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31 Manipulation of Nucleophilic Displacement Reactions by Host-Guest Complexes Models for Enzyme Analogue Catalysis and Inhibition Hans-Jörg Schneider, Rainer Busch, Rüdiger Kramer, Ulrich Schneider, and Isolde Theis Fachrichtung Organische Chemie der Universität des Saarlandes, D-6600 Saarbrücken 11, West Germany

Most of the examples in this review involve encapsulation of an organic substrate in the cavity of a macrocyclic ammonium ion in aqueous solution. Methods for the preparation of the macrocycles and for the characterization of the complexes are briefly discussed. This chapter describes how S 2-type reactions are catalyzed by positively charged host compounds and S -type reactions, apart from salt effects, by a negative environment. The shape of the cavity largely determines the substrate selectivity; a discrimination between S and S 2-type reactions on the basis of different transition-state stabilization leads to a drastic regioselectivity change with nitrite as the ambident nucleophile. Selective inhibition is observed by competitive binding either of unreactive organic compounds or of inorganic nucleophiles in the case of smaller cavities. N

N1

N1

N

INÎuCLEOPHILIC SUBSTITUTIONS BELONG TO THE MOST IMPORTANT and most thoroughly studied reactions of organic chemistry; these substitutions play, however, only a minor role in biological systems. Probably for this reason simple aliphatic or aromatic nucleophilic displacement reactions have only recently been studied in the context of enzyme-analogue catalysis. Most of the efforts in the application of host-guest complexes for catalysis have been directed toward the simulation of specific enzyme reactions, such as acyl transfer or transamination processes. Several reviews (1—5) are avail able on the exciting progress in biomimetic catalysis, which allows us to

0065-2393/87/0215-0457$06.50/0 © 1987 American Chemical Society

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restrict ourselves to some basic principles and prerequisites for artificial enzyme analogues and then to proceed to their use in the catalysis of nucleophilic substitutions.


Crown Ethers, Cryptâtes,

and Other Chelating Reagents

Heteromacrocycles containing vicinal oxygen, nitrogen, or sulfur linkages are thus far the most prominent representatives both for specific encapsula tion of guest molecules in macrocyclic cavities and for the use of such complexation capability for the catalysis of organic reactions, including nu cleophilic substitutions. Synthesis, structure, dynamic behavior, and ap plications of these compounds, which are already of considerable commercial importance, have been aptly reviewed (6-10). The essential features of the crown ethers and related macrocycles are their strong binding capacity mostly for metal ions and their ability to extract the corresponding salts into organic solvents by virtue of the lipophilic nature of the exterior walls of the cavities. Chart I shows dicyclohexyl-18-crown-6, an often used compound, as well as a cryptate, which is an even stronger binder. Not only do salts such as alkali halides become soluble in unpolar organic solvents, but also the reactivity of the corresponding counteranions can be increased dramatically in the presence of these agents. This result is ascribed to their increased

Crown Ethers

Cryptâtes

Essential Features: 1. 2. 3. 4.

Mask metal ions—make salts lipophilic Extract salts into organic solvents Activate anions for S reactions Open chain polyethers often almost as effective N

Chart I. Crown ethers, cryptâtes: essential features.


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Enzyme Analogue Catalysis and Inhibition

459

desolvation as compared to protic solutions. Moreover, encapsulation of the metal ions by the macrocycle prevents formation of less reactive internal ion pairs, at least in polar aprotic solvents. As a consequence, many nucleophilic displacements proceed much faster, in particular those involving usually weak nucleophiles such as carboxylate anions. In this way, crown ethers and related systems serve essentially the same purpose as phase-transfer catalysts (11-14), which most often are onium ions with lipophilic alkyl substituents. The role of the phase-transfer catalyst, be it onium salt or metal chelating agent, is essentially an auxiliary one: this catalyst provides for the extraction of the salt into the organic solvent and therefore also for anion activation. In nucleophilic substitutions of enolates, which, in this context, may be better characterized as anion alkylations (13, 14), often synthetically useful changes of regioselectivity are also obtained. For a more detailed discussion of catalytic effects in phase-transfer reactions including macrocyclic ion bind ers, see recent extensive monographs and reviews on this subject (11-14). Phase-transfer reagents are still expected to dominate many practical ap plications with respect to nucleophilic substitutions in the future, although similar results can often be obtained in aprotic polar solvents. Macrocyclic chelating agents, on the other hand, can often be substituted by structurally related so-called podands (15), which bear the chelating groups in openchain sidearm tentacles, or simply by inexpensive polyethylene glycols (16). The common feature of macrocyclic chelating agents and enzyme ana logues with lipophilic cavities of course must be seen in the encapsulation of either ions or uncharged organic molecules by virtue of so-called nonbonded interactions. The fit and the association constants between host and guest molecules can not only be tailored by the ring geometry and the nature of the groups inside the cavity but also be altered by additional sidearms flanking those parts of the guest molecule that are not immersed in the cavity. The careful engineering of suitable host structures has already led to new methods for separations of, for example, metal cations (17) or of chiral ammonium salts (2).

Properties of Enzyme Analogous Host Catalysts Essential characteristics of synthetic enzyme analogues are summarized in the Box on page 460. Many of these features are closely interrelated, such as complexation, saturation kinetics, and substrate selectivity, as well as com petitive inhibition by stronger binding substrates, which are less reactive or completely unreactive. Regio- or stereoselectivity, if applicable, can change in comparison to the uncatalyzed process by a variation in structure or by disposition of the transition state, for example, from early to late or from an S 1 to an S 2 mechanism. The effectiveness of a catalyst can be described in terms of the rate enhancement achieved by stabilization of the transition state ( = k ) and of N

N

cat

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NUCLEOPHILICITY


Enzyme Analogues—Essential Characteristics Complexation in molecular cavity Rate enhancements—saturation kinetics Substrate selectivity Reaction selectivity Competitive inhibition Important Contributions to Catalysis Selective binding Proximity effects Entropy effects Electrostatic interactions Reaction field changes

the association constant between substrate and catalyst (= K ) (18, 19). Thus, an increase in effectiveness by a factor of 100 can be obtained in principle by an association constant of 100 alone, provided the rate of product formation is not lowered. This picture is oversimplified as it involves, for example, the rate constant comparison between the unimolecular reaction from the com plex to the product with the uncatalyzed reaction of higher order. Also, too strong an association with the substrates or the related products can lead to inhibition or rate retardation. A thorough discussion of these factors and the factors affecting the performance of an enzymatic catalyst can be found in suitable reviews and monographs (18, 19). The Box lists only those elements that are essential for the understanding of the systems to be discussed. Several principal differences exist between most host-guest catalysts and enzymes that are the result of the optimization of the enzymes, which has been accomplished by nature over many millions of years. In construct ing synthetic enzyme analogues (1-5), strong—although not necessarily selective—binding to different substrates is less difficult to obtain than is an optimal stabilization of transition states, which usually requires not only a fitting of van der Waals contacts but also the optimal alignment of reacting groups, dipoles, and so on. The first step in developing host enzyme analo gues should therefore be the characterization of a complexation, preferably by spectroscopic techniques, complemented by molecular modeling, which can be aided by interactive computer graphics. a

Molecular Structures with Large Lipophilic Cavities The most well-known compounds of this type are cycloamyloses or cyclodextrins (20-22), which form nearly cylindrical cavities of 5-8-A inner diameter,


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depending on the chosen natural product. Chemical modification at the rim of the cavity, as well as improved binding by adding caps on the top, has already led to many promising biomimetic catalysts. Aside from their limited stability, the limitation of the cyclodextrins lies in the fact that as a gift of nature they come with a basically invariable cavity structure. Although in a preliminary study cyclodextrins did show moderate enhancements of hydro lysis rates with a tertiary alkyl chloride (23), cyclodextrins have so far not been used for the catalysis of nucleophilic displacement reactions. In view of the electroneutral nature of the cycloamyloses, this usage would probably require the introduction of polar groups or charges in the host structure. In contrast to cyclodextrins, azamacrocycles (24) not only are accessible in variable geometries by synthesis but also can be converted to charged ammonium ions. The positively charged cavities make these systems promis ing candidates for the stabilization of negatively charged S 2 transition states, whereas S 1 reactions should be accelerated by negatively charged surroundings, if it is not the leaving group, but rather the organic substrate that is complexed. Moreover, multiple charges on the rings provide for water solubility even of macrocyclic structures containing up to 70 nonhydrogen atoms and approaching molecular weights of 1000. Solubility in aqueous solutions is a prerequisite for the application of many receptor and enzyme analogues, because an important driving force for the encapsulation of organic substrates derives from hydrophobic interactions. Complexations of anions instead o£ or in addition to, lipophilic moieties also were observed in several macrocyclic ammonium ions (25, 26); their impact on nucleophilic substitution reactions will be discussed. In the last few years, Tabushi et al. (27), Koga and co-workers (24, 28), Jarvi and Whitlock (29), Breslow and co-workers (30), Diederich and co workers (31, 32), and Vogtle and co-workers (33, 34) as well as our group (35) have shown that azacyclophanes in the form of their ammonium salts can very effectively complex lipophilic substrates. Even hydrocarbons bind with association constants of 1000 or more in aqueous solutions. Our own studies of such host-guest systems were initiated by the desire to use complexations of alkanes for the selective functionalization of paraffins (23, 36) [in addition to our interest (37, 38) in conformations of complex ring systems and their study by N M R methods as well as by force field model calculations]. N

N

Methods for the Characterization of Host-Guest Catalysts Methods for the study of host-guest complexes in solution have been re viewed (39) with emphasis on crown ethers or cryptâtes and on the bonding of ions; measurements of the often weaker complexes with lipophilic sub strates are preferably done by N M R shift titration. Because K values of 10 require measurements in a concentration range of 10~ M in order to see uncomplexed as well as complexed material, N M R is a more convenient 3

a

3


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method for such complexes as, for example, U V or fluorescence spec troscopy, which require more dilute solutions. U V spectra, moreover, often show only small changes upon complexation. Older methods based on solubility changes upon complexation, or on partition coefficients between aqueous solutions and hydrophobic solvents, have been shown to lead to gross errors as compared to spectroscopic techniques (40) that are also less sensitive to the formation of emulsions, micelles, and so on. The traditional X-ray analysis of inclusion compounds is of limited significance for establishing complexation between lipophilic sub strates and macrocyclic host, particularly in aqueous solution. The essential hydrophobic driving force for complexation, of course, is nonexistent in the crystal. The future development of N M R methods including shielding cal culations and measurements of intermolecular nuclear Overhauser effects is expected to provide the most reliable information on intercavity inclusion complexes in solution as the basis for catalytic applications. Considering the complex kinetic behavior of most enzymatically con trolled reactions (41), the formal treatment of simple catalytic analogues should not pose additional problems. However, one consequence of the less perfect, but for most practical and mechanistical purposes sufficient perform ance of synthetic catalysts in comparison to enzymes is that in many kinetic studies, a large excess of substrate over the catalyst cannot be used, because then the uncatalyzed reaction will be too fast. Consequently, kinetic studies under catalyst saturation, or the steady-state methods that are most often used in the investigation of enzymes (18, 19, 41), are not suitable here. The formal treatment of the resulting, often quite complex, kinetics is greatly facilitated by computer-aided numerical simulations, which also help to design proper experimental conditions. Synthesis of Heteromacrocycles (6, 8 - 1 0 , 34) As early as 1935, Luttringhaus obtained large heterocyclic systems by reac tion o£ for example, Ι,ω-dihalogen alkanes with bisphenols (42, 43). The principal reaction sequence, starting from complementary bifunctional spacers A and B , is shown in Scheme I. The formation of smaller and larger rings, D R and TR, respectively, from two or four spacer units was also reported already by Luttringhaus. The low yields often observed for cyclizations can indeed be also due to the easily overlooked simultaneous formation of different ring sizes (44). The condensation of Ι,ω-ditosylamides with Ι,ωdihaloalkanes was introduced by Stetter and co-workers (45-47) and Fuson and House (48) and opened a widely used access to azamacrocyclic com pounds. The high dilution, which is particularly necessary for the reaction with highly reactive educts, such as with dicarboxylic acid halides, to sup press excessive polymerization, however, means that sometimes only milli gram quantities can be obtained over several days. This time factor is likely

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A + Β

— • AB Dimer

•

A

B

463

DR

AB + A — • ABA


AB + β

ABA + Β BAB + A

^

BAB

v

-•ABAB

Tetramer

•

/^ Β

A

>

\

Β

TR

ABAB + A , Β - ^ O l i g o / P o l y m e r s = Ρ Scheme I. Reaction sequence for the formation of smaller and larger rings (DR and TR).

to be one of the reasons the majority of the many synthesized potential host compounds have until now rarely been subjected to further examination. By adjustment of the time scale and concentration of the cyclization on the basis of computer simulations (Figure 1), as well as by use of potassium carbonate as the base in heterogenous dimethylformamide ( D M F ) solutions (46, 48), both quantities as yields of the condensation reactions with tosylamides can be improved considerably (44) (Table I). The limited solubility of potassium carbonate in D M F leads to stationary concentration of the reactive deprotonated amide of

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