Host–guest chemistry

Closely related to host–guest chemistry are inclusion compounds (also known as an inclusion complexes). Here, a chemical complex in which one chemical compound (the "host") has a cavity into which a "guest" compound can be accommodated. The interaction between the host and guest involves purely van der Waals bonding. The definition of inclusion compounds is very broad, extending to channels formed between molecules in a crystal lattice in which guest molecules can fit.

Yet another related class of compounds are clathrates, which often consist of a lattice that traps or contains molecules.^[11] The word clathrate is derived from the Latin clathratus (clatratus), meaning 'with bars, latticed'.^[12]

Molecular encapsulation concerns the confinement of a guest within a larger host. In some cases, true host–guest reversibility is observed, in other cases, the encapsulated guest cannot escape.^[13]

An important implication of encapsulation (and host–guest chemistry in general) is that the guest behaves differently from the way it would when in solution. Guest molecules that would react by bimolecular pathways are often stabilized because they cannot combine with other reactants. The spectroscopic signatures of trapped guests are of fundamental interest. Compounds normally highly unstable in solution have been isolated at room temperature when molecularly encapsulated. Examples include cyclobutadiene,^[15] arynes or cycloheptatetraene.^[16][17] Large metalla-assemblies, known as metallaprisms, contain a conformationally flexible cavity that allows them to host a variety of guest molecules. These assemblies have shown promise as agents of drug delivery to cancer cells.

Encapsulation can control reactivity. For instance, excited state reactivity of free 1-phenyl-3-tolyl-2-proponanone (abbreviated A-CO-B) yields products A-A, B-B, and AB, which result from decarbonylation followed by random recombination of radicals A• and B•. Whereas, the same substrate upon encapsulation reacts to yield the controlled recombination product A-B, and rearranged products (isomers of A-CO-B).^[18]

Organic hosts are occasionally called cavitands. The original definition proposed by Cram includes many classes of molecules: cyclodextrins, calixarenes, pillararenes and cucurbiturils.^[19]

Calixarenes and related formaldehyde-arene condensates (resorcinarenes and pyrogallolarenes) form a class of hosts that form inclusion compounds.^[5][20] A related family of formaldehyde-derived oligomeric rings are pillararenes (pillered arenes). One famous illustration of the stabilizing effect of host–guest complexation is the stabilization of cyclobutadiene by such an organic host.^[21]

Cyclodextrins (CDs) are tubular molecules composed of several glucose units connected by ether bonds. The three kinds of CDs, α-CD (six units), β-CD (seven units), and γ-CD (eight units) differ in their cavity sizes: 5, 6, and 8 Å, respectively. α-CD can thread onto one PEG chain, while γ-CD can thread onto two PEG chains. β-CD can bind with thiophene-based molecule.^[5] Cyclodextrins are well established hosts for the formation of inclusion compounds.^[1][2][3] Illustrative is the case of ferrocene which is inserted into the cyclodextrin at 100 °C under hydrothermal conditions.^[22]

Cucurbiturils are macrocyclic molecules made of glycoluril (=C₄H₂N₄O₂=) monomers linked by methylene bridges (−CH₂−). The oxygen atoms are located along the edges of the band and are tilted inwards, forming a partly enclosed cavity (cavitand). Cucurbit[n]urils have similar size of γ-CD, which also behave similarly (e.g., one cucurbit[n]uril can thread onto two PEG chains).^[5]

The structure of cryptophanes contain six phenyl rings, mainly connected in four ways. Due to the phenyl groups and aliphatic chains, the cages inside cryptophanes are highly hydrophobic, suggesting the capability of capturing non-polar molecules. Based on this, cryptophanes can be employed to capture xenon in aqueous solution, which could be helpful in biological studies.^[5]

Crown ethers bind cations. Small crown ethers, e.g. 12-crown-4 bind well to small ions such as Li+ and large crowns, such as 24-crown-8 bind better to larger ions.^[5] Beyond binding ionic guests, crown ethers also bind to some neutral molecules, e.g., 1, 2, 3- triazole. Crown ethers can also be threaded with slender linear molecules and/or polymers, giving rise to supramolecular structures called rotaxanes. Given that the crown ethers are not bound to the chains, they can move up and down the threading molecule.^[8] Crown ether complexes of metal cations (and the corresponding complexes of cryptands) are not considered to be inclusion complexes since the guest is bound by forces stronger than van der Waals bonding.

Zeolites have open framework structures with cavities in which guest species can reside. Aluminosilicates being their composition, zeolites are rigid. Many structures are known, some of which are considerably useful as catalysts and for separations.^[11]

Silica clathrasil are compounds structurally similar to clathrate hydrates with a SiO₂ framework and can be found in a range of marine sediment.^[23]

Clathrate compounds with formula A₈B₁₆X₃₀, where A is an alkaline earth metal, B is a group III element, and X is an element from group IV have been explored for thermoelectric devices. Thermoelectric materials follow a design strategy called the phonon glass electron crystal concept.^[24][25] Low thermal conductivity and high electrical conductivity is desired to produce the Seebeck Effect. When the guest and host framework are appropriately tuned, clathrates can exhibit low thermal conductivity, i.e., phonon glass behavior, while electrical conductivity through the host framework is undisturbed allowing clathrates to exhibit electron crystal.

Hofmann clathrates are coordination polymers with the formula Ni(CN)₄·Ni(NH₃)₂(arene). These materials crystallize with small aromatic guests (benzene, certain xylenes), and this selectivity has been exploited commercially for the separation of these hydrocarbons.^[11] Metal organic frameworks (MOFs) form clathrates.

Urea, a small molecule with the formula O=C(NH₂)₂, has the peculiar property of crystallizing in open but rigid networks. The cost of efficient molecular packing is compensated by hydroge-bonding. Ribbons of hydrogen-bonded urea molecules form tunnel-like host into which many organic guests bind. Urea-clathrates have been well investigated for separations.^[26] Beyond urea, several other organic molecules form clathrates: thiourea, hydroquinone, and Dianin's compound.^[11]

When the host and guest molecules combine to form a single complex, the equilibrium is represented as

${\displaystyle H+G\leftrightharpoons HG}$

and the equilibrium constant, K, is defined as

${\displaystyle K={\frac {[HG]}{[H][G]}}}$

where [X] denotes the concentration of a chemical species X (all activity coefficients are assumed to have a numerical values of 1). The mass-balance equations, at any data point,

${\displaystyle T_{H}=[H]+K[H][G]}$

${\displaystyle T_{G}=[G]+K[H][G]}$

where ${\displaystyle T_{G}}$ and ${\displaystyle T_{H}}$ represent the total concentrations, of host and guest, can be reduced to a single quadratic equation in, say, [G] and so can be solved analytically for any given value of K. The concentrations [H] and [HG] can then derived.

${\displaystyle [H]=T_{H}-T_{G}+[G]}$

${\displaystyle [HG]=K[H][G]}$

The next step in the calculation is to calculate the value, ${\displaystyle X_{i}^{calc}}$, of a quantity corresponding to the quantity observed ${\displaystyle X_{i}^{obs}}$. Then, a sum of squares, U, over all data points, np, can be defined as

${\displaystyle U=\sum _{i=1,np}(X_{i}^{obs}-X_{i}^{calc})^{2}}$

and this can be minimized with respect to the stability constant value, K, and a parameter such as the chemical shift of the species HG (nmr data) or its molar absorbency (uv/vis data). This procedure is applicable to 1:1 adducts.

With nuclear magnetic resonance (NMR) spectra the observed chemical shift value, δ, arising from a given atom contained in a reagent molecule and one or more complexes of that reagent, will be the concentration-weighted average of all shifts of those chemical species. Chemical exchange is assumed to be rapid on the NMR time-scale.

Using UV-vis spectroscopy, the absorbance of each species is proportional to the concentration of that species, according to the Beer–Lambert law.

${\displaystyle A_{\lambda }=\ell \sum _{i=1}^{N}\varepsilon _{i,\lambda }c_{i}}$

where λ is a wavelength, ${\displaystyle \ell }$ is the optical path length of the cuvette which contains the solution of the N compounds (chromophores), ${\displaystyle \varepsilon _{i,\lambda }}$ is the molar absorbance (also known as the extinction coefficient) of the ith chemical species at the wavelength λ, c_i is its concentration. When the concentrations have been calculated as above and absorbance has been measured for samples with various concentrations of host and guest, the Beer–Lambert law provides a set of equations, at a given wavelength, that can be solved by a linear least-squares process for the unknown extinction coefficient values at that wavelength.

Host–guest structures can be probed by their luminescence. A rigid matrix protects emitters from being quenched, extending the lifetime of phosphorescence.^[27] In this circumstance, α-CD and CB could be used,^[28][29] in which the phosphor is served as a guest to interact with the host. For example, 4-phenylpyridium derivatives interacted with CB, and copolymerize with acrylamide. The resulting polymer yielded ~2 s of phosphorescence lifetime. Additionally, Zhu et al. used crown ether and potassium ion to modify the polymer, and enhance the emission of phosphorescence.^[30]

Another technique for evaluating host–guest interactions is calorimetry.

Host guest complexation is pervasive in biochemistry. Many protein hosts recognize and hence selectively bind other biomolecules. When the protein host is an enzyme, the guests are called substrates. While these concepts are well established in biological systems, the applications of synthetic host–guest chemistry remain mostly in the realm of aspiration. One major exception are zeolites where host–guest chemistry is their raison d'etre.

A self-healing hydrogel can be constructed from modified cyclodextrin and adamantane.^[31][33] Another strategy is to use the interaction between the polymer backbone and host molecule (host molecule threading onto the polymer). If the threading process is fast enough, self-healing can also be achieved.^[32]

Cyclodextrin forms inclusion compounds with fragrances which are more stable towards exposure to light and air. When incorporated into textiles the fragrance lasts much longer due to the slow-release action.^[34]

Photolytically sensitive caged compounds have been examined as containers for releasing drugs or reagents.^[35][36]

An encryption system constructed by pillar[5]arene, spiropyran and pentanenitrile (free state and grafted to polymer) was constructed by Wang et al.. After UV irradiation, spiropyran would transform into merocyanine. When the visible light was shined on the material, the merocyanine close to the pillar[5]arene-free pentanenitrile complex had faster transformation to spiropyran; on the contrary, the one close to pillar[5]arene-grafted pentanenitrile complex has much slower transformation rate. This spiropyran–merocyanine transformation can be used for message encryption.^[37] Another strategy is based on the metallacages and polycyclic aromatic hydrocarbons.^[38] Because of the fluorescence emission differences between the complex and the cages, the information could be encrypted.

Although some host–guest interactions are not strong, increasing the amount of the host–guest interaction can improve the mechanical properties of the materials. As an example, threading the host molecules onto the polymer is one of the commonly used strategies for increasing the mechanical properties of the polymer. It takes time for the host molecules to de-thread from the polymer, which can be a way of energy dissipation.^[33][39][40] Another method is to use the slow exchange host–guest interaction. Though the slow exchange improves the mechanical properties, simultaneously, self-healing properties will be sacrificed.^[41]

Silicon surfaces functionalized with tetraphosphonate cavitands have been used to singularly detect sarcosine in water and urine solutions.^[42]

Traditionally, chemical sensing has been approached with a system that contains a covalently bound indicator to a receptor though a linker. Once the analyte binds, the indicator changes color or fluoresces. This technique is called the indicator–spacer–receptor approach (ISR).^[43] In contrast to ISR, indicator-displacement assay (IDA) utilizes a non-covalent interaction between a receptor (the host), indicator, and an analyte (the guest). Similar to ISR, IDA also utilizes colorimetric (C-IDA) and fluorescence (F-IDA) indicators. In an IDA assay, a receptor is incubated with the indicator. When the analyte is added to the mixture, the indicator is released to the environment. Once the indicator is released it either changes color (C-IDA) or fluoresces (F-IDA).^[44]

IDA offers several advantages versus the traditional ISR chemical sensing approach. First, it does not require the indicator to be covalently bound to the receptor. Secondly, since there is no covalent bond, various indicators can be used with the same receptor. Lastly, the media in which the assay may be used is diverse.^[45]

Chemical sensing techniques such as C-IDA have biological implications. For example, protamine is a coagulant that is routinely administered after cardiopulmonary surgery that counter acts the anti-coagulant activity of herapin. In order to quantify the protamine in plasma samples, a colorimetric displacement assay is used. Azure A dye is blue when it is unbound, but when it is bound to herapin it shows a purple color. The binding between Azure A and heparin is weak and reversible. This allows protamine to displace Azure A. Once the dye is liberated it displays a purple color. The degree to which the dye is displaced is proportional to the amount of protamine in the plasma.^[46]

F-IDA has been used by Kwalczykowski and co-workers to monitor the activities of helicase in E. coli. In this study they used thiazole orange as the indicator. The helicase unwinds the dsDNA to make ssDNA. The fluorescence intensity of thiazole orange has a greater affinity for dsDNA than ssDNA and its fluorescence intensity is higher when it is bound to dsDNA than when it is unbound.^[47][48]

A crystalline solid has been traditionally viewed as a static entity where the movements of its atomic components are limited to its vibrational equilibrium. As seen by the transformation of graphite to diamond, solid to solid transformation can occur under physical or chemical pressure. It has been proposed that the transformation from one crystal arrangement to another occurs in a cooperative manner.^[49][50] Most of these studies have been focused in studying an organic or metal-organic framework.^[51][52] In addition to studies of macromolecular crystalline transformation, there are also studies of single-crystal molecules that can change their conformation in the presence of organic solvents. An organometallic complex has been shown to morph into various orientations depending on whether it is exposed to solvent vapors or not.^[53]

Host guest systems have been proposed to remove hazardous materials. Certain calix[4]arenes bind cesium-137 ions, which could in principle be applied to clean up radioactive wastes. Some receptors bind carcinogens.^[54][55]

According to food chemist Udo Pollmer of the European Institute of Food and Nutrition Sciences in Munich, alcohol can be molecularly encapsulated in cyclodextrines, a sugar derivate. In this way, encapsuled in small capsules, the fluid can be handled as a powder. The cyclodextrines can absorb an estimated 60 percent of their own weight in alcohol.^[56] A US patent has been registered for the process as early as 1974.^[57]

• Cryptophane