Acid-base bifunctional catalysis

The rich variety of active sites that can be present in zeolites (i) protonic acidic sites, which catalyze acid reactions (ii) Lewis-acid sites, which often act in association with basic sites (acid-base catalysis) (iii) basic sites (iv) redox sites, incorporated either in the zeolite framework (e.g., Ti of titanosHicates) or in the channels or cages (e.g., Pt clusters, metal complexes). Moreover, redox and acidic or basic sites can act in a concerted way for catalyzing bifunctional processes. 

Jencks (1972) has concluded that concerted bifunctional acid-base catalysis is rare or nonexistent because of the improbability of meeting simultaneously at two sites on reactant and catalyst the conditions of the rule which he has proposed for concerted reactions. The rule states that concerted general acid-base catalysis of complex reactions in aqueous solution can occur only (a) at sites that undergo a large change in pAT in the course of the reaction, and (b) when this change in pAf converts 2m unfavourable to a favourable proton transfer with respect to the catalyst, i.e., the pAT-value of the catalyst is intermediate between the initial and final pAf-vadues of the substrate site. 

This reaction encompasses a number of interesting features (general Brpnsted acid/ Brpnsted base catalysis, bifunctional catalysis, enantioselective organocatalysis, very short hydrogen bonds, similarity to serine protease mechanism, oxyanion hole), and we were able to obtain a complete set of DFT based data for the entire reaction path, from the starting catalyst-substrate complex to the product complex. 

Push-pull and bifunctional acid-base catalysis... 

In enzymes, the active site may possess acid and base groups intimately associated with the conjugate base and acid functions, respectively, of the complexed substrate the push-pull mechanism is possible but might not be a driving force. The halogenation of acetone in the presence of aqueous solutions of carboxylic acid buffers exhibits the rate law of Equation 11.2 where the third-order term, although small, has been shown to be significant and due to bifunctional concerted acid-base catalysis (Scheme 11.13) ... 

Scheme 11.13 Bifunctional acid-base catalysis in the halogenation of acetone via its enol.

Scheme 11.14 Bifunctional acid-base catalysis of the proton switch which traps the zwitterionic intermediate in methoxyaminolysis of phenyl acetate.

Push-pull acid-base catalysis has been proposed to account for the proton switch mechanism which occurs in the methoxyaminolysis of phenyl acetate (Scheme 11.14) where a bifunctional catalyst traps the zwitterionic intermediate. A requirement of efficient bi-functional catalysis is that the reaction should proceed through an unstable intermediate which has p values permitting conversion to the stable intermediate or product by two proton transfers after encounter with the bifunctional catalyst the proton transfer with monofunctional catalysts should also be weak. 

Bronsted acid/base catalysis is the most common enzymatic mechanism, since nearly all enzymatic reactions involve a proton transfer. This means that nearly all enzymes have acidic and/or basic groups in their active site. In add catalysis, the substrate is protonated by one of the amino add residues at the active site (typically aspartic acid, glutamic acid, histidine, cysteine, lysine, or tyrosine). This residue itself must therefore be protonated at the readion pH (typically between pH 5 and 9), with a pKa just above this value. Conversely, in base catalysis, the pJCa of the deprotonating residue must be just below the physiological pH. Some enzymes can even carry out bifunctional catalysis, by protonating and deprotonating two different sites on the same substrate molecule simultaneously. 

Cyclodextrins with two imidazole groups on the primary hydroxyl side can enhance the enolate formation [86] of a simple bound ketone by bifunctional acid-base catalysis and accelerating the intramolecular aldol condensation of bound ketoaldehyde and dialdehyde. The aldolase mimics which catalyzed crossed aldol condensations were obtained by the assembly of (i-CD and various amino moieties as Schiff base [87]. 

As an alternative to the highly specific catalysis indicated by formulas I, II, and III, it is possible that the metal chelate compound merely participates in a generalized type of acid-base catalysis. Thus, the function of the metal would be to increase the acidity of the substrate through molecular association and thereby increase its susceptibility toward attack by other bases present such as hydroxide ion or water molecules. Under these conditions the diaquo chelate A would be an acid catalyst, the monohydroxy chelate Bi would be considered to be bifunctional in its effect, and the dihydroxy chelate B2 would probably be a weak basic catalyst. 

The present piece of research deals with the use of solid ba.se catalyst in Organic Synthesis. We will also comment briclly on bifunctional acid-base catalysis, although due to its importance it deserves a more extensive review, which is currently in preparation. 

Crystalline materials, whose lattice constants (M-0 distance) can be determined by X-Ray diffraction, permit easy prediction of whether they should be suitable as bifunctional catalysts for particular reaction molecules. However, since most acid-base catalysis are more or less amorphous, it is difficult to determine the M-O distance accurately. 

R. Breslow, Bifunctional acid-base catalysis by imidazole groups in enzyme mimics, J. Mol. Cat., 1994, 91, 161-174. 

Figure 5.1 Reactivity modes for proline eatalysis. (a) bifunctional acid/base catalysis (b) iminium catalysis (c) metal-complexes and (d) enamine catalysis.

Nevertheless, it now seems doubtful whether the third-order kinetics observed by Swain and Brown necessarily imply a concerted acid-base catalysis, and whether the abnormally high activity of some bifunctional catalysts can be attributed simply to the presence of acidic and basic centres in the same molecule. It was first pointed out by Pocker that a... 

For the first, third, and fourth catalysts in (84) the two tautomers are chemically identical, and the same is true for ions such as HCOJ, HPO4", H2PO2, and H2ASO4, which have been reported to have an abnormally high catalytic activity in some reactions.It is clear that the effectiveness of this kind of catalyst is related to its particular electronic structure rather than to its acid-base properties, and the process is more appropriately described as tautomeric catalysis than as bifunctional or concerted acid-base catalysis. It is of interest that a theoretical treatment of some molecules in which acidic and basic groups form part of the same TT-electron system shows some parallelism between catalytic activity and the coupling constants of the molecular orbital theory moreover, a very general treatment of concerted proton transfers indicates that simple bifunctional acid-base catalysis is likely to be of importance only under very restricted conditions. ... 

A synchronous transfer of two protons, which in reaction (9.14) competes with a two-step process, is in some cases the predominant proton exchange mechanism. Such double proton migrations play an important role in many chemical and biochemical reactions in which the steric hindrances impeding proton transfer in a substrate molecule are removed thanks to the double proton exchange between substrate and enzyme [79]. The double proton transfers determine the mechanism of the bifunctional acid-base catalysis[80, 81]. The interest in the mechanism of double proton migrations in the H-bound complexes became especially keen after Lowdin [82] advanced in 1963 the hypothesis to the effect that it is precisely such processes in the DNA molecules that underlie the nature of spontaneous mutations. 

In 1972, Jencks (76) concluded that concerted bifunctional acid-base catalysis is rare or nonexistent because of the improbability of the reactant and catalyst meeting simultaneously. Furthermore, bifunctional catalysis does not necessarily represent a favorable process in aqueous solution even when a second functional group is held sterically in proper position to participate in the reaction. Caution should then be used in assuming that most enzymes are utilizing bifunctional or multifunctional catalysis. Nevertheless, this idea has played a leading role in concepts of enzyme catalysis. 

Fig. 24.29 (a) Chemical structure of l,3-guanidinocalix[4]arene 77. (b) Bifunctional general acid-base catalysis of monoprotonated guanidinocalix[4]arene in the transesterification of HPNP. (c) Diribonucleotide phosphate cleavage [91, 92]... 

Chen et al. [26] reported the use of a bifunctional thiourea catalyst 61 during the organocatalyzed thia-Michael addition of thiophenol to unsaturated imide 58c (Scheme 3.29). Michael adduct 60c was obtained in 60% ee and 97% yield by conducting the reaction in dichloromethane at -78°C. The authors speculated that while the tertiary amine of the bifunctional catalyst 61 would act as a proton shuttle according to a Brpnsted acid/base catalysis, the presence of the thiourea moiety might possibly cooperate in the stabilization of the more stable Z-enolate intermediate via hydrogen bond formation as illustrated in Scheme 3.31. 

Abstract Acid-base catalysis with bifunctional catalysts is a very prominent catalytic strategy in both small-molecule organocatalysts as well as enzyme catalysis. In both worlds, small-molecule catalysts and enzymatic catalysis, a variety of different general acids or hydrogen bond donors are used. In this chapter, important parallels between small molecule catalysts and enzymes are discussed, and a comparison is also made to the emerging field of frustrated Lewis pair catalysis. 

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