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Supramolecular Reactivity and Catalysis
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DOI: 10.1002/3527607439.ch5
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Applied Catalysis A: General 113 ( 1994) 105-I 14
Supramolecular reactivity and catalysis
J.M. Lehn
Co&e de France, Paris. France
Universit6 Louis Pasteur, Strasbourg, France
Reactivity and catalysis represent major features of the functional properties of
supramolecular systems. Molecular receptors bearing appropriate reactive groups
in addition to binding sites may complex a substrate (with given stability, selectivity, and kinetic features), react with it (with given rate, selectivity, and turnover),
and release the products, thus regenerating the reagent for a new cycle (Fig. 1) .
Supramolecular reactivity and catalysis thus involve two main steps: binding
which selects the substrate and trunsfomzation of the bound species into products
within the supermolecule formed. Both steps take part in the molecular recognition
of the pruductiue 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. The design of efficient and
selective supramolecular reagents and catalysts may give mechanistic insight into
the elementary steps of catalysis, provide new types of chemical reagents, and effect
reactions that renewal factors contributing to enzymatic catalysis. This has led to
i
reaction
binding
EElI
+
E
x
t
catalyst
substrate(s)
(Cl
(51
I
t
product
(C-S) complex
stability
rote
selectivity
selectiwty
turnover
Fig. I. Schematic representation
OThe Nobel Foundation
Kt
of the supramolecular
1988
0926-860X/94/$07.00
0 1994 Elsevier Science B.V. All rights reserved
SSDIO926-860X
(94)00054-U
catalysis process.
k.)
106
J.M. Lehn /Applied Catalysis A: General 113 (1994) 105-114
numerous investigations, which have made use mainly of reagents based on functionalized cw-cyclodextrin, macrocyclic polyethers, and cyclophanes [ l-121.
Catalysis by reactive cation receptor molecules
Ester cleavage processes have been most frequently investigated in enzyme
model studies. Macrocyclic polyethers fitted with side chains bearing thiol groups
la,X=H
lb, X=CO,o
lc,X=CONY
Y'
Scheme 1.
14.
ROOC
"COOR
/
SH
SH
E,R=CH,
Scheme 2.
J.M. Lehn /Applied
Catalysis A: General I13 (1994) 105-I 14
107
3, X-CONHnBu
Scheme 3.
cleave activated esters with marked rate enhancements and chiral discrimination
between optically active substrates [ 13-161. The tetra-L-cysteinyl derivative of
macrocycle lc binds p-nitrophenyl (PNP) esters of amino acids and peptides, and
reacts with the bound species releasing p-nitrophenol as shown in 2 [ 14,151. The
reaction displays ( 1) substrate selectivity with (2) marked rate enhancements in
favour 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. Binding of pyridinium
substrates to a macrocycle of type lc bearing 1,4_dihydropyridyl side chains led to
enhanced rates of hydrogen transfer from dihydropyridine to pyridinium within the
supramolecular species 3 formed. The first-order intracomplex reaction was inhibited and became bimolecular on displacement of the bound substrate by complexable cations [ 171.
Activation and orientation by binding was observed for the hydrolysis of Oacetylhydroxylamine.
CH,COONH,+ forms such a stable complex with the macrocyclic tetracarboxylate lb that it remains protonated and bound even at neutral pH,
despite the low p& of the free species (ca. 2.15). As a consequence, its hydrolysis
is accelerated and exclusively gives acetate and hydroxylamine, whereas in the
presence of K+ ions, which displace the substrate, the latter rearranges to acetylhydroxamic acid, CH,CONH-OH
(ca. 50%) [ 181. Thus, strong binding may be
108
J.M. Lehn/Applied
Catalysis A: General I13 (1994) 105-114
sufficient for markedly accelerating a reaction and affecting its course, a result that
also bears on enzyme-catalyzed reactions.
Catalysis by reactive anion receptor molecules
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, [ 241 -N602 6 strongly binds ATP and markedly accelerates its hydrolysis to ADP and inorganic phosphate over a wide pH range [ 19,201.
The reaction presents first-order kinetics and is catalytic with turnover. It proceeds
via initial formation of a complex between ATP and protonated 6, 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-6 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 hydrolysed. Studies with analogues of ATP indicated that the mechanism was dissociative
in character within a preassociative scheme resulting from receptor substrate bind-
5
Scheme 4.
6
Scheme 5.
J.M. L.&n/Applied
109
Catalysis A: General 113 (1994) 105-114
ing [ 2 11. In this process, catalyst 6 presents prototypical ATPase activity; i.e., it
behaves as a proto-ATPase.
&catalysis:
Catalysis of synthetic reactions
A further step lies in the design of systems capable of inducing bondfomzation
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 in which subunits may cooperate
for substrate binding and transformation. They should be able to perform cocatulysis
by bringing together substrate(s) and cofactor(s) and mediating reactions between
them within the supramolecular structure (Fig. 2).
A process of this type has been realized recently [ 22,231. Indeed, when the same
macrocycle 6 used in the studies of ATP hydrolysis was employed as catalyst for
the hydrolysis of acetylphosphate ( AcP= CH,COOPO$- ) , it was found to mediate
the synthesis ufpyrophosphate from AcP. Substrate consumption was accelerated
and catalytic with turnover. The results obtained agree with a catalytic cycle involving the following steps: ( 1) substrate AcP binding by the protonated molecular
catalyst 6; (2) phosphorylation of 6 within the supramolecular complex, giving the
phosphorylated intermediate PN 5; (3) binding of the substrate HPOZ- (P) ; (4)
P- -!
regeneration
#+
intramolecular
reaction
‘;
transfer
G
@L-Y
/
~
’
mi
’
_
ligation
)
Fig. 2. Schematic illustration of cocatalysis processes: group transfer and ligation reactions occurring within the
supramolecular complex formed by the binding of substrates to the two macrocyclic subunits of a macrotricyclic
coreceptor molecule.
110
J.M. L.ehn/Applied Catalysis A: General 113 (1994) 105-114
ph?sphoryl+
transfer
Fig. 3. Cocatalysis: pyrophosphate
rylated intermediate 5.
synthesis by phosphoryl
transfer mediated by macrocycle
6 via the phospho-
phosphor-y1 transfer from PN to P with formation of pyrophosphate PP (Fig. 3) ;
(5) release of the product and of the free catalyst for a new cycle.
The fact the 6 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 phosphor-y1 transfer via the ammonium sites, in providing an unprotonated nitrogen site for PN formation, and in
mediating phosphor-y1 transfer from PN to P. Thus 6 would combine electrostatic
and nucleophilic catalysis in a defined structural arrangement suitable for PP synthesis via two successive phosphoryl transfers, displaying protokinase-type activity
(Fig. 3). This bond-making process extends supramolecular reactivity to cocatalysis, mediating synthetic reactions within the supramolecular entities formed by
coreceptor molecules. The formation of PP when ATP is hydrolysed by 6 in the
presence of divalent metal ions has also been reported [ 241.
Functionalized macrocyclic polyethers were used for peptide bond formation in
two successive intracomplex steps [ 251 and a macrobicyclic cyclophane bearing a
thiazolium group was shown to effect supramolecular catalysis of the benzoin
condensation of two benzaldehyde molecules [ 26,271.
The systems described in this section possess the properties that define supramolecular reactivity and catalysis: substrate recognition, reaction within the supermolecule, rate acceleration, inhibition by competitively bound species, structural
and chiral selectivity, and catalytic turnover. Many other types of processes may
be imagined. Thus, supramolecular catalysis of the hydrolysis of unactivated esters
and of amides presents a challenge [ 281 that chemistry has met in natural enzymatic
reagents but not yet in abiotic catalysts. Designing modified enzymes by chemical
mutation [ 291, or by protein engineering [ 30-331, and producing catalytic proteins
by antibody induction [ 34-361 represent biochemical approaches to artificial catalysts. Of particular interest is the 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.
Supramolecular catalysts are by nature abiotic reagents, chemical catalysts that
may perform the same overall processes as enzymes, without following the detailed
J.M. L.ehn/Applied
CatalysisA:
General I13 (1994) 105-114
111
pathway by which the enzymes actually realize them. This chemistry may develop
reagents effecting highly efficient and selective processes that enzymes do not
perform or realizing enzymatic ones under conditions in which enzymes do not
operate.
(taken from J.-M. Lehn, Angew. Chem. Int. Ed. English, 27 ( 1988) 89-112).
References
[ 1] F. Cramer, Einshlussverbindungen,
Springer, Berlin, 1954.
[2] M.L. Bender and M. Komiyama, Cyclodextrin Chemistry, Springer, Berlin, 1978.
[3] R. Breslow, Science (Washington),
218 (1982) 432.
[4] R.M. Kellog, Top. Curr. Chem., 101 (1982) 111.
[5] I. Tabushi and K. Yamamura, Top. Cum Chem., 113 (1983) 145.
[6] Y. Murakami, Top. Curr. Chem., 115 (1983) 107.
[ 71 C. Sirlin, Bull. Sot. Chim. Fr. II, (1984) 5.
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[ 91 R.M. Kellogg, Angew. Chem. Int. Ed. Engl., 23 ( 1984) 782.
[IO] V.T. D’Souza and M. Bender, Act. Chem. Res., 20 (1987) 146.
[ 111 J.-M. Lehn, Pure Appl. Chem., 51 ( 1979) 979.
[ 121 J.-M. Lehn, Ann. N.Y. Aca. Sci., 471 (1986) 41.
[ 131 Y. Chao, G.R. Weisman, G.D.Y. Sogah and D.J. Cram, J. Am. Chem. Sot., 101 (1979) 4948.
[ 141 J.-M. Lehn and C. Sirlin, J. Chem. Sot. Chem. Commun., ( 1978) 949.
[ 151 J.-M. Lehn and C. Sirlin, New J. Chem., 11 (1987) 693.
[ 161 S. Sasaki and K. Koga, Heterocycles, 12 (1979) 1305.
[ 171 J.-P. Behr and J.-M. Lehn, J. Chem. Sot. Chem. Commun., (1978) 143.
[ 181 J.-M. Lehn and T. Nishiya, Chem. L&t., (1987) 215.
[ 191 M.W. Hosseini, J.-M. Lehn and M.P. Mertes, Helv. Chim. Acta, 66 (1983) 2454.
[20] M.W. Hosseini, J.-M. Lehn, L. Maggiora, K.B. Mertes and M.P. Mertes, J. Am. Chem. Sot., 109 ( 1987)
537.
[21] G.M. Blackbum, G.R.J. Thatcher, M.W. Hosseini and J.-M. Lehn, Tetrahedron Lett., 28 ( 1987) 2779.
[ 221 M.W. Hosseini and J.-M. Lehn, J. Chem. Sot. Chem. Commun., ( 1985) 1155.
1231 M.W. Hosseini and J.-M. Lehn, J. Am. Chem. Sot., 109 (1987) 7047.
[24] P.G. Yohannes, M.P. Mertes and K.B. Mertes, J. Am. Chem. Sot., 107 ( 1985) 8288.
[25] S. Sasaki, M. Shionoya and K. Koga, J. Am. Chem. Sot., 107 ( 1985) 3371.
[26] H.-D. Lutter and F. Diederich, Angew. Chem., 98 (1986) 1125.
[27] H.-D. Lutter and F. Diederich, Angew. Chem Int. Ed. Engl., 25 (1986) 1125.
[28] F.M. Menger and M. Ladika, J. Am. Chem. Sot., 109 (1987) 3145.
[29] E.T. Kaiser and D.S. Lawrence, Science (Washington),
226 ( 1984) 505.
[30] A.R. Fersht, J.P. Shi, A.J. Wilkinson, D.M. Blow, P. Carter, M.M.Y. Waye and G.P. Winter, Angew. Chem.,
96 (1984) 455.
[31] A.R. Fersht, J.P. Shi, A.J. Wilkinson, D.M. Blow, P. Carter, M.M.Y. Waye andG.P. Winter, Angew. Chem.
Int. Ed. Engl., 23 (1984) 467.
1321 J.A. Gerlt, Chem. Rev., 87 (1987) 1079.
[33] A.J. Russell and A.R. Fersht, Chem. Rev., 328 ( 1987) 496.
[34] A. Tramontano, K.D. Janda and R.A. Lemer, Science (Washington),
234 ( 1986) 1566.
[35] S.J. Pollack, J.W. Jacobs and P.G. Schultz, Science (Washington),
234 ( 1986) 1570.
[ 361 R.A. Lemer and A. Tramontano, Trends B&hem. Sci., 12 (1987) 427.
References to recent work
M.W. Hosseini and J.-M. Lehn, Supramolecular catalysis: substrate phosphorylations
and adenosine triphosphate
synthesis with acetylphosphate by a macrocycle polyamine, J. Chem. Sot., Chem. Commun., (1988) 397.
112
J.M. Lehn /Applied Catalysis A: General I13 (1994) 105-I 14
M.W. Hosseini, A.J. Blacker and J.-M. Lehn, Multiple molecular recognition and catalysis. Nucleotide binding
and ATP hydrolysis by a receptor molecule bearing an anion binding site, an intercalator group, and a catalytic
site, J. Chem. Sot. Chem. Commun., (1988) 597.
M.W. Hosseini, J.-M. Lehn, KC. Jones, K.E. Plute, K.B. Mertes and M.P. Mertes, Supramolecular catalysis:
polyammonium
macrocycles as enzyme mimics for phosphoryl transfer in ATP hydrolysis, J. Am. Chem.
Sot., 111 ( 1989) 6330.
M.W. Hosseini, A.J. Blacker and J.-M. Lehn, Multiple molecular recognition and catalysis. A multifunctional
anion receptor bearing an anion binding site, an intercalating group, and catalytic site for nucleotide binding
and hydrolysis, J. Am. Chem. Sot., 112 ( 1990) 3896.
M.W. Hosseini and J.-M. Lehn, Supramolecular catalysis of adenosine triphosphate synthesis in aqueous solution
mediated by a macrocyclic polyamine and divalent metal cations, J. Chem. Sot., Chem. Commun., ( 1991)
451.
H. Fenniri and J.-M. Lehn, Coupling of Supramolecular Synthesis of ATP with ATP-consuming Enzyme Systems,
J. Chem. Sot., Chem. Commun., (1993) 1819.
Prof. J.M. Lehn
Discussion
Cairns: One thing I find fascinating is the possibility of having multi-receptors.
When you were talking about ATP, I wondered if you considered having another
receptor there to deal specifically with ADP - in fact you talked about that - but
do you agree that this is one of the ways this field could really go because you
could use one receptor to deal with the first molecule coming in and the second one
to preferentially remove unwanted product?
Lehn: Absolutely. In fact, I think we probably can do that already. We haven’t
done it simply because we wanted to study the mechanism of how ATP works, but
it is quite true that if you want to remove ADP so as not to have it competing with
the ATP, there are binding agents for ADP which might just take it out.
J.M. L.ehn/Applied
Caralysis A: General 113 (1994) 105-114
113
Tanabe: I am interested in the macrocyclic polyamine catalyzing the hydrolysis
of ATP from the viewpoint of homogeneous and heterogeneous catalysis. If you
support the macrocycle on a solid surface, like weakly acidic or weakly basic
materials, maybe some activity change could be expected.
Lehn: That is a very interesting point. Maybe even the protonated substrate which
could be there would transfer a proton to the macrocycle. One thing we thought
about is to try to make antibodies against a macrocycle. You would then have an
antibody which has no active site so to say. Then you add the macrocycle, the cofactor which goes in and then the whole thing reacts. That we haven’t done. And
then perhaps also the selectivity will be quite high, because you could take the
macrocycle, attach an analog of ATP, a nonhydrolysable one, and make an antibody
against that; the combination of the antibody with the macrocycle should then
handle ATP very well.
Cusumano: I would like to make a more philosophical comment about this work.
It is an observation that I personally have made in the field of catalysis, and it has
been going on for many decades but I think that we are in a position to change now.
If you look at the dichotomy of types of skills in catalysis, people are sometimes
divided into what are called heterogeneous catalytic chemists, homogeneous catalytic chemists, and perhaps biocatalytic chemists. For the most part people in
homogeneous and heterogeneous catalysis are more comfortable with small molecules and things like ethylene oxide, propylene oxide, methylmethacrylate,
or
even much smaller molecules. Yet what the biologist and the chemist do are
basically the same thing: the catalytic chemist talks about an adsorption site, and
the biologist about receptors, we talk about selective adsorption, the biologists talk
about molecular recognition and the list goes on. It is just nomenclature. What you
and your colleagues are doing is true molecular engineering. Biology is really just
chemistry in a living system, and it just does not function without catalysis. The
important point is that it is now possible to think about bringing those pieces
together. I think people in heterogeneous catalysis (the area that I am educated in)
are not so comfortable with the nomenclature and we need to begin to recognize
that there is a tremendous opportunity in some of these fields that you are talking
about. We perhaps need to recognize what types of products we may first have an
impact on. Then there are things like diagnostics, therapeutic sensors, fine chemicals, pharmaceuticals, and perhaps chiral catalysis. I hope that people working in
these other areas will become more comfortable cooperating, because I think that
interface between what you and some biologists are doing in heterogeneous/homogeneous catalysis is a fantastic opportunity for the next decade. We need to get past
that level of discomfort and train students -- perhaps even ourselves relearn - how
to do some of these things.
Lehn: I think it is a very good point, and in some ways it is being solved. Some
people are trying to insolubilize homogeneous catalysts by attaching it to something
as Professor Tanabe just proposed. What about taking a macrocycle and putting it
on a solid surface? It begins to come together thanks to polymer chemistry, where
114
J.M. L.ehn/Applied Catalysis A: General II3 (1994) 105-114
people like Wulf speak about imprinting. Now, imprinting is recognition. So there
is a bridge being built between soluble recognition and insoluble recognition, in
other words recognition on the surface. The nomenclature is still somewhat different
but it is beginning to merge.
Haber: It seems to me that the analogy can be pushed a step further. Many years
ago when zeolites and matrixes were very fashionable, there was a proposal to use
a strong electrolyte theory to explain the behaviour of molecules in zeolites. In
making zeolites we simply create a medium of which there is an analog, a strong
electrolyte. In fact, what you are doing here, is also creating a medium which is a
strong electrolyte. So the whole thing can in fact be reduced to a distribution of
charges which will generate an electric field in which the molecules will become
properly polarised.
Lehn: That is the simplest part of it because you also want a reaction group. Not
being a catalytic chemist from the start, I have always been surprised by this strict
separation between heterogeneous and homogeneous catalysis: of course, this is an
experimental separation. The techniques really are very different. You want to
create an environment. Whether it is solid or soluble, but you want to create an
environment.
Roth: It is interesting to observe here the rediscovery of the community between
homogeneous and heterogeneous catalysis. It was about 20 years ago, in 1973, that
the first international conference on relations between homogeneous and heterogeneous catalysis was held in Brussels. It has been a continuing series, so there has
been some recognition of the relationships but perhaps the development of intellectual support for that has been slower than we might wish it to be.
Delmon: This is illustrated by the drift observed in this series of symposia, where
for many years a mixture of isolated topics was presented with no attempt to make
a synthesis. But now the original line has been reestablished since the last congress
in Japan.
Cusumano: But you see the gulf between what you’re talking about, which is
more biologically oriented, and the group of home/heterogeneous
catalytic studies
is even greater in my view. I think that is much more significant and really needs
to be crossed.
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