User:Zhoudeng1234/Host–guest chemistry

Host-guest interaction has raised dramatical attention since it was discovered. It is an important field, because many biological processes require the host-guest interaction, and it can be useful in some material designs. There are several typical host molecules, such as, cyclodextrin, crown ether, et al. In this article, the author will briefly introduce some examples of the host-guest molecules, discuss the thermodynamic and kinetic parameters, and discuss some applications.

Introduction
Although van de waals postulated the intermolecular interaction in 1873, in 1894, Fischer built a philosophical root for the supramolecular chemistry, as he pointed out that the enzyme-protein interaction take the form of lock and key. This is the fundamental of the host-guest chemistry. Then in 1920, Latimer and Rodebush described the hydrogen bonding. With the deeper understanding of the non-covalent interactions, for example, the clear elucidation of DNA structure, chemists started to emphasize the importance of non-covalent interactions. In 1967, Charles J. Pedersen discovered crown ether, which is a “ring-like structure”, and able to capture certain metallic atoms. The metallic atoms can be included in this organic compound. Then, in 1969, Jean-Marie Lehn found a molecule similar to crown ether, called cryptands. After that, Donald J. Cram discovered a molecule which can attach to certain atom or molecule by themselves. The three scientists were awarded the Nobel Prize in Chemistry in 1987 “for their development and use of molecules with structure-specific interactions of high selectivity”. In 2016, three other scientists, whose name are Bernard L. Feringa, Sir J. Fraser Stoddart and Jean-Pierre Sauvage, were awarded the Nobel Prize in Chemistry, "for the design and synthesis of molecular machines". This opened a gate for the supramolecular chemistry.

Supramolecular chemistry refers to the chemical systems that contains discrete number chemical components. The strengths of the systems vary from the intermolecular forces to covalent bindings. The researchers mentioned above created and enlarged the area of host-guest interaction, one of the most important concepts of the supramolecular chemistry fields. There are two significant components in the host-guest interaction. One is the "host molecules", which usually have "pore-like" structure that is able to capture some other molecules. The another one is the "guest molecules", which are generally smaller than the host molecules, and capable of binding the host molecules. The driving forces of the interaction might vary in different cases, such as hydrophobic effect, chelate effect, van der Waals force, et al. Different bindings will provide variant properties for the materials, i.e., stimuli-responsiveness, self-healing, matrix rigidification. As a consequence, the host-guest interaction can be applied for self-healing materials, stimuli-responsive materials, room-temperature phosphorescence (RTP), improvement of mechanical properties, et al. The sizes of the host and guest molecules play an essential role in the interactions, and some typical examples of the host interactions will be discussed as followed.

Crown ether
Crown ether is a ring-like structure, with several units of ethylene glycol (Figure 1a). Because the radius of a pore is similar to that of alkali metal ion, the crown ether is well known for its ability to bind metallic ion. For example, 12-crown-4, 15-crwon-5, 18-crown-6, 21-crown-7, and 24-crown-8 interact with potassium, sodium, ammonium, and calcium ion, respectively. Among the above crown ether, all the ions have the strongest binding affinity with 18-crown-6, for the reason that the size of 18-crown-6 matches the ions most. Besides the ion, crown ether can also bind to neutral molecules, i.e., 1, 2, 3- triazole (Figure 1b). Since the crown ether is not fixed upon the molecular chain, it can move from one triazole unit to another one, in other words, the ring can slide across the molecular chain. This structure is called rotaxane.

Cyclodextrin
Cyclodextrin (CD) is composed of several glucose units and connects by ether bonds (Figure 1c). There are three kinds of CDs, α-CD (6 units), β-CD (7 units), and γ-CD (8 units). The heights of the structure are all around 8 Å, while the cavity sizes of them are different, around 5, 6, and 8 Å, respectively. By comparing the size of the guest molecule and the CD, the binding behavior can be predicted. For instance, if the guest molecule is larger than the CD, it can be assumed that the binding will not occur. Typically, the α-CD can thread onto one PEG chain (Figure 1c), while γ-CD can thread onto 2 PEG chains. β-CD can bind with thiophene-based molecule (Figure 1d).

Cryptophanes
The structure of cryptophanes contain 6 phenyl rings, mainly connected in 4 ways (Figure 2a). Due to the phenyl group and aliphatic chain, the cage inside cryptophanes is highly hydrophobic, suggesting the capability of capturing some non-polar molecule. Based on this, cryptophanes can be employed to capture xenon in aqueous solution, which might be helpful in biological study.

Resorcinarenes and Pyrogallolarenes
One of the classic structures of resorcinarenes and pyrogallolarenes is shown below (Figure 2b). Because of the phenol group, some hydrogen bonds are foromed among the molecules. Sometimes, the binding ratio of the host and guest could reach 2 : 1.

Other receptors (cucurbit[n]urils, CB)
Cucurbit[n]urils (Figure 2c) have similar size of γ-CD, which also behave similarly (i.e., 1 eq. of cucurbit[n]urils can thread onto 2 eq. PEG chains).

Determination of thermodynamic parameters
The thermodynamic benefits of host–guest chemistry are derived from the idea that there is a lower overall Gibbs free energy due to the interaction between host and guest molecules. Chemists are exhaustively trying to measure the energy and thermodynamic properties of these non-covalent interactions found throughout supramolecular chemistry; and by doing so hope to gain further insight into the combinatorial outcome of these many, small, non-covalent forces that are used to generate an overall effect on the supramolecular structure.

An association constant, $$K^\ominus_a$$ can be defined by the expression


 * $$K^\ominus_a = \frac{\{HG\}}{\{H\}\{G\}} = \frac{[HG]}{[H][G]} \times \Gamma $$

where {HG} is the thermodynamic activity of the complex at equilibrium. {H} represents the activity of the host and {G} the activity of the guest. The quantities $$[HG]$$, $$[H]$$ and $$[G]$$ are the corresponding concentrations and $$\Gamma$$ is a quotient of activity coefficients.

In practice the equilibrium constant is usually defined in terms of concentrations.


 * $$K_a =\frac{[HG]}{[H][G]}$$

When this definition is used, it is implied that the quotient of activity coefficients has a numerical value of one. It then appears that the equilibrium constant, $$K_A$$ has the dimension 1/concentration, but that cannot be true since the standard Gibbs free energy change, $$\Delta G^\ominus$$ is proportional to the logarithm of K.


 * $$\Delta G^\ominus = -RT \ln{K} $$

To describe the limitation of a specific thermo process, the thermodynamic values (K, binding affinity;, enthalpy change; , entropy change; , Gibbs energy) are essential. Because of the sensitivity of several characterization methods to the chemically environmental changes (i.e., nuclear magnetic resonance (NMR); UV-vis absorption; Raman Spectroscopy; fluorescence data; isothermal titration calorimetry (ITC); et al), they can be applied for thermodynamic parameters measurements. NMR could be used for characterizing chemical shift of the host/guest signals before and after binding. The formation of new complex might result in UV absorption or fluorescence changes. Chemical structure change might cause Raman spectrum differences. ITC can be utilized to measure the heat change during the binding process. These thermodynamic parameters will tell people the equilibrium point of the binding process, however, how long it will take to reach the equilibrium point is not elucidated. Based on this, the kinetic parameters are needed.

Kinetic parameters
The binding process is reversible, indicating that the associate constant (ka) is not far larger than disassociate constant (kd). Combing the rate of the reaction, ka, kd, concentration, and time, the relation of the free guest molecule and time can be calculated. By calculating the integration of UV spectrum or NMR, the concentration as a function of time curve can be obtained.

Self-healing
Because of the non-covalent host-guest interaction, the polymer backbone can have enough flexibility to diffuse. If a crack exists in the materials, after compressing the two materials around the crack, because of the fast exchange of the host-guest molecular structure, the crack will rejoin again revealing good self-healing properties. Harada et al reported a self-healing hydrogel constructed by vinyl-group-modified cyclodextrin and adamantane (Figure 4a). 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 (Figure 4b).

Room-Temperature Phosphorescence
Generally, it is not easy to achieve pure organic phosphorescence, partly because of the instability of the triplet state (easily be quenched by moisture, oxygen, etc). Host-guest structures can provide a rigid matrix, which protects the triplet state from being quenched. In this circumstance, α-CD and CB could be used, 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.

Stimuli-responsive materials
Some guest molecules are charged compounds, which might be oxidized or reduced by certain chemicals. This type of guest molecule can present redox responsiveness. Some host molecules (i.e., α-CD) or guest molecules (i.e., tetra ammonium ion) are pH-sensitive, different pH can result in different species, which significantly influences the binding behavior, giving the material pH responsive properties. Some guest molecules may change their configurations under different lights, which makes the material photo-responsive. Cai et al employed a halogen bond to prepare a host-guest system, and the materials are heat- and mechano-responsive with long persistent emission.

Encryption
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 is 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. Another strategy is based on the metallacages and polycyclic aromatic hydrocarbons. Because of the fluorescnece emission differences between the complex and the cages, the information could be encrypted.

Mechanical property
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. 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.

Biological application
Dendrimers in drug-delivery systems is an example of various host–guest interactions. The interaction between host and guest, the dendrimer and the drug, respectively, can either be hydrophobic or covalent. Hydrophobic interaction between host and guest is considered "encapsulated" while covalent interactions are considered to be conjugated. The use of dendrimers in medicine has shown to improve drug delivery by increasing the solubility and bioavailability of the drug. In conjunction, dendrimers can increase both cellular uptake and targeting ability, and decrease drug resistance.

Sensing (molecular recognition)
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).[23] 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).

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.