Surface Catalysis-3-16

1.
Learning Outcomes
After studying this module, you shall be able to:
 Supramolcular catalysis process.
 Host-guest interactions and types of receptor molecules.
 Biological mimics
 Cocatalysis
2. Introduction
In this module basically we focus on supramolecular chemical reactivity predominantly in
accelerating or understanding chemical reactions.
reactions There are close parallels between artificial,
abiotic supramolecular reactivity and biochemistry, for example in the study of enzymes and
Nature’s catalysts. Synthetic catalysts can both model natural ones and allow the design of new
different kinds of reactions. Supramolecular catalysis lies somewhere between chemical catalysis
(transition metal and organocatalysis) and biology.
biology
Supramolecular catalytic reactions involve binding of a well defined substrate (reactant) to the
receptor (catalyst) and the catalytic process complete in three steps (see Figure 1) 1) Selective
binding of reactant(s) based on their recognition by the receptor that may bear reactive group(s).
2) Transformation of the bound species. 3) Release of the products and regeneration of the
catalyst. First two steps binding and transformation in this catalytic process, are the important
steps because both steps take part in the molecular recognition of the productive substrate and
require the correct molecular information in the reactive receptor. Compared to molecular
catalysis, a binding step is involved that selects the substrate and precedes the reaction itself.
Figure 1 Schematic representation of the supramolecular catalysis process.
Supramolecular catalysis obeys the general rule stating that catalytic action consists in stabilization
of a transition state of the reaction and in the rapid release of the product (see Figure 2). In a
reaction catalyzed by the formation of a supramolecular transition state complex, substrates are
inserted into either an active site of an enzyme, a host cavity, a layer, a micelle, a vesicle or
micropores bringing their functional groups into a close contact for relatively long time. In
addition, the incorporation can stabilize favorable conformations of the substrates.
CHEMISTRY Paper 14: Organic Chemistry-

Chemistry IV (Advanced Organic Synthesis,
supramolecular chemistry and carbocyclic rings)
Module 19: Supramolecular reactivity and catalysis
Functional groups in the active site or cavity such as hydrogen bonding donor or acceptor groups
can additionally exert ‘true’ catalytic action.
Supramolecular catalysis may be divided according to the type of the aggregate involved since it
can be based on a catalytic action of a macrocyclic host, that of microemulsions, micelles or
vesicles or on the catalytic activity of mesoporous materials.
Figure 2 Transition state plots for the supramolecular catalysis process.
3. Catalysis by Reactive Macrocyclic Cation Receptor Molecules

The most important example for catalysis by reactive macrocyclic cation receptors is the
deacylation of O-acetylhydroxylamine CH3COONH2 in presence of the macrocyclic polyether
bearing four carbonyl groups derived from tartaric acid. The ability of [18]-O6 macrocyclic
polyethers to bind primary ammonium ions opens the possibility to induce chemical
transformations on such substrates (see Figure 3). Activation and orientation by binding was
observed for the hydrolysis of O-acetylhydroxylamine,
acetylhydroxylamine, which forms such a stable complex with
the macrocyclic tetracarboxylate receptor that it remains protonated and bound even at neutral pH,
despite the low pKa (ca. 2.15) of the free species. As a consequence, its hydrolysis is

accelerated and exclusively gives acetate and hydroxylamine, whereas in the presence of K+ ions,
which displace the substrate, it yields also acetylhydroxamic acid, CH3CONH-OH (ca. 50%).
Thus, strong binding may be sufficient for markedly accelerating a reaction and affecting its
course, a result that also bears on enzyme-catalysed
catalysed reactions. Chemical transformations may be
induced by reaction between a bound substrate and functional groups borne by the macrocyclic
receptor unit.
Figure 3: Scheme of binding of a primary ammonium group by the NH3+ to the cavity of [18]-O6
macrocyclic polyether.
Ester cleavage processes have been most frequently investigated in enzyme model studies.
Macrocyclic polyethers fitted with side chains bearing thiol groups cleave activated esters with
marked rate enhancements and chiral discrimination between optically active substrate. The tetra-
L-cysteinyl derivative of macrocycle [18]-O6 polyether binds p-nitrophenyl (PNP) esters of amino
acids and peptides, and reacts with the bound species, releasing p-nitrophenol as shown in Figure
4. The reaction displays (1) substrate selectivity with (2) marked rate enhancements in favor of
dipeptide ester substrates, (3) inhibition by complexable metal cations that displace the bound
substrate, (4) high chiral recognition between enantiomeric dipeptide esters, and (5) slow but
definite catalytic turnover.

Figure 4: Schematic representation of the complex of receptor [18]-O6 with the dipeptide
substrate, glycyl-glycine p-nitrophenyl ester salt.
A well-understood example as mimics for transacylases has also been addressed by Cram, who
used chiral corands as shown in Figure 5, bearing thiolate nucleophiles situated above and below
the plane of the macrocycle. Corands of this type can bind primary ammonium cations via charge-
assisted N-H···O hydrogen bonds. The host is complementary to the organic cation because of the
matching of the three-fold symmetry of the -NH3+ 3 group with the pseudo-six-fold arrangement of
the corand binding sites. In the case of chiral guests, chiral recognition is observed as a
consequence of steric interactions between the substituents on the naphthenyl groups (-CH2SH in
corand) and the substituents on the guest. Guest binding was accompanied by transacylation, in
which an acyl group is transferred from guest to the host thiol group as a result of nucleophilic
attack by the thiol (see Figure 6). In each case, the resolved S-host was used, and it was found that
in the intermediate the stabilisation of the S-host/Lamino
host/Lamino ester pair was significantly greater than
the S–D diastereoisomer. The system thus displays kinetic selectivity in the sense that the
substrates of L-handedness react more quickly than those of D-chirality because the reaction
transition state is more stable for the S–L pair. This kinetic selectivity depends strongly on the
nature of the amino acid derivative, which determines the identity of the R group on the substrate.
For small amino esters such as alanine derivatives (R = Me), the ratio kS,L/kR,L is 1, i.e. no
selectivity. The selectivity increases rapidly with the bulk of R, however, with rate selectivity
factors of 6.4 for R = Me2CHCH2, 8.2 for R = C6H5CH2 and 9.4 for R = Me3CH.

Figure 5: Key features of chiral corand transacylase mimics.
Figure 6: Scheme of transacylation step carried out by above described corand (Ar = p -
C6H4NO2).
Hydrogen transfer has been induced with macrocyclic receptors bearing 1,4-dihydropyridyl (DHP)
groups. Bound pyridinium substrates are reduced by hydrogen transfer from DHP side chains
within the supramolecular species (1); the first order intra complex reaction is inhibited and
becomes bimolecular on displacement of the bound substrate by complexable cations. Reactions
with carbonyl or sulphonium substrates have been performed with other DHP containing
macrocycles, such as (2).

4. Catalysis by Reactive Anion Receptor Molecules
Generally, the anion hosts are also obey the same rules that govern the magnitude of binding
constants and host selectivity in cation hosts (primarily based on preorganisation,
complementarity, salvation and size and shape effects), their application is made much more diffi
cult because of some of the intrinsic properties of anions, listed below.
 Anions are relatively large and therefore require receptors of considerably greater size
than cations. For example, one of the smallest anions, F-, is comparable in ionic radius to
K+ (1.33Å versus 1.38Å).
 Even simple inorganic anions occur in a range of shapes and geometries, e.g. spherical
(halides), linear (SCN-, N 3-), planar (NO 3-, PtCl 42-), tetrahedral (PO 43-, SO 42-), octahedral
(PF6-, Fe(CN)63-) as well as more complicated examples as in the case of biologically
important oligophosphate anions.
 In comparison to cations of similar size, anions have high free energies of solvation and
hence anion hosts must compete more effectively with the surrounding medium, e.g.
ΔGhydration(F-) = -465 kJ mol-1, ΔGhydration(K+) = -295 kJ mol-1.
 Many anions exist only in a relatively narrow pH window, which can cause problems
especially in the case of receptors based upon polyammonium salts where the host may
not be fully protonated in the pH region in which the anion is present in the desired form.
 Anions are usually coordinatively saturated and therefore bind only via weak forces such
as hydrogen bonding and van der Waals interactions, although they can form dative
bonds.
The development of anion coordination chemistry and anion receptor molecules has made it
possible to perform molecular catalysis on anionic substrates of chemical and biochemical interest,
such as adenosine triphosphate (ATP). ATP hydrolysis was found' to be catalyzed by a number of
protonated macrocyclic polyamines. In particular, [24]-N6O2 (3) strongly binds ATP and markedly
accelerates its hydrolysis to ADP and inorganic phosphate over a wide pH range. The reaction
presents first-order kinetics and is catalytic with turnover. It proceeds via initial formation of a
complex between ATP and protonated (3), followed by an intracomplex reaction which may
involve a combination of acid, electrostatic, and nucleophilic catalysis. Structure (4) represents
one possible binding mode of the ATP-(3) complex and indicates how cleavage of the terminal
phosphoryl groups might take place. A transient intermediate, identified as phosphoramidate (5), is
formed by phosphorylation of the macrocycle by ATP and is subsequently hydrolyzed. Studies
with analogues of ATP indicated that the mechanism was dissociative in character within a
preassociative scheme resulting from receptorsubstrate binding. In this process, catalyst (3)
presents prototypical ATPase activity; i.e., it behaves as a proto- ATPase.
Multiple recognition and catalysis in ATP hydrolysis with increased ATP/ADP selectivity has
been achieved with a multifunctional anion receptor containing a macrocyclic polyamine as anion
binding site, an acridine group as stacking site and a catalytic site for hydrolysis (structure (6)).
Phosphoryl transfer is accelerated by other types of hydrogen-bonding receptors.

5. Catalysis with Cyclophane Type Receptors
The term ‘cyclophane’ literally means any organic molecule containing a bridged aromatic ring.
By definition, cyclophane hosts (e. g. calixarenes and resorcarenes) must contain at least one
macrocyclic ring and thus must achieve closure by some means of curvature. Cyclophane hosts
commonly bind both neutral molecules and organic cations, and there is sometimes even some
ambiguity as to whether a guest is protonated by, for example, a hydrogen bond acid host or vice
versa, resulting in charge-assisted binding. Cyclophanes may or may not contain a molecular
cavity large enough to host guest species, but in some cases cavities are unnecessary to achieve
high binding affi nity as long as binding sites exhibiting stereoelectronic (steric and electronic)
complementary to the guest and are properly positioned (preorganised) on the surface of the host.
Thus cyclophanes can exhibit capsular or nesting types of binding, or even apolar surface
interactions, often leading to aggregation. Cavities are frequently encountered however, because
of the entropic and enthalpic gains associated with spherical or three-dimensional encapsulation of
the guest by a host with convergent binding sites.
A number of studies have made use of functionalized cyclophanes for developing supramolecular
catalysts and enzyme models. Their catalytic behaviour is based on the implementation of
electrostatic, hydrophobic and metal coordination features for effecting various reactions in
aqueous media. Hydrophobic species bearing hydrocarbon chains present vitamin B12 or vitamin
B6 type activity. Such systems lend themselves to inclusion in membrane or micellar media. They
thus provide a link with catalysis in more or less organized media such as membranes, vesicles,
micelles, polymers. Water soluble cyclophanes showing, for example, transaminase, acetyl
transfer, pyruvate oxidase or nucleophilic substitution activity have been described. Cyclophane
catalysts offer a rich playground for developing novel reactions and enzyme models in view of the
variety of their structural types, the large cavities they contain and the possibility to attach several
functional groups.
6. Supramolecular Metallocatalysis
Supramolecular metallocatalysts consist in principle of the combination of a recognition subunit
(such as a macrocycle, a cyclodextrin, a cyclophane, etc.) that selects the substrate(s) and of a
metal ion, bound to another subunit that is the reactive site. Complexed metal ions presenting free
coordination positions may present a variety of substrate activation and functionalization
properties. Heterotopic coreceptors such as (7) bind simultaneously a substrate and a metal ion
bringing them into proximity, thus potentially allowing reaction between them. Approaches
towards the development of artificial metalloenzymes have been made, based on cyclodextrins or
macrocycles and involving various metal ions, such as Zn(ll), Cu(ll), Co(lll), for facilitating
hydrolysis, epoxidation, hydrogen transfer, etc. Metalloporphyrins have been used for epoxidation
and hydroxylation and a phosphine-rhodium complex for isomerization and hydrogenation.
Cytochrome P-450 model systems are represented by a porphyrin-bridged cyclophane,
macrobicyclic transition metal cyclidenes or β-cyclodextrin
cyclodextrin-linked porphyrin complexes that may
bind substrates and perform oxygenation reactions on them. A cyclodextrin connected to a
coenzyme B12 unit forms a potential enzyme-coenzyme
coenzyme mimic. Recognition directed, specific
DNA cleavage reagents also make use of the reactivity features of various complexed metallic
sites. The remarkable facilitation of amide hydrolysis by dinuclear copper complexes and related
processes may open routes towards metallocleavage of proteins. Selective metalloprocesses, in
particular asymmetric reactions utilizing external chiral ligands, such as hydrogenation,
epoxidation, hydroxylation, etc. are of great value for organic synthesis and are being actively
investigated. Supermolecular metallocatalysts, by combining a substrate recognition unit with a
catalytic metallic site, offer powerful entries to catalysts presenting shape, regioand
stereoselectivity.

7. Cocatalysis: Catalysis of Synthetic Reactions
A further step lies in the design of systems capable of inducing bond formation rather than bond
cleavage, thus effecting synthetic reactions as compared to degradative ones. To this end, the
presence of several binding and reactive groups is essential. Such is the case for coreceptor
molecules (7) in which subunits may cooperate for substrate binding and transformation. They
should be able to perform cocatalysis by bringing together substrate(s) and cofactor(s) and
mediating reactions between them within the supramolecular structure (Figure 5).

Figure 5: Schematic illustration of cocatalysis processes: group transfer and ligation reactions
occuring within the supramolecular complex formed by the binding of substrates to the two
macrocyclic subunits of a macrotricyclic coreceptor molecule.
Figure 6: Cocatalysis: pyrophosphate synthesis by phosphoryl transfer mediated by macrocycle

(3) Via the phosphorylated intermediate (5).
Processes of this type have been realized in supramolecular phosphorylation reactions. Indeed, the
same [24]-N6O2 macrocycle (3) as that already used in the studies of ATP hydrolysis was also

found to mediate the synthesis of pyrophosphate from acetylphosphate (AcP). Substrate
consumption was accelerated and catalytic with turnover following the steps: (1) substrate AcP
binding by the protonated molecular catalyst (3); (2) phosphorylation of (3) within the
supramolecular 2-complex, giving the phosphorylated intermediate PN (5); (3) binding of the
substrate HPO4 (P); (4) phosphoryl transfer from PN to P with formation of pyrophosphate PP
(Figure 6); (5) release of the product and of the free catalyst for a new cycle. PP is also formed in
the hydrolysis of ATP in the presence of divalent metal ions. The fact that (3) is a ditopic
coreceptor containing two diethylenetriamine subunits is of special significance for both PN and
PP formation. These subunits may cooperate in binding AcP and activating it for phosphoryl
transfer via the ammonium sites, in providing an unprotonated nitrogen site for PN formation and
in mediating phosphoryl transfer from PN 81 to P. Thus (3) would combine electrostatic and
nucleophilic catalysis in a defined structural arrangement suitable for PP synthesis via two
successive phosphoryl transfers, displaying kinase type activity (Figure 6). This process was
extended to the phosphorylation of various substrates, in particular to the synthesis of ATP from
ADP in mixed solvent and in aqueous solution in the presence of Mg2+, probably via formation of
a ternary catalytic species (8). The latter abiotic ATP generating system has been coupled to sets
of ATP consuming enzymes resulting in the production of NADH by a combined artificial/natural
enzymatic process (Figure 7).
Figure 7: Sequence of transformations catalysed by the supramolecular ATP-generating system

[(3), AcP, Mg2+, ADP] ((3) = [24]-N6O2) and the enzymes hexokinase (HK), glucose-6-phosphate
dehydrogenase (G-6-PDH) and 6-phospho-gluconate
gluconate dehydrogenase (6-P-GDH).

Templates possessing two hydrogen bonding subunits bind two substrates forming a ternary
complex in which the substrates are positioned so as to facilitate bond formation between them. In
a related way, the rate and stereoselectivity of a bimolecular Diels-Alder reaction are substantially
increased by binding both the diene and the dienophile within the cavity of a tris- porphyrin
macrocycle. A macrobicyclic thiazolium cyclophane (9) functions as a model of
thiamine pyrophosphate-dependent ligases and effects benzoin condensations. Acyl transfer is
catalysed by formation of a ternary complex between a cyclophane receptor and two substrates.
Difunctional binding and catalysis has been observed in functionalized cyclodextrins and in a
hydrogen bonding cleft. Functionalized crown ethers have been used as reagent for peptide
synthesis.
8. Biomolecular and Abiotic Catalysis

The design of supramolecular catalysts may make use of biological materials and processes for
tailoring appropriate recognition sites and achieving high rates and selectivities of reactions.
Modified enzymes obtained by chemical mutation or by protein engineering represent biochemical
approaches to artificial catalysts. This is also the case for the generation of catalytic proteins by
induction of antibodies. Antibodies to reactive haptens are able to facilitate the transformation of
the bound species. Generating antibodies against analogues of transition states should lead to
transition state stabilization and facilitate the process.
process Such catalytic antibodies or abzymes have
been produced for a variety of reaction and an active field of research has developed along such
lines. It represents an approach to substrate specific, efficient and selective catalysis of
supramolecular type which is of much basic and applied interest. The strong affinity for the
transition state (TS) of the reaction of a given substrate leads it along the way and thus facilitates
the process. In line with the remarks made at the beginning of this chapter, the antibodies should
be generated not against a transition state analogues (TSA) itself but against a (TSA-X) isoster
lacking the group(s) X, which belong(s) to the reactive function(s) of the protein that is (are)
expected to perform the reaction. This requires designing a (TSA-X) species in which the face
presenting the (-X) gap be ideally chosen so as to lead to the induction in the antibody of the
desired reactive functional group at the correct position.
position
9. Summary
In this module you have learnt that:
 Supramolecular reactivity and catalysis possess several properties such as: substrate
recognition, reaction within the supermolecule, rate acceleration, inhibition by competitively
bound species, structural and chiral selectivity, and catalytic turnover.
 In particular, the transacylation reactions mentioned above operate on activated esters as
substrates, but the hydrolysis of unactivated esters and especially of amides under "biological"
conditions, presents a challenge that chemistry has met in enzymes but not yet in abiotic
supramolecular catalysts.
 Development of supramolecular catalysts performing synthetic reactions that create new bonds
rather than cleave them. By virtue of their multiple binding features, coreceptors open the way
to the design of cocatalysts for ligation, metallocatalysis, and cofactor reactions, which act on
two or more co-bound and spatially oriented substrates.
substrates
 Supramolecular catalysts are by nature abiotic chemical reagents that may perform the same
overall processes as enzymes, without following the detailed pathway by which the enzymes
actually effect them or under conditions in which enzymes do not operate.


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1.

Figure 1 Schematic representation of the supramolecular catalysis process.

CHEMISTRY Paper 14: Organic Chemistry-

Figure 2 Transition state plots for the supramolecular catalysis process.

3. Catalysis by Reactive Macrocyclic Cation Receptor Molecules

CHEMISTRY Paper 14: Organic Chemistry-

CHEMISTRY Paper 14: Organic Chemistry-

CHEMISTRY Paper 14: Organic Chemistry-

CHEMISTRY Paper 14: Organic Chemistry-

CHEMISTRY Paper 14: Organic Chemistry-

CHEMISTRY Paper 14: Organic Chemistry-

CHEMISTRY Paper 14: Organic Chemistry-

Figure 6: Cocatalysis: pyrophosphate synthesis by phosphoryl transfer mediated by macrocycle

CHEMISTRY Paper 14: Organic Chemistry-

Figure 7: Sequence of transformations catalysed by the supramolecular ATP-generating system

CHEMISTRY Paper 14: Organic Chemistry-

8. Biomolecular and Abiotic Catalysis

CHEMISTRY Paper 14: Organic Chemistry-

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