Formation of inclusion complexes

Formation of Inclusion Complexes 1. Detection of Complex-Formation 

A variety of techniques can be used for studying complex-formation, a number of which are now listed. 

Although the techniques just considered have been widely used for the development of practical uses of the cyclodextrins, the underlying forces responsible for the stability of the inclusion complexes, as well as the mechanism of their formation, are at present not completely understood. 

Values of AH° and AS° for complex-formation between alpha and beta cyclodextrin and a variety of guest molecules are shown in Tables II and III. If AH° is plotted against AS°, a linear relationship is observed, in which AH° and AS° are compensating (see Figs. 4 and 5). The slope of the graph is called the compensation temperature or isoequilibrium 

Standard Formation Enthalpies and Entropies of Cyciomaitohexaose Inclusion 

Complexation is a molecular phenomenon where one molecule of guest and one molecule of CD come into contact with each other to associate and form a complex [3,10]. The beneficial effects of complexation of a with CD include increased solubility of the guest stabihzation of the guest to prevent volatilization, oxidation, and degradation due to exposure to light and heat elimination or 

The inclusion of a guest in a CD cavity consists basically of a substitution of the included water molecules by the less polar guest. The process is energetically favored by the interactions of the guest molecule with the solvated hydrophobic cavity of the host. In this process entropy and enthalpy changes have an important role [9]. In spite of the fact that the driving force of complexation is not yet completely understood, it seems that it is the result of various effects [9]  

The type of bond established between the guest and the host is non-covalent. A variety of non-covalent forces such as van der Waals forces, hydrogen bonding, dipole-dipole interaction, London dispersion forces and other hydrophobic interactions are responsible for the formation of a stable complex. Also, a force responsible for complexation for one series of molecules may not hold for another series of molecules. A single force cannot be found as the only factor responsible for complexation of all molecules. Several forces seem to be involved in the complexation. As a result, it is difficult or impossible to predict how well a particular molecule might bind with CDs [2,3,9]. 

Looking for the most appropriate host, CDs with various cavity diameters and chemically modified CDs must be discriminated. Using the higher soluble CD derivatives, high solubilizing effects can be attained [9]. 

The inclusion complex formation constants between LR-CD (CD9-CD17) and various anions have been measured by capillary electrophoresis. The findings showed that LR-CDs have a certain extent of inclusion ability [1,7]. -CD was the best overall complex former with the chosen range of guest molecules followed by a- and y-CDs. The stability constants decreased for CD9 and CD 10. CD 10 revealed itself as the poorest overall complex former with the guest molecules studied (e.g., 4-tert.-butylbenzoate and the ibuprofen anion) [1]. 

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The theory and development of a solvent-extraction scheme for polynuclear aromatic hydrocarbons (PAHs) is described. The use of y-cyclodextrin (CDx) as an aqueous phase modifier makes this scheme unique since it allows for the extraction of PAHs from ether to the aqueous phase. Generally, the extraction of PAHS into water is not feasible due to the low solubility of these compounds in aqueous media. Water-soluble cyclodextrins, which act as hosts in the formation of inclusion complexes, promote this type of extraction by partitioning PAHs into the aqueous phase through the formation of complexes. The stereoselective nature of CDx inclusion-complex formation enhances the separation of different sized PAH molecules present in a mixture. For example, perylene is extracted into the aqueous phase from an organic phase anthracene-perylene mixture in the presence of CDx modifier. Extraction results for a variety of PAHs are presented, and the potential of this method for separation of more complex mixtures is discussed. 

Hamai S. and Sakurai H., Capilary electrophoretic separation of positional isomers of hydroxynaphthalenecarboxylic acids through the formation of inclusion complexes with P-cyclodextrin, Anal. Chim. Acta, 402, 53, 1999. 

Asymmetric Allylation. One of the recent new developments on this subject is the asymmetric allylation reaction. It was found that native and trimethylated cyclodextrins (CDs) promote enantiose-lective allylation of 2-cyclohexenone and aldehydes using Zn dust and alkyl halides in 5 1 H2O-THF. Moderately optically active products with ee up to 50% were obtained.188 The results can be rationalized in terms of the formation of inclusion complexes between the substrates and the CDs and of their interaction with the surface of the metal. 

Optically active Diels-Alder adducts were also prepared by using a one-pot preparative method and enantioselective formation of inclusion complex with optically active hosts in a water suspension medium.68 For example, A-ethylmaleimide reacts with 2-methyl-1,3-butadiene in water to give the racemic adduct 1. Racemic 1 and the optically active host 2 form enantioselectively a 1 1 inclusion complex of 2 with (+)-l in a water suspension. The inclusion complex can be filtered and heated to release (+)-l with 94% ee (Eq. 12.23). 

A final source of evidence for the formation of inclusion complexes in solution has been derived from kinetic measurements. Rate accelerations imposed by the cycloamyloses are competitively inhibited by the addition of small amounts of inert reagents such as cyclohexanol (VanEtten et al., 1967a). Competitive inhibition, a phenomenon frequently observed in enzymatic catalyses, requires a discrete site for which the substrate and the inhibitor can compete. The only discrete site associated with the cycloamyloses is their cavity. 

The conclusions of the preceding discussion can be briefly summarized as follows. The formation of inclusion complexes in both the crystalline state as well as in solution has been convincingly demonstrated by spectral and kinetic techniques. Whereas the crystalline complexes are seldom stoichiometric, the solution complexes are usually formed in a 1 1 ratio. Although the geometries within the inclusion complexes cannot be accurately defined, it is reasonable to assume that an organic substrate is included in such a way to allow maximum contact of the hydrophobic portion of the substrate with the apolar cycloamylose cavity. The hydrophilic portion of the substrate, on the other hand, probably remains near the surface of the complex to allow maximum contact with the solvent and the cycloamylose hydroxyl groups. The implications of inclusion complex formation for specificity and catalysis will be elucidated in subsequent sections of this article. 

Finally, we come to enzyme models. D. W. Griffiths and M. L. Bender describe the remarkable catalytic property of certain cycloamyloses which act through formation of inclusion complexes, and in this respect recall the clefts containing the active sites in enzymes such as lysozyme and papain. 

Monflier and co-workers recently described a new approach based on the use of chemically modified /3-cyclodextrins to peform efficiently the functionalization of water-insoluble olefins in a two-phase system. These compounds behave as inverse phase transfer catalysis, i.e., they transfer olefins into the aqueous phase via the formation of inclusion complexes.322... 

Recently, it has become clear to the author that cyclodextrin is one of the promising hosts for macromolecular recognition, with the finding that the cylindrical channel formed when it is stacked in a linear row is able to accommodate one or more long-chain guests. Thus, he and his coworkers launched a series of experiments to explore the formation of inclusion complexes between... 

Evaporation Precipitation, flocculation Flotation Adsorption Formation of inclusion complexes Extraction processes Stripping Reduction chemical, electrochemical ... 

The formation of inclusion complexes is influenced mainly by steric parameters of ligands (geometry and size) and by the possibility of creating hydrophobic interactions and hydrogen bonds (physicochemical properties). Hydrophobic interactions predominate in the cavity, and they can act in concert with polar interactions that occur with hydroxyl groups located at the outer lip of the CDs. There are no covalent bonds (14). 

An unusual and complicated array of heterocycles results from the inclusion of hydroxide moieties into a similar ferf-butylaluminium oxide system to [(f-Bu)A10]8 [50]. In this context, the product which results from the hydrolysis of [(f-Bu)Al(/T3-0)]6 [24] - [(f-Bu)Al]6(/T3-0)4(/r3-0H)4 - is best viewed as comprising an octahedron of aluminium centres each face of which is /X3-capped by either an oxide or a hydroxide group (Fig. 11) [63]. This species was the first to exhibit penta-coordinate Al-centres in an alumoxane context. Moreover, the polyhedral architecture incorporated an interstitial void which, it was suggested, might facilitate the formation of inclusion complexes. The predilection for (AlO) (n = 2) metallocycles does not hold for the tetracyclic array of n = 3 rings displayed by the mixed oxide-hydroxide... 

It should be stressed that there is not alwaysjustice in reseach evaluation. The selective formation of inclusion complexes by cyclodextrins (such as 11) was established by Cramer [6] at least 15 years earlier than that by crown ethers. However, cyclodextrin studies forming an independent branch of host-guest chemistry seem underestimated in spite of their considerably greater practical importance at present than that of other host macrocycles (crown ethers 17, calixarenes 18, etc.). Sometimes they are even totally neglected by discussing inclusion phenomena [7]. 

Let us compare the methods applied by Pedersen for establishing the complex formation with a modern approach. Today tedious solubility studies are carried out almost exclusively with practical applications in mind, but they are not performed to prove the complex formation. For instance, one ofthe main reasons for the use of cyclodextrin complexes in the pharmaceutical industry is their solubilizing effect on drugs [8]. There, and almost only there, solubility studies are a must. As concerns spectroscopic methods, at present the NMR technique is one ofthe main tools enabling one to prove the formation of inclusion complex, carry out structural studies (for instance, making use of the NOE effect [9a]), determine the complex stability [9b, c] and mobility of its constituent parts [9d]. However, at the time when Pedersen performed his work, the NMR method was in the early stage of development, and thus inaccurate, and its results proved inconclusive. UV spectra retained their significance in supramolecular chemistry, whilst at present the IR method is used to prove the complex formation only in very special cases. 

Pitha, J. and T. Hoshino (1992). Effect of ethanol on formation of inclusion complexes of hydroxypropylcyc-lodextrins with testosterone or with methyl orantjit. J. Pharm., 80 243-251. 

The chiral resolution on CD-based CSPs depends on the formation of inclusion complexes in the cavities and, therefore, the structures and sizes of analytes are very important for the chiral resolution of racemates on these phases. Amino acids often are considered to be the best class of racemic compounds to use in structural studies. In 1987, Han and Armstrong [55] studied the chiral resolution of amino acids on -CD-based CSPs. It was observed that different retention, separation, and resolution factor values were obtained for different amino acids under identical chromatographic conditions, which indicated that the structures and sizes of amino acids govern their chiral resolution. The same observations may be found in the work of Fujimura et al. [70]. 

Formation of inclusion complexes with a variety of small organic molecules in which O—H- O hydrogen bonds play an important role has been discussed by Toda [43], Toda and Akagi [44] reported that diacetylene diol forms crystalline stoichiometric inclusion complexes with a variety of small molecules. The salient features that assist complex formation are hydrogen-bonding between the poten-... 

Effect of /3-cyclodc trin on cis trans isomerization of azobenzenes was studied by Sanchez and de Rossi [26], It was found that the cis-trans thermal isomerization of / -Mcthvl Red, o-Methyl Red and Methyl Orange is inhibited by fi-CD at constant pH. The isomerization rate decreases 4, 8, and 1.67 times, respectively, in a solution containing 0.01 M /J-CD. This effect was attributed to the formation of inclusion complexes hindering rotation of the -N=N- bond. Isomerization of Methyl Yellow and naphthalene-l-azo-[4 -(dimethylamino)benzene] requiring mixed organic-aqueous... 

Cyclodextrins have been covalently modified for catalytic oxidation, such as compounds 57, 62-65 (Schemes 3.14 to 3.16) [44, 45]. Enantioselective epoxidation of styrene derivatives, and carene using 20-100 mol% of the CD-ketoester 57 has been achieved. The inclusion-complex formation was confirmed by aH NMR titration experiments, confirming the 1 1 substrate catalyst stoichiometry under the reaction conditions. In the oxidation of carene, NOE and ROESY experiments showed different behavior according to the size of the R group (Scheme 13.14). Evidence was found for the formation of inclusion complexes with compounds 58 and 59. On the other hand, compounds 60 and 61 proved to interact with the catalyst via a tail inclusion vide infra). The increased diastereoselectivity observed with compounds 58 and 59 might be explained by a closer proximity to the covalently linked dioxirane. 

One rarely used but powerful means of maximizing both content uniformity (as mentioned above) and stability aspects of low-dose pharmaceuticals is the formation of inclusion complexes to increase both the drug load in the formulation as well as the stability of the API. One specific example is the complexation of ethinyl estradiol in the form of its /3-cyclodextrin clathrate for use in pharmaceutical formulations.23 This inclusion complex has been successfully applied in the development of an ultralow-dose formulation of this steroid.24... 

Figure 5. CD within the near-UV region of azanaphthalenes after formation of inclusion complexes with B-cyclodextrin. Spectra are shown for (a) quinoline, (b) phthalazine, (c) isoquinoline, and (d) cinnoline (data adapted from reference [38]).

Figure 3 Schematic representation of the formation of inclusion complexes based on the recognition of a guest molecule by a host receptor (a), of a clathrate based on the inclusion of guest molecules within cavities generated upon packing of clathrands in the solid state (b), and of a 1-D inclusion molecular network named koilate formed through interconnection of hollow tectons (koilands) by connector molecules (c).

Certain fundamental characteristics of MECC that influence retention have been investigated (5). The technique has been used in the analysis of a variety of samples including phenolic compounds (1), phenylthiohydantoin—amino acids (6), and metabolites of vitamin Bg (7). In related electrokinetic separation techniques, substituted benzene compounds have been separated based on the formation of inclusion complexes with an ionic cyclodextrin derivative in the mobile phase (8) and polyaromatic hydrocarbons have been separated based on solvophobic interactions with a tetraakyl— ammonium ion in the mobile phase (9). The effects of injection procedures on efficiency have also been studied (10). 

The rigid structure of the cyclodextrin host results in well defined but different inclusion and interaction patterns for any potential guest molecule. Treating a mixture of compounds with a dissolved or solid, immobilized CD, leads to the formation of inclusion complexes of different stability and solubility. Consequently separations can be based either on strongly modified solubility in water of the CD-complex of a certain component, or on the... 

The macrostructure and microstructure of starch lead to the ready formation of inclusion complexes and surface adsorbates.1 Inclusion complexes form by involvement of the inner core of the amylose helix, the intergranular... 

It was realized long ago that a number of organic compounds can obscure the blue reaction.97 This effect is caused by the formation of inclusion complexes by such compounds. Hence, the iodine reaction is widely used as the test for complexation of starch, mainly amylose, with many organic... 

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