The Stability of Cyclodextrin Complexes in Solution.

Cyclodextrins are extremely attractive components of artificial enzymes and other biomimetic materials. They are readily available, they bind hydrophobic substrates into their cavities in water solution, and they have two rims of hydroxyl groups (Figure 1) that can either react with substrates themselves or be used to attach other catalytic and functional groups. Of course, they have disadvantages. For one, unless they are extensively modified their complexes with substrates can be rather flexible and, perhaps, with unpredictable preferred geometry. They are also unstable to strong acid. Thus for some purposes such synthetic cavity species as calixerenes1 or synthetic macrocycles2-4 may have advantages. However, one of the chief advantages of cyclodextrins is highly attractivesthey are readily available, so it is possible to avoid the synthesis of a binding group and go directly to studies of what can be achieved with their use. Afterward, the lessons learned may be applied to other systems with advantage. This review will cover all the literature on reactions in which cyclodextrins bind substrates and then either catalyze their reactions or mimic a step in an enzymatic catalytic sequence. However, it will not describe work in which cyclodextrins simply change the course of a reaction without playing an obvious catalytic role involving substrate binding. For example, there are systems in which the main function of the cyclodextrin seems to be to complex a metal ion and keep it in solution.5-11 There are other studies in which binding into a cyclodextrin simply alters the selectivity of attack by an external reagent in some way12-24 or causes solubilization to facilitate phase transfer catalysis.12,25,26 Presumably such other areas are described elsewhere in this volume. While much work on artificial enzymes using cyclodextrins has been done in the author’s laboratory, and will be described, every effort is made to describe all the relevant work in the field. Several reviews of this subject already exist and should be consulted for further information.2,27-70 The readily Ronald Breslow, born in 1931 in Rahway, NJ, completed his B.A. in chemistry in1952, his M.A. in medical science in 1953, and his Ph.D. in chemistry in 1955 with R. B. Woodward, all at Harvard University. After a postdoctoral year with Alexander Todd in Cambridge, he came to Columbia University where he is now University Professor and Professor of Chemistry. His work on enzyme models, on novel conjugated aromatic and antiaromatic molecules, on electrochemical and hydrophobic methods in mechanistic chemistry, and on anticancer cytodifferentiating agents has been recognized by a number of awards, including the U.S. National Medal of Science. In 1996, he served as President of the American Chemical Society.

Biomimetic Reactions Catalyzed by Cyclodextrins and Their Derivatives.

Supramolecular chemistry has expanded dramatically in recent years both in terms of potential applications and in its relevance to analogous biological systems. The formation and function of supramolecular complexes occur through a multiplicity of often difficult to differentiate noncovalent forces. The aim of this Review is to describe the crucial interaction mechanisms in context, and thus classify the entire subject. In most cases, organic host-guest complexes have been selected as examples, but biologically relevant problems are also considered. An understanding and quantification of intermolecular interactions is of importance both for the rational planning of new supramolecular systems, including intelligent materials, as well as for developing new biologically active agents.

Binding Mechanisms in Supramolecular Complexes

Organic Reactions Mediated by Cyclodextrins.

On the basis of many literature measurements, a critical overview is given on essential noncovalent interactions in synthetic supramolecular complexes, accompanied by analyses with selected proteins. The methods, which can be applied to derive binding increments for single noncovalent interactions, start with the evaluation of consistency and additivity with a sufficiently large number of different host–guest complexes by applying linear free energy relations. Other strategies involve the use of double mutant cycles, of molecular balances, of dynamic combinatorial libraries, and of crystal structures. Promises and limitations of these strategies are discussed. Most of the analyses stem from solution studies, but a few also from gas phase. The empirically derived interactions are then presented on the basis of selected complexes with respect to ion pairing, hydrogen bonding, electrostatic contributions, halogen bonding, π–π-stacking, dispersive forces, cation−π and anion−π interactions, and contributions f...

Experimental Binding Energies in Supramolecular Complexes

The carcinogens 4-aminobiphenyl and 2-aminofluorene are metabolized to hydroxylamine esters that undergo N-O heterolysis to produce arylnitrenium ions that react with DNA, especially at guanine residues. These nitrenium ions and a number of their derivatives have been studied by the laser flash photolysis technique, to provide direct kinetic information about the lifetimes of the electrophiles in water and their reactivities with added nucleophiles. Arylnitrenium ions ArNH+ are longer-lived in water than arylcarbenium analogs ArCH2+, in some cases significantly longer-lived. The nitrenium ions do react with azide ion at the diffusion limit (providing the cation is not highly stabilized). This behaviour completely parallels that of carbenium ions. The biphenylyl- and fluorenylnitrenium ions react with guanine derivatives such as 2-deoxyguanosine (dG) with rate constants that are close to or at the diffusion limit (2 × 109 M-1 s-1) for the more reactive cations. Thus, in spite of cation lifetimes of the ord...

1997 Alfred Bader Award Lecture Reactivities of arylnitrenium ions with guanine derivatives and other nucleophiles

Various species that form guest-host complexes with cyclodextrins (CDs) inhibit the cleavage of m-nitrophenyl acetate (mNPA) by CDs in basic aqueous solution, in quantitative agreement with their binding constants. In contrast, many alcohols, alkanesulfonate ions, and alkanoate ions do not inhibit the cleavage of p-nitrophenyl acetate (pNPA) by α- and β-CD to the same extent, and in several cases, actual rate enhancements are found. The observed kinetics require the presence of a process whereby one molecule of the potential inhibitor (PI) is involved in the ester cleavage by CD in some way. Rate constants k a for the apparent reaction of the CD-pNPA complex with a series of PIs show a dependence on structure which is strongly correlated to the ability of the PIs to bind to CD

Spectators in the cleavage of p-nitrophenyl acetate by cyclodextrins in basic solution. Catalysis by potential inhibitors

Laser flash photolysis (UV-LFP) studies of benzylchlorodiazirine (1a), phenylchlorodiazirine (1b), phenylmethoxydiazirine (1c), 2,2-dimethoxy-5,5-dimethyl-Δ3-1,3,4-oxadiazoline (6a), 3,4-diaza-2,2-dimethoxy-1-oxa[4.3]spirooct-3-ene (6b), 5‘,5‘-dimethoxyspiro[adamantane]-2,2‘-[Δ3-1,3,4-oxadiazoline] (6c), and diazofluorene (DAF) in the presence of oxiranes and thiiranes are reported. These compounds, upon irradiation, afford benzylchlorocarbene (2a), phenylchlorocarbene (2b), methoxyphenylcarbene (2c), dimethylcarbene (8a), cyclobutylidene (8b), adamantylidene (8c), and fluorenylidene (FL), respectively. Absolute rate constants for the transfer of oxygen and sulfur atoms to these carbenes have been determined in both acetonitrile and cyclohexane solvents. These carbenes abstract oxygen and sulfur atoms with bimolecular rate constants ranging from 104 to 1010 M-1 s-1 at 22 °C. Ylides from attack of carbenes onto heteroatom donors were not observed for any of the heteroatom transfer reactions. It was found t...

Laser Flash Photolysis Studies of Oxygen and Sulfur Atom Transfer Reactions from Oxiranes and Thiiranes to Singlet Carbenes1

Dissociation constants (Kd) of host–guest complexes formed from β-cyclodextrin or "hydroxypropyl-β-cyclodextrin" (β-CD and Hp-β-CD) and several types of aliphatic guests (alcohols, alkanesulfonate ions, alkylamines, and α-amino acids), with up to eight carbons in a chain, are reported. These constants were determined by inhibition kinetics and by a spectrofluorometric displacement method based on competition with 1-anilino-8-naphthalenesulfonate ion as a fluorescent probe. The value of Kd for a particular amine is close to that for the corresponding alcohol. For linear alkyl derivatives, there are strong correlations between pKd (= −log Kd) and the chain length of the guest, with slopes around 0.5, complementing trends that were noted earlier. Furthermore, the strengths of binding of various aliphatic derivatives to β-CD and to Hp-β-CD are close, with Kd values for the two CDs usually being within a factor of 2 of each other. Overall, for the binding of over 50 alkyl-bearing derivatives, there is a good c...

Timothy A. Gadosy

Papers

1997 Alfred Bader Award Lecture Reactivities of arylnitrenium ions with guanine derivatives and other nucleophiles

Spectators in the cleavage of p-nitrophenyl acetate by cyclodextrins in basic solution. Catalysis by potential inhibitors

Laser Flash Photolysis Studies of Oxygen and Sulfur Atom Transfer Reactions from Oxiranes and Thiiranes to Singlet Carbenes1

Dissociation constants of host–guest complexes of alkyl-bearing compounds with β-cyclodextrin and "hydroxypropyl-β-cyclodextrin"

Catalysis of the reaction of p-nitrophenyl alkanoates with cyclodextrins by potential inhibitors : simple allosteric activation