the fact that they belong to the class of
[1.1.1]orthocyclophanes).

Cryptophanes exist in two distinct varieties with anti 6.85 and syn 6.86 orientations of the substituent
groups on the two hemispheres, generally exhibiting D3-anti or C3h-syn symmetry. The cryptophanes have
been named chronologically in the order of their discovery, thus cryptophane-A and cryptophane-B are the
anti/syn derivatives with X = (CH2)2 bridges, while in cryptophane-E and -F, X = –(CH2)3–.
Cryptophanes-C and -D have (CH2)2 bridges like cryptophane-A/B, but lack OMe groups on one
hemisphere.

X = (CH2)n, CH2CH=CHCH2, alkyne, C6H4

Figure 6.43 X-ray crystal structure of the CHCl3 complex of cryptophane-E

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Carcerands and Hemicarcerands
A carcerand is defined as a closed molecular container or capsule without portals of significant size
through which guests can either enter or leave (from the Latin carcer meaning ‘prison’). Guest molecules
within a carcerand are therefore permanently trapped or ‘incarcerated’ within the internal volume, unless
covalent bond breakage within the host occurs. A carcerand that contains a guest giving an incarcerated
host–guest complex is termed a carceplex.

Given this definition, it is necessary also to employ another term, hemicarcerand, which describes
closed molecular containers from which guests can enter and exit with a measurable activation barrier. In
the presence of guest species, hemicarcerands form hemicarceplexes. Good examples of hemicarcerands are
the cryptophanes, which are able to reversibly entrap relatively small guests such as methane, haloalkanes
etc.

While the cryptophanes are highly successful hosts for binding single molecules, their overall cavity
volume (80–90 Å3) is too small to bind simultaneously two guest species in order to admit the possibility of
intracavity reactivity and catalysis. Work by Cram et al. has focused upon the larger [4]resorcarenes related
to 6.3. Adopting a similar strategy to cryptophane synthesis, Cram was able to couple the upper rims of two
resorcarene bowls 6.95 and 6.96 under high-dilution conditions to give a pseudo-spherical cavity-containing
capsule (6.97, Scheme 6.18).

Scheme 6.18 Synthesis of the first carcerand

Carcerand 6.97 was designed by Cram’s group, just as they had designed the spherands, with the aid
of CPK molecular models. In his Nobel Prize address, writing just two years after the preparation of 6.97,
Cram describes his interest in the host–guest chemistry of this new capsule:

The first question to be answered was: what guest compound would be trapped inside during the
shell closure? This question is akin to asking whether two soup bowls closed rim-to-rim under the surface of
a kettle of stew would net any stew. The answer was that [6.97] ‘contained’ essentially every kind of
component of the medium present during ring closure.
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 The reaction product from Scheme 6.18 proved to be extremely insoluble in all solvents, and as a
result its characterization was a painstaking procedure. Impurities and unreacted starting materials were
extracted by treatment of the product mixture with the most powerful solvents of every type (polar, non-
polar, hydrogen bonding, dipolar aprotic etc.). The remaining product (various carceplexes – i.e. host–guest
complexes – of 6.97) was analyzed by elemental analysis for the elements C, H, S, O, N, Cl and Cs, all of
which proved to present in varying amounts, the ratio between Cs and Cl being stoichiometric. A solid-state
infrared spectrum revealed the presence of the reaction solvent, dimethyl formamide, from observation of
the characteristic C=O band. Analysis of the mixture by mass spectrometry (fast-atom bombardment)
revealed the presence of all of the carceplexes shown in Figure 6.47. No peaks were found at molecular
masses higher than the heaviest carceplex, and no other peaks were observed. Clearly, once ring closure
occurs any species present in the inner region of the forming carcerand are completely unable to escape,
even argon gas!

Figure 6.47 Carceplexes formed in the preparation of 6.97 (denoted by grey oval)

Figure 6.49 Cartoon view of an asymmetric analogue of the complex in which the different ‘feet’ render Ha and Hb
inequivalent, allowing the rate of rotation about the pyrazene N–N C2 axis to be measured.

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